Jason Andrews

All Publications

• Mass incarceration as a driver of the tuberculosis epidemic in Latin America and projected effects of policy alternatives: a mathematical modelling study. The Lancet. Public health Liu, Y. E., Mabene, Y., Camelo, S., Rueda, Z. V., Pelissari, D. M., Dockhorn Costa Johansen, F., Huaman, M. A., Avalos-Cruz, T., Alarcón, V. A., Ladutke, L. M., Bergman, M., Cohen, T., Goldhaber-Fiebert, J. D., Croda, J., Andrews, J. R. 2024

  Abstract

  Tuberculosis incidence is increasing in Latin America, where the incarcerated population has nearly quadrupled since 1990. We aimed to quantify the impact of historical and future incarceration policies on the tuberculosis epidemic, accounting for effects in and beyond prisons.In this modelling study, we calibrated dynamic compartmental transmission models to historical and contemporary data from Argentina, Brazil, Colombia, El Salvador, Mexico, and Peru, which comprise approximately 80% of the region's incarcerated population and tuberculosis burden. The model was fit independently for each country to incarceration and tuberculosis data from 1990 to 2023 (specific dates were country dependent). The model does not include HIV, drug resistance, gender or sex, or age structure. Using historical counterfactual scenarios, we estimated the transmission population attributable fraction (tPAF) for incarceration and the excess population-level burden attributable to increasing incarceration prevalence since 1990. We additionally projected the effect of alternative incarceration policies on future population tuberculosis incidence.Population tuberculosis incidence in 2019 was 29·4% (95% uncertainty interval [UI] 23·9-36·8) higher than expected without the rise in incarceration since 1990, corresponding to 34 393 (28 295-42 579) excess incident cases across countries. The incarceration tPAF in 2019 was 27·2% (20·9-35·8), exceeding estimates for other risk factors like HIV, alcohol use disorder, and undernutrition. Compared with a scenario where incarceration rates remain stable at current levels, a gradual 50% reduction in prison admissions and duration of incarceration by 2034 would reduce population tuberculosis incidence by over 10% in all countries except Mexico.The historical rise in incarceration in Latin America has resulted in a large excess tuberculosis burden that has been under-recognised to date. International health agencies, ministries of justice, and national tuberculosis programmes should collaborate to address this health crisis with comprehensive strategies, including decarceration.National Institutes of Health.

  View details for DOI 10.1016/S2468-2667(24)00192-0

  View details for PubMedID 39419058

• A Nanopore Sequencing-based Pharmacogenomic Panel to Personalize Tuberculosis Drug Dosing. American journal of respiratory and critical care medicine Verma, R., Silva, K. E., Rockwood, N., Wasmann, R. E., Yende, N., Song, T., Kim, E., Denti, P., Wilkinson, R. J., Andrews, J. R. 2024

  Abstract

  Standardized dosing of anti-tubercular (TB) drugs leads to variable plasma drug levels, which are associated with adverse drug reactions, delayed treatment response, and relapse. Mutations in genes affecting drug metabolism explain considerable interindividual pharmacokinetic variability; however, pharmacogenomic (PGx) assays that predict metabolism of anti-TB drugs have been lacking.To develop a Nanopore sequencing panel and validate its performance in active TB patients to personalize treatment dosing.We developed a Nanopore sequencing panel targeting 15 single nucleotide polymorphisms (SNP) in 5 genes affecting the metabolism of anti-tuberculous drugs. For validation, we sequenced DNA samples (n=48) from the 1000 genomes project and compared variant calling accuracy with Illumina genome sequencing. We then sequenced DNA samples from patients with active TB (n=100) from South Africa on a MinION Mk1C and evaluated the relationship between genotypes and pharmacokinetic parameters for INH and RIF.The PGx panel achieved 100% concordance with Illumina sequencing in variant identification for the samples from the 1000 Genomes Project. In the clinical cohort, coverage was >100x for 1498/1500 (99.8%) amplicons across the 100 samples. One third (33%) of participants were identified as slow, 47% were intermediate and 20% were rapid isoniazid acetylators. Isoniazid clearance was 2.2 times higher among intermediate acetylators and 3.8 times higher among rapid acetylators compared with slow acetylators (p<0.0001).. Rifampin clearance was 17.3% (2.50-29.9) lower in individuals with homozygous AADAC rs1803155 G>A substitutions (p=0.0015).Targeted sequencing can enable detection of polymorphisms influencing TB drug metabolism on a low-cost, portable instrument to personalize dosing for TB treatment or prevention. This article is open access and distributed under the terms of the Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/).

  View details for DOI 10.1164/rccm.202309-1583OC

  View details for PubMedID 38647526

• Effect of BCG vaccination against Mycobacterium tuberculosis infection in adult Brazilian health-care workers: a nested clinical trial. The Lancet. Infectious diseases Dos Santos, P. C., Messina, N. L., de Oliveira, R. D., da Silva, P. V., Puga, M. A., Dalcolmo, M., Dos Santos, G., de Lacerda, M. V., Jardim, B. A., de Almeida E Val, F. F., Curtis, N., Andrews, J. R., Croda, J. 2024

  Abstract

  The effectiveness of BCG vaccine for adult pulmonary tuberculosis remains uncertain. In this study, we aimed to evaluate the effect of vaccination with BCG-Denmark to prevent initial and sustained interferon-γ release assay conversion in Brazilian health-care workers.This substudy is a nested randomised controlled trial embedded within the BRACE trial (NCT04327206). Specifically, this substudy enrolled Brazilian health-care workers (aged ≥18 years) from three sites in Brazil (Manaus, Campo Grande, and Rio de Janeiro) irrespective of previously receiving BCG vaccination. Participants were excluded if they had contraindications to BCG vaccination, more than 1 month of treatment with specific tuberculosis treatment drugs, previous adverse reactions to BCG, recent BCG vaccination, or non-compliance with assigned interventions. Those eligible were randomly assigned (1:1) to either the BCG group (0·1 mL intradermal injection of BCG-Denmark [Danish strain 1331; AJ Vaccines, Copenhagen]) or the placebo group (intradermal injection of 0·9% saline) using a web-based randomisation process in variable-length blocks (2, 4, or 6), and were stratified based on the study site, age (<40, ≥40 to <60, ≥60 years), and comorbidity presence (diabetes, chronic respiratory disease, cardiac condition, hypertension). Sealed syringes were used to prevent inadvertent disclosure of group assignments. The QuantiFERON-TB Gold (QFT) Plus test (Qiagen; Hilden, Germany) was used for baseline and 12-month tuberculosis infection assessments. The primary efficacy outcome was QFT Plus conversion (≥0·35 IU/mL) by 12 months following vaccination in participants who had a negative baseline result (<0·35 IU/mL).Between Oct 7, 2020, and April 12, 2021, 1985 (77·3%) of 2568 participants were eligible for QFT Plus assessment at 12 months and were included in this substudy; 996 (50·2%) of 1985 were in the BCG group and 989 (49·8%) were in the placebo group. Overall, 1475 (74·3%) of 1985 participants were women and 510 (25·7%) were men, and the median age was 39 years (IQR 32-47). During the first 12 months, QFT Plus conversion occurred in 66 (3·3%) of 1985 participants, with no significant differences by study site (p=0·897). Specifically, 34 (3·4%) of 996 participants had initial QFT conversion in the BCG group compared with 32 (3·2%) of 989 in the placebo group (risk ratio 1·09 [95% CI 0·67-1·77]; p=0·791).BCG-Denmark vaccination did not reduce initial QFT Plus conversion risk in Brazilian health-care workers. This finding underscores the need to better understand tuberculosis prevention in populations at high risk.Bill & Melinda Gates Foundation, the Minderoo Foundation, Sarah and Lachlan Murdoch, the Royal Children's Hospital Foundation, Health Services Union NSW, the Peter Sowerby Foundation, SA Health, the Insurance Advisernet Foundation, the NAB Foundation, the Calvert-Jones Foundation, the Modara Pines Charitable Foundation, the United Health Group Foundation, Epworth Healthcare, and individual donors.For the Portuguese translation of the abstract see Supplementary Materials section.

  View details for DOI 10.1016/S1473-3099(23)00818-6

  View details for PubMedID 38423021

• Global, regional, and national estimates of tuberculosis incidence and case detection among incarcerated individuals from 2000 to 2019: a systematic analysis. The Lancet. Public health Martinez, L., Warren, J. L., Harries, A. D., Croda, J., Espinal, M. A., Olarte, R. A., Avedillo, P., Lienhardt, C., Bhatia, V., Liu, Q., Chakaya, J., Denholm, J. T., Lin, Y., Kawatsu, L., Zhu, L., Horsburgh, C. R., Cohen, T., Andrews, J. R. 2023; 8 (7): e511-e519

  Abstract

  People who are incarcerated are at high risk of developing tuberculosis. We aimed to estimate the annual global, regional, and national incidence of tuberculosis among incarcerated populations from 2000 to 2019.We collected and aggregated data for tuberculosis incidence and prevalence estimates among incarcerated individuals in published and unpublished literature, annual tuberculosis notifications among incarcerated individuals at the country level, and the annual number of incarcerated individuals at the country level. We developed a joint hierarchical Bayesian meta-regression framework to simultaneously model tuberculosis incidence, notifications, and prevalence from 2000 to 2019. Using this model, we estimated trends in absolute tuberculosis incidence and notifications, the incidence and notification rates, and the case detection ratio by year, country, region, and globally.In 2019, we estimated a total of 125 105 (95% credible interval [CrI] 93 736-165 318) incident tuberculosis cases among incarcerated individuals globally. The estimated incidence rate per 100 000 person-years overall was 1148 (95% CrI 860-1517) but varied greatly by WHO region, from 793 (95% CrI 430-1342) in the Eastern Mediterranean region to 2242 (1515-3216) in the African region. Global incidence per 100 000 person-years between 2000 and 2012 among incarcerated individuals decreased from 1884 (95% CrI 1394-2616) to 1205 (910-1615); however, from 2013 onwards, tuberculosis incidence per 100 000 person-years was stable, from 1183 (95% CrI 876-1596) in 2013 to 1148 (860-1517) in 2019. In 2019, the global case detection ratio was estimated to be 53% (95% CrI 42-64), the lowest over the study period.Our estimates suggest a high tuberculosis incidence rate among incarcerated individuals globally with large gaps in tuberculosis case detection. Tuberculosis in incarcerated populations must be addressed with interventions specifically tailored to improve diagnoses and prevent transmission as a part of the broader global tuberculosis control effort.National Institutes of Health.

  View details for DOI 10.1016/S2468-2667(23)00097-X

  View details for PubMedID 37393090

• Infant BCG vaccination and risk of pulmonary and extrapulmonary tuberculosis throughout the life course: a systematic review and individual participant data meta-analysis. The Lancet. Global health Martinez, L., Cords, O., Liu, Q., Acuna-Villaorduna, C., Bonnet, M., Fox, G. J., Carvalho, A. C., Chan, P. C., Croda, J., Hill, P. C., Lopez-Varela, E., Donkor, S., Fielding, K., Graham, S. M., Espinal, M. A., Kampmann, B., Reingold, A., Huerga, H., Villalba, J. A., Grandjean, L., Sotgiu, G., Egere, U., Singh, S., Zhu, L., Lienhardt, C., Denholm, J. T., Seddon, J. A., Whalen, C. C., García-Basteiro, A. L., Triasih, R., Chen, C., Singh, J., Huang, L. M., Sharma, S., Hannoun, D., Del Corral, H., Mandalakas, A. M., Malone, L. L., Ling, D. L., Kritski, A., Stein, C. M., Vashishtha, R., Boulahbal, F., Fang, C. T., Boom, W. H., Netto, E. M., Lemos, A. C., Hesseling, A. C., Kay, A., Jones-López, E. C., Horsburgh, C. R., Lange, C., Andrews, J. R. 2022; 10 (9): e1307-e1316

  Abstract

  BCG vaccines are given to more than 100 million children every year, but there is considerable debate regarding the effectiveness of BCG vaccination in preventing tuberculosis and death, particularly among older children and adults. We therefore aimed to investigate the age-specific impact of infant BCG vaccination on tuberculosis (pulmonary and extrapulmonary) development and mortality.In this systematic review and individual participant data meta-analysis, we searched MEDLINE, Web of Science, BIOSIS, and Embase without language restrictions for case-contact cohort studies of tuberculosis contacts published between Jan 1, 1998, and April 7, 2018. Search terms included "mycobacterium tuberculosis", "TB", "tuberculosis", and "contact". We excluded cohort studies that did not provide information on BCG vaccination or were done in countries that did not recommend BCG vaccination at birth. Individual-level participant data for a prespecified list of variables, including the characteristics of the exposed participant (contact), the index case, and the environment, were requested from authors of all eligible studies. Our primary outcome was a composite of prevalent (diagnosed at or within 90 days of baseline) and incident (diagnosed more than 90 days after baseline) tuberculosis in contacts exposed to tuberculosis. Secondary outcomes were pulmonary tuberculosis, extrapulmonary tuberculosis, and mortality. We derived adjusted odds ratios (aORs) using mixed-effects, binary, multivariable logistic regression analyses with study-level random effects, adjusting for the variable of interest, baseline age, sex, previous tuberculosis, and whether data were collected prospectively or retrospectively. We stratified our results by contact age and Mycobacterium tuberculosis infection status. This study is registered with PROSPERO, CRD42020180512.We identified 14 927 original records from our database searches. We included participant-level data from 26 cohort studies done in 17 countries in our meta-analysis. Among 68 552 participants, 1782 (2·6%) developed tuberculosis (1309 [2·6%] of 49 686 BCG-vaccinated participants vs 473 [2·5%] of 18 866 unvaccinated participants). The overall effectiveness of BCG vaccination against all tuberculosis was 18% (aOR 0·82, 95% CI 0·74-0·91). When stratified by age, BCG vaccination only significantly protected against all tuberculosis in children younger than 5 years (aOR 0·63, 95% CI 0·49-0·81). Among contacts with a positive tuberculin skin test or IFNγ release assay, BCG vaccination significantly protected against tuberculosis among all participants (aOR 0·81, 95% CI 0·69-0·96), participants younger than 5 years (0·68, 0·47-0·97), and participants aged 5-9 years (0·62, 0·38-0·99). There was no protective effect among those with negative tests, unless they were younger than 5 years (0·54, 0·32-0·90). 14 cohorts reported on whether tuberculosis was pulmonary or extrapulmonary (n=57 421). BCG vaccination significantly protected against pulmonary tuberculosis among all participants (916 [2·2%] in 41 119 vaccinated participants vs 334 [2·1%] in 16 161 unvaccinated participants; aOR 0·81, 0·70-0·94) but not against extrapulmonary tuberculosis (106 [0·3%] in 40 318 vaccinated participants vs 38 [0·2%] in 15 865 unvaccinated participants; 0·96, 0·65-1·41). In the four studies with mortality data, BCG vaccination was significantly protective against death (0·25, 0·13-0·49).Our results suggest that BCG vaccination at birth is effective at preventing tuberculosis in young children but is ineffective in adolescents and adults. Immunoprotection therefore needs to be boosted in older populations.National Institutes of Health.

  View details for DOI 10.1016/S2214-109X(22)00283-2

  View details for PubMedID 35961354

• The international and intercontinental spread and expansion of antimicrobial-resistant Salmonella Typhi: a genomic epidemiology study. The Lancet. Microbe da Silva, K. E., Tanmoy, A. M., Pragasam, A. K., Iqbal, J., Sajib, M. S., Mutreja, A., Veeraraghavan, B., Tamrakar, D., Qamar, F. N., Dougan, G., Bogoch, I., Seidman, J. C., Shakya, J., Vaidya, K., Carey, M. E., Shrestha, R., Irfan, S., Baker, S., Luby, S. P., Cao, Y., Dyson, Z. A., Garrett, D. O., John, J., Kang, G., Hooda, Y., Saha, S. K., Saha, S., Andrews, J. R. 2022

  Abstract

  The emergence of increasingly antimicrobial-resistant Salmonella enterica serovar Typhi (S Typhi) threatens to undermine effective treatment and control. Understanding where antimicrobial resistance in S Typhi is emerging and spreading is crucial towards formulating effective control strategies.In this genomic epidemiology study, we sequenced the genomes of 3489 S Typhi strains isolated from prospective enteric fever surveillance studies in Nepal, Bangladesh, Pakistan, and India (between 2014 and 2019), and combined these with a global collection of 4169 S Typhi genome sequences isolated between 1905 and 2018 to investigate the temporal and geographical patterns of emergence and spread of antimicrobial-resistant S Typhi. We performed non-parametric phylodynamic analyses to characterise changes in the effective population size of fluoroquinolone-resistant, extensively drug-resistant (XDR), and azithromycin-resistant S Typhi over time. We inferred timed phylogenies for the major S Typhi sublineages and used ancestral state reconstruction methods to estimate the frequency and timing of international and intercontinental transfers.Our analysis revealed a declining trend of multidrug resistant typhoid in south Asia, except for Pakistan, where XDR S Typhi emerged in 2016 and rapidly replaced less-resistant strains. Mutations in the quinolone-resistance determining region (QRDR) of S Typhi have independently arisen and propagated on at least 94 occasions, nearly all occurring in south Asia. Strains with multiple QRDR mutations, including triple mutants with high-level fluoroquinolone resistance, have been increasing in frequency and displacing strains with fewer mutations. Strains containing acrB mutations, conferring azithromycin resistance, emerged in Bangladesh around 2013 and effective population size of these strains has been steadily increasing. We found evidence of frequent international (n=138) and intercontinental transfers (n=59) of antimicrobial-resistant S Typhi, followed by local expansion and replacement of drug-susceptible clades.Independent acquisition of plasmids and homoplastic mutations conferring antimicrobial resistance have occurred repeatedly in multiple lineages of S Typhi, predominantly arising in south Asia before spreading to other regions.Bill & Melinda Gates Foundation.

  View details for DOI 10.1016/S2666-5247(22)00093-3

  View details for PubMedID 35750070

• Estimating typhoid incidence from community-based serosurveys: a multicohort study. The Lancet. Microbe Aiemjoy, K., Seidman, J. C., Saha, S., Munira, S. J., Islam Sajib, M. S., Sium, S. M., Sarkar, A., Alam, N., Zahan, F. N., Kabir, M. S., Tamrakar, D., Vaidya, K., Shrestha, R., Shakya, J., Katuwal, N., Shrestha, S., Yousafzai, M. T., Iqbal, J., Dehraj, I. F., Ladak, Y., Maria, N., Adnan, M., Pervaiz, S., Carter, A. S., Longley, A. T., Fraser, C., Ryan, E. T., Nodoushani, A., Fasano, A., Leonard, M. M., Kenyon, V., Bogoch, I. I., Jeon, H. J., Haselbeck, A., Park, S. E., Zellweger, R. M., Marks, F., Owusu-Dabo, E., Adu-Sarkodie, Y., Owusu, M., Teunis, P., Luby, S. P., Garrett, D. O., Qamar, F. N., Saha, S. K., Charles, R. C., Andrews, J. R. 2022

  Abstract

  The incidence of enteric fever, an invasive bacterial infection caused by typhoidal Salmonellae (Salmonella enterica serovars Typhi and Paratyphi), is largely unknown in regions without blood culture surveillance. The aim of this study was to evaluate whether new diagnostic serological markers for typhoidal Salmonella can reliably estimate population-level incidence.We collected longitudinal blood samples from patients with blood culture-confirmed enteric fever enrolled from surveillance studies in Bangladesh, Nepal, Pakistan, and Ghana between 2016 and 2021 and conducted cross-sectional serosurveys in the catchment areas of each surveillance site. We used ELISAs to measure quantitative IgA and IgG antibody responses to hemolysin E and S Typhi lipopolysaccharide. We used Bayesian hierarchical models to fit two-phase power-function decay models to the longitudinal antibody responses among enteric fever cases and used the joint distributions of the peak antibody titres and decay rate to estimate population-level incidence rates from cross-sectional serosurveys.The longitudinal antibody kinetics for all antigen-isotypes were similar across countries and did not vary by clinical severity. The seroincidence of typhoidal Salmonella infection among children younger than 5 years ranged between 58·5 per 100 person-years (95% CI 42·1-81·4) in Dhaka, Bangladesh, to 6·6 per 100 person-years (4·3-9·9) in Kavrepalanchok, Nepal, and followed the same rank order as clinical incidence estimates.The approach described here has the potential to expand the geographical scope of typhoidal Salmonella surveillance and generate incidence estimates that are comparable across geographical regions and time.Bill & Melinda Gates Foundation.For the Nepali, Bengali and Urdu translations of the abstract see Supplementary Materials section.

  View details for DOI 10.1016/S2666-5247(22)00114-8

  View details for PubMedID 35750069

• All-cause and cause-specific mortality during and following incarceration in Brazil: A retrospective cohort study. PLoS medicine Liu, Y. E., Lemos, E. F., Gonçalves, C. C., de Oliveira, R. D., Santos, A. d., do Prado Morais, A. O., Croda, M. G., de Lourdes Delgado Alves, M., Croda, J., Walter, K. S., Andrews, J. R. 2021; 18 (9): e1003789

  Abstract

  Mortality during and after incarceration is poorly understood in low- and middle-income countries (LMICs). The need to address this knowledge gap is especially urgent in South America, which has the fastest growing prison population in the world. In Brazil, insufficient data have precluded our understanding of all-cause and cause-specific mortality during and after incarceration.We linked incarceration and mortality databases for the Brazilian state of Mato Grosso do Sul to obtain a retrospective cohort of 114,751 individuals with recent incarceration. Between January 1, 2009 and December 31, 2018, we identified 3,127 deaths of individuals with recent incarceration (705 in detention and 2,422 following release). We analyzed age-standardized, all-cause, and cause-specific mortality rates among individuals detained in different facility types and following release, compared to non-incarcerated residents. We additionally modeled mortality rates over time during and after incarceration for all causes of death, violence, or suicide. Deaths in custody were 2.2 times the number reported by the national prison administration (n = 317). Incarcerated men and boys experienced elevated mortality, compared with the non-incarcerated population, due to increased risk of death from violence, suicide, and communicable diseases, with the highest standardized incidence rate ratio (IRR) in semi-open prisons (2.4; 95% confidence interval [CI]: 2.0 to 2.8), police stations (3.1; 95% CI: 2.5 to 3.9), and youth detention (8.1; 95% CI: 5.9 to 10.8). Incarcerated women experienced increased mortality from suicide (IRR = 6.0, 95% CI: 1.2 to 17.7) and communicable diseases (IRR = 2.5, 95% CI: 1.1 to 5.0). Following release from prison, mortality was markedly elevated for men (IRR = 3.0; 95% CI: 2.8 to 3.1) and women (IRR = 2.4; 95% CI: 2.1 to 2.9). The risk of violent death and suicide was highest immediately post-release and declined over time; however, all-cause mortality remained elevated 8 years post-release. The limitations of this study include inability to establish causality, uncertain reliability of data during incarceration, and underestimation of mortality rates due to imperfect database linkage.Incarcerated individuals in Brazil experienced increased mortality from violence, suicide, and communicable diseases. Mortality was heightened following release for all leading causes of death, with particularly high risk of early violent death and elevated all-cause mortality up to 8 years post-release. These disparities may have been underrecognized in Brazil due to underreporting and insufficient data.

  View details for DOI 10.1371/journal.pmed.1003789

  View details for PubMedID 34534214

• A Rapid Pharmacogenomic Assay to Detect NAT2 Polymorphisms and Guide Isoniazid Dosing for Tuberculosis Treatment. American journal of respiratory and critical care medicine Verma, R., Patil, S., Zhang, N., Moreira, F. M., Vitorio, M. T., Santos, A. d., Wallace, E., Gnanashanmugam, D., Persing, D., Savic, R., Croda, J., Andrews, J. R. 2021

  Abstract

  Standardized dosing of anti-tubercular drugs contributes to a substantial incidence of toxicities, inadequate treatment response, and relapse, in part due to variable drug levels achieved. Single nucleotide polymorphisms (SNPs) in the N-acetyltransferase-2 (NAT2) gene explain the majority of interindividual pharmacokinetic variability of isoniazid (INH). However, an obstacle to implementing pharmacogenomic-guided dosing is the lack of a point-of-care assay.To develop and test a NAT2 classification algorithm, validate its performance in predicting isoniazid clearance, and develop a prototype pharmacogenomic assay.We trained random forest models to predict NAT2 acetylation genotype from unphased SNP data using a global collection of 8,561 phased genomes. We enrolled 48 pulmonary TB patients, performed sparse pharmacokinetic sampling, and tested the acetylator prediction algorithm accuracy against estimated INH clearance. We then developed a cartridge-based multiplex qPCR assay on the GeneXpert platform and assessed its analytical sensitivity on whole blood samples from healthy individuals.With a 5-SNP model trained on two-thirds of the data (n=5,738), out-of-sample acetylation genotype prediction accuracy on the remaining third (n=2,823) was 100%. Among the 48 TB patients, predicted acetylator types were: 27 (56.2%) slow, 16 (33.3%) intermediate and 5 (10.4%) rapid. INH clearance rates were lowest in predicted slow acetylators (median 14.5 L/hr), moderate in intermediate acetylators (median 40.3 L/hr) and highest in fast acetylators (median 53.0 L/hr). The cartridge-based assay accurately detected all allele patterns directly from 25 ul of whole blood.An automated pharmacogenomic assay on a platform widely used globally for tuberculosis diagnosis could enable personalized dosing of isoniazid.

  View details for DOI 10.1164/rccm.202103-0564OC

  View details for PubMedID 34375564

• Incidence and prevalence of tuberculosis in incarcerated populations: a systematic review and meta-analysis. The Lancet. Public health Cords, O. n., Martinez, L. n., Warren, J. L., O'Marr, J. M., Walter, K. S., Cohen, T. n., Zheng, J. n., Ko, A. I., Croda, J. n., Andrews, J. R. 2021

  Abstract

  Prisons are recognised as high-risk environments for tuberculosis, but there has been little systematic investigation of the global and regional incidence and prevalence of tuberculosis, and its determinants, in prisons. We did a systematic review and meta-analysis to assess the incidence and prevalence of tuberculosis in incarcerated populations by geographical region.In this systematic review and meta-analysis, we searched MEDLINE, Embase, Web of Knowledge, and the LILACS electronic database from Jan 1, 1980, to Nov 15, 2020, for cross-sectional and cohort studies reporting the incidence of Mycobacterium tuberculosis infection, incidence of tuberculosis, or prevalence of tuberculosis among incarcerated individuals in all geographical regions. We extracted data from individual studies, and calculated pooled estimates of incidence and prevalence through hierarchical Bayesian meta-regression modelling. We also did subgroup analyses by region. Incidence rate ratios between prisons and the general population were calculated by dividing the incidence of tuberculosis in prisons by WHO estimates of the national population-level incidence.We identified 159 relevant studies; 11 investigated the incidence of M tuberculosis infection (n=16 318), 51 investigated the incidence of tuberculosis (n=1 858 323), and 106 investigated the prevalence of tuberculosis (n=6 727 513) in incarcerated populations. The overall pooled incidence of M tuberculosis infection among prisoners was 15·0 (95% credible interval [CrI] 3·8-41·6) per 100 person-years. The incidence of tuberculosis (per 100 000 person-years) among prisoners was highest in studies from the WHO African (2190 [95% CrI 810-4840] cases) and South-East Asia (1550 [240-5300] cases) regions and in South America (970 [460-1860] cases), and lowest in North America (30 [20-50] cases) and the WHO Eastern Mediterranean region (270 [50-880] cases). The prevalence of tuberculosis was greater than 1000 per 100 000 prisoners in all global regions except for North America and the Western Pacific, and highest in the WHO South-East Asia region (1810 [95% CrI 670-4000] cases per 100 000 prisoners). The incidence rate ratio between prisons and the general population was much higher in South America (26·9; 95% CrI 17·1-40·1) than in other regions, but was nevertheless higher than ten in the WHO African (12·6; 6·2-22·3), Eastern Mediterranean (15·6; 6·5-32·5), and South-East Asia (11·7; 4·1-27·1) regions.Globally, people in prison are at high risk of contracting M tuberculosis infection and developing tuberculosis, with consistent disparities between prisons and the general population across regions. Tuberculosis control programmes should prioritise preventive interventions among incarcerated populations.US National Institutes of Health.

  View details for DOI 10.1016/S2468-2667(21)00025-6

  View details for PubMedID 33765455

• The escalating tuberculosis crisis in central and South American prisons. Lancet (London, England) Walter, K. S., Martinez, L. n., Arakaki-Sanchez, D. n., Sequera, V. G., Estigarribia Sanabria, G. n., Cohen, T. n., Ko, A. I., García-Basteiro, A. L., Rueda, Z. V., López-Olarte, R. A., Espinal, M. A., Croda, J. n., Andrews, J. R. 2021

  Abstract

  In the past decade, tuberculosis incidence has declined in much of the world, but has risen in central and South America. It is not yet clear what is driving this reversal of progress in tuberculosis control. Since 2000, the incarcerated population in central and South America has grown by 206%, the greatest increase in the world. Over the same period, notified tuberculosis cases among the incarcerated population (hereinafter termed persons deprived of their liberty [PDL], following the Inter-American Commission on Human Rights) have risen by 269%. In both central and South America, the rise of disease among PDL more than offsets tuberculosis control gains in the general population. Tuberculosis is increasingly concentrated among PDL; currently, 11% of all notified tuberculosis cases in central and South America occur among PDL who comprise less than 1% of the population. The extraordinarily high risk of acquiring tuberculosis within prisons creates a health and human rights crisis for PDL that also undermines wider tuberculosis control efforts. Controlling tuberculosis in this region will require countries to take urgent measures to prioritise the health of PDL.

  View details for DOI 10.1016/S0140-6736(20)32578-2

  View details for PubMedID 33838724

• The risk of tuberculosis in children after close exposure: a systematic review and individual-participant meta-analysis. Lancet (London, England) Martinez, L. n., Cords, O. n., Horsburgh, C. R., Andrews, J. R. 2020; 395 (10228): 973–84

  Abstract

  Tens of millions of children are exposed to Mycobacterium tuberculosis globally every year; however, there are no contemporary estimates of the risk of developing tuberculosis in exposed children. The effectiveness of contact investigations and preventive therapy remains poorly understood.In this systematic review and meta-analysis, we investigated the development of tuberculosis in children closely exposed to a tuberculosis case and followed for incident disease. We restricted our search to cohort studies published between Jan 1, 1998, and April 6, 2018, in MEDLINE, Web of Science, BIOSIS, and Embase electronic databases. Individual-participant data and a pre-specified list of variables were requested from authors of all eligible studies. These included characteristics of the exposed child, the index case, and environmental characteristics. To be eligible for inclusion in the final analysis, a dataset needed to include: (1) individuals below 19 years of age; (2) follow-up for tuberculosis for a minimum of 6 months; (3) individuals with household or close exposure to an individual with tuberculosis; (4) information on the age and sex of the child; and (5) start and end follow-up dates. Studies assessing incident tuberculosis but without dates or time of follow-up were excluded. Our analysis had two primary aims: (1) estimating the risk of developing tuberculosis by time-period of follow-up, demographics (age, region), and clinical attributes (HIV, tuberculosis infection status, previous tuberculosis); and (2) estimating the effectiveness of preventive therapy and BCG vaccination on the risk of developing tuberculosis. We estimated the odds of prevalent tuberculosis with mixed-effects logistic models and estimated adjusted hazard ratios (HRs) for incident tuberculosis with mixed-effects Poisson regression models. The effectiveness of preventive therapy against incident tuberculosis was estimated through propensity score matching. The study protocol is registered with PROSPERO (CRD42018087022).In total, study groups from 46 cohort studies in 34 countries-29 (63%) prospective studies and 17 (37%) retrospective-agreed to share their data and were included in the final analysis. 137 647 tuberculosis-exposed children were evaluated at baseline and 130 512 children were followed for 429 538 person-years, during which 1299 prevalent and 999 incident tuberculosis cases were diagnosed. Children not receiving preventive therapy with a positive result for tuberculosis infection had significantly higher 2-year cumulative tuberculosis incidence than children with a negative result for tuberculosis infection, and this incidence was greatest among children below 5 years of age (19·0% [95% CI 8·4-37·4]). The effectiveness of preventive therapy was 63% (adjusted HR 0·37 [95% CI 0·30-0·47]) among all exposed children, and 91% (adjusted HR 0·09 [0·05-0·15]) among those with a positive result for tuberculosis infection. Among all children <5 years of age who developed tuberculosis, 83% were diagnosed within 90 days of the baseline visit.The risk of developing tuberculosis among exposed infants and young children is very high. Most cases occurred within weeks of contact investigation initiation and might not be preventable through prophylaxis. This suggests that alternative strategies for prevention are needed, such as earlier initiation of preventive therapy through rapid diagnosis of adult cases or community-wide screening approaches.National Institutes of Health.

  View details for DOI 10.1016/S0140-6736(20)30166-5

  View details for PubMedID 32199484

• Evaluating strategies for control of tuberculosis in prisons and prevention of spillover into communities: An observational and modeling study from Brazil. PLoS medicine Mabud, T. S., de Lourdes Delgado Alves, M. n., Ko, A. I., Basu, S. n., Walter, K. S., Cohen, T. n., Mathema, B. n., Colijn, C. n., Lemos, E. n., Croda, J. n., Andrews, J. R. 2019; 16 (1): e1002737

  Abstract

  It has been hypothesized that prisons serve as amplifiers of general tuberculosis (TB) epidemics, but there is a paucity of data on this phenomenon and the potential population-level effects of prison-focused interventions. This study (1) quantifies the TB risk for prisoners as they traverse incarceration and release, (2) mathematically models the impact of prison-based interventions on TB burden in the general population, and (3) generalizes this model to a wide range of epidemiological contexts.We obtained individual-level incarceration data for all inmates (n = 42,925) and all reported TB cases (n = 5,643) in the Brazilian state of Mato Grosso do Sul from 2007 through 2013. We matched individuals between prisoner and TB databases and estimated the incidence of TB from the time of incarceration and the time of prison release using Cox proportional hazards models. We identified 130 new TB cases diagnosed during incarceration and 170 among individuals released from prison. During imprisonment, TB rates increased from 111 cases per 100,000 person-years at entry to a maximum of 1,303 per 100,000 person-years at 5.2 years. At release, TB incidence was 229 per 100,000 person-years, which declined to 42 per 100,000 person-years (the average TB incidence in Brazil) after 7 years. We used these data to populate a compartmental model of TB transmission and incarceration to evaluate the effects of various prison-based interventions on the incidence of TB among prisoners and the general population. Annual mass TB screening within Brazilian prisons would reduce TB incidence in prisons by 47.4% (95% Bayesian credible interval [BCI], 44.4%-52.5%) and in the general population by 19.4% (95% BCI 17.9%-24.2%). A generalized model demonstrates that prison-based interventions would have maximum effectiveness in reducing community incidence in populations with a high concentration of TB in prisons and greater degrees of mixing between ex-prisoners and community members. Study limitations include our focus on a single Brazilian state and our retrospective use of administrative databases.Our findings suggest that the prison environment, more so than the prison population itself, drives TB incidence, and targeted interventions within prisons could have a substantial effect on the broader TB epidemic.

  View details for PubMedID 30677013

• Serial QuantiFERON testing and tuberculosis disease risk among young children: an observational cohort study. The Lancet. Respiratory medicine Andrews, J. R., Nemes, E., Tameris, M., Landry, B. S., Mahomed, H., McClain, J. B., Fletcher, H. A., Hanekom, W. A., Wood, R., McShane, H., Scriba, T. J., Hatherill, M. 2017

  Abstract

  The value of quantitative interferon-γ release assay results for predicting progression from Mycobacterium tuberculosis infection to active disease is unknown. We aimed to investigate the relation between QuantiFERON-TB Gold In-Tube (QFT) conversion interferon-γ values and risk of subsequent active tuberculosis disease and of QFT reversion.We analysed data from a reported vaccine efficacy trial of the tuberculosis vaccine MVA85A in South Africa. QFT negative, HIV uninfected young children aged 18-24 weeks were enrolled. We stratified participants by quantitative QFT result (interferon-γ <0·35 IU/mL, 0·35-4·00 IU/mL, and >4·00 IU/mL) at the intermediate study visit (day 336) and determined risk of progression to active tuberculosis disease over the subsequent 6-24 months. No QFT differences were observed between placebo and MVA85A groups at day 336 or end of study; therefore, both groups were included in analyses. Study clinicians were not masked to QFT values, but strict case definitions were used that excluded QFT results. We used generalised additive models to evaluate the quantitative relation between day 336 QFT value and subsequent disease risk, and we compared disease rates between QFT strata using a two-sample Poisson test.Among 2512 young children with QFT tests done at day 336, 172 (7%) were positive; 87 (7%) of 1267 in placebo group and 85 (7%) of 1245 in the MVA85A group (p=1·00). Compared with QFT non-converters (tuberculosis disease incidence 0·7 per 100 person-years [95% CI 0·4-1·1]), children with QFT conversion at interferon-γ values between 0·35-4·00 IU/mL did not have significantly increased risk of disease (2·5 per 100 person-years [95% CI 0·4-9·4]; incidence rate ratio (IRR) 3·7 (95% CI 0·4-15·8; p=0·23). However, QFT conversion at interferon-γ values higher than 4·00 IU/mL was associated with substantially increased disease incidence (28·0 per 100 person-years [95% CI 14·9-45·7]) compared with non-converters (IRR 42·5 [95% CI 17·2-99·7]; p<0·0001), and compared with children with interferon-γ values between 0·35-4·00 IU/mL (IRR 11·4 [95% CI 2·4-107·2]; p=0·00047). Among 91 QFT converters who were given a repeat test, 53 (58%) reverted from positive to negative. QFT reversion risk was inversely associated with interferon-γ value at QFT conversion and was highest with interferon-γ values less than 4·00 IU/mL (47 [77%] of 61).In young children, tuberculosis disease risk was not significantly increased, and QFT reversion was common, following QFT conversion at interferon-γ values up to 10 times the recommended test threshold (0·35 IU/mL). By contrast, QFT conversion at very high interferon-γ values (>4·00 IU/mL) warrants intensified diagnostic and preventive intervention because of the extremely high risk of tuberculosis disease in these young children.Aeras, Wellcome Trust, and Oxford-Emergent Tuberculosis Consortium (OETC) were the funders of the MVA85A 020 Trial. National Institute of Allergy and Infectious Diseases supported this analysis.

  View details for DOI 10.1016/S2213-2600(17)30060-7

  View details for PubMedID 28215501

• Assessment of global guidelines for preventive chemotherapy against schistosomiasis and soil-transmitted helminthiasis: a cost-effectiveness modelling study LANCET INFECTIOUS DISEASES Lo, N. C., Lai, Y., Karagiannis-Voules, D., Bogoch, I. I., Coulibaly, J. T., Bendavid, E., Utzinger, J., Vounatsou, P., Andrews, J. R. 2016; 16 (9): 1065-1075

  Abstract

  WHO guidelines recommend annual treatment for schistosomiasis or soil-transmitted helminthiasis when prevalence in school-aged children is at or above a threshold of 50% and 20%, respectively. Separate treatment guidelines are used for these two helminthiases, and integrated community-wide treatment is not recommended. We assessed the cost-effectiveness of changing prevalence thresholds and treatment guidelines under an integrated delivery framework.We developed a dynamic, age-structured transmission and cost-effectiveness model that simulates integrated preventive chemotherapy programmes against schistosomiasis and soil-transmitted helminthiasis. We assessed a 5-year treatment programme with praziquantel (40 mg/kg per treatment) against schistosomiasis and albendazole (400 mg per treatment) against soil-transmitted helminthiasis at 75% coverage. We defined strategies as highly cost-effective if the incremental cost-effectiveness ratio was less than the World Bank classification for a low-income country (gross domestic product of US$1045 per capita). We calculated the prevalence thresholds for cost-effective preventive chemotherapy of various strategies, and estimated treatment needs for sub-Saharan Africa.Annual preventive chemotherapy against schistosomiasis was highly cost-effective in treatment of school-aged children at a prevalence threshold of 5% (95% uncertainty interval [UI] 1·7-5·2; current guidelines recommend treatment at 50% prevalence) and for community-wide treatment at a prevalence of 15% (7·3-18·5; current recommendation is unclear, some community treatment recommended at 50% prevalence). Annual preventive chemotherapy against soil-transmitted helminthiasis was highly cost-effective in treatment of school-aged children at a prevalence of 20% (95% UI 5·4-30·5; current guidelines recommend treatment at 20% prevalence) and the entire community at 60% (35·3-85·1; no guidelines available). When both helminthiases were co-endemic, prevalence thresholds using integrated delivery were lower. Using this revised treatment framework, we estimated that treatment needs would be six times higher than WHO guidelines for praziquantel and two times higher for albendazole. An additional 21·3% (95% Bayesian credible interval 20·4-22·2) of the population changed from receiving non-integrated treatment under WHO guidelines to integrated treatment (both praziquantel and albendazole). Country-specific economic differences resulted in heterogeneity around these prevalence thresholds.Annual preventive chemotherapy programmes against schistosomiasis and soil-transmitted helminthiasis are likely to be highly cost-effective at prevalences lower than WHO recommendations. These findings support substantial treatment scale-up, community-wide coverage, integrated treatment in co-endemic settings that yield substantial cost synergies, and country-specific treatment guidelines.Doris Duke Charitable Foundation, Mount Sinai Hospital-University Health Network AMO Innovation Fund, and Stanford University Medical Scholars Programme.

  View details for DOI 10.1016/S1473-3099(16)30073-1

  View details for Web of Science ID 000381655200036

  View details for PubMedID 27286968

• Comparison of community-wide, integrated mass drug administration strategies for schistosomiasis and soil-transmitted helminthiasis: a cost-effectiveness modelling study. The Lancet. Global health Lo, N. C., Bogoch, I. I., Blackburn, B. G., Raso, G., N'Goran, E. K., Coulibaly, J. T., Becker, S. L., Abrams, H. B., Utzinger, J., Andrews, J. R. 2015; 3 (10): e629-38

  Abstract

  More than 1·5 billion people are affected by schistosomiasis or soil-transmitted helminthiasis. WHO's recommendations for mass drug administration (MDA) against these parasitic infections emphasise treatment of school-aged children, using separate treatment guidelines for these two helminthiases groups. We aimed to evaluate the cost-effectiveness of expanding integrated MDA to the entire community in four settings in Côte d'Ivoire.We extended previously published, dynamic, age-structured models of helminthiases transmission to simulate costs and disability averted with integrated MDA (of praziquantel and albendazole) for schistosomiasis and soil-transmitted helminthiasis. We calibrated the model to data for prevalence and intensity of species-specific helminth infection from surveys undertaken in four communities in Côte d'Ivoire between March, 1997, and September, 2010. We simulated a 15-year treatment programme with 75% coverage in only school-aged children; school-aged children and preschool-aged children; adults; and the entire community. Treatment costs were estimated at US$0·74 for school-aged children and $1·74 for preschool-aged children and adults. The incremental cost-effectiveness ratio (ICER) was calculated in 2014 US dollars per disability-adjusted life-year (DALY) averted.Expanded community-wide treatment was highly cost effective compared with treatment of only school-aged children (ICER $167 per DALY averted) and WHO guidelines (ICER $127 per DALY averted), and remained highly cost effective even if treatment costs for preschool-aged children and adults were ten times greater than those for school-aged children. Community-wide treatment remained highly cost effective even when elimination of helminth infections was not achieved. These findings were robust across the four diverse communities in Côte d'Ivoire, only one of which would have received annual MDA for both schistosomiasis and soil-transmitted helminthiasis under the latest WHO guidelines. Treatment every 6 months was also highly cost effective in three out of four communities.Integrated, community-wide MDA programmes for schistosomiasis and soil-transmitted helminthiasis can be highly cost effective, even in communities with low disease burden in any helminth group. These results support an urgent need to re-evaluate current global guidelines for helminthiases control programmes to include community-wide treatment, increased treatment frequency, and consideration for lowered prevalence thresholds for integrated treatment.Stanford University Medical Scholars Programme, Mount Sinai Hospital-University Health Network AMO Innovation Fund.

  View details for DOI 10.1016/S2214-109X(15)00047-9

  View details for PubMedID 26385302

• Risk of Progression to Active Tuberculosis Following Reinfection With Mycobacterium tuberculosis CLINICAL INFECTIOUS DISEASES Andrews, J. R., Noubary, F., Walensky, R. P., Cerda, R., Losina, E., Horsburgh, C. R. 2012; 54 (6): 784-791

  Abstract

  The risk of progression to active tuberculosis is greatest in the several years following initial infection. The extent to which latent tuberculosis infection reduces the risk of progressive disease following reexposure and reinfection is not known. Indirect estimates from population models have been highly variable.We reviewed prospective cohort studies of persons exposed to individuals with infectious tuberculosis that were published prior to the widespread treatment of latent tuberculosis to estimate the incidence of tuberculosis among individuals with latent tuberculosis infection (LTBI group) and without latent tuberculosis (uninfected; UI group). We calculated the incidence rate ratio (IRR) of tuberculosis disease following infection between these 2 groups. We then adjusted incidence for expected reactivation, proportion of each group that was infected, and median time of observation following infection during the study.We identified 18 publications reporting tuberculosis incidence among 23 paired cohorts of individuals with and without latent infection (total N = 19 886). The weighted mean adjusted incidence rate of tuberculosis in the LTBI and UI groups attributable to reinfection was 13.5 per 1000 person-years (95% confidence interval [CI]: 5.0-26.2 per 1000 person-years) and that attributable to primary infection was 60.1 per 1000 person-years (95% CI: 38.6-87.4 per 1000 person-years). The adjusted IRR for tuberculosis in the LTBI group compared with the UI group was 0.21 (95% CI: .14-.30).Individuals with latent tuberculosis had 79% lower risk of progressive tuberculosis after reinfection than uninfected individuals. The risk reduction estimated in this study is greater than most previous estimates made through population models.

  View details for DOI 10.1093/cid/cir951

  View details for Web of Science ID 000300790900009

  View details for PubMedID 22267721

• Transmission dynamics and control of cholera in Haiti: an epidemic model LANCET Andrews, J. R., Basu, S. 2011; 377 (9773): 1248-1255

  Abstract

  Official projections of the cholera epidemic in Haiti have not incorporated existing disease trends or patterns of transmission, and proposed interventions have been debated without comparative estimates of their effect. We used a mathematical model of the epidemic to provide projections of future morbidity and mortality, and to produce comparative estimates of the effects of proposed interventions.We designed mathematical models of cholera transmission based on existing models and fitted them to incidence data reported in Haiti for each province from Oct 31, 2010, to Jan 24, 2011. We then simulated future epidemic trajectories from March 1 to Nov 30, 2011, to estimate the effect of clean water, vaccination, and enhanced antibiotic distribution programmes.We project 779,000 cases of cholera in Haiti (95% CI 599,000-914,000) and 11,100 deaths (7300-17,400) between March 1 and Nov 30, 2011. We expect that a 1% per week reduction in consumption of contaminated water would avert 105,000 cases (88,000-116,000) and 1500 deaths (1100-2300). We predict that the vaccination of 10% of the population, from March 1, will avert 63,000 cases (48,000-78,000) and 900 deaths (600-1500). The proposed extension of the use of antibiotics to all patients with severe dehydration and half of patients with moderate dehydration is expected to avert 9000 cases (8000-10,000) and 1300 deaths (900-2000).A decline in cholera prevalence in early 2011 is part of the natural course of the epidemic, and should not be interpreted as indicative of successful intervention. Substantially more cases of cholera are expected than official estimates used for resource allocation. Combined, clean water provision, vaccination, and expanded access to antibiotics might avert thousands of deaths.National Institutes of Health.

  View details for DOI 10.1016/S0140-6736(11)60273-0

  View details for Web of Science ID 000289597300031

  View details for PubMedID 21414658

• Exogenous reinfection as a cause of multidrug-resistant and extensively drug-resistant tuberculosis in rural South Africa. Journal of Infectious Diseases Andrews, J. R., Gandhi, N. R., Prashini, M., N, S. S., Louise, B., Moll, A. P., Pillay, M., Friedland, G., Sturm, A. W. 2008; 198 (11): 1582-9
• Evaluation of a point-of-care immunochromatographic assay for enteric fever in Dhaka, Bangladesh: a prospective diagnostic accuracy study. The Lancet. Microbe Munira, S. J., Islam, N., Prithe, N. T., Sarkar, A., Esfandiari, J., Gunasekera, D., Islam, S., Akter, T., Garrett, D. O., Saha, S. K., Andrews, J. R., Saha, S., Charles, R. C. 2024: 100983

  Abstract

  There is a shortage of rapid, accurate, and low-cost assays for diagnosing enteric fever. The dual-path platform for typhoid (DPPT) assay had high accuracy in retrospective studies with banked plasma samples. We aimed to evaluate the diagnostic accuracy of the DPPT assay in a prospective study using fingerstick capillary blood.For this prospective diagnostic accuracy study, we enrolled children younger than 18 years, who presented at the Bangladesh Shishu Hospital and Institute (Dhaka, Bangladesh) with at least 3 days of fever. We collected blood and nasal swabs, and did the following assays to assess the accuracy of DPPT: blood culture, serological assays for typhoid fever (DPPT assay, Widal, and Test-it), and molecular assays to identify alternative aetiologies (eg, respiratory syncytial virus [RSV], influenza, dengue virus, and Rickettsia spp). The primary outcomes of the study were the sensitivity and specificity of the DPPT assay for diagnosis of enteric fever. We evaluated the accuracy of combined anti-haemolysin E and anti-lipopolysaccharide IgA readings using the DPPT assay in distinguishing culture-confirmed enteric fever from alternative aetiologies using receiver operating characteristic area under the curve (AUC). Given the imperfect reference standard diagnostics for enteric fever, we used Bayesian latent class models, incorporating results from the typhoid and alternative aetiology diagnostics, to estimate the sensitivity and specificity of the DPPT assay. We also did subgroup analyses for the assay across multiple biological variables.Between Aug 17, 2021, and July 16, 2022, we enrolled 501 participants who presented with at least 3 days of fever. 223 (45%) of 501 participants were female and 278 (55%) were male. 77 participants had culture-confirmed enteric fever (62 Salmonella enterica serotype Typhi and 15 Salmonella enterica serotype Paratyphi A) and 70 were culture-negative with PCR-confirmed alternative aetiology (34 influenza A or B, 22 dengue virus, seven Rickettsia spp, six RSV, and one participant co-infected with RSV and dengue virus). The AUC for DPPT on fingerstick capillary blood in distinguishing typhoid from alternative aetiologies was 0·969 (95% CI 0·943-0·994). In latent class analysis, the sensitivity of DPPT was 93% (95% credible interval [CrI] 87-97) and specificity was 89% (85-93). The balanced accuracy was higher for DPPT (91%, 95% CrI 87-94) than blood culture (81%, 78-85), Test-it (77%, 74-79), or Widal (70%, 67-73). Assay performance did not vary by sex, age, duration of fever at presentation, antibiotic use before presentation, Salmonella serotype, or sample type.The point-of-care DPPT assay achieved high diagnostic accuracy for enteric fever in a highly endemic community. This assay has the potential to improve clinical outcomes for enteric fever, allowing rapid diagnosis and treatment, and could facilitate more appropriate antimicrobial use.National Institute of Health, Bill & Melinda Gates Foundation, and Child Health Research Foundation.

  View details for DOI 10.1016/j.lanmic.2024.100983

  View details for PubMedID 39701118

• Implementing Oral Antibiotics for Bone and Joint Infections: Lessons Learned and Opportunities for Improvement. Open forum infectious diseases Hawkins, M. R., Thottacherry, E., Juthani, P., Aronson, J., Chang, A., Amanatullah, D. F., Markovits, J., Shen, S., Holubar, M., Andrews, J. R., Parsonnet, J., Furukawa, D. 2024; 11 (12): ofae683

  Abstract

  Although intravenous antibiotics have historically been the standard of care for bone and joint infections, clinical trial data have highlighted the safety and efficacy of oral antibiotics. Despite this, intravenous antibiotics are still commonly used, and evaluations of institutional guidelines advancing oral antibiotic use are limited.In April 2023, we implemented a new institutional guideline to preferentially treat patients with bone and joint infections with oral antibiotics. The postguideline cohort was compared with a historical preguideline cohort via retrospective chart review. The primary outcome was the proportion of patients discharged exclusively on oral antibiotics. Secondary outcomes included 90-day treatment failure, length of stay, and adverse effects.One hundred eighty-six patients (53 preguideline and 133 postguideline) were included in the analysis. Patients in the postguideline cohort were more likely to be discharged exclusively on oral antibiotics (25% vs 70%; P < .01), with no difference in 90-day treatment failure (8% vs 9%; P = .75). Patients in the postguideline cohort had a shorter length of stay than preguideline (median, 8 vs 7 days; P = .04) and trended toward fewer peripherally inserted central catheter-related adverse events (6% vs 1%; P = .07).An institutional guideline was effective in increasing the proportion of patients with bone and joint infections discharged on oral antibiotics. We observed similar clinical outcomes after implementing the guidelines while reducing length of hospital stay.

  View details for DOI 10.1093/ofid/ofae683

  View details for PubMedID 39660026

  View details for PubMedCentralID PMC11629981

• Signatures of transmission in within-host Mycobacterium tuberculosis complex variation: a retrospective genomic epidemiology study. The Lancet. Microbe Walter, K. S., Cohen, T., Mathema, B., Colijn, C., Sobkowiak, B., Comas, I., Goig, G. A., Croda, J., Andrews, J. R. 2024: 100936

  Abstract

  Mycobacterium tuberculosis complex (MTBC) species evolve slowly, so isolates from individuals linked in transmission often have identical or nearly identical genomes, making it difficult to reconstruct transmission chains. Finding additional sources of shared MTBC variation could help overcome this problem. Previous studies have reported MTBC diversity within infected individuals; however, whether within-host variation improves transmission inferences remains unclear. Here, we aimed to quantify within-host MTBC variation and assess whether such information improves transmission inferences.We conducted a retrospective genomic epidemiology study in which we reanalysed publicly available sequence data from household transmission studies published in PubMed from database inception until Jan 31, 2024, for which both genomic and epidemiological contact data were available, using household membership as a proxy for transmission linkage. We quantified minority variants (ie, positions with two or more alleles each supported by at least five-fold coverage and with a minor allele frequency of 1% or more) outside of PE and PPE genes, within individual samples and shared across samples. We used receiver operator characteristic (ROC) curves to compare the performance of a general linear model for household membership that included shared minority variants and one that included only fixed genetic differences.We identified three MTBC household transmission studies with publicly available whole-genome sequencing data and epidemiological linkages: a household transmission study in Vitória, Brazil (Colangeli et al), a retrospective population-based study of paediatric tuberculosis in British Columbia, Canada (Guthrie et al), and a retrospective population-based study in Oxfordshire, England (Walker et al). We found moderate levels of minority variation present in MTBC sequence data from cultured isolates that varied significantly across studies: mean 168·6 minority variants (95% CI 151·4-185·9) for the Colangeli et al dataset, 5·8 (1·5-10·2) for Guthrie et al (p<0·0001, Wilcoxon rank sum test, vs Colangeli et al), and 7·1 (2·4-11·9) for Walker et al (p<0·0001, Wilcoxon rank sum test, vs Colangeli et al). Isolates from household pairs shared more minority variants than did randomly selected pairs of isolates: mean 97·7 shared minority variants (79·1-116·3) versus 9·8 (8·6-11·0) in Colangeli et al, 0·8 (0·1-1·5) versus 0·2 (0·1-0·2) in Guthrie et al, and 0·7 (0·1-1·3) versus 0·2 (0·2-0·2) in Walker et al (all p<0·0001, Wilcoxon rank sum test). Shared within-host variation was significantly associated with household membership (odds ratio 1·51 [95% CI 1·30-1·71], p<0·0001), for one standard deviation increase in shared minority variants. Models that included shared within-host variation versus models without within-host variation improved the accuracy of predicting household membership in all three studies: area under the ROC curve 0·95 versus 0·92 for the Colangeli et al study, 0·99 versus 0·95 for the Guthrie et al study, and 0·93 versus 0·91 for the Walker et al study.Within-host MTBC variation persists through culture of sputum and could enhance the resolution of transmission inferences. The substantial differences in minority variation recovered across studies highlight the need to optimise approaches to recover and incorporate within-host variation into automated phylogenetic and transmission inference.National Institutes of Health.

  View details for DOI 10.1016/j.lanmic.2024.06.003

  View details for PubMedID 39615498

• Elucidating the role of internal migration in the spread of M. tuberculosis. Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases Da Silva, K. E., Andrews, J. R. 2024

  View details for DOI 10.1016/j.cmi.2024.10.011

  View details for PubMedID 39433122

• Evaluation of a point-of-care multiplex immunochromatographic assay for the diagnosis of typhoid: results from a retrospective diagnostic accuracy study. Journal of clinical microbiology Hasan, R., Azizullah, Z., Shams, H., Dittrich, S., Andrews, J. R., Charles, R. C., Esfandiari, J., Gunasekera, D., Tetteh, K. K., Sapkota, J. 2024: e0042824

  Abstract

  There is a clear medical need for an accurate diagnostic test for typhoid that can be performed at point of care. Two antigens (lipopolysaccharide [LPS] and hemolysin E [HlyE]) have recently been identified that can distinguish typhoid from other bacterial infections. Here, we present the results of a diagnostic accuracy study of the Dual Path Platform (DPP) Typhoid assay (Chembio) that detects IgA to both LPS and HlyE using blood culture as the reference standard. This was a retrospective, observational, laboratory study conducted at the Aga Khan University research laboratory, Pakistan, to evaluate the sensitivity and specificity of the DPP Typhoid assay, using archived frozen serum samples collected during a previous typhoid diagnostic accuracy study (NCT04801602). The sensitivity, specificity, and accuracy (area under the receptor operating characteristics curve [AUC]) were then assessed using the manufacturer's and Youden's optimal thresholds. In total, 385 samples were included in the analysis. Using the manufacturer's thresholds, the sensitivity, specificity, and AUC were 97.8% (95% confidence interval [CI] 94.6-99.2), 65.3% (95% CI 58.5-71.6), and 81.5% (95% CI 75.5-85.3), respectively. At Youden's optimal threshold, the overall sensitivity of the DPP Typhoid assay was 89.7% and the specificity was 82.2%. In latent class modeling compared with other nine rapid diagnostic tests evaluated from the same cohort sample, the DPP Typhoid assay demonstrated the highest balanced accuracy (89.2%). The DPP Typhoid assay demonstrated a high diagnostic accuracy for typhoid fever. However, further adjustment to new thresholds is recommended to enhance its performance capabilities.Currently available diagnostic tests for typhoid have several limitations, including low sensitivity and specificity. Dual Path Platform Typhoid assay is a multiplex rapid test that detects IgA antibodies to lipopolysaccharide and hemolysin E antigen. It is considered to have high sensitivity and specificity, and its results were found to be highly correlated with ELISA results. However, very few studies have been conducted to evaluate this test and limited information about the accuracy of this test is present. Hence, this study evaluated the new typhoid test.

  View details for DOI 10.1128/jcm.00428-24

  View details for PubMedID 39302169

• Global burden of bacterial antimicrobial resistance 1990-2021: a systematic analysis with forecasts to 2050. Lancet (London, England) 2024

  Abstract

  Antimicrobial resistance (AMR) poses an important global health challenge in the 21st century. A previous study has quantified the global and regional burden of AMR for 2019, followed with additional publications that provided more detailed estimates for several WHO regions by country. To date, there have been no studies that produce comprehensive estimates of AMR burden across locations that encompass historical trends and future forecasts.We estimated all-age and age-specific deaths and disability-adjusted life-years (DALYs) attributable to and associated with bacterial AMR for 22 pathogens, 84 pathogen-drug combinations, and 11 infectious syndromes in 204 countries and territories from 1990 to 2021. We collected and used multiple cause of death data, hospital discharge data, microbiology data, literature studies, single drug resistance profiles, pharmaceutical sales, antibiotic use surveys, mortality surveillance, linkage data, outpatient and inpatient insurance claims data, and previously published data, covering 520 million individual records or isolates and 19 513 study-location-years. We used statistical modelling to produce estimates of AMR burden for all locations, including those with no data. Our approach leverages the estimation of five broad component quantities: the number of deaths involving sepsis; the proportion of infectious deaths attributable to a given infectious syndrome; the proportion of infectious syndrome deaths attributable to a given pathogen; the percentage of a given pathogen resistant to an antibiotic of interest; and the excess risk of death or duration of an infection associated with this resistance. Using these components, we estimated disease burden attributable to and associated with AMR, which we define based on two counterfactuals; respectively, an alternative scenario in which all drug-resistant infections are replaced by drug-susceptible infections, and an alternative scenario in which all drug-resistant infections were replaced by no infection. Additionally, we produced global and regional forecasts of AMR burden until 2050 for three scenarios: a reference scenario that is a probabilistic forecast of the most likely future; a Gram-negative drug scenario that assumes future drug development that targets Gram-negative pathogens; and a better care scenario that assumes future improvements in health-care quality and access to appropriate antimicrobials. We present final estimates aggregated to the global, super-regional, and regional level.In 2021, we estimated 4·71 million (95% UI 4·23-5·19) deaths were associated with bacterial AMR, including 1·14 million (1·00-1·28) deaths attributable to bacterial AMR. Trends in AMR mortality over the past 31 years varied substantially by age and location. From 1990 to 2021, deaths from AMR decreased by more than 50% among children younger than 5 years yet increased by over 80% for adults 70 years and older. AMR mortality decreased for children younger than 5 years in all super-regions, whereas AMR mortality in people 5 years and older increased in all super-regions. For both deaths associated with and deaths attributable to AMR, meticillin-resistant Staphylococcus aureus increased the most globally (from 261 000 associated deaths [95% UI 150 000-372 000] and 57 200 attributable deaths [34 100-80 300] in 1990, to 550 000 associated deaths [500 000-600 000] and 130 000 attributable deaths [113 000-146 000] in 2021). Among Gram-negative bacteria, resistance to carbapenems increased more than any other antibiotic class, rising from 619 000 associated deaths (405 000-834 000) in 1990, to 1·03 million associated deaths (909 000-1·16 million) in 2021, and from 127 000 attributable deaths (82 100-171 000) in 1990, to 216 000 (168 000-264 000) attributable deaths in 2021. There was a notable decrease in non-COVID-related infectious disease in 2020 and 2021. Our forecasts show that an estimated 1·91 million (1·56-2·26) deaths attributable to AMR and 8·22 million (6·85-9·65) deaths associated with AMR could occur globally in 2050. Super-regions with the highest all-age AMR mortality rate in 2050 are forecasted to be south Asia and Latin America and the Caribbean. Increases in deaths attributable to AMR will be largest among those 70 years and older (65·9% [61·2-69·8] of all-age deaths attributable to AMR in 2050). In stark contrast to the strong increase in number of deaths due to AMR of 69·6% (51·5-89·2) from 2022 to 2050, the number of DALYs showed a much smaller increase of 9·4% (-6·9 to 29·0) to 46·5 million (37·7 to 57·3) in 2050. Under the better care scenario, across all age groups, 92·0 million deaths (82·8-102·0) could be cumulatively averted between 2025 and 2050, through better care of severe infections and improved access to antibiotics, and under the Gram-negative drug scenario, 11·1 million AMR deaths (9·08-13·2) could be averted through the development of a Gram-negative drug pipeline to prevent AMR deaths.This study presents the first comprehensive assessment of the global burden of AMR from 1990 to 2021, with results forecasted until 2050. Evaluating changing trends in AMR mortality across time and location is necessary to understand how this important global health threat is developing and prepares us to make informed decisions regarding interventions. Our findings show the importance of infection prevention, as shown by the reduction of AMR deaths in those younger than 5 years. Simultaneously, our results underscore the concerning trend of AMR burden among those older than 70 years, alongside a rapidly ageing global community. The opposing trends in the burden of AMR deaths between younger and older individuals explains the moderate future increase in global number of DALYs versus number of deaths. Given the high variability of AMR burden by location and age, it is important that interventions combine infection prevention, vaccination, minimisation of inappropriate antibiotic use in farming and humans, and research into new antibiotics to mitigate the number of AMR deaths that are forecasted for 2050.UK Department of Health and Social Care's Fleming Fund using UK aid, and the Wellcome Trust.

  View details for DOI 10.1016/S0140-6736(24)01867-1

  View details for PubMedID 39299261

• Molecular epidemiology and evolutionary characteristics of dengue virus 2 in East Africa. Nature communications Nyathi, S., Rezende, I. M., Walter, K. S., Thongsripong, P., Mutuku, F., Ndenga, B., Mbakaya, J. O., Aswani, P., Musunzaji, P. S., Chebii, P. K., Maina, P. W., Mutuku, P. S., Ng'ang'a, C. M., Malumbo, S. L., Jembe, Z., Vu, D. M., Mordecai, E. A., Bennett, S., Andrews, J. R., LaBeaud, A. D. 2024; 15 (1): 7832

  Abstract

  Despite the increasing burden of dengue, the regional emergence of the virus in Kenya has not been examined. This study investigates the genetic structure and regional spread of dengue virus-2 in Kenya. Viral RNA from acutely ill patients in Kenya was enriched and sequenced. Six new dengue-2 genomes were combined with 349 publicly available genomes and phylogenies used to infer gene flow between Kenya and other countries. Analyses indicate two dengue-2 Cosmopolitan genotype lineages circulating in Kenya, linked to recent outbreaks in coastal Kenya and Burkina Faso. Lineages circulating in Western, Southern, and Eastern Africa exhibiting similar evolutionary features are also reported. Phylogeography suggests importation of dengue-2 into Kenya from East and Southeast Asia and bidirectional geneflow. Additional lineages circulating in Africa are also imported from East and Southeast Asia. These findings underscore how intermittent importations from East and Southeast Asia drive dengue-2 circulation in Kenya and Africa more broadly.

  View details for DOI 10.1038/s41467-024-51018-0

  View details for PubMedID 39244569

  View details for PubMedCentralID 3651993

• Factors Influencing Vaccine Receipt During a 2018 Pediatric Typhoid Conjugate Vaccine Campaign in Navi Mumbai, India. The American journal of tropical medicine and hygiene Borhade, P., LeBoa, C., Jayaprasad, N., Date, K., Haldar, P., Harvey, P., Shimpi, R., An, Q., Zhang, C., Horng, L., Fagerli, K., Yewale, V. N., Daruwalla, S., Dharmapalan, D., Gavhane, J., Joshi, S., Rai, R., Rathod, V., Shetty, K., Warrier, D. S., Yadav, S., Chakraborty, D., Bahl, S., Katkar, A., Kunwar, A., Andrews, J. R., Bhatnagar, P., Dutta, S., Luby, S. P., Hoffman, S. A. 2024

  Abstract

  In 2018, the Navi Mumbai Municipal Corporation implemented phase 1 of a public sector typhoid conjugate vaccine campaign in Navi Mumbai, India, targeting all children aged 9 months to 14 years within its administrative boundaries. To assess associations with receipt of vaccine in phase 1, we used generalized estimating equations to calculate estimates of vaccination by child-, household-, and community-level demographics (child education and age; household head education, income, and occupation; community informal settlement percent). Campaign vaccine receipt was most associated with children enrolled in school (odds ratio [OR] = 3.84, 95% CI: 2.18-6.77), the lowest household income tertile when divided into three equal parts (OR = 1.64, 95% CI: 1.43-1.84), and lower community-level socioeconomic status (OR = 1.06, 95% CI: 1.04-1.08 per 10% informal settlement proportion). The campaign was successful in reaching the most underserved populations of its target communities.

  View details for DOI 10.4269/ajtmh.24-0182

  View details for PubMedID 39348826

• Cost-effectiveness and health impact of screening and treatment of Mycobacterium tuberculosis infection among formerly incarcerated individuals in Brazil: a Markov modelling study. The Lancet. Global health van Lieshout Titan, A., Klaassen, F., Pelissari, D. M., de Barros Silva, J. N., Alves, K., Alves, L. C., Sanchez, M., Bartholomay, P., Johansen, F. D., Croda, J., Andrews, J. R., Castro, M. C., Cohen, T., Vuik, C., Menzies, N. A. 2024; 12 (9): e1446-e1455

  Abstract

  Individuals who were formerly incarcerated have high tuberculosis incidence, but are generally not considered among the risk groups eligible for tuberculosis prevention. We investigated the potential health impact and cost-effectiveness of Mycobacterium tuberculosis infection screening and tuberculosis preventive treatment (TPT) for individuals who were formerly incarcerated in Brazil.Using published evidence for Brazil, we constructed a Markov state transition model estimating tuberculosis-related health outcomes and costs among individuals who were formerly incarcerated, by simulating transitions between health states over time. The analysis compared tuberculosis infection screening and TPT, to no screening, considering a combination of M tuberculosis infection tests and TPT regimens. We quantified health effects as reductions in tuberculosis cases, tuberculosis deaths, and disability-adjusted life-years (DALYs). We assessed costs from a tuberculosis programme perspective. We report intervention cost-effectiveness as the incremental costs per DALY averted, and tested how results changed across subgroups of the target population.Compared with no intervention, an intervention incorporating tuberculin skin testing and treatment with 3 months of isoniazid and rifapentine would avert 31 (95% uncertainty interval 14-56) lifetime tuberculosis cases and 4·1 (1·4-5·8) lifetime tuberculosis deaths per 1000 individuals, and cost US$242 per DALY averted. All test and regimen combinations were cost-effective compared with no screening. Younger age, longer incarceration, and more recent prison release were each associated with significantly greater health benefits and more favourable cost-effectiveness ratios, although the intervention was cost-effective for all subgroups examined.M tuberculosis infection screening and TPT for individuals who were formerly incarcerated appears cost-effective, and would provide valuable health gains.National Institutes of Health.For the Portuguese translation of the abstract see Supplementary Materials section.

  View details for DOI 10.1016/S2214-109X(24)00221-3

  View details for PubMedID 39151980

• Severity-dependent test-seeking behaviors and test-negative designs: impact on estimated vaccine effectiveness and utility of analytic and design choices. American journal of epidemiology Amin, A. B., Hitchings, M. D., Ranzani, O. T., Andrews, J. R., Cummings, D. A., Ko, A. I., Croda, J., Dean, N. E. 2024

  Abstract

  Test-negative designs are increasingly used to evaluate vaccine effectiveness because of desirable properties like reduced confounding due to healthcare-seeking behaviors and lower cost compared to other study designs. An individual's decision to seek care often depends on their disease severity, with severe disease more likely to be captured than mild disease. As many vaccines likely attenuate disease severity, this phenomenon generally results in an upward-biased estimate of vaccine effectiveness against symptomatic disease. To address the resulting bias, analytic solutions like adjusting for or matching on severity have been suggested. In this paper, we examine the performance of the test-negative design under different vaccine effects on disease severity and the utility of adjusting or matching on severity. We further consider the implications of studies that focus only on milder disease by restricting recruitment to outpatient settings. Through an analytic framework and simulations accompanied by a real-world example, we demonstrate that, when vaccination attenuates disease severity, the magnitude of bias is influenced by the degree of under-ascertainment of mild disease relative to severe disease. When vaccination does not attenuate disease severity, bias is not present. We further show that analytic fixes negligibly impact bias and that outpatient-only studies frequently produce downward-biased estimates.

  View details for DOI 10.1093/aje/kwae303

  View details for PubMedID 39191656

• Field Effectiveness of a Typhoid Conjugate Vaccine: The 2018 Navi Mumbai Pediatric TCV Campaign. The American journal of tropical medicine and hygiene Date, K., LeBoa, C., Hoffman, S. A., Haldar, P., Harvey, P., An, Q., Zhang, C., Yewale, V. N., Daruwalla, S., Dharmapalan, D., Gavhane, J., Joshi, S., Rai, R., Rathod, V., Shetty, K., Warrier, D. S., Yadav, S., Shimpi, R., Jayaprasad, N., Horng, L., Fagerli, K., Borhade, P., Chakraborty, D., Katkar, A., Kunwar, A., Andrews, J. R., Bahl, S., Bhatnagar, P., Dutta, S., Luby, S. P. 2024

  Abstract

  Typbar-TCV®, a typhoid conjugate vaccine (TCV), was prequalified by the World Health Organization in 2017. We evaluated its effectiveness in a mass vaccination program targeting children 9 months to 14 years in Navi Mumbai, India, from September 2018 to July 2020. We compared laboratory-confirmed typhoid cases from six clinical sites with age-matched community controls. Of 38 cases, three (8.6%) received TCV through the campaign, compared with 53 (37%) of 140 controls. The adjusted odds ratio of typhoid fever among vaccinated children was 0.16 (95% CI: 0.05-0.55), equivalent to a vaccine effectiveness of 83.7% (95% CI: 45.0-95.3). Vaccine effectiveness of Typbar-TCV in this large public sector vaccine introduction was similar to prior randomized controlled trials, providing reassurance to policymakers that TCV effectiveness is robust in a large-scale implementation.

  View details for DOI 10.4269/ajtmh.24-0181

  View details for PubMedID 39137766

• Hepatitis E virus in the Kathmandu Valley: Insights from a representative longitudinal serosurvey. PLoS neglected tropical diseases Katuwal, N., Thapa, M., Shrestha, S., Vaidya, K., Bogoch, I. I., Shrestha, R., Andrews, J. R., Tamrakar, D., Aiemjoy, K. 2024; 18 (8): e0012375

  Abstract

  Hepatitis-E virus (HEV), an etiologic agent of acute inflammatory liver disease, is a significant cause of morbidity and mortality in South Asia. HEV is considered endemic in Nepal; but data on population-level infection transmission is sparse.We conducted a longitudinal serosurvey in central Nepal to assess HEV exposure. At each visit, capillary blood samples were collected and analyzed for the presence of anti-HEV IgG antibodies. The study took place between February 2019 and April 2021, with up to 4 visits per participant approximately 6 months apart.We collected 2513 samples from 923 participants aged 0-25 years, finding a seroprevalence of 4.8% and a seroincidence rate of 10.9 per 1000 person-years. Young adults and individuals consuming surface water faced the highest incidence of infection. Geospatial analysis identified potential HEV clusters, suggesting a need for targeted interventions.Our findings demonstrate that HEV is endemic in Nepal and that the risk of infection increases with age.

  View details for DOI 10.1371/journal.pntd.0012375

  View details for PubMedID 39102451

• Natural history of shedding and household transmission of severe acute respiratory syndrome coronavirus 2 using intensive high-resolution sampling. PloS one Altamirano, J., Govindarajan, P., Blomkalns, A. L., Leary, S., Robinson, I., Chun, L. X., Shaikh, N. J., Robinson, M. L., Lopez, M., Tam, G. K., Carrington, Y. J., De Araujo, M. B., Walter, K. S., Andrews, J. R., Burns, J., Hogan, C., Pinsky, B. A., Maldonado, Y. 2024; 19 (7): e0305300

  Abstract

  The COVID-19 pandemic has led to 775 million documented cases and over 7 million deaths worldwide as of March 2024 and is an ongoing health crisis. To limit viral spread within households and in the community, public health officials have recommended self-isolation, self-quarantine of exposed household contacts, and mask use. Yet, risk of household transmission (HHT) may be underestimated due to low frequency of sampling, and risk factors for HHT are not well understood.To estimate the secondary attack rate of SARS-CoV-2 within households and to define the risk factors for new infections in household members who are in close contact with the index case.In this prospective cohort study, from March 2020-December 2021 we enrolled 60 households with index cases who tested positive for SARS-CoV-2. All household contacts and index cases were tested daily for SARS-CoV-2 via reverse transcription polymerase chain reaction (RT-PCR) using self-collected anterior nares specimens. Households were followed until all study participants in the household tested negative for SARS-CoV-2 for seven consecutive days. We collected sex, age, race/ethnicity, comorbidities, and relationship to index case for secondary contacts, household level characteristics including primary income, household density, and square feet per person on property. We compared the sociodemographic variables between COVID-19 positive and negative household members and between households where secondary transmission did and did not occur.Daily anterior nares swabs were tested for SARS-CoV-2 using RT-PCR, in order to assess duration of nasal shedding of SARS-CoV-2, as well as risk of transmission to secondary household contacts.Of the 163 participants in this study, 84 (51.5%) were women; median age (IQR) was 36.0 (17.0-54.0) years of age; 78 (47.8%) were white and 48 (29.5%) were Hispanic/LatinX. Of the fifty households with household contacts, at least one secondary case occurred in twenty-six households (52.0%) and forty-five household contacts (43.7%) were infected. Secondary attack rate was lowest among children of index cases (6/23, 26.1%). Modified Poisson regression identified that the risk of transmission to household contacts increases significantly with age (Risk ratio for each increase in years of age = 1.01, 95% CI = 1.00-1.02). Mixed effects regression models identified that participants with chronic diseases, such as asthma, diabetes, cancer, or cardiac disease, had higher Cts at baseline when compared to participants without chronic diseases (6.62, 95% CI: 1.46-11.77, p = 0.02) and show a slower rate of increase in Ct over time (-0.43, 95% CI: -0.77 to -0.09, p = 0.02).This study suggests that HHT represents a key source of community-based infection of SARS-CoV-2. Allocation of resources for contact investigations and prevention interventions should focus on the individuals at highest risk of infection in households, especially those with higher density homes.

  View details for DOI 10.1371/journal.pone.0305300

  View details for PubMedID 39052659

• Recasting resistance to Mycobacterium tuberculosis. Nature immunology Andrews, J. R. 2024

  View details for DOI 10.1038/s41590-024-01907-9

  View details for PubMedID 39048789

  View details for PubMedCentralID 11065701

• The impact of COVID-19 national lockdowns on drug-resistant tuberculosis in KwaZulu-Natal, South Africa: a spatial analysis. Annals of epidemiology Harrington, K. R., Gandhi, N. R., Shah, N. S., Naidoo, K., Auld, S. C., Andrews, J. R., Brust, J. C., Lutchminarain, K., Coe, M., Willis, F., Campbell, A., Cohen, T., Jenness, S., Waller, L. 2024

  Abstract

  We sought to understand the impact of the initial COVID-19 mitigation strategies in 2020 on drug-resistant (DR) TB diagnoses in KwaZulu-Natal province (KZN), South Africa.We compared the number, spatial distribution, and characteristics of DR TB diagnoses before and after the initial COVID-19 lockdown on March 26th, 2020. Information on DR TB diagnoses was collected from the CONTEXT prospective cohort study and municipality characteristics were collected from Statistics South Africa. We used Bayesian conditional autoregressive models and relative-risk surface maps to examine spatial correlates and patterns of DR TB notifications.Between October 2018 and February 2022, there were 693 individuals diagnosed with DR TB in KZN, South Africa. The rate of diagnoses per year was 274 and 155 prior and after to the initial lockdowns, respectively, corresponding to a 43% decrease in the notification rate of cases. Compared to cases diagnosed before the lockdown, cases diagnosed after were less likely to have a fuel source for heating, piped water, a flush toilet, or own a phone (p-values≤0.02). Changes in notifications were not homogenously distributed, with predominantly rural northeastern and southwestern municipalities having significantly greater relative-risks after the lockdown.We found a reduction in the rate of DR TB diagnoses after the COVID-19 pandemic lockdowns and observed that individuals diagnosed after the lockdowns had worse living conditions, fewer household resources, and more adults living in their household compared to before the pandemic.

  View details for DOI 10.1016/j.annepidem.2024.07.044

  View details for PubMedID 39038747

• Likelihood of COVID-19 Outbreaks in US Immigration and Customs Enforcement (ICE) Detention Centers, 2020‒2021. American journal of public health Woods, E. C., Andrews, J. R., Goldhaber-Fiebert, J. D. 2024: e1-e4

  Abstract

  Objectives. To determine facility-level factors associated with COVID-19 outbreaks in US Immigration and Customs Enforcement (ICE) detention centers. Methods. We obtained COVID-19 case counts at 88 ICE detention facilities from May 6, 2020, through June 21, 2021, from the COVID Prison Project. We obtained information about facility population size, facility type (dedicated to immigrants or mixed with other incarcerated populations), and facility operator (public vs private contractor) from third-party sources. We defined the threshold for a COVID-19 outbreak as a cumulative 3-week incidence of 10% or more of the detained population. Results. Sixty-three facilities (72%) had at least 1 outbreak. Facilities with any outbreak were significantly more likely to be privately operated (P < .001), to have larger populations (113 vs 37; P = .002), and to have greater changes in their population size over the study period (‒56% vs -26%; P < .001). Conclusions. Several facility-level factors were associated with the occurrence of COVID-19 outbreaks in ICE facilities. Public Health Implications. Structural and organizational factors that promote respiratory infection spread in ICE facilities must be addressed to protect detainee health. (Am J Public Health. Published online ahead of print June 20, 2024:e1-e4. https://doi.org/10.2105/AJPH.2024.307704).

  View details for DOI 10.2105/AJPH.2024.307704

  View details for PubMedID 38900981

• Estimating the Seroincidence of Scrub Typhus using Antibody Dynamics after Infection. The American journal of tropical medicine and hygiene Aiemjoy, K., Katuwal, N., Vaidya, K., Shrestha, S., Thapa, M., Teunis, P., Bogoch, I. I., Trowbridge, P., Blacksell, S. D., Paris, D. H., Wangrangsimakul, T., Varghese, G. M., Maude, R. J., Tamrakar, D., Andrews, J. R. 2024

  Abstract

  Scrub typhus, a vector-borne bacterial infection, is an important but neglected disease globally. Accurately characterizing the burden is challenging because of nonspecific symptoms and limited diagnostics. Prior seroepidemiology studies have struggled to find consensus cutoffs that permit comparisons of estimates across contexts and time. In this study, we present a novel approach that does not require a cutoff and instead uses information about antibody kinetics after infection to estimate seroincidence. We use data from three cohorts of scrub typhus patients in Chiang Rai, Thailand, and Vellore, India, to characterize antibody kinetics after infection and two population serosurveys in the Kathmandu Valley, Nepal, and Tamil Nadu, India, to estimate seroincidence. The samples were tested for IgM and IgG responses to Orientia tsutsugamushi-derived recombinant 56-kDa antigen using commercial enzyme-linked immunosorbent assay kits. We used Bayesian hierarchical models to characterize antibody responses after scrub typhus infection and used the joint distributions of the peak antibody titers and decay rates to estimate population-level incidence rates in the cross-sectional serosurveys. Median responses persisted above an optical density (OD) of 1.8 for 23.6 months for IgG and an OD of 1 for 4.5 months for IgM. Among 18- to 29-year-olds, the seroincidence was 10 per 1,000 person-years (95% CI, 5-19) in Tamil Nadu, India, and 14 per 1,000 person-years (95% CI: 10-20) in the Kathmandu Valley, Nepal. When seroincidence was calculated with antibody decay ignored, the disease burden was underestimated by more than 50%. The approach can be deployed prospectively, coupled with existing serosurveys, or leverage banked samples to efficiently generate scrub typhus seroincidence estimates.

  View details for DOI 10.4269/ajtmh.23-0475

  View details for PubMedID 38861980

• Rapid and Comprehensive Screening for Urogenital and Gastrointestinal Schistosomiasis with Handheld Digital Microscopy Combined with Circulating Cathodic Antigen Testing. The American journal of tropical medicine and hygiene Coulibaly, J. T., Silue, K. D., de León Derby, M. D., Fletcher, D. A., Fisher, K. N., Andrews, J. R., Bogoch, I. I. 2024

  Abstract

  Novel methods are required to aid the monitoring of schistosomiasis control and elimination initiatives through mass drug administration. Portable digital and mobile phone microscopy is a promising tool for this purpose. This cross-sectional study evaluated the diagnostic operating characteristics of a converted mobile phone microscope (the SchistoScope) for the detection of Schistosoma haematobium eggs, as determined by community-based field workers and expert microscopists, compared with a field gold standard of light microscopy. Three hundred sixty-five urine samples were evaluated by conventional light microscopy, with 49 (13.4%) positive for S. haematobium. Compared with light microscopy, the sensitivity and specificity of S. haematobium detection by field microscopists trained to use the SchistoScope were 26.5% (95% CI: 14.9-41.1%) and 98.4% (95% CI: 96.3-99.5%), respectively. The sensitivity and specificity of S. haematobium detection by expert microscopists using the SchistoScope was 74% (95% CI: 59.7-85.4%) and 98.1% (95% CI: 95.9-99.3%), respectively, compared with light microscopy. The sensitivity rose to 96.1% and 100% when evaluating for egg counts greater than five and 10 eggs per 10 mL, respectively. A point-of-care circulating cathodic anion (POC CCA) test was used to evaluate Schistosoma mansoni; however, there were too few positive samples to reliably comment on diagnostic characteristics. This study demonstrated that a "urine-only" approach to rapidly screen for schistosomiasis at the point of sample collection can be conducted with mobile phone microscopy (S. haematobium) coupled with POC CCA (S. mansoni). Such an approach may aid in streamlined schistosomiasis control and elimination initiatives.

  View details for DOI 10.4269/ajtmh.24-0043

  View details for PubMedID 38861962

• Effectiveness of the fourth dose of COVID-19 vaccines against severe COVID-19 among adults 40 years or older in Brazil: a population-based cohort study. Lancet regional health. Americas Lazar Neto, F., Hitchings, M. D., Amin, A. B., de França, G. V., Lind, M. L., Scaramuzzini Torres, M. S., Tsuha, D. H., de Oliveira, R. D., Cummings, D. A., Dean, N. E., Andrews, J. R., Ko, A. I., Croda, J., Ranzani, O. T. 2024; 34: 100755

  Abstract

  The emergence of COVID-19 variants with immune scape and the waning of primary vaccine schemes effectiveness have prompted many countries to indicate first and second booster COVID-19 vaccine doses to prevent severe COVID-19. However, current available evidence on second booster dose effectiveness are mostly limited to high-income countries, older adults, and mRNA-based vaccination schemes scenarios. We aimed to investigate the relative vaccine effectiveness (rVE) of the fourth dose compared to three doses for severe COVID-19 outcomes in Brazil; and compare the rVE of a fourth dose with an mRNA vaccine compared to adenovirus-based product in the same settings.We performed a target emulated trial using a population-based cohort of individuals aged 40 years or older who have received a homologous primary scheme of CoronaVac, ChAdOx1, or BNT162b2, and any third dose product and were eligible for the fourth dose in Brazil. The primary outcome was COVID-19 associated hospitalization or death. We built Cohort A matching individuals vaccinated with a fourth dose to individuals who received three doses to estimate the rVE of the fourth dose. We built Cohort B, a subset of Cohort A, matching mRNA-based (mRNA) to adenovirus-based fourth dose vaccinated individuals to compare their relative hazards for severe COVID-19.46,693,484 individuals were included in Cohort A and 6,763,016 in Cohort B. 45% of them were aged between 40 and 60 years old, and 48% between 60 and 79 years old. In Cohort A, the most common previous series was a ChAdOx1 two-dose followed by BNT162b2 (44%), and a CoronaVac two-dose followed by a BNT162b2 (36%). Among those fourth dose vaccinated, 36.9% received ChAdOx1, 32.7% Ad26.COV2.S, 25.8% BNT162b2, and 4.7% CoronaVac. In Cohort B, among those who received an adenovirus fourth dose, 53.7% received ChAdOx1 and 46.3% received Ad26.COV2.S. The estimated rVE for the primary outcome of four doses compared to three doses was 44.1% (95% CI 42.3-46.0), with some waning during follow-up (rVE 7-60 days 46.8% [95% CI 44.4-49.1], rVE after 120 days 33.8% [95% CI 18.0-46.6]). Among fourth dose vaccinated individuals, mRNA-based vaccinated individuals had lower hazards for hospitalization or death compared to adenovirus-vaccinated individuals (HR 0.81, 95% CI 0.75-0.87). After 120 days, no difference in hazards between groups was observed (HR 1.35, 95% CI 0.93-1.97). Similar findings were observed for hospitalization and death separately, except no evidence for differences between fourth dose brands for death in Cohort B.In a heterogeneous scenario of primary and first booster vaccination combinations, a fourth dose provided meaningful and durable protection against severe COVID-19 outcomes. Compared to adenovirus-based booster, a fourth dose wild-type mRNA vaccine was associated with immediate lower hazards of hospitalization or death unsustained after 120 days.None.

  View details for DOI 10.1016/j.lana.2024.100755

  View details for PubMedID 38737773

  View details for PubMedCentralID PMC11087726

• Rates and causes of death after release from incarceration among 1 471 526 people in eight high-income and middle-income countries: an individual participant data meta-analysis. Lancet (London, England) Borschmann, R., Kinner, S. A. 2024

  Abstract

  Formerly incarcerated people have exceptionally poor health profiles and are at increased risk of preventable mortality when compared with their general population peers. However, not enough is known about the epidemiology of mortality in this population-specifically the rates, causes, and timing of death in specific subgroups and regions-to inform the development of targeted, evidence-based responses. We aimed to document the incidence, timing, causes, and risk factors for mortality after release from incarceration.We analysed linked administrative data from the multi-national Mortality After Release from Incarceration Consortium (MARIC) study. We examined mortality outcomes for 1 471 526 people released from incarceration in eight countries (Australia, Brazil, Canada, New Zealand, Norway, Scotland, Sweden, and the USA) from 1980 to 2018, across 10 534 441 person-years of follow-up (range 0-24 years per person). We combined data from 18 cohort studies using two-step individual participant data meta-analyses to estimate pooled all-cause and cause-specific crude mortality rates (CMRs) per 100 000 person-years, for specific time periods (first, daily from days 1-14; second, weekly from weeks 3-12; third, weeks 13-52 combined; fourth, weeks 53 and over combined; and fifth, total follow-up) after release, overall and stratified by age, sex, and region.75 427 deaths were recorded. The all-cause CMR during the first week following release (1612 [95% CI 1048-2287]) was higher than during all other time periods (incidence rate ratio [IRR] compared with week 2: 1·5 [95% CI 1·2-1·8], I2=26·0%, weeks 3-4: 2·0 [1·5-2·6], I2=53·0%, and weeks 9-12: 2·2 [1·6-3·0], I2=70·5%). The highest cause-specific mortality rates during the first week were due to alcohol and other drug poisoning (CMR 657 [95% CI 332-1076]), suicide (135 [36-277]), and cardiovascular disease (71 [16-153]). We observed considerable variation in cause-specific CMRs over time since release and across regions. Pooled all-cause CMRs were similar between males (731 [95% CI 630-839]) and females (660 [560-767]) and were higher in older age groups.The markedly elevated rate of death in the first week post-release underscores an urgent need for investment in evidence-based, coordinated transitional healthcare, including treatment for mental illness and substance use disorders to prevent post-release deaths due to suicide and overdose. Temporal variations in rates and causes of death highlight the need for routine monitoring of post-release mortality.Australia's National Health and Medical Research Council.

  View details for DOI 10.1016/S0140-6736(24)00344-1

  View details for PubMedID 38614112

• Incidence of typhoid fever in Burkina Faso, Democratic Republic of the Congo, Ethiopia, Ghana, Madagascar, and Nigeria (the Severe Typhoid in Africa programme): a population-based study. The Lancet. Global health Marks, F., Im, J., Park, S. E., Pak, G. D., Jeon, H. J., Wandji Nana, L. R., Phoba, M. F., Mbuyi-Kalonji, L., Mogeni, O. D., Yeshitela, B., Panzner, U., Cruz Espinoza, L. M., Beyene, T., Owusu-Ansah, M., Twumasi-Ankrah, S., Yeshambaw, M., Alemu, A., Adewusi, O. J., Adekanmbi, O., Higginson, E., Adepoju, A., Agbi, S., Cakpo, E. G., Ogunleye, V. O., Tunda, G. N., Ikhimiukor, O. O., Mbuyamba, J., Toy, T., Agyapong, F. O., Osei, I., Amuasi, J., Razafindrabe, T. J., Raminosoa, T. M., Nyirenda, G., Randriamampionona, N., Seo, H. W., Seo, H., Siribie, M., Carey, M. E., Owusu, M., Meyer, C. G., Rakotozandrindrainy, N., Sarpong, N., Razafindrakalia, M., Razafimanantsoa, R., Ouedraogo, M., Kim, Y. J., Lee, J., Zellweger, R. M., Kang, S. S., Park, J. Y., Crump, J. A., Hardy, L., Jacobs, J., Garrett, D. O., Andrews, J. R., Poudyal, N., Kim, D. R., Clemens, J. D., Baker, S. G., Kim, J. H., Dougan, G., Sugimoto, J. D., Van Puyvelde, S., Kehinde, A., Popoola, O. A., Mogasale, V., Breiman, R. F., MacWright, W. R., Aseffa, A., Tadesse, B. T., Haselbeck, A., Adu-Sarkodie, Y., Teferi, M., Bassiahi, A. S., Okeke, I. N., Lunguya-Metila, O., Owusu-Dabo, E., Rakotozandrindrainy, R. 2024; 12 (4): e599-e610

  Abstract

  Typhoid Fever remains a major cause of morbidity and mortality in low-income settings. The Severe Typhoid in Africa programme was designed to address regional gaps in typhoid burden data and identify populations eligible for interventions using novel typhoid conjugate vaccines.A hybrid design, hospital-based prospective surveillance with population-based health-care utilisation surveys, was implemented in six countries in sub-Saharan Africa. Patients presenting with fever (≥37·5°C axillary or ≥38·0°C tympanic) or reporting fever for three consecutive days within the previous 7 days were invited to participate. Typhoid fever was ascertained by culture of blood collected upon enrolment. Disease incidence at the population level was estimated using a Bayesian mixture model.27 866 (33·8%) of 82 491 participants who met inclusion criteria were recruited. Blood cultures were performed for 27 544 (98·8%) of enrolled participants. Clinically significant organisms were detected in 2136 (7·7%) of these cultures, and 346 (16·2%) Salmonella enterica serovar Typhi were isolated. The overall adjusted incidence per 100 000 person-years of observation was highest in Kavuaya and Nkandu 1, Democratic Republic of the Congo (315, 95% credible interval 254-390). Overall, 46 (16·4%) of 280 tested isolates showed ciprofloxacin non-susceptibility.High disease incidence (ie, >100 per 100 000 person-years of observation) recorded in four countries, the prevalence of typhoid hospitalisations and complicated disease, and the threat of resistant typhoid strains strengthen the need for rapid dispatch and implementation of effective typhoid conjugate vaccines along with measures designed to improve clean water, sanitation, and hygiene practices.The Bill & Melinda Gates Foundation.

  View details for DOI 10.1016/S2214-109X(24)00007-X

  View details for PubMedID 38485427

• Cost-effectiveness and public health impact of typhoid conjugate vaccine introduction strategies in Bangladesh. Vaccine Weyant, C., Hooda, Y., Munira, S. J., Lo, N. C., Ryckman, T., Tanmoy, A. M., Kanon, N., Seidman, J. C., Garrett, D., Saha, S. K., Goldhaber-Fiebert, J. D., Saha, S., Andrews, J. R. 2024

  Abstract

  Typhoid fever causes substantial morbidity and mortality in Bangladesh. The government of Bangladesh plans to introduce typhoid conjugate vaccines (TCV) in its expanded program on immunization (EPI) schedule. However, the optimal introduction strategy in addition to the costs and benefits of such a program are unclear.We extended an existing mathematical model of typhoid transmission to integrate cost data, clinical incidence data, and recently conducted serosurveys in urban, semi-urban, and rural areas. In our primary analysis, we evaluated the status quo (i.e., no vaccination) and eight vaccine introduction strategies including routine and 1-time campaign strategies, which differed by age groups targeted and geographic focus. Model outcomes included clinical incidence, seroincidence, deaths, costs, disability-adjusted life years (DALYs), and incremental cost-effectiveness ratios (ICERs) for each strategy. We adopted a societal perspective, 10-year model time horizon, and 3 % annual discount rate. We performed probabilistic, one-way, and scenario sensitivity analyses including adopting a healthcare perspective and alternate model time horizons.We projected that all TCV strategies would be cost saving compared to the status quo. The preferred strategy was a nationwide introduction of TCV at 9-12 months of age with a single catch-up campaign for children ages 1-15, which was cost saving compared to all other strategies and the status quo. In the 10 years following implementation, we projected this strategy would avert 3.77 million cases (95 % CrI: 2.60 - 5.18), 11.31 thousand deaths (95 % CrI: 3.77 - 23.60), and save $172.35 million (95 % CrI: -14.29 - 460.59) compared to the status quo. Our findings were broadly robust to changes in parameter values and willingness-to-pay thresholds.We projected that nationwide TCV introduction with a catch-up campaign would substantially reduce typhoid incidence and very likely be cost saving in Bangladesh.

  View details for DOI 10.1016/j.vaccine.2024.03.035

  View details for PubMedID 38531727

• Global, regional, and national age-specific progress towards the 2020 milestones of the WHO End TB Strategy: a systematic analysis for the Global Burden of Disease Study 2021. The Lancet. Infectious diseases 2024

  Abstract

  Global evaluations of the progress towards the WHO End TB Strategy 2020 interim milestones on mortality (35% reduction) and incidence (20% reduction) have not been age specific. We aimed to assess global, regional, and national-level burdens of and trends in tuberculosis and its risk factors across five separate age groups, from 1990 to 2021, and to report on age-specific progress between 2015 and 2020.We used the Global Burden of Diseases, Injuries, and Risk Factors Study 2021 (GBD 2021) analytical framework to compute age-specific tuberculosis mortality and incidence estimates for 204 countries and territories (1990-2021 inclusive). We quantified tuberculosis mortality among individuals without HIV co-infection using 22 603 site-years of vital registration data, 1718 site-years of verbal autopsy data, 825 site-years of sample-based vital registration data, 680 site-years of mortality surveillance data, and 9 site-years of minimally invasive tissue sample (MITS) diagnoses data as inputs into the Cause of Death Ensemble modelling platform. Age-specific HIV and tuberculosis deaths were established with a population attributable fraction approach. We analysed all available population-based data sources, including prevalence surveys, annual case notifications, tuberculin surveys, and tuberculosis mortality, in DisMod-MR 2.1 to produce internally consistent age-specific estimates of tuberculosis incidence, prevalence, and mortality. We also estimated age-specific tuberculosis mortality without HIV co-infection that is attributable to the independent and combined effects of three risk factors (smoking, alcohol use, and diabetes). As a secondary analysis, we examined the potential impact of the COVID-19 pandemic on tuberculosis mortality without HIV co-infection by comparing expected tuberculosis deaths, modelled with trends in tuberculosis deaths from 2015 to 2019 in vital registration data, with observed tuberculosis deaths in 2020 and 2021 for countries with available cause-specific mortality data.We estimated 9·40 million (95% uncertainty interval [UI] 8·36 to 10·5) tuberculosis incident cases and 1·35 million (1·23 to 1·52) deaths due to tuberculosis in 2021. At the global level, the all-age tuberculosis incidence rate declined by 6·26% (5·27 to 7·25) between 2015 and 2020 (the WHO End TB strategy evaluation period). 15 of 204 countries achieved a 20% decrease in all-age tuberculosis incidence between 2015 and 2020, eight of which were in western sub-Saharan Africa. When stratified by age, global tuberculosis incidence rates decreased by 16·5% (14·8 to 18·4) in children younger than 5 years, 16·2% (14·2 to 17·9) in those aged 5-14 years, 6·29% (5·05 to 7·70) in those aged 15-49 years, 5·72% (4·02 to 7·39) in those aged 50-69 years, and 8·48% (6·74 to 10·4) in those aged 70 years and older, from 2015 to 2020. Global tuberculosis deaths decreased by 11·9% (5·77 to 17·0) from 2015 to 2020. 17 countries attained a 35% reduction in deaths due to tuberculosis between 2015 and 2020, most of which were in eastern Europe (six countries) and central Europe (four countries). There was variable progress by age: a 35·3% (26·7 to 41·7) decrease in tuberculosis deaths in children younger than 5 years, a 29·5% (25·5 to 34·1) decrease in those aged 5-14 years, a 15·2% (10·0 to 20·2) decrease in those aged 15-49 years, a 7·97% (0·472 to 14·1) decrease in those aged 50-69 years, and a 3·29% (-5·56 to 9·07) decrease in those aged 70 years and older. Removing the combined effects of the three attributable risk factors would have reduced the number of all-age tuberculosis deaths from 1·39 million (1·28 to 1·54) to 1·00 million (0·703 to 1·23) in 2020, representing a 36·5% (21·5 to 54·8) reduction in tuberculosis deaths compared to those observed in 2015. 41 countries were included in our analysis of the impact of the COVID-19 pandemic on tuberculosis deaths without HIV co-infection in 2020, and 20 countries were included in the analysis for 2021. In 2020, 50 900 (95% CI 49 700 to 52 400) deaths were expected across all ages, compared to an observed 45 500 deaths, corresponding to 5340 (4070 to 6920) fewer deaths; in 2021, 39 600 (38 300 to 41 100) deaths were expected across all ages compared to an observed 39 000 deaths, corresponding to 657 (-713 to 2180) fewer deaths.Despite accelerated progress in reducing the global burden of tuberculosis in the past decade, the world did not attain the first interim milestones of the WHO End TB Strategy in 2020. The pace of decline has been unequal with respect to age, with older adults (ie, those aged >50 years) having the slowest progress. As countries refine their national tuberculosis programmes and recalibrate for achieving the 2035 targets, they could consider learning from the strategies of countries that achieved the 2020 milestones, as well as consider targeted interventions to improve outcomes in older age groups.Bill & Melinda Gates Foundation.

  View details for DOI 10.1016/S1473-3099(24)00007-0

  View details for PubMedID 38518787

• Tuberculosis infection and hypertension: prevalence estimates from the US National Health and Nutrition Examination Survey. BMJ open Salindri, A. D., Auld, S. C., Gujral, U. P., Urbina, E. M., Andrews, J. R., Huaman, M. A., Magee, M. J. 2024; 14 (3): e075176

  Abstract

  Tuberculosis infection (TBI) is marked by dynamic host-pathogen interactions with persistent low-grade inflammation and is associated with increased risk of cardiovascular diseases (CVD) including acute coronary syndrome, myocardial infarction and stroke. However, few studies assess the relationship between TBI and hypertension, an intermediate of CVD. We sought to determine the association between TBI and hypertension using data representative of the adult US population.We performed cross-sectional analyses using data from the 2011-2012 US National Health and Nutrition Examination Survey (NHANES). Eligible participants included adults with valid QuantiFERON-TB Gold In-Tube (QFT-GIT) test results who also had blood pressure measures and no history of TB disease. TBI was defined by a positive QFT-GIT. We defined hypertension by either elevated measured blood pressure levels (ie, systolic ≥130 mm Hg or diastolic ≥80 mm Hg) or known hypertension indications (ie, self-reported previous diagnosis or use of antihypertensive medications). Analyses were performed using robust quasi-Poisson regressions and accounted for the stratified probability sampling design of NHANES.The overall prevalence of TBI was 5.7% (95% CI 4.7% to 6.7%) and hypertension was present among 48.9% (95% CI 45.2% to 52.7%) of participants. The prevalence of hypertension was higher among those with TBI (58.5%, 95% CI 52.4% to 64.5%) than those without TBI (48.3%, 95% CI 44.5% to 52.1%) (prevalence ratio (PR) 1.2, 95% CI 1.1 to 1.3). However, after adjusting for confounders, the prevalence of hypertension was similar for those with and without TBI (adjusted PR 1.0, 95% CI 1.0 to 1.1). The unadjusted prevalence of hypertension was higher among those with TBI versus no TBI, especially among individuals without CVD risk factors including those with normal body mass index (PR 1.6, 95% CI 1.2 to 2.0), euglycaemia (PR 1.3, 95% CI 1.1 to 1.5) or non-smokers (PR 1.2, 95% CI 1.1 to 1.4).More than half of adults with TBI in the USA had hypertension. Importantly, we observed a relationship between TBI and hypertension among those without established CVD risk factors.The prevalence of hypertension was high (59%) among adults with TBI in the USA. In addition, we found that the prevalence of hypertension was significantly higher among adults with positive QFT without established hypertension risk factors.

  View details for DOI 10.1136/bmjopen-2023-075176

  View details for PubMedID 38479740

• Estimating the subnational prevalence of antimicrobial resistant Salmonella enterica serovars Typhi and Paratyphi A infections in 75 endemic countries, 1990-2019: a modelling study. The Lancet. Global health 2024; 12 (3): e406-e418

  Abstract

  Enteric fever, a systemic infection caused by Salmonella enterica serovars Typhi and Paratyphi A, remains a major cause of morbidity and mortality in low-income and middle-income countries. Enteric fever is preventable through the provision of clean water and adequate sanitation and can be successfully treated with antibiotics. However, high levels of antimicrobial resistance (AMR) compromise the effectiveness of treatment. We provide estimates of the prevalence of AMR S Typhi and S Paratyphi A in 75 endemic countries, including 30 locations without data.We used a Bayesian spatiotemporal modelling framework to estimate the percentage of multidrug resistance (MDR), fluoroquinolone non-susceptibility (FQNS), and third-generation cephalosporin resistance in S Typhi and S Paratyphi A infections for 1403 administrative level one districts in 75 endemic countries from 1990 to 2019. We incorporated data from a comprehensive systematic review, public health surveillance networks, and large multicountry studies on enteric fever. Estimates of the prevalence of AMR and the number of AMR infections (based on enteric fever incidence estimates by the Global Burden of Diseases study) were produced at the country, super-region, and total endemic area level for each year of the study.We collated data from 601 sources, comprising 184 225 isolates of S Typhi and S Paratyphi A, covering 45 countries over 30 years. We identified a decline of MDR S Typhi in south Asia and southeast Asia, whereas in sub-Saharan Africa, the overall prevalence increased from 6·0% (95% uncertainty interval 4·3-8·0) in 1990 to 72·7% (67·7-77·3) in 2019. Starting from low levels in 1990, the prevalence of FQNS S Typhi increased rapidly, reaching 95·2% (91·4-97·7) in south Asia in 2019. This corresponded to 2·5 million (1·5-3·8) MDR S Typhi infections and 7·4 million (4·7-11·3) FQNS S Typhi infections in endemic countries in 2019. The prevalence of third-generation cephalosporin-resistant S Typhi remained low across the whole endemic area over the study period, except for Pakistan where prevalence of third-generation cephalosporin resistance in S Typhi reached 61·0% (58·0-63·8) in 2019. For S Paratyphi A, we estimated low prevalence of MDR and third-generation cephalosporin resistance in all endemic countries, but a drastic increase of FQNS, which reached 95·0% (93·7-96·1; 3·5 million [2·2-5·6] infections) in 2019.This study provides a comprehensive and detailed analysis of the prevalence of MDR, FQNS, and third-generation cephalosporin resistance in S Typhi and S Paratyphi A infections in endemic countries, spanning the last 30 years. Our analysis highlights the increasing levels of AMR in this preventable infection and serves as a resource to guide urgently needed public health interventions, such as improvements in water, sanitation, and hygiene and typhoid fever vaccination campaigns.Fleming Fund, UK Department of Health and Social Care; Wellcome Trust; and Bill and Melinda Gates Foundation.

  View details for DOI 10.1016/S2214-109X(23)00585-5

  View details for PubMedID 38365414

• Excess tuberculosis risk during and following incarceration in Paraguay: a retrospective cohort study. Lancet regional health. Americas Sequera, G., Estigarribia-Sanabria, G., Aguirre, S., Piñanez, C., Martinez, L., Lopez-Olarte, R., Andrews, J. R., Walter, K. S., Croda, J., Garcia-Basteiro, A. L. 2024; 31: 100668

  Abstract

  The increased risk of tuberculosis (TB) among people deprived of liberty (PDL) is due to individual and institution-level factors. We followed a cohort of PDL from 5 prisons in Paraguay to describe the risk of TB during incarceration and after they were released.We linked a 2013 national census of prisons with TB records from the TB Program from 2010 to 2021 to identify TB notifications among incarcerated and formerly incarcerated individuals. We used multivariable Cox regression models to quantify the risk of TB during and following incarceration and to identify risk factors associated with TB.Among 2996 individuals incarcerated, 451 (15.1%) were diagnosed with TB. Of these, 262 (58.1%) cases occurred during incarceration and 189 (41.9%) occurred in the community after release. In prison, the hazard ratio of developing TB was 1.97 (95% CI: 1.52-2.61) after six months of incarceration and increased to 2.78 (95% CI: 1.82-4.24) after 36 months compared with the first six months. The overall TB notification rate was 2940 per 100,000 person-years. This rate increased with the duration of incarceration from 1335 per 100,000 person-years in the first year to 8455 per 100,000 person-years after 8 years. Among former prisoners, the rate of TB decreased from 1717 in the first year after release to 593 per 100 000 person-years after 8 years of follow up.Our study shows the alarming risk of TB associated with prison environments in Paraguay, and how this risk persists for years following incarceration. Effective TB control measures to protect the health of people during and following incarceration are urgently needed.Paraguay National Commission of Science and Technology grant CONACYT PIN 15-705 (GS, GES, SA).

  View details for DOI 10.1016/j.lana.2023.100668

  View details for PubMedID 38500958

  View details for PubMedCentralID PMC10945421

• Incarceration and TB: the epidemic beyond prison walls. BMJ global health Sequera, G., Aguirre, S., Estigarribia, G., Walter, K. S., Horna-Campos, O., Liu, Y. E., Andrews, J. R., Croda, J., Garcia-Basteiro, A. L. 2024; 9 (2)

  View details for DOI 10.1136/bmjgh-2023-014722

  View details for PubMedID 38382977

• Serial Mass Screening for Tuberculosis among Incarcerated Persons in Brazil. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Pivetta de Araujo, R. C., Martinez, L., da Silva Santos, A., Ferreira Lemos, E., Dias de Oliveira, R., Croda, M., Batestin Silva, D. P., Lemes, I. B., Cunha, E. A., Gonçalves, T. O., Dos Santos, P. C., da Silva, B. O., Gonçalves, C. C., Andrews, J. R., Croda, J. 2024

  Abstract

  Active search for tuberculosis cases through mass screening is widely described as a tool to improve case detection in hyperendemic settings. However, its effectiveness in high-risk populations, such as incarcerated people, is debated.Between 2017 and 2021, three rounds of mass screening were carried out in three Brazilian prisons. Social and health questionnaires, chest X-rays and Xpert MTB/RIF were performed.Over 80% of the prison population was screened. Overall, 684 cases of pulmonary tuberculosis were diagnosed. Prevalence across screening rounds was not statistically different. Among incarcerated persons with symptoms, the overall prevalence of tuberculosis per 100,000 persons was 8,497 (95% CI, 7,346-9,811), 11,115 (95% CI, 9,471-13,082), and 7,957 (95% CI, 6,380-9,882) in screening rounds one, two and three, respectively. Similar to our overall results, there were no statistical differences between screening rounds and within individual prisons. We found no statistical differences in CAD4TB scores across screening rounds among people with tuberculosis - the median scores in rounds 1, 2, and 3 were 82 (IQR, 63-97), 77 (IQR, 60-94), and 81 (IQR, 67-92), respectively.In this environment with hyperendemic rates of tuberculosis, three rounds of mass screening did not reduce the overall tuberculosis burden. In prisons, where a substantial amount of TB is undiagnosed annually, a range of complementary interventions and more frequent TB screening may be required.

  View details for DOI 10.1093/cid/ciae055

  View details for PubMedID 38324908

• Detection of Salmonella Typhi bacteriophages in surface waters as a scalable approach to environmental surveillance. PLoS neglected tropical diseases Shrestha, S., Da Silva, K. E., Shakya, J., Yu, A. T., Katuwal, N., Shrestha, R., Shakya, M., Shahi, S. B., Naga, S. R., LeBoa, C., Aiemjoy, K., Bogoch, I. I., Saha, S., Tamrakar, D., Andrews, J. R. 2024; 18 (2): e0011912

  Abstract

  Environmental surveillance, using detection of Salmonella Typhi DNA, has emerged as a potentially useful tool to identify typhoid-endemic settings; however, it is relatively costly and requires molecular diagnostic capacity. We sought to determine whether S. Typhi bacteriophages are abundant in water sources in a typhoid-endemic setting, using low-cost assays.We collected drinking and surface water samples from urban, peri-urban and rural areas in 4 regions of Nepal. We performed a double agar overlay with S. Typhi to assess the presence of bacteriophages. We isolated and tested phages against multiple strains to assess their host range. We performed whole genome sequencing of isolated phages, and generated phylogenies using conserved genes.S. Typhi-specific bacteriophages were detected in 54.9% (198/361) of river and 6.3% (1/16) drinking water samples from the Kathmandu Valley and Kavrepalanchok. Water samples collected within or downstream of population-dense areas were more likely to be positive (72.6%, 193/266) than those collected upstream from population centers (5.3%, 5/95) (p=0.005). In urban Biratnagar and rural Dolakha, where typhoid incidence is low, only 6.7% (1/15, Biratnagar) and 0% (0/16, Dolakha) river water samples contained phages. All S. Typhi phages were unable to infect other Salmonella and non-Salmonella strains, nor a Vi-knockout S. Typhi strain. Representative strains from S. Typhi lineages were variably susceptible to the isolated phages. Phylogenetic analysis showed that S. Typhi phages belonged to the class Caudoviricetes and clustered in three distinct groups.S. Typhi bacteriophages were highly abundant in surface waters of typhoid-endemic communities but rarely detected in low typhoid burden communities. Bacteriophages recovered were specific for S. Typhi and required Vi polysaccharide for infection. Screening small volumes of water with simple, low-cost (~$2) plaque assays enables detection of S. Typhi phages and should be further evaluated as a scalable tool for typhoid environmental surveillance.

  View details for DOI 10.1371/journal.pntd.0011912

  View details for PubMedID 38329937

• Old tools, new applications: Use of environmental bacteriophages for typhoid surveillance and evaluating vaccine impact. PLoS neglected tropical diseases Hooda, Y., Islam, S., Kabiraj, R., Rahman, H., Sarkar, H., da Silva, K. E., Raju, R. S., Luby, S. P., Andrews, J. R., Saha, S. K., Saha, S. 2024; 18 (2): e0011822

  Abstract

  Typhoid-conjugate vaccines (TCVs) provide an opportunity to reduce the burden of typhoid fever, caused by Salmonella Typhi, in endemic areas. As policymakers design vaccination strategies, accurate and high-resolution data on disease burden is crucial. However, traditional blood culture-based surveillance is resource-extensive, prohibiting its large-scale and sustainable implementation. Salmonella Typhi is a water-borne pathogen, and here, we tested the potential of Typhi-specific bacteriophage surveillance in surface water bodies as a low-cost tool to identify where Salmonella Typhi circulates in the environment. In 2021, water samples were collected and tested for the presence of Salmonella Typhi bacteriophages at two sites in Bangladesh: urban capital city, Dhaka, and a rural district, Mirzapur. Salmonella Typhi-specific bacteriophages were detected in 66 of 211 (31%) environmental samples in Dhaka, in comparison to 3 of 92 (3%) environmental samples from Mirzapur. In the same year, 4,620 blood cultures at the two largest pediatric hospitals of Dhaka yielded 215 (5%) culture-confirmed typhoid cases, and 3,788 blood cultures in the largest hospital of Mirzapur yielded 2 (0.05%) cases. 75% (52/69) of positive phage samples were collected from sewage. All isolated phages were tested against a panel of isolates from different Salmonella Typhi genotypes circulating in Bangladesh and were found to exhibit a diverse killing spectrum, indicating that diverse bacteriophages were isolated. These results suggest an association between the presence of Typhi-specific phages in the environment and the burden of typhoid fever, and the potential of utilizing environmental phage surveillance as a low-cost tool to assist policy decisions on typhoid control.

  View details for DOI 10.1371/journal.pntd.0011822

  View details for PubMedID 38358956

• Development of prediction models to identify hotspots of schistosomiasis in endemic regions to guide mass drug administration. Proceedings of the National Academy of Sciences of the United States of America Singer, B. J., Coulibaly, J. T., Park, H. J., Andrews, J. R., Bogoch, I. I., Lo, N. C. 2024; 121 (2): e2315463120

  Abstract

  Schistosomiasis is a neglected tropical disease affecting over 150 million people. Hotspots of Schistosoma transmission-communities where infection prevalence does not decline adequately with mass drug administration-present a key challenge in eliminating schistosomiasis. Current approaches to identify hotspots require evaluation 2-5 y after a baseline survey and subsequent mass drug administration. Here, we develop statistical models to predict hotspots at baseline prior to treatment comparing three common hotspot definitions, using epidemiologic, survey-based, and remote sensing data. In a reanalysis of randomized trials in 589 communities in five endemic countries, a regression model predicts whether Schistosoma mansoni infection prevalence will exceed the WHO threshold of 10% in year 5 ("prevalence hotspot") with 86% sensitivity, 74% specificity, and 93% negative predictive value (NPV; assuming 30% hotspot prevalence), and a regression model for Schistosoma haematobium achieves 90% sensitivity, 90% specificity, and 96% NPV. A random forest model predicts whether S. mansoni moderate and heavy infection prevalence will exceed a public health goal of 1% in year 5 ("intensity hotspot") with 92% sensitivity, 79% specificity, and 96% NPV, and a boosted trees model for S. haematobium achieves 77% sensitivity, 95% specificity, and 91% NPV. Baseline prevalence is a top predictor in all models. Prediction is less accurate in countries not represented in training data and for a third hotspot definition based on relative prevalence reduction over time ("persistent hotspot"). These models may be a tool to prioritize high-risk communities for more frequent surveillance or intervention against schistosomiasis, but prediction of hotspots remains a challenge.

  View details for DOI 10.1073/pnas.2315463120

  View details for PubMedID 38181058

• The impact of sputum quality on Xpert positivity in active case-finding for TB. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease Oliveira da Silva, B., Salindri, A. D., Gonçalves, T. O., Cunha, E. A., da Silva Santos, A., Dos Santos, P. C., Lemes, I. B., Silva, D. P., da Silva Oliveira, V., Croda, J., de Oliveira, R. D., Andrews, J. R. 2024; 28 (1): 29-36

  Abstract

  BACKGROUND: Studies evaluating sputum quality and Xpert® MTB/RIF positivity in the context of active case finding are scarce. We aimed to determine whether sputum quality is associated with Xpert positivity and whether the association differed according to demographic and clinical characteristics.METHODS: A cross-sectional analysis using data from a mass screening programme in Brazilian prisons was conducted from 2017 to 2021. We administered a standardised questionnaire, obtained a chest X-ray and collected a spot sputum sample for Xpert testing. Sputum quality was classified as 'salivary', 'mucoid/mucopurulent' or 'blood-stained'. We used log binomial regressions to estimate the relationship between sputum quality and Xpert positivity, assessing interactions with participant characteristics.RESULTS: Among 4,368 participants for whom sputum quality was assessed, 957 (21.9%) produced salivary specimens, 3,379 (77.4%) had mucoid/mucopurulent sputum and 32 (0.7%) had blood-stained sputum. Xpert positivity was higher among those with mucoid/mucopurulent sputum than among those with salivary samples (12.0% vs. 3.7%). Mucopurulent sputum independently predicted Xpert positivity among individuals with and without symptoms, current smoking and abnormal chest radiographs on CAD4TB.CONCLUSIONS: In our study, sputum appearance independently predicted Xpert positivity, and could be used together with chest X-ray and symptom screening to inform use of Xpert in individual or pooled testing.

  View details for DOI 10.5588/ijtld.23.0244

  View details for PubMedID 38178289

• Effects of Mitigation and Control Policies in Realistic Epidemic Models Accounting for Household Transmission Dynamics. Medical decision making : an international journal of the Society for Medical Decision Making Alarid-Escudero, F., Andrews, J. R., Goldhaber-Fiebert, J. D. 2023: 272989X231205565

  Abstract

  Compartmental infectious disease (ID) models are often used to evaluate nonpharmaceutical interventions (NPIs) and vaccines. Such models rarely separate within-household and community transmission, potentially introducing biases in situations in which multiple transmission routes exist. We formulated an approach that incorporates household structure into ID models, extending the work of House and Keeling.We developed a multicompartment susceptible-exposed-infectious-recovered-susceptible-vaccinated (MC-SEIRSV) modeling framework, allowing nonexponentially distributed duration in exposed and infectious compartments, that tracks within-household and community transmission. We simulated epidemics that varied by community and household transmission rates, waning immunity rate, household size (3 or 5 members), and numbers of exposed and infectious compartments (1-3 each). We calibrated otherwise identical models without household structure to the early phase of each parameter combination's epidemic curve. We compared each model pair in terms of epidemic forecasts and predicted NPI and vaccine impacts on the timing and magnitude of the epidemic peak and its total size. Meta-analytic regressions characterized the relationship between household structure inclusion and the size and direction of biases.Otherwise similar models with and without household structure produced equivalent early epidemic curves. However, forecasts from models without household structure were biased. Without intervention, they were upward biased on peak size and total epidemic size, with biases also depending on the number of exposed and infectious compartments. Model-estimated NPI effects of a 60% reduction in community contacts on peak time and size were systematically overestimated without household structure. Biases were smaller with a 20% reduction NPI. Because vaccination affected both community and household transmission, their biases were smaller.ID models without household structure can produce biased outcomes in settings in which within-household and community transmission differ.Infectious disease models rarely separate household transmission from community transmission. The pace of household transmission may differ from community transmission, depends on household size, and can accelerate epidemic growth.Many infectious disease models assume exponential duration distributions for infected states. However, the duration of most infections is not exponentially distributed, and distributional choice alters modeled epidemic dynamics and intervention effectiveness.We propose a mathematical framework for household and community transmission that allows for nonexponential duration times and a suite of interventions and quantified the effect of accounting for household transmission by varying household size and duration distributions of infected states on modeled epidemic dynamics.Failure to include household structure induces biases in the modeled overall course of an epidemic and the effects of interventions delivered differentially in community settings. Epidemic dynamics are faster and more intense in populations with larger household sizes and for diseases with nonexponentially distributed infectious durations. Modelers should consider explicitly incorporating household structure to quantify the effects of non-pharmaceutical interventions (e.g., shelter-in-place).

  View details for DOI 10.1177/0272989X231205565

  View details for PubMedID 37953597

• Genomic characterization of SARS-CoV-2 from an indigenous reserve in Mato Grosso do Sul, Brazil. Frontiers in public health de Oliveira, L. A., de Rezende, I. M., Navarini, V. J., Marchioro, S. B., Torres, A. J., Croda, J., Croda, M. G., Gonçalves, C. C., Xavier, J., de Castro, E., Lima, M., Iani, F., Adelino, T., Aburjaile, F., Ferraz Demarchi, L. H., Taira, D. L., Zardin, M. C., Fonseca, V., Giovanetti, M., Andrews, J., Alcantara, L. C., Simionatto, S. 2023; 11: 1195779

  Abstract

  The COVID-19 pandemic had a major impact on indigenous populations. Understanding the viral dynamics within this population is essential to create targeted protection measures.A total of 204 SARS-CoV-2 positive samples collected between May 2020 and November 2021 from an indigenous area in Mato Grosso do Sul (MS), Midwestern Brazil, were screened. Samples were submitted to whole genome sequencing using the Nanopore sequencing platform. Clinical, demographic, and phylogenetic data were analyzed.We found the co-circulation of six main SARS-CoV-2 lineages in the indigenous population, with the Zeta lineage being the most prevalent (27.66%), followed by B.1.1 (an ancestral strain) (20.21%), Gamma (14.36%) and Delta (13.83%). Other lineages represent 45.74% of the total. Our phylogenetic reconstruction indicates that multiple introduction events of different SARS-CoV-2 lineages occurred in the indigenous villages in MS. The estimated indigenous population mortality rate was 1.47%. Regarding the ethnicity of our cohort, 64.82% belong to the Guarani ethnicity, while 33.16% belong to the Terena ethnicity, with a slightly higher prevalence of males (53.43%) among females. Other ethnicities represent 2.01%. We also observed that almost all patients (89.55%) presented signs and symptoms related to COVID-19, being the most prevalent cough, fever, sore throat, and headache.Our results revealed that multiple independent SARS-CoV-2 introduction events had occurred through time, probably due to indigenous mobility, since the villages studied here are close to urban areas in MS. The mortality rate was slightly below of the estimation for the state in the period studied, which we believe could be related to the small number of samples evaluated, the underreporting of cases and deaths among this population, and the inconsistency of secondary data available for this study.In this study, we showed the circulation of multiple SARS-CoV-2 variants in this population, which should be isolated and protected as they belong to the most fragile group due to their socioeconomic and cultural disparities. We reinforce the need for constant genomic surveillance to monitor and prevent the spread of new emerging viruses and to better understand the viral dynamics in these populations, making it possible to direct specific actions.

  View details for DOI 10.3389/fpubh.2023.1195779

  View details for PubMedID 37965526

  View details for PubMedCentralID PMC10641392

• Environmental sampling for typhoidal Salmonellas in household and surface waters in Nepal identifies potential transmission pathways. PLoS neglected tropical diseases LeBoa, C., Shrestha, S., Shakya, J., Naga, S. R., Shrestha, S., Shakya, M., Yu, A. T., Shrestha, R., Vaidya, K., Katuwal, N., Aiemjoy, K., Bogoch, I. I., Uzzell, C. B., Garrett, D. O., Luby, S. P., Andrews, J. R., Tamrakar, D. 2023; 17 (10): e0011341

  Abstract

  Salmonella Typhi and Salmonella Paratyphi, fecal-oral transmitted bacterium, have temporally and geographically heterogeneous pathways of transmission. Previous work in Kathmandu, Nepal implicated stone waterspouts as a dominant transmission pathway after 77% of samples tested positive for Salmonella Typhi and 70% for Salmonella Paratyphi. Due to a falling water table, these spouts no longer provide drinking water, but typhoid fever persists, and the question of the disease's dominant pathway of transmission remains unanswered.We used environmental surveillance to detect Salmonella Typhi and Salmonella Paratyphi A DNA from potential sources of transmission. We collected 370, 1L drinking water samples from a population-based random sample of households in the Kathmandu and Kavre Districts of Nepal between February and October 2019. Between November 2019 and July 2021, we collected 380, 50mL river water samples from 19 sentinel sites on a monthly interval along the rivers leading through the Kathmandu and Kavre Districts. We processed drinking water samples using a single qPCR and processed river water samples using differential centrifugation and qPCR at 0 and after 16 hours of liquid culture enrichment. A 3-cycle threshold (Ct) decrease of Salmonella Typhi or Salmonella Paratyphi, pre- and post-enrichment, was used as evidence of growth. We also performed structured observations of human-environment interactions to understand pathways of potential exposure.Among 370 drinking water samples, Salmonella Typhi was detected in 7 samples (1.8%) and Salmonella Paratyphi A was detected in 4 (1.0%) samples. Among 380 river water samples, Salmonella Typhi was detected in 171 (45%) and Salmonella Paratyphi A was detected in 152 (42%) samples. Samples located upstream of the Kathmandu city center were positive for Salmonella Typhi 12% of the time while samples from locations in and downstream were positive 58% and 67% of the time respectively. Individuals were observed bathing, washing clothes, and washing vegetables in the rivers.These results suggest that drinking water was not the dominant pathway of transmission of Salmonella Typhi and Salmonella Paratyphi A in the Kathmandu Valley in 2019. The high degree of river water contamination and its use for washing vegetables raises the possibility that river systems represent an important source of typhoid exposure in Kathmandu.

  View details for DOI 10.1371/journal.pntd.0011341

  View details for PubMedID 37851667

• Prioritizing persons deprived of liberty in global guidelines for tuberculosis preventive treatment. PLoS medicine Narayan, A., Salindri, A. D., Keshavjee, S., Muyoyeta, M., Velen, K., Rueda, Z. V., Croda, J., Charalambous, S., García-Basteiro, A. L., Shenoi, S. V., Gonçalves, C. C., Ferreira da Silva, L., Possuelo, L. G., Aguirre, S., Estigarribia, G., Sequera, G., Grandjean, L., Telisinghe, L., Herce, M. E., Dockhorn, F., Altice, F. L., Andrews, J. R. 2023; 20 (10): e1004288

  Abstract

  In this Policy Forum piece, Aditya Narayan and colleagues discuss the challenges and opportunities for tuberculosis preventive treatment in carceral settings.

  View details for DOI 10.1371/journal.pmed.1004288

  View details for PubMedID 37788448

  View details for PubMedCentralID PMC10547494

• Rapid emergence and transmission of virulence-associated mutations in the oral poliovirus vaccine following vaccination campaigns. NPJ vaccines Walter, K. S., Altamirano, J., Huang, C., Carrington, Y. J., Zhou, F., Andrews, J. R., Maldonado, Y. 2023; 8 (1): 137

  Abstract

  There is an increasing burden of circulating vaccine-derived polioviruses (cVDPVs) due to the continued use of oral poliovirus vaccine (OPV). However, the informativeness of routine OPV VP1 sequencing for the early identification of viruses carrying virulence-associated reversion mutations has not been directly evaluated in a controlled setting. We prospectively collected 15,331 stool samples to track OPV shedding from children receiving OPV and their contacts for ten weeks following an immunization campaign in Veracruz State, Mexico and sequenced VP1 genes from 358 samples. We found that OPV was genetically unstable and evolves at an approximately clocklike rate that varies across serotypes and by vaccination status. Overall, 61% (11/18) of OPV-1, 71% (34/48) OPV-2, and 96% (54/56) OPV-3 samples with available data had evidence of a reversion at the key 5' UTR attenuating position and 28% (13/47) of OPV-1, 12% (14/117) OPV-2, and 91% (157/173) OPV-3 of Sabin-like viruses had ≥1 known reversion mutations in the VP1 gene. Our results are consistent with previous work documenting rapid reversion to virulence of OPV and underscores the need for intensive surveillance following OPV use.

  View details for DOI 10.1038/s41541-023-00740-9

  View details for PubMedID 37749086

  View details for PubMedCentralID 9712124

• Global diversity and antimicrobial resistance of typhoid fever pathogens: Insights from a meta-analysis of 13,000 Salmonella Typhi genomes. eLife Carey, M. E., Dyson, Z. A., Ingle, D. J., Amir, A., Aworh, M. K., Chattaway, M. A., Chew, K. L., Crump, J. A., Feasey, N. A., Howden, B. P., Keddy, K. H., Maes, M., Parry, C. M., Van Puyvelde, S., Webb, H. E., Afolayan, A. O., Alexander, A. P., Anandan, S., Andrews, J. R., Ashton, P. M., Basnyat, B., Bavdekar, A., Bogoch, I. I., Clemens, J. D., da Silva, K. E., De, A., de Ligt, J., Diaz Guevara, P. L., Dolecek, C., Dutta, S., Ehlers, M. M., Francois Watkins, L., Garrett, D. O., Godbole, G., Gordon, M. A., Greenhill, A. R., Griffin, C., Gupta, M., Hendriksen, R. S., Heyderman, R. S., Hooda, Y., Hormazabal, J. C., Ikhimiukor, O. O., Iqbal, J., Jacob, J. J., Jenkins, C., Jinka, D. R., John, J., Kang, G., Kanteh, A., Kapil, A., Karkey, A., Kariuki, S., Kingsley, R. A., Koshy, R. M., Lauer, A. C., Levine, M. M., Lingegowda, R. K., Luby, S. P., Mackenzie, G. A., Mashe, T., Msefula, C., Mutreja, A., Nagaraj, G., Nagaraj, S., Nair, S., Naseri, T. K., Nimarota-Brown, S., Njamkepo, E., Okeke, I. N., Perumal, S. P., Pollard, A. J., Pragasam, A. K., Qadri, F., Qamar, F. N., Rahman, S. I., Rambocus, S. D., Rasko, D. A., Ray, P., Robins-Browne, R., Rongsen-Chandola, T., Rutanga, J. P., Saha, S. K., Saha, S., Saigal, K., Sajib, M. S., Seidman, J. C., Shakya, J., Shamanna, V., Shastri, J., Shrestha, R., Sia, S., Sikorski, M. J., Singh, A., Smith, A. M., Tagg, K. A., Tamrakar, D., Tanmoy, A. M., Thomas, M., Thomas, M. S., Thomsen, R., Thomson, N. R., Tupua, S., Vaidya, K., Valcanis, M., Veeraraghavan, B., Weill, F. X., Wright, J., Dougan, G., Argimón, S., Keane, J. A., Aanensen, D. M., Baker, S., Holt, K. E. 2023; 12

  Abstract

  The Global Typhoid Genomics Consortium was established to bring together the typhoid research community to aggregate and analyse Salmonella enterica serovar Typhi (Typhi) genomic data to inform public health action. This analysis, which marks 22 years since the publication of the first Typhi genome, represents the largest Typhi genome sequence collection to date (n=13,000).This is a meta-analysis of global genotype and antimicrobial resistance (AMR) determinants extracted from previously sequenced genome data and analysed using consistent methods implemented in open analysis platforms GenoTyphi and Pathogenwatch.Compared with previous global snapshots, the data highlight that genotype 4.3.1 (H58) has not spread beyond Asia and Eastern/Southern Africa; in other regions, distinct genotypes dominate and have independently evolved AMR. Data gaps remain in many parts of the world, and we show the potential of travel-associated sequences to provide informal 'sentinel' surveillance for such locations. The data indicate that ciprofloxacin non-susceptibility (>1 resistance determinant) is widespread across geographies and genotypes, with high-level ciprofloxacin resistance (≥3 determinants) reaching 20% prevalence in South Asia. Extensively drug-resistant (XDR) typhoid has become dominant in Pakistan (70% in 2020) but has not yet become established elsewhere. Ceftriaxone resistance has emerged in eight non-XDR genotypes, including a ciprofloxacin-resistant lineage (4.3.1.2.1) in India. Azithromycin resistance mutations were detected at low prevalence in South Asia, including in two common ciprofloxacin-resistant genotypes.The consortium's aim is to encourage continued data sharing and collaboration to monitor the emergence and global spread of AMR Typhi, and to inform decision-making around the introduction of typhoid conjugate vaccines (TCVs) and other prevention and control strategies.No specific funding was awarded for this meta-analysis. Coordinators were supported by fellowships from the European Union (ZAD received funding from the European Union's Horizon 2020 research and innovation programme under the Marie Sklodowska-Curie grant agreement No 845681), the Wellcome Trust (SB, Wellcome Trust Senior Fellowship), and the National Health and Medical Research Council (DJI is supported by an NHMRC Investigator Grant [GNT1195210]).

  View details for DOI 10.7554/eLife.85867

  View details for PubMedID 37697804

• Cost effectiveness of low-complexity screening tests in community-based case-finding for tuberculosis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Brümmer, L. E., Thompson, R. R., Malhotra, A., Shrestha, S., Kendall, E. A., Andrews, J. R., Phillips, P., Nahid, P., Cattamanchi, A., Marx, F. M., Denkinger, C. M., Dowdy, D. W. 2023

  Abstract

  In high-burden settings, low-complexity screening tests for tuberculosis (TB) could expand the reach of community-based case-finding efforts. The potential costs and cost-effectiveness of approaches incorporating these tests are poorly understood.We developed a microsimulation model assessing three approaches to community-based case-finding in hypothetical populations (India-, South Africa-, The Philippines-, Uganda-, and Vietnam-like settings) with TB prevalence four times that of national estimates: (1) screening with a point-of-care C-reactive protein (CRP) test or (2) screening with a more sensitive "Hypothetical Screening test" (95% sensitive for Xpert Ultra-positive TB, 70% specificity; equipment/labor costs similar to Xpert Ultra, but using a $2 cartridge) followed by sputum Xpert Ultra if positive, or (3) testing all individuals with sputum Xpert Ultra. Costs are expressed in 2023 US dollars and include treatment costs.Universal Xpert Ultra was estimated to cost a mean $4.0 million (95% uncertainty range: $3.5 to $4.6 million) and avert 3,200 (2,600 to 3,900) TB-related disability-adjusted life years (DALYs) per 100,000 people screened ($670 [The Philippines] to $2000 [Vietnam] per DALY averted). CRP was projected to cost $550 (The Philippines) to $1500 (Vietnam) per DALY averted, but with 44% fewer DALYs averted. The Hypothetical Screening test showed minimal benefit compared to universal Xpert Ultra, but if specificity were improved to 95% and per-test cost to $4.5 (all-inclusive), this strategy could cost $390 (The Philippines) to $940 (Vietnam) per DALY averted.Screening tests can meaningfully improve the cost-effectiveness of community-based case-finding for TB, but only if they are sensitive, specific, and inexpensive.

  View details for DOI 10.1093/cid/ciad501

  View details for PubMedID 37623745

• Evidence of leaky protection following COVID-19 vaccination and SARS-CoV-2 infection in an incarcerated population. Nature communications Lind, M. L., Dorion, M., Houde, A. J., Lansing, M., Lapidus, S., Thomas, R., Yildirim, I., Omer, S. B., Schulz, W. L., Andrews, J. R., Hitchings, M. D., Kennedy, B. S., Richeson, R. P., Cummings, D. A., Ko, A. I. 2023; 14 (1): 5055

  Abstract

  Whether SARS-CoV-2 infection and COVID-19 vaccines confer exposure-dependent ("leaky") protection against infection remains unknown. We examined the effect of prior infection, vaccination, and hybrid immunity on infection risk among residents of Connecticut correctional facilities during periods of predominant Omicron and Delta transmission. Residents with cell, cellblock, and no documented exposure to SARS-CoV-2 infected residents were matched by facility and date. During the Omicron period, prior infection, vaccination, and hybrid immunity reduced the infection risk of residents without a documented exposure (HR: 0.36 [0.25-0.54]; 0.57 [0.42-0.78]; 0.24 [0.15-0.39]; respectively) and with cellblock exposures (0.61 [0.49-0.75]; 0.69 [0.58-0.83]; 0.41 [0.31-0.55]; respectively) but not with cell exposures (0.89 [0.58-1.35]; 0.96 [0.64-1.46]; 0.80 [0.46-1.39]; respectively). Associations were similar during the Delta period and when analyses were restricted to tested residents. Although associations may not have been thoroughly adjusted due to dataset limitations, the findings suggest that prior infection and vaccination may be leaky, highlighting the potential benefits of pairing vaccination with non-pharmaceutical interventions in crowded settings.

  View details for DOI 10.1038/s41467-023-40750-8

  View details for PubMedID 37598213

  View details for PubMedCentralID 8824301

• Retrospective Review of Blood Culture-Confirmed Cases of Enteric Fever in Navi Mumbai, India: 2014-2018. The American journal of tropical medicine and hygiene Jayaprasad, N., Borhade, P., LeBoa, C., Date, K., Joshi, S., Shimpi, R., Andrews, J. R., Luby, S. P., Hoffman, S. A. 2023

  Abstract

  India has one of the highest estimated burdens of enteric fever globally. Prior to the implementation of Typbar-TCV typhoid conjugate vaccine (TCV) in a public sector pediatric immunization campaign in Navi Mumbai, India, we conducted a retrospective review of blood culture-confirmed cases of typhoid and paratyphoid fevers to estimate the local burden of disease. This review included all blood cultures processed at a central microbiology laboratory, serving multiple hospitals, in Navi Mumbai (January 2014-May 2018) that tested positive for either Salmonella Typhi or Salmonella Paratyphi A. Of 40,670 blood cultures analyzed, 1,309 (3.2%) were positive for S. Typhi (1,201 [92%]) or S. Paratyphi A (108 [8%]). Culture positivity was highest in the last months of the dry season (April-June). Our findings indicate a substantial burden of enteric fever in Navi Mumbai and support the importance of TCV immunization campaigns and improved water, sanitation, and hygiene.

  View details for DOI 10.4269/ajtmh.23-0102

  View details for PubMedID 37549903

• Public health impact and cost-effectiveness of screening for active tuberculosis disease or infection among children in South Africa. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Brough, J., Martinez, L., Hatherill, M., Zar, H. J., Lo, N. C., Andrews, J. R. 2023

  Abstract

  Although tuberculosis disease is a leading cause of global childhood mortality, there remain major gaps in diagnosis, treatment and prevention in children, as tuberculosis control programs rely predominantly on presentation of symptomatic children or contact tracing. We assessed the public health impact and cost-effectiveness of age-based routine screening and contact tracing in children in South Africa.We used a deterministic mathematical model to evaluate age-based routine screening in 1-year increments from ages 0 to 5, with and without contact tracing and preventive treatment. Screening incorporated symptom history and tuberculin skin testing, with chest X-ray and GeneXpert Ultra for confirmatory testing. We projected tuberculosis cases, deaths, disability-adjusted life years (DALYs) and costs (2021 U.S. Dollars) and evaluated the incremental cost-effectiveness ratios (ICERs) comparing each intervention.Routine screening at age 2 with contact tracing and preventive treatment averted 11,900 tuberculosis cases (95% confidence interval (CI), 6,160-15,730), 1,360 deaths (95% CI, 260-3,800), and 40,000 DALYs (95% CI, 13,000-100,000) in the South Africa pediatric population over 1 year compared with the status quo. This combined strategy was cost-effective (ICER $9,050 per DALY; 95% CI, 2,890-22,920) and remained cost-effective above an annual risk of infection of 1.6%. For annual risk of infection between 0.8% and 1.6%, routine screening at age 2 was the dominant strategy.Routine screening for tuberculosis among young children combined with contact tracing and preventive treatment would have a large public health impact and be cost-effective in preventing pediatric tuberculosis deaths in high incidence settings like South Africa.

  View details for DOI 10.1093/cid/ciad449

  View details for PubMedID 37542465

• Population structure and antimicrobial resistance patterns of Salmonella Typhi and Paratyphi A amid a phased municipal vaccination campaign in Navi Mumbai, India. mBio da Silva, K. E., Date, K., Hirani, N., LeBoa, C., Jayaprasad, N., Borhade, P., Warren, J., Shimpi, R., Hoffman, S. A., Mikoleit, M., Bhatnagar, P., Cao, Y., Haldar, P., Harvey, P., Zhang, C., Daruwalla, S., Dharmapalan, D., Gavhane, J., Joshi, S., Rai, R., Rathod, V., Shetty, K., Warrier, D. S., Yadav, S., Chakraborty, D., Bahl, S., Katkar, A., Kunwar, A., Yewale, V., Dutta, S., Luby, S. P., Andrews, J. R. 2023: e0117923

  Abstract

  We performed whole-genome sequencing of 174 Salmonella Typhi and 54 Salmonella Paratyphi A isolates collected through prospective surveillance in the context of a phased typhoid conjugate vaccine introduction in Navi Mumbai, India. We investigate the temporal and geographical patterns of emergence and spread of antimicrobial resistance. We evaluated the relationship between the spatial distance between households and genetic clustering of isolates. Most isolates were non-susceptible to fluoroquinolones, with nearly 20% containing ≥3 quinolone resistance-determining region mutations. Two H58 isolates carried an IncX3 plasmid containing blaSHV-12, associated with ceftriaxone resistance, suggesting that the ceftriaxone-resistant isolates from India independently evolved on multiple occasions. Among S. Typhi, we identified two main clades circulating (2.2 and 4.3.1 [H58]); 2.2 isolates were closely related following a single introduction around 2007, whereas H58 isolates had been introduced multiple times to the city. Increasing geographic distance between isolates was strongly associated with genetic clustering (odds ratio [OR] = 0.72 per km; 95% credible interval [CrI]: 0.66-0.79). This effect was seen for distances up to 5 km (OR = 0.65 per km; 95% CrI: 0.59-0.73) but not seen for distances beyond 5 km (OR = 1.02 per km; 95% CrI: 0.83-1.26). There was a non-significant reduction in odds of clustering for pairs of isolates in vaccination communities compared with non-vaccination communities or mixed pairs compared with non-vaccination communities. Our findings indicate that S. Typhi was repeatedly introduced into Navi Mumbai and then spread locally, with strong evidence of spatial genetic clustering. In addition to vaccination, local interventions to improve water and sanitation will be critical to interrupt transmission. IMPORTANCE Enteric fever remains a major public health concern in many low- and middle-income countries, as antimicrobial resistance (AMR) continues to emerge. Geographical patterns of typhoidal Salmonella spread, critical to monitoring AMR and planning interventions, are poorly understood. We performed whole-genome sequencing of S. Typhi and S. Paratyphi A isolates collected in Navi Mumbai, India before and after a typhoid conjugate vaccine introduction. From timed phylogenies, we found two dominant circulating lineages of S. Typhi in Navi Mumbai-lineage 2.2, which expanded following a single introduction a decade prior, and 4.3.1 (H58), which had been introduced repeatedly from other parts of India, frequently containing "triple mutations" conferring high-level ciprofloxacin resistance. Using Bayesian hierarchical statistical models, we found that spatial distance between cases was strongly associated with genetic clustering at a fine scale (<5 km). Together, these findings suggest that antimicrobial-resistant S. Typhi frequently flows between cities and then spreads highly locally, which may inform surveillance and prevention strategies.

  View details for DOI 10.1128/mbio.01179-23

  View details for PubMedID 37504577

• Enduring injustice: infectious disease outbreaks in carceral settings. The Journal of infectious diseases Andrews, J. R., Liu, Y. E., Croda, J. 2023

  View details for DOI 10.1093/infdis/jiad290

  View details for PubMedID 37493282

• Delay in the diagnosis and treatment of tuberculosis in prisons in Mato Grosso do Sul, Brazil. Revista da Sociedade Brasileira de Medicina Tropical Ribeiro, C. C., Santos, A. d., Tshua, D. H., Oliveira, R. D., Lemos, E. F., Bourdillon, P., Laranjeira, A., Gonçalves, C. C., Andrews, J., Ko, A., Croda, J. 2023; 56: e00152023

  Abstract

  The number of tuberculosis (TB) cases in prisons is higher than that in the general population and has been reported as the most common cause of death in prisons. This study evaluated the delay in the diagnosis and treatment of TB in Brazilian prisons.A retrospective cohort study was conducted between 2007 and 2015 using data from the five largest male prisons in Mato Grosso do Sul, Brazil. TB case data was collected from the National Database of Notifiable Diseases (SINAN), GAL-LACEN, and prison medical records. The following variables were recorded: prison, year of diagnosis, age, race, education, HIV status, smoking status, comorbidities, number of symptoms, percentage of cures, delay in diagnosis, patient delay, provider delay, laboratory delay, and delay in treatment. Descriptive statistics were used for the variables of interest.A total of 362 pulmonary TB cases were identified. The average time between the first symptom and reporting of data was 94 days. The mean time between symptom onset and laboratory diagnosis was 91 days. The average time from symptom onset to first consultation was 80 days. The time between diagnosis and treatment initiation was 5 days.Delays were significant between reporting of the first symptoms and diagnosis and significantly smaller from the time between notification and start of treatment. Control strategies should be implemented to diagnose cases through active screening, to avoid delays in diagnosis and treatment, and to reduce TB transmission.

  View details for DOI 10.1590/0037-8682-0015-2023

  View details for PubMedID 37493729

• The Importance of Including Non-Household Environments in Dengue Vector Control Activities. Viruses Peña-García, V. H., Mutuku, F. M., Ndenga, B. A., Mbakaya, J. O., Ndire, S. O., Agola, G. A., Mutuku, P. S., Malumbo, S. L., Ng'ang'a, C. M., Andrews, J. R., Mordecai, E. A., LaBeaud, A. D. 2023; 15 (7)

  Abstract

  Most vector control activities in urban areas are focused on household environments; however, information relating to infection risks in spaces other than households is poor, and the relative risk that these spaces represent has not yet been fully understood. We used data-driven simulations to investigate the importance of household and non-household environments for dengue entomological risk in two Kenyan cities where dengue circulation has been reported. Fieldwork was performed using four strategies that targeted different stages of mosquitoes: ovitraps, larval collections, Prokopack aspiration, and BG-sentinel traps. Data were analyzed separately between household and non-household environments to assess mosquito presence, the number of vectors collected, and the risk factors for vector presence. With these data, we simulated vector and human populations to estimate the parameter m and mosquito-to-human density in both household and non-household environments. Among the analyzed variables, the main difference was found in mosquito abundance, which was consistently higher in non-household environments in Kisumu but was similar in Ukunda. Risk factor analysis suggests that small, clean water-related containers serve as mosquito breeding places in households as opposed to the trash- and rainfall-related containers found in non-household structures. We found that the density of vectors (m) was higher in non-household than household environments in Kisumu and was also similar or slightly lower between both environments in Ukunda. These results suggest that because vectors are abundant, there is a potential risk of transmission in non-household environments; hence, vector control activities should take these spaces into account.

  View details for DOI 10.3390/v15071550

  View details for PubMedID 37515236

• Use of rapid molecular TB diagnostics for incarcerated people in Brazil. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease Fajer, E. B., Costa, F. D., Pelissari, D. M., Diaz Quijano, F. A., Coelho de Brito, A., Cunha, E. A., Croda, J., Andrews, J. R., Walter, K. S. 2023; 27 (5): 416-418

  View details for DOI 10.5588/ijtld.22.0642

  View details for PubMedID 37143225

• Seroepidemiology for Enteric Fever: Emerging Approaches and Opportunities. Open forum infectious diseases Aiemjoy, K., Seidman, J. C., Charles, R. C., Andrews, J. R. 2023; 10 (Suppl 1): S21-S25

  Abstract

  Safe and effective typhoid conjugate vaccines (TCVs) are available, but many countries lack the high-resolution data needed to prioritize TCV introduction to the highest-risk communities. Here we discuss seroepidemiology-an approach using antibody response data to characterize infection burden-as a potential tool to fill this data gap. Serologic tests for typhoid have existed for over a hundred years, but only recently were antigens identified that were sensitive and specific enough to use as epidemiologic markers. These antigens, coupled with new methodological developments, permit estimating seroincidence-the rate at which new infections occur in a population-from cross-sectional serosurveys. These new tools open up many possible applications for enteric fever seroepidemiology, including generating high-resolution surveillance data, monitoring vaccine impact, and integrating with other serosurveillance initiatives. Challenges remain, including distinguishing Salmonella Typhi from Salmonella Paratyphi infections and accounting for reinfections. Enteric fever seroepidemiology can be conducted at a fraction of the cost, time, and sample size of surveillance blood culture studies and may enable more efficient and scalable surveillance for this important infectious disease.

  View details for DOI 10.1093/ofid/ofad021

  View details for PubMedID 37274530

  View details for PubMedCentralID PMC10236506

• Burden of Typhoid and Paratyphoid Fever in India. The New England journal of medicine John, J., Bavdekar, A., Rongsen-Chandola, T., Dutta, S., Gupta, M., Kanungo, S., Sinha, B., Srinivasan, M., Shrivastava, A., Bansal, A., Singh, A., Koshy, R. M., Jinka, D. R., Thomas, M. S., Alexander, A. P., Thankaraj, S., Ebenezer, S. E., Karthikeyan, A. S., Kumar, D., Njarekkattuvalappil, S. K., Raju, R., Sahai, N., Veeraraghavan, B., Murhekar, M. V., Mohan, V. R., Natarajan, S. K., Ramanujam, K., Samuel, P., Lo, N. C., Andrews, J., Grassly, N. C., Kang, G. 2023; 388 (16): 1491-1500

  Abstract

  In 2017, more than half the cases of typhoid fever worldwide were projected to have occurred in India. In the absence of contemporary population-based data, it is unclear whether declining trends of hospitalization for typhoid in India reflect increased antibiotic treatment or a true reduction in infection.From 2017 through 2020, we conducted weekly surveillance for acute febrile illness and measured the incidence of typhoid fever (as confirmed on blood culture) in a prospective cohort of children between the ages of 6 months and 14 years at three urban sites and one rural site in India. At an additional urban site and five rural sites, we combined blood-culture testing of hospitalized patients who had a fever with survey data regarding health care use to estimate incidence in the community.A total of 24,062 children who were enrolled in four cohorts contributed 46,959 child-years of observation. Among these children, 299 culture-confirmed typhoid cases were recorded, with an incidence per 100,000 child-years of 576 to 1173 cases in urban sites and 35 in rural Pune. The estimated incidence of typhoid fever from hospital surveillance ranged from 12 to 1622 cases per 100,000 child-years among children between the ages of 6 months and 14 years and from 108 to 970 cases per 100,000 person-years among those who were 15 years of age or older. Salmonella enterica serovar Paratyphi was isolated from 33 children, for an overall incidence of 68 cases per 100,000 child-years after adjustment for age.The incidence of typhoid fever in urban India remains high, with generally lower estimates of incidence in most rural areas. (Funded by the Bill and Melinda Gates Foundation; NSSEFI Clinical Trials Registry of India number, CTRI/2017/09/009719; ISRCTN registry number, ISRCTN72938224.).

  View details for DOI 10.1056/NEJMoa2209449

  View details for PubMedID 37075141

• Programmatic Effectiveness of a Pediatric Typhoid Conjugate Vaccine Campaign in Navi Mumbai, India. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Hoffman, S. A., LeBoa, C., Date, K., Haldar, P., Harvey, P., Shimpi, R., An, Q., Zhang, C., Jayaprasad, N., Horng, L., Fagerli, K., Borhade, P., Chakraborty, D., Bahl, S., Katkar, A., Kunwar, A., Yewale, V., Andrews, J. R., Bhatnagar, P., Dutta, S., Luby, S. P. 2023

  Abstract

  The WHO recommends vaccines for prevention and control of typhoid fever, especially where antimicrobial-resistant typhoid circulates. In 2018 the Navi Mumbai Municipal Corporation (NMMC), implemented a TCV campaign. The campaign targeted all children aged 9-months through 14-years within NMMC boundaries (∼320,000 children) over 2 vaccination phases. The phase 1 campaign occurred from July 14-August 25, 2018 (71% coverage, ∼113,420 children). We evaluated the phase 1 campaign's programmatic effectiveness in reducing typhoid cases at the community level.We established prospective, blood culture-based surveillance at 6 hospitals in Navi Mumbai, offering blood cultures to children presenting with fever ≥ 3 days. We employed a cluster-randomized (by administrative boundary) test-negative design to estimate the effectiveness of the vaccination campaign on pediatric typhoid cases. We matched test-positive, culture-confirmed typhoid cases with up to 3 test-negative, culture-negative controls by age and date of blood culture and assessed community vaccine campaign phase as an exposure using conditional logistic regression.Between September 1, 2018-March 31, 2021, we identified 81 typhoid cases and matched these with 238 controls. Cases were 0.44 times as likely to live in vaccine campaign communities (programmatic effectiveness, 56%, 95%CI: 25%-74%, p=0.002). Cases ≥ 5-years-old were 0.37 times as likely (95% CI: 0.19-0.70; p-value = 0.002) and cases during the first year of surveillance were 0.30 times as likely (95% CI: 0.14-0.64; p-value = 0.002) to live in vaccine campaign communities.Our findings support the use of TCV mass vaccination campaigns as effective population-based tools to combat typhoid fever.

  View details for DOI 10.1093/cid/ciad132

  View details for PubMedID 36947143

• Scaling up evidence-based approaches to tuberculosis screening in prisons. The Lancet. Public health Charalambous, S., Velen, K., Rueda, Z., Croda, J., Herce, M. E., Shenoi, S. V., Altice, F. L., Muyoyeta, M., Telisinghe, L., Grandjean, L., Keshavjee, S., Andrews, J. R. 2023

  Abstract

  People deprived of liberty have among the highest rates of tuberculosis globally. The incidence of tuberculosis is ten times greater than the incidence of tuberculosis in the general population. In 2021, WHO updated its guidance to strongly recommend systematic screening for tuberculosis in prisons and penitentiary systems. Which case-finding strategies should be adopted, and how to effectively implement these strategies in these settings, will be crucial questions facing ministries of health and justice. In this Viewpoint, we review the evidence base for tuberculosis screening and diagnostic strategies in prisons, highlighting promising approaches and knowledge gaps. Drawing upon past experiences of implementing active case-finding and care programmes in settings with a high tuberculosis burden, we discuss challenges and opportunities for improving the tuberculosis diagnosis and treatment cascade in these settings. We argue that improved transparency in reporting of tuberculosis notifications and outcomes in prisons and renewed focus and resourcing from WHO and other stakeholders will be crucial for building the commitment and investments needed from countries to address the continued crisis of tuberculosis in prisons.

  View details for DOI 10.1016/S2468-2667(23)00002-6

  View details for PubMedID 36780916

• Challenges in Harnessing Shared Within-Host Severe Acute Respiratory Syndrome Coronavirus 2 Variation for Transmission Inference. Open forum infectious diseases Walter, K. S., Kim, E., Verma, R., Altamirano, J., Leary, S., Carrington, Y. J., Jagannathan, P., Singh, U., Holubar, M., Subramanian, A., Khosla, C., Maldonado, Y., Andrews, J. R. 2023; 10 (2): ofad001

  Abstract

  The limited variation observed among severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) consensus sequences makes it difficult to reconstruct transmission linkages in outbreak settings. Previous studies have recovered variation within individual SARS-CoV-2 infections but have not yet measured the informativeness of within-host variation for transmission inference.We performed tiled amplicon sequencing on 307 SARS-CoV-2 samples, including 130 samples from 32 individuals in 14 households and 47 longitudinally sampled individuals, from 4 prospective studies with household membership data, a proxy for transmission linkage.Consensus sequences from households had limited diversity (mean pairwise distance, 3.06 single-nucleotide polymorphisms [SNPs]; range, 0-40). Most (83.1%, 255 of 307) samples harbored at least 1 intrahost single-nucleotide variant ([iSNV] median, 117; interquartile range [IQR], 17-208), above a minor allele frequency threshold of 0.2%. Pairs in the same household shared significantly more iSNVs (mean, 1.20 iSNVs; 95% confidence interval [CI], 1.02-1.39) than did pairs in different households infected with the same viral clade (mean, 0.31 iSNVs; 95% CI, .28-.34), a signal that decreases with increasingly stringent minor allele frequency thresholds. The number of shared iSNVs was significantly associated with an increased odds of household membership (adjusted odds ratio, 1.35; 95% CI, 1.23-1.49). However, the poor concordance of iSNVs detected across sequencing replicates (24.8% and 35.0% above a 0.2% and 1% threshold) confirms technical concerns that current sequencing and bioinformatic workflows do not consistently recover low-frequency within-host variants.Shared within-host variation may augment the information in consensus sequences for predicting transmission linkages. Improving sensitivity and specificity of within-host variant identification will improve the informativeness of within-host variation.

  View details for DOI 10.1093/ofid/ofad001

  View details for PubMedID 36751652

  View details for PubMedCentralID PMC9898879

• Spread of Mycobacterium tuberculosis in Southern Brazilian persons deprived of liberty: a molecular epidemiology study. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology Busatto, C., Possuelo, L. G., Bierhals, D., de Oliveira, C. L., de Souza, M. Q., Fanfa, D., Barreto, É., Schwarzbold, P., Von Groll, A., Portugal, I., Perdigão, J., Croda, J., Andrews, J. R., da Silva, P. A., Ramis, I. B. 2023

  Abstract

  To evaluate the genetic diversity and clustering rates of M. tuberculosis strains to better understand transmission among persons deprived of liberty (PDL) in Rio Grande do Sul (RS), southern Brazil. This is a cross-sectional study, including strains of M. tuberculosis isolated from PDL, stored at the Central Laboratory of RS, in the period from 2013 to 2018. The molecular characterization was performed using the MIRU-VNTR 15 loci method. A total of 598 M. tuberculosis strains were genotyped, and 37.5% were grouped into 53 clusters. Cluster sizes ranged from 2 to 34 strains. The largest cluster of the study had strains from 34 PDL, and 58.8% of the PDL of this cluster were in P01. Among the clusters formed, in 60.3%, there was at least one strain from P01. The most common strains in RS were LAM (53.2%) and Haarlem (31.1%). The LAM strain was the most likely to form clusters, and Haarlem was associated with anti-TB drug resistance. This was translational research, and the results can collaborate with the TB control programs, leading to improved strategies that allow the reduction of the TB burden in prisons.

  View details for DOI 10.1007/s10096-023-04546-4

  View details for PubMedID 36701032

• Phylogeography and transmission of Mycobacterium tuberculosis spanning prisons and surrounding communities in Paraguay. Nature communications Sanabria, G. E., Sequera, G., Aguirre, S., Méndez, J., Dos Santos, P. C., Gustafson, N. W., Godoy, M., Ortiz, A., Cespedes, C., Martínez, G., García-Basteiro, A. L., Andrews, J. R., Croda, J., Walter, K. S. 2023; 14 (1): 303

  Abstract

  Recent rises in incident tuberculosis (TB) cases in Paraguay and the increasing concentration of TB within prisons highlight the urgency of targeting strategies to interrupt transmission and prevent new infections. However, whether specific cities or carceral institutions play a disproportionate role in transmission remains unknown. We conducted prospective genomic surveillance, sequencing 471 Mycobacterium tuberculosis complex genomes, from inside and outside prisons in Paraguay's two largest urban areas, Asunción and Ciudad del Este, from 2016 to 2021. We found genomic evidence of frequent recent transmission within prisons and transmission linkages spanning prisons and surrounding populations. We identified a signal of frequent M. tuberculosis spread between urban areas and marked recent population size expansion of the three largest genomic transmission clusters. Together, our findings highlight the urgency of strengthening TB control programs to reduce transmission risk within prisons in Paraguay, where incidence was 70 times that outside prisons in 2021.

  View details for DOI 10.1038/s41467-023-35813-9

  View details for PubMedID 36658111

• Evaluation of chest X-ray with automated interpretation algorithms for mass tuberculosis screening in prisons: a cross-sectional study. Lancet regional health. Americas Soares, T. R., Oliveira, R. D., Liu, Y. E., Santos, A. d., Santos, P. C., Monte, L. R., Oliveira, L. M., Park, C. M., Hwang, E. J., Andrews, J. R., Croda, J. 2023; 17: 100388

  Abstract

  The World Health Organization (WHO) recommends systematic tuberculosis (TB) screening in prisons. Evidence is lacking for accurate and scalable screening approaches in this setting. We aimed to assess the accuracy of artificial intelligence-based chest x-ray interpretation algorithms for TB screening in prisons.We performed prospective TB screening in three male prisons in Brazil from October 2017 to December 2019. We administered a standardized questionnaire, performed a chest x-ray in a mobile unit, and collected sputum for confirmatory testing using Xpert MTB/RIF and culture. We evaluated x-ray images using three algorithms (CAD4TB version 6, Lunit version 3.1.0.0 and qXR version 3) and compared their accuracy. We utilized multivariable logistic regression to assess the effect of demographic and clinical characteristics on algorithm accuracy. Finally, we investigated the relationship between abnormality scores and Xpert semi-quantitative results.Among 2075 incarcerated individuals, 259 (12.5%) had confirmed TB. All three algorithms performed similarly overall with area under the receiver operating characteristic curve (AUC) of 0.88-0.91. At 90% sensitivity, only LunitTB and qXR met the WHO Target Product Profile requirements for a triage test, with specificity of 84% and 74%, respectively. All algorithms had variable performance by age, prior TB, smoking, and presence of TB symptoms. LunitTB was the most robust to this heterogeneity but nonetheless failed to meet the TPP for individuals with previous TB. Abnormality scores of all three algorithms were significantly correlated with sputum bacillary load.Automated x-ray interpretation algorithms can be an effective triage tool for TB screening in prisons. However, their specificity is insufficient in individuals with previous TB.This study was supported by the US National Institutes of Health (grant numbers R01 AI130058 and R01 AI149620) and the State Secretary of Health of Mato Grosso do Sul.

  View details for DOI 10.1016/j.lana.2022.100388

  View details for PubMedID 36776567

  View details for PubMedCentralID PMC9904090

• Comparison of model predictions of typhoid conjugate vaccine public health impact and cost-effectiveness. Vaccine Burrows, H., Antillón, M., Gauld, J. S., Kim, J. H., Mogasale, V., Ryckman, T., Andrews, J. R., Lo, N. C., Pitzer, V. E. 2022

  Abstract

  Models are useful to inform policy decisions on typhoid conjugate vaccine (TCV) deployment in endemic settings. However, methodological choices can influence model-predicted outcomes. To provide robust estimates for the potential public health impact of TCVs that account for structural model differences, we compared four dynamic and one static mathematical model of typhoid transmission and vaccine impact. All models were fitted to a common dataset of age-specific typhoid fever cases in Kolkata, India. We evaluated three TCV strategies: no vaccination, routine vaccination at 9 months of age, and routine vaccination at 9 months with a one-time catch-up campaign (ages 9 months to 15 years). The primary outcome was the predicted percent reduction in symptomatic typhoid cases over 10 years after vaccine introduction. For three models with economic analyses (Models A-C), we also compared the incremental cost-effectiveness ratios (ICERs), calculated as the incremental cost (US$) per disability-adjusted life-year (DALY) averted. Routine vaccination was predicted to reduce symptomatic cases by 10-46 % over a 10-year time horizon under an optimistic scenario (95 % initial vaccine efficacy and 19-year mean duration of protection), and by 2-16 % under a pessimistic scenario (82 % initial efficacy and 6-year mean protection). Adding a catch-up campaign predicted a reduction in incidence of 36-90 % and 6-35 % in the optimistic and pessimistic scenarios, respectively. Vaccine impact was predicted to decrease as the relative contribution of chronic carriers to transmission increased. Models A-C all predicted routine vaccination with or without a catch-up campaign to be cost-effective compared to no vaccination, with ICERs varying from $95-789 per DALY averted; two models predicted the ICER of routine vaccination alone to be greater than with the addition of catch-up campaign. Despite differences in model-predicted vaccine impact and cost-effectiveness, routine vaccination plus a catch-up campaign is likely to be impactful and cost-effective in high incidence settings such as Kolkata.

  View details for DOI 10.1016/j.vaccine.2022.12.032

  View details for PubMedID 36586741

• Paratype: a genotyping tool for Salmonella Paratyphi A reveals its global genomic diversity. Nature communications Tanmoy, A. M., Hooda, Y., Sajib, M. S., da Silva, K. E., Iqbal, J., Qamar, F. N., Luby, S. P., Dougan, G., Dyson, Z. A., Baker, S., Garrett, D. O., Andrews, J. R., Saha, S. K., Saha, S. 2022; 13 (1): 7912

  Abstract

  Salmonella Paratyphi A, the primary etiology of paratyphoid, is estimated to cause 3.4 million infections annually, worldwide. With rising antimicrobial resistance and no licensed vaccines, genomic surveillance is key to track and monitor transmission, but there is currently no reliable genotyping framework for this pathogen. Here, we sequence 817 isolates from South Asia and add 562 publicly available genomes to build a global database representing 37 countries, covering 1917-2019. We develop a single nucleotide polymorphism-based genotyping scheme, Paratype, that segregates Salmonella Paratyphi A population into three primary and nine secondary clades, and 18 genotypes. Each genotype is assigned a unique allele definition located on an essential gene. Using Paratype, we identify spatiotemporal genomic variation and antimicrobial resistance markers. We release Paratype as an open-access tool that can use raw read files from both Illumina and Nanopore platforms, and thus can assist surveillance studies tracking Salmonella Paratyphi A across the globe.

  View details for DOI 10.1038/s41467-022-35587-6

  View details for PubMedID 36564386

• Plasmodium infection is associated with cross-reactive antibodies to carbohydrate epitopes on the SARS-CoV-2 Spike protein. Scientific reports Lapidus, S., Liu, F., Casanovas-Massana, A., Dai, Y., Huck, J. D., Lucas, C., Klein, J., Filler, R. B., Strine, M. S., Sy, M., Deme, A. B., Badiane, A. S., Dieye, B., Ndiaye, I. M., Diedhiou, Y., Mbaye, A. M., Diagne, C. T., Vigan-Womas, I., Mbengue, A., Sadio, B. D., Diagne, M. M., Moore, A. J., Mangou, K., Diallo, F., Sene, S. D., Pouye, M. N., Faye, R., Diouf, B., Nery, N., Costa, F., Reis, M. G., Muenker, M. C., Hodson, D. Z., Mbarga, Y., Katz, B. Z., Andrews, J. R., Campbell, M., Srivathsan, A., Kamath, K., Baum-Jones, E., Faye, O., Sall, A. A., Vélez, J. C., Cappello, M., Wilson, M., Ben-Mamoun, C., Tedder, R., McClure, M., Cherepanov, P., Somé, F. A., Dabiré, R. K., Moukoko, C. E., Ouédraogo, J. B., Boum, Y., Shon, J., Ndiaye, D., Wisnewski, A., Parikh, S., Iwasaki, A., Wilen, C. B., Ko, A. I., Ring, A. M., Bei, A. K. 2022; 12 (1): 22175

  Abstract

  Sero-surveillance can monitor and project disease burden and risk. However, SARS-CoV-2 antibody test results can produce false positive results, limiting their efficacy as a sero-surveillance tool. False positive SARS-CoV-2 antibody results are associated with malaria exposure, and understanding this association is essential to interpret sero-surveillance results from malaria-endemic countries. Here, pre-pandemic samples from eight malaria endemic and non-endemic countries and four continents were tested by ELISA to measure SARS-CoV-2 Spike S1 subunit reactivity. Individuals with acute malaria infection generated substantial SARS-CoV-2 reactivity. Cross-reactivity was not associated with reactivity to other human coronaviruses or other SARS-CoV-2 proteins, as measured by peptide and protein arrays. ELISAs with deglycosylated and desialated Spike S1 subunits revealed that cross-reactive antibodies target sialic acid on N-linked glycans of the Spike protein. The functional activity of cross-reactive antibodies measured by neutralization assays showed that cross-reactive antibodies did not neutralize SARS-CoV-2 in vitro. Since routine use of glycosylated or sialated assays could result in false positive SARS-CoV-2 antibody results in malaria endemic regions, which could overestimate exposure and population-level immunity, we explored methods to increase specificity by reducing cross-reactivity. Overestimating population-level exposure to SARS-CoV-2 could lead to underestimates of risk of continued COVID-19 transmission in sub-Saharan Africa.

  View details for DOI 10.1038/s41598-022-26709-7

  View details for PubMedID 36550362

• A robust host-response-based signature distinguishes bacterial and viral infections across diverse global populations. Cell reports. Medicine Rao, A. M., Popper, S. J., Gupta, S., Davong, V., Vaidya, K., Chanthongthip, A., Dittrich, S., Robinson, M. T., Vongsouvath, M., Mayxay, M., Nawtaisong, P., Karmacharya, B., Thair, S. A., Bogoch, I., Sweeney, T. E., Newton, P. N., Andrews, J. R., Relman, D. A., Khatri, P. 2022; 3 (12): 100842

  Abstract

  Limited sensitivity and specificity of current diagnostics lead to the erroneous prescription of antibiotics. Host-response-based diagnostics could address these challenges. However, using 4,200 samples across 69 blood transcriptome datasets from 20 countries from patients with bacterial or viral infections representing a broad spectrum of biological, clinical, and technical heterogeneity, we show current host-response-based gene signatures have lower accuracy to distinguish intracellular bacterial infections from viral infections than extracellular bacterial infections. Using these 69 datasets, we identify an 8-gene signature to distinguish intracellular or extracellular bacterial infections from viral infections with an area under the receiver operating characteristic curve (AUROC) > 0.91 (85.9% specificity and 90.2% sensitivity). In prospective cohorts from Nepal and Laos, the 8-gene classifier distinguished bacterial infections from viral infections with an AUROC of 0.94 (87.9% specificity and 91% sensitivity). The 8-gene signature meets the target product profile proposed by the World Health Organization and others for distinguishing bacterial and viral infections.

  View details for DOI 10.1016/j.xcrm.2022.100842

  View details for PubMedID 36543117

• High Sensitivity of Mobile Phone Microscopy Screening for Schistosoma haematobium in Azaguié, Côte d'Ivoire. The American journal of tropical medicine and hygiene Coulibaly, J. T., Silue, K. D., Armstrong, M., Díaz de León Derby, M., D'Ambrosio, M. V., Fletcher, D. A., Keiser, J., Fisher, K., Andrews, J. R., Bogoch, I. I. 2022

  Abstract

  Schistosomiasis infections continue to impact African settings disproportionately, and there is an urgent need for novel tools to evaluate infection control and elimination strategies at the community level. Mobile phone microscopes are portable and semiautomated devices with multiple applications for screening neglected tropical diseases. In a community-based schistosomiasis screening program in Azaguié, Côte d'Ivoire, mobile phone microscopy demonstrated a sensitivity of 85.7% (95% CI: 69.7-95.2%) and specificity of 93.3% (95% CI: 87.7-96.9%) for Schistosoma haematobium identification compared with conventional light microscopy, and 95% sensitivity (95% CI: 74.1-99.8%) with egg concentrations of five or more per 10 mL of urine. Mobile phone microscopy is a promising tool for schistosomiasis control and elimination efforts.

  View details for DOI 10.4269/ajtmh.22-0527

  View details for PubMedID 36509050

• Association between primary or booster COVID-19 mRNA vaccination and Omicron lineage BA.1 SARS-CoV-2 infection in people with a prior SARS-CoV-2 infection: A test-negative case-control analysis. PLoS medicine Lind, M. L., Robertson, A. J., Silva, J., Warner, F., Coppi, A. C., Price, N., Duckwall, C., Sosensky, P., Di Giuseppe, E. C., Borg, R., Fofana, M. O., Ranzani, O. T., Dean, N. E., Andrews, J. R., Croda, J., Iwasaki, A., Cummings, D. A., Ko, A. I., Hitchings, M. D., Schulz, W. L. 2022; 19 (12): e1004136

  Abstract

  The benefit of primary and booster vaccination in people who experienced a prior Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection remains unclear. The objective of this study was to estimate the effectiveness of primary (two-dose series) and booster (third dose) mRNA vaccination against Omicron (lineage BA.1) infection among people with a prior documented infection.We conducted a test-negative case-control study of reverse transcription PCRs (RT-PCRs) analyzed with the TaqPath (Thermo Fisher Scientific) assay and recorded in the Yale New Haven Health system from November 1, 2021, to April 30, 2022. Overall, 11,307 cases (positive TaqPath analyzed RT-PCRs with S-gene target failure [SGTF]) and 130,041 controls (negative TaqPath analyzed RT-PCRs) were included (median age: cases: 35 years, controls: 39 years). Among cases and controls, 5.9% and 8.1% had a documented prior infection (positive SARS-CoV-2 test record ≥90 days prior to the included test), respectively. We estimated the effectiveness of primary and booster vaccination relative to SGTF-defined Omicron (lineage BA.1) variant infection using a logistic regression adjusted for date of test, age, sex, race/ethnicity, insurance, comorbidities, social venerability index, municipality, and healthcare utilization. The effectiveness of primary vaccination 14 to 149 days after the second dose was 41.0% (95% confidence interval (CI): 14.1% to 59.4%, p 0.006) and 27.1% (95% CI: 18.7% to 34.6%, p < 0.001) for people with and without a documented prior infection, respectively. The effectiveness of booster vaccination (≥14 days after booster dose) was 47.1% (95% CI: 22.4% to 63.9%, p 0.001) and 54.1% (95% CI: 49.2% to 58.4%, p < 0.001) in people with and without a documented prior infection, respectively. To test whether booster vaccination reduced the risk of infection beyond that of the primary series, we compared the odds of infection among boosted (≥14 days after booster dose) and booster-eligible people (≥150 days after second dose). The odds ratio (OR) comparing boosted and booster-eligible people with a documented prior infection was 0.79 (95% CI: 0.54 to 1.16, p 0.222), whereas the OR comparing boosted and booster-eligible people without a documented prior infection was 0.54 (95% CI: 0.49 to 0.59, p < 0.001). This study's limitations include the risk of residual confounding, the use of data from a single system, and the reliance on TaqPath analyzed RT-PCR results.In this study, we observed that primary vaccination provided significant but limited protection against Omicron (lineage BA.1) infection among people with and without a documented prior infection. While booster vaccination was associated with additional protection against Omicron BA.1 infection in people without a documented prior infection, it was not found to be associated with additional protection among people with a documented prior infection. These findings support primary vaccination in people regardless of documented prior infection status but suggest that infection history may impact the relative benefit of booster doses.

  View details for DOI 10.1371/journal.pmed.1004136

  View details for PubMedID 36454733

• Comparative Analysis of Commercially Available Typhoid Point-of-Care Tests: Results of a Prospective and Hybrid Retrospective Multicenter Diagnostic Accuracy Study in Kenya and Pakistan. Journal of clinical microbiology Sapkota, J., Hasan, R., Onsare, R., Arafah, S., Kariuki, S., Shakoor, S., Qamar, F., Mundalo, S., Njeru, F., Too, R., Ndegwa, E., Andrews, J. R., Dittrich, S. 2022: e0100022

  Abstract

  Blood and bone marrow cultures are considered the gold standard for the diagnosis of typhoid, but these methods require infrastructure and skilled staff that are not always available in low- and middle-income countries where typhoid is endemic. The objective of the study is to evaluate the sensitivity and specificity of nine commercially available Salmonella Typhi rapid diagnostic tests (RDTs) using blood culture as a reference standard in a multicenter study. This was a prospective and retrospective multicenter diagnostic accuracy study conducted in two geographically distant areas where typhoid is endemic (Pakistan and Kenya; NCT04801602). Nine RDTs were evaluated, including the Widal test. Point estimates for sensitivity and specificity were calculated using the Wilson method. Latent class analyses were performed using R to address the imperfect gold standard. A total of 531 serum samples were evaluated (264 blood culture positive; 267 blood culture negative). The sensitivity of RDTs varied widely (range, 0 to 78.8%), with the best overall performance shown by Enterocheck WB (72.7% sensitivity, 86.5% specificity). In latent class modeling, CTK IgG was found to have the highest sensitivity (79.1%), while the highest overall accuracy was observed with Enterocheck (73.8% sensitivity, 94.5% specificity). All commercially available Salmonella Typhi RDTs evaluated in the study had sensitivity and specificity values that fell below the required levels to be recommended for an accurate diagnosis. There were minimal differences in RDT performances between regions of endemicity. These findings highlight the clear need for new and more-accurate Salmonella Typhi tests.

  View details for DOI 10.1128/jcm.01000-22

  View details for PubMedID 36448816

• Seroincidence of Enteric Fever, Juba, South Sudan. Emerging infectious diseases Aiemjoy, K., Rumunu, J., Hassen, J. J., Wiens, K. E., Garrett, D., Kamenskaya, P., Harris, J. B., Azman, A. S., Teunis, P., Seidman, J. C., Wamala, J. F., Andrews, J. R., Charles, R. C. 2022; 28 (11)

  Abstract

  We applied a new serosurveillance tool to estimate typhoidal Salmonella burden using samples collected during 2020 from a population in Juba, South Sudan. By using dried blood spot testing, we found an enteric fever seroincidence rate of 30/100 person-years and cumulative incidence of 74% over a 4-year period.

  View details for DOI 10.3201/eid2811.220239

  View details for PubMedID 36286224

• Gauging the skin resident Leishmania parasites through a loop mediated isothermal amplification (LAMP) assay in post-kala-azar dermal leishmaniasis. Scientific reports Ghosh, P., Chowdhury, R., Maruf, S., Picado, A., Hossain, F., Owen, S. I., Nath, R., Baker, J., Hasnain, M. G., Shomik, M. S., Ghosh, D., Rashid, M., Rashid, M. U., Sagar, S. K., Rahat, M. A., Basher, A., Nath, P., Edwards, T., Andrews, J. R., Duthie, M. S., de Souza, D. K., Adams, E. R., Ndungu, J., Cruz, I., Mondal, D. 2022; 12 (1): 18069

  Abstract

  Despite the availability of highly sensitive polymerase chain reaction (PCR)-based methods, the dearth of remotely deployable diagnostic tools circumvents the early and accurate detection of individuals with post-kala-azar dermal leishmaniasis (PKDL). Here, we evaluate a design-locked loop-mediated isothermal amplification (LAMP) assay to diagnose PKDL. A total of 76 snip-skin samples collected from individuals with probable PKDL (clinical presentation and a positive rK39 rapid diagnostic test (RDT)) were assessed by microscopy, qPCR, and LAMP. An equal number of age and sex-matched healthy controls were included to determine the specificity of the LAMP assay. The LAMP assay with a Qiagen DNA extraction (Q-LAMP) showed a promising sensitivity of 72.37% (95% CI: 60.91-82.01%) for identifying the PKDL cases. LAMP assay sensitivity declined when the DNA was extracted using a boil-spin method. Q-qPCR showed 68.42% (56.75-78.61%) sensitivity, comparable to LAMP and with an excellent agreement, whereas the microscopy exhibited a weak sensitivity of 39.47% (28.44-51.35%). When microscopy and/or qPCR were considered the gold standard, Q-LAMP exhibited an elevated sensitivity of 89.7% (95% CI: 78.83-96.11%) for detection of PKDL cases and Bayesian latent class modeling substantiated the excellent sensitivity of the assay. All healthy controls were found to be negative. Notwithstanding the optimum efficiency of the LAMP assay towards the detection of PKDL cases, further optimization of the boil-spin method is warranted to permit remote use of the assay.

  View details for DOI 10.1038/s41598-022-21497-6

  View details for PubMedID 36302782

• Protection against Omicron from Vaccination and Previous Infection in a Prison System. The New England journal of medicine Chin, E. T., Leidner, D., Lamson, L., Lucas, K., Studdert, D. M., Goldhaber-Fiebert, J. D., Andrews, J. R., Salomon, J. A. 2022

  Abstract

  Information regarding the protection conferred by vaccination and previous infection against infection with the B.1.1.529 (omicron) variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is limited.We evaluated the protection conferred by mRNA vaccines and previous infection against infection with the omicron variant in two high-risk populations: residents and staff in the California state prison system. We used a retrospective cohort design to analyze the risk of infection during the omicron wave using data collected from December 24, 2021, through April 14, 2022. Weighted Cox models were used to compare the effectiveness (measured as 1 minus the hazard ratio) of vaccination and previous infection across combinations of vaccination history (stratified according to the number of mRNA doses received) and infection history (none or infection before or during the period of B.1.617.2 [delta]-variant predominance). A secondary analysis used a rolling matched-cohort design to evaluate the effectiveness of three vaccine doses as compared with two doses.Among 59,794 residents and 16,572 staff, the estimated effectiveness of previous infection against omicron infection among unvaccinated persons who had been infected before or during the period of delta predominance ranged from 16.3% (95% confidence interval [CI], 8.1 to 23.7) to 48.9% (95% CI, 41.6 to 55.3). Depending on previous infection status, the estimated effectiveness of vaccination (relative to being unvaccinated and without previous documented infection) ranged from 18.6% (95% CI, 7.7 to 28.1) to 83.2% (95% CI, 77.7 to 87.4) with two vaccine doses and from 40.9% (95% CI, 31.9 to 48.7) to 87.9% (95% CI, 76.0 to 93.9) with three vaccine doses. Incremental effectiveness estimates of a third (booster) dose (relative to two doses) ranged from 25.0% (95% CI, 16.6 to 32.5) to 57.9% (95% CI, 48.4 to 65.7) among persons who either had not had previous documented infection or had been infected before the period of delta predominance.Our findings in two high-risk populations suggest that mRNA vaccination and previous infection were effective against omicron infection, with lower estimates among those infected before the period of delta predominance. Three vaccine doses offered significantly more protection than two doses, including among previously infected persons.

  View details for DOI 10.1056/NEJMoa2207082

  View details for PubMedID 36286260

• Tuberculosis in prison inmates in Southern Brazil: investigating the epidemiological and operational indicators. Revista da Sociedade Brasileira de Medicina Tropical Busatto, C., Mespaque, J., Schwarzbold, P., Souza, C. D., Jarczewski, C. A., Meucci, R. D., Andrews, J., Croda, J., Silva, P. E., Ramis, I. B., Possuelo, L. G. 2022; 55: e00522022

  Abstract

  Tuberculosis is a worldwide public health problem and is more prevalent in specific populations, such as prisoners. The aim of this study was to analyze the epidemiological and operational indicators of tuberculosis in prisoners in a southern region of Brazil.This was a descriptive, observational study, utilizing secondary data from the Notifiable Diseases Information System on tuberculosis cases diagnosed in prisoners in the state of Rio Grande do Sul, southern Brazil, from 2014 to 2018. Prisoner data used to calculate incidence were extracted from reports by the National Penitentiary Department.From 2014 to 2018, 3,557 tuberculosis cases were reported in Rio Grande do Sul prisoners. The incidence rate of tuberculosis in prisoners was 1,235/100,000 individuals in 2014 and 1,430/100,000 individuals in 2018. The proportion of new TB cases tested for HIV was high, 83.4% in this period; among those tested, 12.9% were HIV coinfected. The proportion of new cases of pulmonary tuberculosis confirmed by laboratory criteria was 52.6% in this period. In total, 18.4% of new pulmonary tuberculosis cases were initiated on directly observed treatment in this period, and 36.4% of contacts of new cases of pulmonary tuberculosis with laboratory confirmation were examined. Among retreatment pulmonary tuberculosis cases, 82.4% were laboratory-confirmed.Tuberculosis incidence is increasing on a per-capita and absolute basis in Rio Grande do Sul. Laboratory confirmation, HIV testing, directly observed treatment, and contact investigation rates were all low, indicating the need to improve medical and public health measures for tuberculosis control in prisons.

  View details for DOI 10.1590/0037-8682-0052-2022

  View details for PubMedID 36287468

• Early immune markers of clinical, virological, and immunological outcomes in patients with COVID-19: a multi-omics study. eLife Hu, Z., van der Ploeg, K., Chakraborty, S., Arunachalam, P. S., Mori, D. A., Jacobson, K. B., Bonilla, H., Parsonnet, J., Andrews, J. R., Holubar, M., Subramanian, A., Khosla, C., Maldonado, Y., Hedlin, H., de la Parte, L., Press, K., Ty, M., Tan, G. S., Blish, C., Takahashi, S., Rodriguez-Barraquer, I., Greenhouse, B., Butte, A. J., Singh, U., Pulendran, B., Wang, T. T., Jagannathan, P. 2022; 11

  Abstract

  The great majority of severe acute respiratory syndrome-related coronavirus 2 (SARS-CoV-2) infections are mild and uncomplicated, but some individuals with initially mild COVID-19 progressively develop more severe symptoms. Furthermore, there is substantial heterogeneity in SARS-CoV-2-specific memory immune responses following infection. There remains a critical need to identify host immune biomarkers predictive of clinical and immunological outcomes in SARS-CoV-2-infected patients.Leveraging longitudinal samples and data from a clinical trial (N=108) in SARS-CoV-2-infected outpatients, we used host proteomics and transcriptomics to characterize the trajectory of the immune response in COVID-19 patients. We characterized the association between early immune markers and subsequent disease progression, control of viral shedding, and SARS-CoV-2-specific T cell and antibody responses measured up to 7 months after enrollment. We further compared associations between early immune markers and subsequent T cell and antibody responses following natural infection with those following mRNA vaccination. We developed machine-learning models to predict patient outcomes and validated the predictive model using data from 54 individuals enrolled in an independent clinical trial.We identify early immune signatures, including plasma RIG-I levels, early IFN signaling, and related cytokines (CXCL10, MCP1, MCP-2, and MCP-3) associated with subsequent disease progression, control of viral shedding, and the SARS-CoV-2-specific T cell and antibody response measured up to 7 months after enrollment. We found that several biomarkers for immunological outcomes are shared between individuals receiving BNT162b2 (Pfizer-BioNTech) vaccine and COVID-19 patients. Finally, we demonstrate that machine-learning models using 2-7 plasma protein markers measured early within the course of infection are able to accurately predict disease progression, T cell memory, and the antibody response post-infection in a second, independent dataset.Early immune signatures following infection can accurately predict clinical and immunological outcomes in outpatients with COVID-19 using validated machine-learning models.Support for the study was provided from National Institute of Health/National Institute of Allergy and Infectious Diseases (NIH/NIAID) (U01 AI150741-01S1 and T32-AI052073), the Stanford's Innovative Medicines Accelerator, National Institutes of Health/National Institute on Drug Abuse (NIH/NIDA) DP1DA046089, and anonymous donors to Stanford University. Peginterferon lambda provided by Eiger BioPharmaceuticals.

  View details for DOI 10.7554/eLife.77943

  View details for PubMedID 36239699

• Effectiveness of an inactivated Covid-19 vaccine with homologous and heterologous boosters against Omicron in Brazil. Nature communications Ranzani, O. T., Hitchings, M. D., de Melo, R. L., de França, G. V., Fernandes, C. d., Lind, M. L., Torres, M. S., Tsuha, D. H., David, L. C., Said, R. F., Almiron, M., de Oliveira, R. D., Cummings, D. A., Dean, N. E., Andrews, J. R., Ko, A. I., Croda, J. 2022; 13 (1): 5536

  Abstract

  The effectiveness of inactivated vaccines (VE) against symptomatic and severe COVID-19 caused by omicron is unknown. We conducted a nationwide, test-negative, case-control study to estimate VE for homologous and heterologous (BNT162b2) booster doses in adults who received two doses of CoronaVac in Brazil in the Omicron context. Analyzing 1,386,544 matched-pairs, VE against symptomatic disease was 8.6% (95% CI, 5.6-11.5) and 56.8% (95% CI, 56.3-57.3) in the period 8-59 days after receiving a homologous and heterologous booster, respectively. During the same interval, VE against severe Covid-19 was 73.6% (95% CI, 63.9-80.7) and 86.0% (95% CI, 84.5-87.4) after receiving a homologous and heterologous booster, respectively. Waning against severe Covid-19 after 120 days was only observed after a homologous booster. Heterologous booster might be preferable to individuals with completed primary series inactivated vaccine.

  View details for DOI 10.1038/s41467-022-33169-0

  View details for PubMedID 36202800

• SARS-CoV-2 infection drives an inflammatory response in human adipose tissue through infection of adipocytes and macrophages. Science translational medicine Martínez-Colón, G. J., Ratnasiri, K., Chen, H., Jiang, S., Zanley, E., Rustagi, A., Verma, R., Chen, H., Andrews, J. R., Mertz, K. D., Tzankov, A., Azagury, D., Boyd, J., Nolan, G. P., Schürch, C. M., Matter, M. S., Blish, C. A., McLaughlin, T. L. 2022: eabm9151

  Abstract

  Obesity, characterized by chronic low-grade inflammation of the adipose tissue, is associated with adverse coronavirus disease 2019 (COVID-19) outcomes, yet the underlying mechanism is unknown. To explore whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection of adipose tissue contributes to pathogenesis, we evaluated COVID-19 autopsy cases and deeply profiled the response of adipose tissue to SARS-CoV-2 infection in vitro. In COVID-19 autopsy cases, we identified SARS-CoV-2 RNA in adipocytes with an associated inflammatory infiltrate. We identified two distinct cellular targets of infection: adipocytes and a subset of inflammatory adipose tissue-resident macrophages. Mature adipocytes were permissive to SARS-CoV-2 infection; although macrophages were abortively infected, SARS-CoV-2 initiated inflammatory responses within both the infected macrophages and bystander preadipocytes. These data suggest that SARS-CoV-2 infection of adipose tissue could contribute to COVID-19 severity through replication of virus within adipocytes and through induction of local and systemic inflammation driven by infection of adipose tissue-resident macrophages.

  View details for DOI 10.1126/scitranslmed.abm9151

  View details for PubMedID 36137009

• Virologic Efficacy of Casirivimab and Imdevimab COVID-19 Antibody Combination in Outpatients With SARS-CoV-2 Infection: A Phase 2 Dose-Ranging Randomized Clinical Trial. JAMA network open Portal-Celhay, C., Forleo-Neto, E., Eagan, W., Musser, B. J., Davis, J. D., Turner, K. C., Norton, T., Hooper, A. T., Hamilton, J. D., Pan, C., Mahmood, A., Baum, A., Kyratsous, C. A., Kim, Y., Parrino, J., Kampman, W., Roque-Guerrero, L., Stoici, R., Fatakia, A., Soo, Y., Geba, G. P., Kowal, B., DiCioccio, A. T., Stahl, N., Lipsich, L., Braunstein, N., Herman, G. A., Yancopoulos, G. D., Weinreich, D. M. 2022; 5 (8): e2225411

  Abstract

  The monoclonal antibody combination of casirivimab and imdevimab reduced viral load, hospitalization, or death when administered as a 1200-mg or greater intravenous (IV) dose in a phase 3 COVID-19 outpatient study. Subcutaneous (SC) and/or lower IV doses should increase accessibility and/or drug supplies for patients.To assess the virologic efficacy of casirivimab and imdevimab across different IV and SC doses compared with placebo.This phase 2, randomized, double-blind, placebo-controlled, parallel-group, dose-ranging study included outpatients with SARS-CoV-2 infection at 47 sites across the United States. Participants could be symptomatic or asymptomatic; symptomatic patients with risk factors for severe COVID-19 were excluded. Data were collected from December 15, 2020, to March 4, 2021.Patients were randomized to a single IV dose (523 patients) of casirivimab and imdevimab at 300, 600, 1200, or 2400 mg or placebo; or a single SC dose (292 patients) of casirivimab and imdevimab at 600 or 1200 mg or placebo.The primary end point was the time-weighted average daily change from baseline (TWACB) in viral load from day 1 (baseline) through day 7 in patients seronegative for SARS-CoV-2 at baseline.Among 815 randomized participants, 507 (282 randomized to IV treatment, 148 randomized to SC treatment, and 77 randomized to placebo) were seronegative at baseline and included in the primary efficacy analysis. Participants randomized to IV had a mean (SD) age of 34.6 (9.6) years (160 [44.6%] men; 14 [3.9%] Black; 121 [33.7%] Hispanic or Latino; 309 [86.1%] White); those randomized to SC had a mean age of 34.1 (10.0) years (102 [45.3%] men; 75 [34.7%] Hispanic or Latino; 6 [2.7%] Black; 190 [84.4%] White). All casirivimab and imdevimab treatments showed significant virologic reduction through day 7. Least-squares mean differences in TWACB viral load for casirivimab and imdevimab vs placebo ranged from -0.56 (95% CI; -0.89 to -0.24) log10 copies/mL for the 1200-mg IV dose to -0.71 (95% CI, -1.05 to -0.38) log10 copies/mL for the 2400-mg IV dose. There were no adverse safety signals or dose-related safety findings, grade 2 or greater infusion-related or hypersensitivity reactions, grade 3 or greater injection-site reactions, or fatalities. Two serious adverse events not related to COVID-19 or the study drug were reported.In this randomized clinical trial including outpatients with asymptomatic and low-risk symptomatic SARS-CoV-2, all IV and SC doses of casirivimab and imdevimab comparably reduced viral load.ClinicalTrials.gov Identifier: NCT04666441.

  View details for DOI 10.1001/jamanetworkopen.2022.25411

  View details for PubMedID 35969402

• Dynamics of Respiratory Infectious Diseases in Incarcerated and Free-Living Populations: A Simulation Modeling Study. Medical decision making : an international journal of the Society for Medical Decision Making Weyant, C., Lee, S., Andrews, J. R., Alarid-Escudero, F., Goldhaber-Fiebert, J. D. 2022: 272989X221115364

  Abstract

  Historically, correctional facilities have had large outbreaks of respiratory infectious diseases like COVID-19. Hence, importation and exportation of such diseases from correctional facilities raises substantial concern.We developed a stochastic simulation model of transmission of respiratory infectious diseases within and between correctional facilities and the community. We investigated the infection dynamics, key governing factors, and relative importance of different infection routes (e.g., incarcerations and releases versus correctional staff). We also developed machine-learning meta-models of the simulation model, which allowed us to examine how our findings depended on different disease, correctional facility, and community characteristics.We find a magnification-reflection dynamic: a small outbreak in the community can cause a larger outbreak in the correction facility, which can then cause a second, larger outbreak in the community. This dynamic is strongest when community size is relatively small as compared with the size of the correctional population, the initial community R-effective is near 1, and initial prevalence of immunity in the correctional population is low. The timing of the correctional magnification and community reflection peaks in infection prevalence are primarily governed by the initial R-effective for each setting. Because the release rates from prisons are low, our model suggests correctional staff may be a more important infection entry route into prisons than incarcerations and releases; in jails, where incarceration and release rates are much higher, our model suggests the opposite.We find that across many combinations of respiratory pathogens, correctional settings, and communities, there can be substantial magnification-reflection dynamics, which are governed by several key factors. Our goal was to derive theoretical insights relevant to many contexts; our findings should be interpreted accordingly.We find a magnification-reflection dynamic: a small outbreak in a community can cause a larger outbreak in a correctional facility, which can then cause a second, larger outbreak in the community.For public health decision makers considering contexts most susceptible to this dynamic, we find that the dynamic is strongest when the community size is relatively small, initial community R-effective is near 1, and the initial prevalence of immunity in the correctional population is low; the timing of the correctional magnification and community reflection peaks in infection prevalence are primarily governed by the initial R-effective for each setting.We find that correctional staff may be a more important infection entry route into prisons than incarcerations and releases; however, for jails, the relative importance of the entry routes may be reversed.For modelers, we combine simulation modeling, machine-learning meta-modeling, and interpretable machine learning to examine how our findings depend on different disease, correctional facility, and community characteristics; we find they are generally robust.

  View details for DOI 10.1177/0272989X221115364

  View details for PubMedID 35904128

• Environmental air sampling for detection and quantification of Mycobacterium tuberculosis in clinical settings: Proof of concept. Infection control and hospital epidemiology Middelkoop, K., Koch, A. S., Hoosen, Z., Bryden, W., Call, C., Seldon, R., Warner, D. F., Wood, R., Andrews, J. R. 2022: 1-6

  Abstract

  Novel approaches are needed to understand and disrupt Mycobacterium tuberculosis transmission. In this proof-of-concept study, we investigated the use of environmental air samplings to detect and quantify M. tuberculosis in different clinic settings in a high-burden area.Cross-sectional, environmental sampling.Primary-care clinic.A portable, high-flow dry filter unit (DFU) was used to draw air through polyester felt filters for 2 hours. Samples were collected in the waiting area and TB room of a primary care clinic. Controls included sterile filters placed directly into collection tubes at the DFU sampling site, and filter samplings performed outdoors. DNA was extracted from the filters, and droplet digital polymerase chain reaction (ddPCR) was used to quantify M. tuberculosis DNA copies. Carbon dioxide (CO2) data loggers captured CO2 concentrations in the sampled areas.The median sampling time was 123 minutes (interquartile range [IQR], 121-126). A median of 121 (IQR, 35-243) M. tuberculosis DNA copies were obtained from 74 clinic samplings, compared to a median of 3 (IQR, 1-33; P < .001) obtained from 47 controls. At a threshold of 320 DNA copies, specificity was 100%, and 18% of clinic samples would be classified as positive.This proof-of-concept study suggests that the potential for airborne M. tuberculosis detection based on M. tuberculosis DNA copy yield to enable the identification of high-risk transmission locations. Further optimization of the M. tuberculosis extraction technique and ddPCR data analysis would improve detection and enable robust interpretation of these data.

  View details for DOI 10.1017/ice.2022.162

  View details for PubMedID 35883280

• Incidence of typhoid and paratyphoid fever in Bangladesh, Nepal, and Pakistan: results of the Surveillance for Enteric Fever in Asia Project. The Lancet. Global health Garrett, D. O., Longley, A. T., Aiemjoy, K., Yousafzai, M. T., Hemlock, C., Yu, A. T., Vaidya, K., Tamrakar, D., Saha, S., Bogoch, I. I., Date, K., Saha, S., Islam, M. S., Sayeed, K. M., Bern, C., Shakoor, S., Dehraj, I. F., Mehmood, J., Sajib, M. S., Islam, M., Thobani, R. S., Hotwani, A., Rahman, N., Irfan, S., Naga, S. R., Memon, A. M., Pradhan, S., Iqbal, K., Shrestha, R., Rahman, H., Hasan, M. M., Qazi, S. H., Kazi, A. M., Saddal, N. S., Jamal, R., Hunzai, M. J., Hossain, T., Marks, F., Carter, A. S., Seidman, J. C., Qamar, F. N., Saha, S. K., Andrews, J. R., Luby, S. P. 2022; 10 (7): e978-e988

  Abstract

  Precise enteric fever disease burden data are needed to inform prevention and control measures, including the use of newly available typhoid vaccines. We established the Surveillance for Enteric Fever in Asia Project (SEAP) to inform these strategies.From September, 2016, to September, 2019, we conducted prospective clinical surveillance for Salmonella enterica serotype Typhi (S Typhi) and Paratyphi (S Paratyphi) A, B, and C at health facilities in predetermined catchment areas in Dhaka, Bangladesh; Kathmandu and Kavrepalanchok, Nepal; and Karachi, Pakistan. Patients eligible for inclusion were outpatients with 3 or more consecutive days of fever in the last 7 days; inpatients with suspected or confirmed enteric fever; patients with blood culture-confirmed enteric fever from the hospital laboratories not captured by inpatient or outpatient enrolment and cases from the laboratory network; and patients with non-traumatic ileal perforation under surgical care. We used a hybrid surveillance model, pairing facility-based blood culture surveillance with community surveys of health-care use. Blood cultures were performed for enrolled patients. We calculated overall and age-specific typhoid and paratyphoid incidence estimates for each study site. Adjusted estimates accounted for the sensitivity of blood culture, the proportion of eligible individuals who consented and provided blood, the probability of care-seeking at a study facility, and the influence of wealth and education on care-seeking. We additionally calculated incidence of hospitalisation due to typhoid and paratyphoid.A total of 34 747 patients were enrolled across 23 facilitates (six tertiary hospitals, surgical wards of two additional hospitals, and 15 laboratory network sites) during the study period. Of the 34 303 blood cultures performed on enrolled patients, 8705 (26%) were positive for typhoidal Salmonella. Adjusted incidence rates of enteric fever considered patients in the six tertiary hospitals. Adjusted incidence of S Typhi, expressed per 100 000 person-years, was 913 (95% CI 765-1095) in Dhaka. In Nepal, the adjusted typhoid incidence rates were 330 (230-480) in Kathmandu and 268 (202-362) in Kavrepalanchok. In Pakistan, the adjusted incidence rates per hospital site were 176 (144-216) and 103 (85-126). The adjusted incidence rates of paratyphoid (of which all included cases were due to S Paratyphi A) were 128 (107-154) in Bangladesh, 46 (34-62) and 81 (56-118) in the Nepal sites, and 23 (19-29) and 1 (1-1) in the Pakistan sites. Adjusted incidence of hospitalisation was high across sites, and overall, 2804 (32%) of 8705 patients with blood culture-confirmed enteric fever were hospitalised.Across diverse communities in three south Asian countries, adjusted incidence exceeded the threshold for "high burden" of enteric fever (100 per 100 000 person-years). Incidence was highest among children, although age patterns differed across sites. The substantial disease burden identified highlights the need for control measures, including improvements to water and sanitation infrastructure and the implementation of typhoid vaccines.Bill & Melinda Gates Foundation.

  View details for DOI 10.1016/S2214-109X(22)00119-X

  View details for PubMedID 35714648

• Detection of M. tuberculosis in the environment as a tool for identifying high-risk locations for tuberculosis transmission. The Science of the total environment Verma, R., Moreira, F. M., do Prado Morais, A. O., Walter, K. S., Dos Santos, P. C., Kim, E., Soares, T. R., de Araujo, R. C., da Silva, B. O., da Silva Santos, A., Croda, J., Andrews, J. R. 2022: 156970

  Abstract

  Tuberculosis (TB) remains a leading cause of infectious mortality globally, yet most cases cannot be epidemiologically linked even with extensive contact investigations and whole genome sequencing. Consequently, there remain major gaps in our understanding of where and when M. tuberculosis (Mtb) exposures occur. We aimed to investigate whether Mtb can be detected in environments where TB patients were recently present, which could serve as a tool for characterizing exposure risk. We collected 389 environment surface (ES) swabs from two high TB burden prisons in Brazil, sampling 41 (n = 340) cells occupied by individuals with active TB and 7 (n = 49) cells from individuals without TB. In a subset of pooled swabs (n = 6) and a swab from a cigarette lighter from the cell with active TB patients, we enriched Mtb DNA using RNA-bait hybrid capture assays and performed whole genome sequencing. In prison cells, Mtb DNA was detected in 55/340 (16 %) of ES swabs from cells occupied by active TB patients and none (0/49) from cells in which no active TB patients were present. Mtb was detected in 13/16 (81 %) prison cells occupied by the individuals with high/medium sputum Xpert Mtb load and 8/25 (32 %) with low/very low sputum Mtb load (p = 0.003). Seven hybrid capture samples had a median genomic coverage of 140×. rpoB mutations conferring high-level rifampin resistance were detected in 3/7 ES swabs. Mtb was frequently detectable in environments recently occupied by individuals with active TB. This approach could be applied in congregate environments to identify and characterize high-risk settings for Mtb exposure.

  View details for DOI 10.1016/j.scitotenv.2022.156970

  View details for PubMedID 35760168

• COVID-19 Preventive Measures in Northern California Jails: Perceived Deficiencies, Barriers, and Unintended Harms. Frontiers in public health Liu, Y. E., LeBoa, C., Rodriguez, M., Sherif, B., Trinidad, C., Del Rosario, M., Allen, S., Clifford, C., Redding, J., Chen, W. T., Rosas, L. G., Morales, C., Chyorny, A., Andrews, J. R. 2022; 10: 854343

  Abstract

  Carceral facilities are high-risk settings for COVID-19 transmission. Little is known about the hidden burden of infection or practical barriers to infection control in these settings, especially in jails. There is also limited research on the mental health impacts of the pandemic among people living and working in carceral facilities.Between July 8, 2020 and April 30, 2021, we performed SARS-CoV-2 rapid antibody testing and administered a questionnaire among residents and staff of four Northern California jails. We utilized multivariable logistic regression, adjusting for demographic and carceral characteristics, to analyze factors associated with prior infection, including perceived likelihood of prior infection and access to new masks. We additionally assessed the implementation of, perceptions toward, and impacts of COVID-19 policies in practice. We engaged stakeholder representatives, including incarcerated individuals, to guide study design, procedures, and results interpretation.We enrolled 788 jail residents and 380 jail staff. Nearly half of residents and two-thirds of staff who were antibody-positive had not previously tested positive for COVID-19. Among residents without a prior COVID-19 diagnosis, antibody positivity was significantly associated with perceived likelihood of prior infection (adjusted OR = 8.9; 95% CI, 3.6-22.0). Residents who had flu-like illness in jail cited inadequate responses to reported illness and deterrents to symptom reporting, including fears of medical isolation and perceptions of medical neglect. Residents also disclosed deficient access to face masks, which was associated with antibody positivity (adjusted OR = 13.8, 95% CI, 1.8-107.0). Worsened mental health was pervasive among residents, attributed not only to fear of COVID-19 and unsanitary jail conditions but also to intensified isolation and deprivation due to pandemic restrictions on in-person visitation, programs, and recreation time.Carceral settings present significant challenges to maintaining infection control and human rights. Custody officials should work diligently to transform the conditions of medical isolation, which could mitigate deterrents to symptom reporting. Furthermore, they should minimize use of restrictive measures like lockdowns and suspension of visitation that exacerbate the mental health harms of incarceration. Instead, custody officials should ensure comprehensive implementation of other preventive strategies like masking, testing, and vaccination, in conjunction with multisector efforts to advance decarceration.

  View details for DOI 10.3389/fpubh.2022.854343

  View details for PubMedID 35774562

  View details for PubMedCentralID PMC9237366

• Change in covid-19 risk over time following vaccination with CoronaVac: test negative case-control study. BMJ (Clinical research ed.) Hitchings, M. D., Ranzani, O. T., Lind, M. L., Dorion, M., D'Agostini, T. L., de Paula, R. C., de Paula, O. F., de Moura Villela, E. F., Scaramuzzini Torres, M. S., de Oliveira, S. B., Schulz, W., Almiron, M., Said, R., de Oliveira, R. D., Vieira da Silva, P., de Araújo, W. N., Gorinchteyn, J. C., Dean, N. E., Andrews, J. R., Cummings, D. A., Ko, A. I., Croda, J. 2022; 377: e070102

  Abstract

  To estimate the change in odds of covid-19 over time following primary series completion of the inactivated whole virus vaccine CoronaVac (Sinovac Biotech) in São Paulo State, Brazil.Test negative case-control study.Community testing for covid-19 in São Paulo State, Brazil.Adults aged ≥18 years who were residents of São Paulo state, had received two doses of CoronaVac, did not have a laboratory confirmed SARS-CoV-2 infection before vaccination, and underwent reverse transcription polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 from 17 January to 14 December 2021. Cases were matched to test negative controls by age (in 5 year bands), municipality of residence, healthcare worker status, and epidemiological week of RT-PCR test.RT-PCR confirmed symptomatic covid-19 and associated hospital admissions and deaths. Conditional logistic regression was adjusted for sex, number of covid-19 associated comorbidities, race, and previous acute respiratory illness.From 202 741 eligible people, 52 170 cases with symptomatic covid-19 and 69 115 test negative controls with covid-19 symptoms were formed into 43 257 matched sets. Adjusted odds ratios of symptomatic covid-19 increased with time since completion of the vaccination series. The increase in odds was greater in younger people and among healthcare workers, although sensitivity analyses suggested that this was in part due to bias. In addition, the adjusted odds ratios of covid-19 related hospital admission or death significantly increased with time compared with the odds 14-41 days after series completion: from 1.25 (95% confidence interval 1.04 to 1.51) at 70-97 days up to 1.94 (1.41 to 2.67) from 182 days onwards.Significant increases in the risk of moderate and severe covid-19 outcomes occurred three months after primary vaccination with CoronaVac among people aged 65 and older. These findings provide supportive evidence for the implementation of vaccine boosters in these populations who received this inactivated vaccine. Studies of waning should include analyses designed to uncover common biases.

  View details for DOI 10.1136/bmj-2022-070102

  View details for PubMedID 35697361

• Protection against Omicron conferred by mRNA primary vaccine series, boosters, and prior infection. medRxiv : the preprint server for health sciences Chin, E. T., Leidner, D., Lamson, L., Lucas, K., Studdert, D. M., Goldhaber-Fiebert, J. D., Andrews, J. R., Salomon, J. A. 2022

  Abstract

  B ackground: Prisons and jails are high-risk settings for Covid-19 transmission, morbidity, and mortality. We evaluate protection conferred by prior infection and vaccination against the SARS-CoV-2 Omicron variant within the California state prison system.M ethods: We employed a test-negative design to match resident and staff cases during the Omicron wave (December 24, 2021-April 14, 2022) to controls according to a case's test-week as well as demographic, clinical, and carceral characteristics. We estimated protection against infection using conditional logistic regression, with exposure status defined by vaccination, stratified by number of mRNA doses received, and prior infection, stratified by periods before or during Delta variant predominance.R esults: We matched 15,783 resident and 8,539 staff cases to 180,169 resident and 90,409 staff controls. Among cases, 29.7% and 2.2% were infected before or during the emergence of the Delta variant, respectively; 30.6% and 36.3% were vaccinated with two or three doses, respectively. Estimated protection from Omicron infection for two and three doses were 14.9% (95% Confidence Interval [CI], 12.3-19.7%) and 43.2% (42.2-47.4%) for those without known prior infections, 47.8% (95% CI, 46.6-52.8%) and 61.3% (95% CI, 60.7-64.8%) for those infected before the emergence of Delta, and 73.1% (95% CI, 69.8-80.1%) and 86.8% (95% CI, 82.1-92.7) for those infected during the period of Delta predominance.C onclusion: A third mRNA dose provided significant, additional protection over two doses, including among individuals with prior infection. Our findings suggest that vaccination should remain a priority-even in settings with high levels of transmission and prior infection.

  View details for DOI 10.1101/2022.05.26.22275639

  View details for PubMedID 35665013

• TNF-alpha+ CD4+ Tcells dominate the SARS-CoV-2 specific T cell response in COVID-19 outpatients and are associated with durable antibodies. Cell reports. Medicine van der Ploeg, K., Kirosingh, A. S., Mori, D. A., Chakraborty, S., Hu, Z., Sievers, B. L., Jacobson, K. B., Bonilla, H., Parsonnet, J., Andrews, J. R., Press, K. D., Ty, M. C., Ruiz-Betancourt, D. R., de la Parte, L., Tan, G. S., Blish, C. A., Takahashi, S., Rodriguez-Barraquer, I., Greenhouse, B., Singh, U., Wang, T. T., Jagannathan, P. 2022: 100640

  Abstract

  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific CD4+ Tcells are likely important in immunity against coronavirus 2019 (COVID-19), but our understanding of CD4+ longitudinal dynamics following infection and of specific features that correlate with the maintenance of neutralizing antibodies remains limited. Here, we characterize SARS-CoV-2-specific CD4+ Tcells in a longitudinal cohort of 109 COVID-19 outpatients enrolled during acute infection. The quality of the SARS-CoV-2-specific CD4+ response shifts from cells producing interferon gamma (IFNgamma) to tumor necrosis factor alpha (TNF-alpha) from 5days to 4months post-enrollment, with IFNgamma-IL-21-TNF-alpha+ CD4+ Tcells the predominant population detected at later time points. Greater percentages of IFNgamma-IL-21-TNF-alpha+ CD4+ Tcells on day 28 correlate with SARS-CoV-2-neutralizing antibodies measured 7months post-infection (⍴= 0.4, p= 0.01). mRNA vaccination following SARS-CoV-2 infection boosts both IFNgamma- and TNF-alpha-producing, spike-protein-specific CD4+ Tcells. These data suggest that SARS-CoV-2-specific, TNF-alpha-producing CD4+ Tcells may play an important role in antibody maintenance following COVID-19.

  View details for DOI 10.1016/j.xcrm.2022.100640

  View details for PubMedID 35588734

• The role of prisons in disseminating tuberculosis in Brazil: A genomic epidemiology study. Lancet Regional Health. Americas Walter, K. S., Dos Santos, P. C., Gonçalves, T. O., da Silva, B. O., da Silva Santos, A., de Cássia Leite, A., da Silva, A. M., Figueira Moreira, F. M., de Oliveira, R. D., Lemos, E. F., Cunha, E., Liu, Y. E., Ko, A. I., Colijn, C., Cohen, T., Mathema, B., Croda, J., Andrews, J. R. 2022; 9

  Abstract

  Globally, prisons are high-incidence settings for tuberculosis. Yet the role of prisons as reservoirs of M. tuberculosis, propagating epidemics through spillover to surrounding communities, has been difficult to measure directly.To quantify the role of prisons in driving wider community M. tuberculosis transmission, we conducted prospective genomic surveillance in Central West Brazil from 2014 to 2019. We whole genome sequenced 1152 M. tuberculosis isolates collected during active and passive surveillance inside and outside prisons and linked genomes to detailed incarceration histories. We applied multiple phylogenetic and genomic clustering approaches and inferred timed transmission trees.M. tuberculosis sequences from incarcerated and non-incarcerated people were closely related in a maximum likelihood phylogeny. The majority (70.8%; 46/65) of genomic clusters including people with no incarceration history also included individuals with a recent history of incarceration. Among cases in individuals with no incarceration history, 50.6% (162/320) were in clusters that included individuals with recent incarceration history, suggesting that transmission chains often span prisons and communities. We identified a minimum of 18 highly probable spillover events, M. tuberculosis transmission from people with a recent incarceration history to people with no prior history of incarceration, occurring in the state's four largest cities and across sampling years. We additionally found that frequent transfers of people between the state's prisons creates a highly connected prison network that likely disseminates M. tuberculosis across the state.We developed a framework for measuring spillover from high-incidence environments to surrounding communities by integrating genomic and spatial information. Our findings indicate that, in this setting, prisons serve not only as disease reservoirs, but also disseminate M. tuberculosis across highly connected prison networks, both amplifying and propagating M. tuberculosis risk in surrounding communities.Brazil's National Council for Scientific and Technological Development and US National Institutes of Health.

  View details for DOI 10.1016/j.lana.2022.100186

  View details for PubMedID 35647574

  View details for PubMedCentralID PMC9140320

• Favipiravir for treatment of outpatients with asymptomatic or uncomplicated COVID-19: a double-blind randomized, placebo-controlled, phase 2 trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Holubar, M., Subramanian, A., Purington, N., Hedlin, H., Bunning, B., Walter, K. S., Bonilla, H., Boumis, A., Chen, M., Clinton, K., Dewhurst, L., Epstein, C., Jagannathan, P., Kaszynski, R. H., Panu, L., Parsonnet, J., Ponder, E. L., Quintero, O., Sefton, E., Singh, U., Soberanis, L., Truong, H., Andrews, J. R., Desai, M., Khosla, C., Maldonado, Y. 2022

  Abstract

  Favipiravir is an oral, RNA-dependent RNA polymerase inhibitor with in vitro activity against SARS-CoV2. Despite limited data, favipiravir is administered to patients with COVID-19 in several countries.We conducted a phase 2 double-blind randomized controlled outpatient trial of favipiravir in asymptomatic or mildly symptomatic adults with a positive SARS-CoV2 RT-PCR within 72 hours of enrollment. Participants were randomized 1: 1 to receive placebo or favipiravir (1800mg BID Day 1, 800 mg BID Days 2-10). The primary outcome was SARS-CoV-2 shedding cessation in a modified intention-to-treat (mITT) cohort of participants with positive enrollment RT-PCRs. Using SARS-CoV-2 amplicon-based sequencing, we assessed favipiravir's impact on mutagenesis.From July 8, 2020 - March 23, 2021, we randomized 149 participants with 116 included in the mITT cohort. The participants' mean age was 43 years (SD 12.5) and 57 (49%) were women. We found no difference in time to shedding cessation by treatment arm overall (HR 0.76 favoring placebo, 95% confidence interval [CI] 0.48-1.20) or in sub-group analyses (age, sex, high-risk comorbidities, seropositivity or symptom duration at enrollment). We observed no difference in time to symptom resolution (initial: HR 0.84, 95% CI 0.54-1.29; sustained: HR 0.87, 95% CI 0.52-1.45). We detected no difference in accumulation of transition mutations in the viral genome during treatment.Our data do not support favipiravir use at commonly used doses in outpatients with uncomplicated COVID-19. Further research is needed to ascertain if higher doses of favipiravir are effective and safe for patients with COVID-19.

  View details for DOI 10.1093/cid/ciac312

  View details for PubMedID 35446944

• Assessing impact of ventilation on airborne transmission of SARS-CoV-2: a cross-sectional analysis of naturally ventilated healthcare settings in Bangladesh. BMJ open Styczynski, A., Hemlock, C., Hoque, K. I., Verma, R., LeBoa, C., Bhuiyan, M. O., Nag, A., Harun, M. G., Amin, M. B., Andrews, J. R. 2022; 12 (4): e055206

  Abstract

  To evaluate the risk of exposure to SARS-CoV-2 in naturally ventilated hospital settings by measuring parameters of ventilation and comparing these findings with results of bioaerosol sampling.Cross-sectional study.The study sample included nine hospitals in Dhaka, Bangladesh. Ventilation characteristics and air samples were collected from 86 healthcare spaces during October 2020 to February 2021.Risk of cumulative SARS-CoV-2 infection by type of healthcare area.Ventilation rates by healthcare space; risk of airborne detection of SARS-CoV-2 across healthcare spaces; impact of room characteristics on absolute ventilation; SARS-CoV-2 detection by naturally ventilated versus mechanically ventilated spaces.The majority (78.7%) of naturally ventilated patient care rooms had ventilation rates that fell short of the recommended ventilation rate of 60 L/s/p. Using a modified Wells-Riley equation and local COVID-19 case numbers, we found that over a 40-hour exposure period, outpatient departments posed the highest median risk for infection (7.7%). SARS-CoV-2 RNA was most frequently detected in air samples from non-COVID wards (50.0%) followed by outpatient departments (42.9%). Naturally ventilated spaces (22.6%) had higher rates of SARS-CoV-2 detection compared with mechanically ventilated spaces (8.3%), though the difference was not statistically significant (p=0.128). In multivariable linear regression with calculated elasticity, open door area and cross-ventilation were found to have a significant impact on ventilation.Our findings provide evidence that naturally ventilated healthcare settings may pose a high risk for exposure to SARS-CoV-2, particularly among non-COVID-designated spaces, but improving parameters of ventilation can mitigate this risk.

  View details for DOI 10.1136/bmjopen-2021-055206

  View details for PubMedID 35428628

• The 2021 WHO catalogue of Mycobacterium tuberculosis complex mutations associated with drug resistance: A genotypic analysis. The Lancet. Microbe Walker, T. M., Miotto, P., Köser, C. U., Fowler, P. W., Knaggs, J., Iqbal, Z., Hunt, M., Chindelevitch, L., Farhat, M., Cirillo, D. M., Comas, I., Posey, J., Omar, S. V., Peto, T. E., Suresh, A., Uplekar, S., Laurent, S., Colman, R. E., Nathanson, C. M., Zignol, M., Walker, A. S., Crook, D. W., Ismail, N., Rodwell, T. C. 2022; 3 (4): e265-e273

  Abstract

  Molecular diagnostics are considered the most promising route to achieving rapid, universal drug susceptibility testing for Mycobacterium tuberculosiscomplex (MTBC). We aimed to generate a WHO endorsed catalogue of mutations to serve as a global standard for interpreting molecular information for drug resistance prediction.A candidate gene approach was used to identify mutations as associated with resistance, or consistent with susceptibility, for 13 WHO endorsed anti-tuberculosis drugs. 38,215 MTBC isolates with paired whole-genome sequencing and phenotypic drug susceptibility testing data were amassed from 45 countries. For each mutation, a contingency table of binary phenotypes and presence or absence of the mutation computed positive predictive value, and Fisher's exact tests generated odds ratios and Benjamini-Hochberg corrected p-values. Mutations were graded as Associated with Resistance if present in at least 5 isolates, if the odds ratio was >1 with a statistically significant corrected p-value, and if the lower bound of the 95% confidence interval on the positive predictive value for phenotypic resistance was >25%. A series of expert rules were applied for final confidence grading of each mutation.15,667 associations were computed for 13,211 unique mutations linked to one or more drugs. 1,149/15,667 (7·3%) mutations were classified as associated with phenotypic resistance and 107/15,667 (0·7%) were deemed consistent with susceptibility. For rifampicin, isoniazid, ethambutol, fluoroquinolones, and streptomycin, the mutations' pooled sensitivity was >80%. Specificity was over 95% for all drugs except ethionamide (91·4%), moxifloxacin (91·6%) and ethambutol (93·3%). Only two resistance mutations were classified for bedaquiline, delamanid, clofazimine, and linezolid as prevalence of phenotypic resistance was low for these drugs.This first WHO endorsed catalogue of molecular targets for MTBC drug susceptibility testing provides a global standard for resistance interpretation. Its existence should encourage the implementation of molecular diagnostics by National Tuberculosis Programmes.UNITAID, Wellcome, MRC, BMGF.

  View details for DOI 10.1016/S2666-5247(21)00301-3

  View details for PubMedID 35373160

  View details for PubMedCentralID PMC7612554

• Use of recently vaccinated individuals to detect bias in test-negative case-control studies of COVID-19 vaccine effectiveness. Epidemiology (Cambridge, Mass.) Hitchings, M. D., Lewnard, J. A., Dean, N. E., Ko, A. I., Ranzani, O. T., Andrews, J. R., Cummings, D. A. 2022

  Abstract

  Post-authorization observational studies play a key role in understanding COVID-19 vaccine effectiveness following the demonstration of efficacy in clinical trials. While bias due to confounding, selection bias, and misclassification can be mitigated through careful study design, unmeasured confounding is likely to remain in these observational studies. Phase III trials of COVID-19 vaccines have shown that protection from vaccination does not occur immediately, meaning that COVID-19 risk should be similar in recently vaccinated and unvaccinated individuals, in the absence of confounding or other bias. Several studies have used the estimated effectiveness among recently vaccinated individuals as a negative control exposure to detect bias in vaccine effectiveness estimates. In this paper we introduce a theoretical framework to describe the interpretation of such a bias-indicator in test-negative studies, and outline strong assumptions that would allow vaccine effectiveness among recently vaccinated individuals to serve as a negative control exposure.

  View details for DOI 10.1097/EDE.0000000000001484

  View details for PubMedID 35384900

• Effectiveness of CoronaVac, ChAdOx1 nCoV-19, BNT162b2, and Ad26.COV2.S among individuals with previous SARS-CoV-2 infection in Brazil: a test-negative, case-control study. The Lancet. Infectious diseases Cerqueira-Silva, T., Andrews, J. R., Boaventura, V. S., Ranzani, O. T., de Araújo Oliveira, V., Paixão, E. S., Júnior, J. B., Machado, T. M., Hitchings, M. D., Dorion, M., Lind, M. L., Penna, G. O., Cummings, D. A., Dean, N. E., Werneck, G. L., Pearce, N., Barreto, M. L., Ko, A. I., Croda, J., Barral-Netto, M. 2022

  Abstract

  COVID-19 vaccines have proven highly effective among individuals without a previous SARS-CoV-2 infection, but their effectiveness in preventing symptomatic infection and severe outcomes among individuals with previous infection is less clear. We aimed to estimate the effectiveness of four COVID-19 vaccines against symptomatic infection, hospitalisation, and death for individuals with laboratory-confirmed previous SARS-CoV-2 infection.Using national COVID-19 notification, hospitalisation, and vaccination datasets from Brazil, we did a test-negative, case-control study to assess the effectiveness of four vaccines (CoronaVac [Sinovac], ChAdOx1 nCoV-19 [AstraZeneca], Ad26.COV2.S [Janssen], and BNT162b2 [Pfizer-BioNtech]) for individuals with laboratory-confirmed previous SARS-CoV-2 infection. We matched cases with RT-PCR positive, symptomatic COVID-19 with up to ten controls with negative RT-PCR tests who presented with symptomatic illnesses, restricting both groups to tests done at least 90 days after an initial infection. We used multivariable conditional logistic regression to compare the odds of test positivity and the odds of hospitalisation or death due to COVID-19, according to vaccination status and time since first or second dose of vaccines.Between Feb 24, 2020, and Nov 11, 2021, we identified 213 457 individuals who had a subsequent, symptomatic illness with RT-PCR testing done at least 90 days after their initial SARS-CoV-2 infection and after the vaccination programme started. Among these, 30 910 (14·5%) had a positive RT-PCR test consistent with reinfection, and we matched 22 566 of these cases with 145 055 negative RT-PCR tests from 68 426 individuals as controls. Among individuals with previous SARS-CoV-2 infection, vaccine effectiveness against symptomatic infection 14 or more days from vaccine series completion was 39·4% (95% CI 36·1-42·6) for CoronaVac, 56·0% (51·4-60·2) for ChAdOx1 nCoV-19, 44·0% (31·5-54·2) for Ad26.COV2.S, and 64·8% (54·9-72·4) for BNT162b2. For the two-dose vaccine series (CoronaVac, ChAdOx1 nCoV-19, and BNT162b2), effectiveness against symptomatic infection was significantly greater after the second dose than after the first dose. Effectiveness against hospitalisation or death 14 or more days from vaccine series completion was 81·3% (75·3-85·8) for CoronaVac, 89·9% (83·5-93·8) for ChAdOx1 nCoV-19, 57·7% (-2·6 to 82·5) for Ad26.COV2.S, and 89·7% (54·3-97·7) for BNT162b2.All four vaccines conferred additional protection against symptomatic infections and severe outcomes among individuals with previous SARS-CoV-2 infection. The provision of a full vaccine series to individuals after recovery from COVID-19 might reduce morbidity and mortality.Brazilian National Research Council, Fundação Carlos Chagas Filho de Amparo à Pesquisa do Estado do Rio de Janeiro, Oswaldo Cruz Foundation, JBS, Instituto de Salud Carlos III, Spanish Ministry of Science and Innovation, and Generalitat de Catalunya.

  View details for DOI 10.1016/S1473-3099(22)00140-2

  View details for PubMedID 35366959

• Point-of-Care Sample Preparation and Automated Quantitative Detection of Schistosoma haematobium Using Mobile Phone Microscopy. The American journal of tropical medicine and hygiene Armstrong, M., Harris, A. R., D'Ambrosio, M. V., Coulibaly, J. T., Essien-Baidoo, S., Ephraim, R. K., Andrews, J. R., Bogoch, I. I., Fletcher, D. A. 2022

  Abstract

  Schistosoma haematobium continues to pose a significant public health burden despite ongoing global control efforts. One of several barriers to sustained control (and ultimately elimination) is the lack of access to highly sensitive diagnostic or screening tools that are inexpensive, rapid, and can be used at the point of sample collection. Here, we report an automated point-of-care diagnostic based on mobile phone microscopy that rapidly images and identifies S. haematobium eggs in urine samples. Parasite eggs are filtered from urine within a specialized, inexpensive cartridge that is then automatically imaged by the mobile phone microscope (the "SchistoScope"). Parasite eggs are captured at a constriction point in the tapered cartridge for easy imaging, and the automated quantification of eggs is obtained upon analysis of the images by an algorithm. We demonstrate S. haematobium egg detection with greater than 90% sensitivity and specificity using this device compared with the field gold standard of conventional filtration and microscopy. With simple sample preparation and image analysis on a mobile phone, the SchistoScope combines the diagnostic performance of conventional microscopy with the analytic performance of an expert technician. This portable device has the potential to provide rapid and quantitative diagnosis of S. haematobium to advance ongoing control efforts.

  View details for DOI 10.4269/ajtmh.21-1071

  View details for PubMedID 35344927

• The effect of incarceration on TB treatment outcomes. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease O Marr, J. M., Gonçalves, C., Arakaki-Sanchez, D., Pelissari, D. M., Costa, F. D., Croda, J., Walter, K. S., Andrews, J. R. 2022; 26 (3): 252-258

  Abstract

  BACKGROUND: TB notifications in Latin American prisons have more than doubled over the past two decades; however, treatment outcomes and their determinants among incarcerated individuals in this region are not well understood.METHODS: Newly diagnosed drug-susceptible TB cases reported to Brazil´s Information System for Notifiable Diseases (Sistema de Informação de Agravos de Notificação, SINAN) between January 2015 and December 2017 were included. Multivariate logistic regression was used to assess socio-economic and clinical factors associated with treatment success among incarcerated individuals.RESULTS: Incarcerated individuals (n = 17,776) had greater treatment success than non-incarcerated individuals (n = 160,728; 82.2% vs. 75.1%; P < 0.0001), including after adjusting for demographic and clinical risk factors (adjusted odds ratio aOR 1.27, 95% CI 1.19-1.34). These differences were partially mediated by increased use of directly observed therapy among incarcerated individuals (DOT) (61% vs. 47%; P < 0.001), which was associated with greater efficacy in the incarcerated population (aOR 2.56 vs. aOR 2.17; P < 0.001). DOT was associated with improved treatment success among incarcerated subpopulations at elevated risk of poor outcomes.CONCLUSION: TB treatment success among incarcerated individuals in Brazil is higher than non-incarcerated individuals, but both fall below WHO targets. Expanding the use of DOT and services for socially and medically vulnerable individuals may improve outcomes in carceral settings.

  View details for DOI 10.5588/ijtld.21.0449

  View details for PubMedID 35197165

• Effect of Subcutaneous Casirivimab and Imdevimab Antibody Combination vs Placebo on Development of Symptomatic COVID-19 in Early Asymptomatic SARS-CoV-2 Infection: A Randomized Clinical Trial. JAMA O'Brien, M. P., Forleo-Neto, E., Sarkar, N., Isa, F., Hou, P., Chan, K. C., Musser, B. J., Bar, K. J., Barnabas, R. V., Barouch, D. H., Cohen, M. S., Hurt, C. B., Burwen, D. R., Marovich, M. A., Brown, E. R., Heirman, I., Davis, J. D., Turner, K. C., Ramesh, D., Mahmood, A., Hooper, A. T., Hamilton, J. D., Kim, Y., Purcell, L. A., Baum, A., Kyratsous, C. A., Krainson, J., Perez-Perez, R., Mohseni, R., Kowal, B., DiCioccio, A. T., Geba, G. P., Stahl, N., Lipsich, L., Braunstein, N., Herman, G., Yancopoulos, G. D., Weinreich, D. M. 2022

  Abstract

  Easy-to-administer anti-SARS-CoV-2 treatments may be used to prevent progression from asymptomatic infection to symptomatic disease and to reduce viral carriage.To evaluate the effect of combination subcutaneous casirivimab and imdevimab on progression from early asymptomatic SARS-CoV-2 infection to symptomatic COVID-19.Randomized, double-blind, placebo-controlled, phase 3 trial of close household contacts of a SARS-CoV-2-infected index case at 112 sites in the US, Romania, and Moldova enrolled July 13, 2020-January 28, 2021; follow-up ended March 11, 2021. Asymptomatic individuals (aged ≥12 years) were eligible if identified within 96 hours of index case positive test collection. Results from 314 individuals positive on SARS-CoV-2 reverse transcriptase-quantitative polymerase chain reaction (RT-qPCR) testing are reported.Individuals were randomized 1:1 to receive 1 dose of subcutaneous casirivimab and imdevimab, 1200 mg (600 mg of each; n = 158), or placebo (n = 156).The primary end point was the proportion of seronegative participants who developed symptomatic COVID-19 during the 28-day efficacy assessment period. The key secondary efficacy end points were the number of weeks of symptomatic SARS-CoV-2 infection and the number of weeks of high viral load (>4 log10 copies/mL).Among 314 randomized participants (mean age, 41.0 years; 51.6% women), 310 (99.7%) completed the efficacy assessment period; 204 were asymptomatic and seronegative at baseline and included in the primary efficacy analysis. Subcutaneous casirivimab and imdevimab, 1200 mg, significantly prevented progression to symptomatic disease (29/100 [29.0%] vs 44/104 [42.3%] with placebo; odds ratio, 0.54 [95% CI, 0.30-0.97]; P = .04; absolute risk difference, -13.3% [95% CI, -26.3% to -0.3%]). Casirivimab and imdevimab reduced the number of symptomatic weeks per 1000 participants (895.7 weeks vs 1637.4 weeks with placebo; P = .03), an approximately 5.6-day reduction in symptom duration per symptomatic participant. Treatment with casirivimab and imdevimab also reduced the number of high viral load weeks per 1000 participants (489.8 weeks vs 811.9 weeks with placebo; P = .001). The proportion of participants receiving casirivimab and imdevimab who had 1 or more treatment-emergent adverse event was 33.5% vs 48.1% for placebo, including events related (25.8% vs 39.7%) or not related (11.0% vs 16.0%) to COVID-19.Among asymptomatic SARS-CoV-2 RT-qPCR-positive individuals living with an infected household contact, treatment with subcutaneous casirivimab and imdevimab antibody combination vs placebo significantly reduced the incidence of symptomatic COVID-19 over 28 days.ClinicalTrials.gov Identifier: NCT04452318.

  View details for DOI 10.1001/jama.2021.24939

  View details for PubMedID 35029629

• Factors associated with COVID-19 vaccine acceptance and hesitancy among residents of Northern California jails. Preventive medicine reports Liu, Y. E., Oto, J., Will, J., LeBoa, C., Doyle, A., Rens, N., Aggarwal, S., Kalish, I., Rodriguez, M., Sherif, B., Trinidad, C., Del Rosario, M., Allen, S., Spencer, R., Morales, C., Chyorny, A., Andrews, J. R. 2022; 27: 101771

  Abstract

  Carceral facilities are high-risk settings for COVID-19 transmission. Factors associated with COVID-19 vaccine acceptance and hesitancy among incarcerated individuals are poorly understood, especially among jail residents. Here, we conducted a retrospective review of electronic health record (EHR) data on COVID-19 vaccine uptake in custody and additionally administered a survey to assess reasons for vaccine hesitancy, sources of COVID-19 information, and medical mistrust among residents of four Northern California jails. We performed multivariate logistic regression to determine associations with vaccine acceptance. Of 2,564 jail residents offered a COVID-19 vaccine between March 19, 2021 and June 30, 2021, 1,441 (56.2%) accepted at least one dose. Among vaccinated residents, 497 (34.5%) had initially refused. Vaccine uptake was higher among older individuals, women, those with recent flu vaccination, and those living in shared housing. Among 509 survey respondents, leading reasons for vaccine hesitancy were concerns around side effects and suboptimal efficacy, with cost and the need for an annual booster being other hypothetical deterrents to vaccination. Vaccine hesitancy was also associated with mistrust of medical personnel in and out of jail, although this association varied by race/ethnicity. Television and friends/family were the most common and most trusted sources of COVID-19 information, respectively. Overall, vaccine acceptance was much lower among jail residents than the local and national general population. Interventions to increase vaccination rates in this setting should utilize accessible and trusted sources of information to address concerns about side effects and efficacy, while working to mitigate medical and institutional mistrust among residents.

  View details for DOI 10.1016/j.pmedr.2022.101771

  View details for PubMedID 35309721

  View details for PubMedCentralID PMC8920969

• Global burden of bacterial antimicrobial resistance in 2019: a systematic analysis. Lancet (London, England) 2022

  Abstract

  Antimicrobial resistance (AMR) poses a major threat to human health around the world. Previous publications have estimated the effect of AMR on incidence, deaths, hospital length of stay, and health-care costs for specific pathogen-drug combinations in select locations. To our knowledge, this study presents the most comprehensive estimates of AMR burden to date.We estimated deaths and disability-adjusted life-years (DALYs) attributable to and associated with bacterial AMR for 23 pathogens and 88 pathogen-drug combinations in 204 countries and territories in 2019. We obtained data from systematic literature reviews, hospital systems, surveillance systems, and other sources, covering 471 million individual records or isolates and 7585 study-location-years. We used predictive statistical modelling to produce estimates of AMR burden for all locations, including for locations with no data. Our approach can be divided into five broad components: number of deaths where infection played a role, proportion of infectious deaths attributable to a given infectious syndrome, proportion of infectious syndrome deaths attributable to a given pathogen, the percentage of a given pathogen resistant to an antibiotic of interest, and the excess risk of death or duration of an infection associated with this resistance. Using these components, we estimated disease burden based on two counterfactuals: deaths attributable to AMR (based on an alternative scenario in which all drug-resistant infections were replaced by drug-susceptible infections), and deaths associated with AMR (based on an alternative scenario in which all drug-resistant infections were replaced by no infection). We generated 95% uncertainty intervals (UIs) for final estimates as the 25th and 975th ordered values across 1000 posterior draws, and models were cross-validated for out-of-sample predictive validity. We present final estimates aggregated to the global and regional level.On the basis of our predictive statistical models, there were an estimated 4·95 million (3·62-6·57) deaths associated with bacterial AMR in 2019, including 1·27 million (95% UI 0·911-1·71) deaths attributable to bacterial AMR. At the regional level, we estimated the all-age death rate attributable to resistance to be highest in western sub-Saharan Africa, at 27·3 deaths per 100 000 (20·9-35·3), and lowest in Australasia, at 6·5 deaths (4·3-9·4) per 100 000. Lower respiratory infections accounted for more than 1·5 million deaths associated with resistance in 2019, making it the most burdensome infectious syndrome. The six leading pathogens for deaths associated with resistance (Escherichia coli, followed by Staphylococcus aureus, Klebsiella pneumoniae, Streptococcus pneumoniae, Acinetobacter baumannii, and Pseudomonas aeruginosa) were responsible for 929 000 (660 000-1 270 000) deaths attributable to AMR and 3·57 million (2·62-4·78) deaths associated with AMR in 2019. One pathogen-drug combination, meticillin-resistant S aureus, caused more than 100 000 deaths attributable to AMR in 2019, while six more each caused 50 000-100 000 deaths: multidrug-resistant excluding extensively drug-resistant tuberculosis, third-generation cephalosporin-resistant E coli, carbapenem-resistant A baumannii, fluoroquinolone-resistantE coli, carbapenem-resistant K pneumoniae, and third-generation cephalosporin-resistant K pneumoniae.To our knowledge, this study provides the first comprehensive assessment of the global burden of AMR, as well as an evaluation of the availability of data. AMR is a leading cause of death around the world, with the highest burdens in low-resource settings. Understanding the burden of AMR and the leading pathogen-drug combinations contributing to it is crucial to making informed and location-specific policy decisions, particularly about infection prevention and control programmes, access to essential antibiotics, and research and development of new vaccines and antibiotics. There are serious data gaps in many low-income settings, emphasising the need to expand microbiology laboratory capacity and data collection systems to improve our understanding of this important human health threat.Bill & Melinda Gates Foundation, Wellcome Trust, and Department of Health and Social Care using UK aid funding managed by the Fleming Fund.

  View details for DOI 10.1016/S0140-6736(21)02724-0

  View details for PubMedID 35065702

• Variation in Severe Acute Respiratory Syndrome Coronavirus 2 Bioaerosol Production in Exhaled Breath. Open forum infectious diseases Verma, R., Kim, E., Degner, N., Walter, K. S., Singh, U., Andrews, J. R. 2022; 9 (1): ofab600

  Abstract

  We developed a simple, noninvasive mask sampling method to quantify and sequence severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) from exhaled breath. We found substantial variation between individuals in SARS-CoV-2 copies exhaled over a 15-minute period, which moderately correlated with nasal swab viral load. Talking was associated with a median of 2 log10 greater exhaled viral copies. Exposure varies substantially between individuals but may be risk stratified by nasal swab viral load and whether the exposure involved conversation.

  View details for DOI 10.1093/ofid/ofab600

  View details for PubMedID 35028332

  View details for PubMedCentralID PMC8753034

• Uptake of COVID-19 Vaccination Among Frontline Workers in California State Prisons JAMA Health Forum Prince, L., Long, E., Studdert, D. M., Leidner, D., Chin, E. T., Andrews, J. R., Salomon, J. A., Goldhaber-Fiebert, J. D. 2022; 3 (3): e220099
• Effectiveness of COVID-19 vaccines among incarcerated people in California state prisons: retrospective cohort study. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Chin, E. T., Leidner, D., Zhang, Y., Long, E., Prince, L., Schrag, S. J., Verani, J. R., Wiegand, R. E., Alarid-Escudero, F., Goldhaber-Fiebert, J. D., Studdert, D. M., Andrews, J. R., Salomon, J. A. 2022

  Abstract

  Prisons and jails are high-risk settings for COVID-19. Vaccines may substantially reduce these risks, but evidence is needed on COVID-19 vaccine effectiveness for incarcerated people, who are confined in large, risky congregate settings.We conducted a retrospective cohort study to estimate effectiveness of mRNA vaccines, BNT162b2 (Pfizer-BioNTech) and mRNA-1273 (Moderna), against confirmed SARS-CoV-2 infections among incarcerated people in California prisons from December 22, 2020 through March 1, 2021. The California Department of Corrections and Rehabilitation provided daily data for all prison residents including demographic, clinical, and carceral characteristics, as well as COVID-19 testing, vaccination, and outcomes. We estimated vaccine effectiveness using multivariable Cox models with time-varying covariates, adjusted for resident characteristics and infection rates across prisons.Among 60,707 cohort members, 49% received at least one BNT162b2 or mRNA-1273 dose during the study period. Estimated vaccine effectiveness was 74% (95% confidence interval [CI], 64-82%) from day 14 after first dose until receipt of second dose and 97% (95% CI, 88-99%) from day 14 after second dose. Effectiveness was similar among the subset of residents who were medically vulnerable: 74% [95% CI, 62-82%] and 92% [95% CI, 74-98%] from 14 days after first and second doses, respectively.Consistent with results from randomized trials and observational studies in other populations, mRNA vaccines were highly effective in preventing SARS-CoV-2 infections among incarcerated people. Prioritizing incarcerated people for vaccination, redoubling efforts to boost vaccination, and continuing other ongoing mitigation practices are essential in preventing COVID-19 in this disproportionately affected population.

  View details for DOI 10.1093/cid/ciab1032

  View details for PubMedID 35083482

• Long Term Accuracy of SARS-CoV-2 Interferon-γ Release Assay and its Application in Household Investigation. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Murugesan, K., Jagannathan, P., Altamirano, J., Maldonado, Y. A., Bonilla, H. F., Jacobson, K. B., Parsonnet, J., Andrews, J. R., Shi, R. Z., Boyd, S., Pinsky, B. A., Singh, U., Banaei, N. 2022

  Abstract

  An immunodiagnostic assay that sensitively detects a cell-mediated immune response to SARS-CoV-2 is needed for epidemiological investigation and for clinical assessment of T cell-mediated immune response to vaccines, particularly in the context of emerging variants that might escape antibody responses.The performance of a whole blood interferon-gamma (IFN-γ) release assay (IGRA) for the detection of SARS-CoV-2 antigen-specific T cells was evaluated in COVID-19 convalescents tested serially up to 10 months post-infection and in healthy blood donors. SARS-CoV-2 IGRA was applied in contacts of households with index cases. Freshly collected blood in the lithium heparin tube was left unstimulated, stimulated with a SARS-CoV-2 peptide pool, and stimulated with mitogen.The overall sensitivity and specificity of IGRA were 84.5% (153/181; 95% confidence interval [CI] 79.0-89.0) and 86.6% (123/142; 95% CI;80.0-91.2), respectively. The sensitivity declined from 100% (16/16; 95% CI 80.6-100) at 0.5-month post-infection to 79.5% (31/39; 95% CI 64.4-89.2) at 10 months post-infection (P<0.01). The IFN-γ response remained relatively robust at 10 months post-infection (3.8 vs. 1.3 IU/mL, respectively). In 14 households, IGRA showed a positivity rate of 100% (12/12) and 65.2% (15/23), and IgG of 50.0% (6/12) and 43.5% (10/23) in index cases and contacts, respectively, exhibiting a difference of +50% (95% CI +25.4-+74.6) and +21.7% (95% CI, +9.23-+42.3), respectively. Either IGRA or IgG was positive in 100% (12/12) of index cases and 73.9% (17/23) of contacts.The SARS-CoV-2 IGRA is a useful clinical diagnostic tool for assessing cell-mediated immune response to SARS-CoV-2.

  View details for DOI 10.1093/cid/ciac045

  View details for PubMedID 35079772

• REGEN-COV Antibody Combination and Outcomes in Outpatients with Covid-19. The New England journal of medicine Weinreich, D. M., Sivapalasingam, S., Norton, T., Ali, S., Gao, H., Bhore, R., Xiao, J., Hooper, A. T., Hamilton, J. D., Musser, B. J., Rofail, D., Hussein, M., Im, J., Atmodjo, D. Y., Perry, C., Pan, C., Mahmood, A., Hosain, R., Davis, J. D., Turner, K. C., Baum, A., Kyratsous, C. A., Kim, Y., Cook, A., Kampman, W., Roque-Guerrero, L., Acloque, G., Aazami, H., Cannon, K., Simón-Campos, J. A., Bocchini, J. A., Kowal, B., DiCioccio, A. T., Soo, Y., Geba, G. P., Stahl, N., Lipsich, L., Braunstein, N., Herman, G., Yancopoulos, G. D. 2021; 385 (23): e81

  Abstract

  In the phase 1-2 portion of an adaptive trial, REGEN-COV, a combination of the monoclonal antibodies casirivimab and imdevimab, reduced the viral load and number of medical visits in patients with coronavirus disease 2019 (Covid-19). REGEN-COV has activity in vitro against current severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern.In the phase 3 portion of an adaptive trial, we randomly assigned outpatients with Covid-19 and risk factors for severe disease to receive various doses of intravenous REGEN-COV or placebo. Patients were followed through day 29. A prespecified hierarchical analysis was used to assess the end points of hospitalization or death and the time to resolution of symptoms. Safety was also evaluated.Covid-19-related hospitalization or death from any cause occurred in 18 of 1355 patients in the REGEN-COV 2400-mg group (1.3%) and in 62 of 1341 patients in the placebo group who underwent randomization concurrently (4.6%) (relative risk reduction [1 minus the relative risk], 71.3%; P<0.001); these outcomes occurred in 7 of 736 patients in the REGEN-COV 1200-mg group (1.0%) and in 24 of 748 patients in the placebo group who underwent randomization concurrently (3.2%) (relative risk reduction, 70.4%; P = 0.002). The median time to resolution of symptoms was 4 days shorter with each REGEN-COV dose than with placebo (10 days vs. 14 days; P<0.001 for both comparisons). REGEN-COV was efficacious across various subgroups, including patients who were SARS-CoV-2 serum antibody-positive at baseline. Both REGEN-COV doses reduced viral load faster than placebo; the least-squares mean difference in viral load from baseline through day 7 was -0.71 log10 copies per milliliter (95% confidence interval [CI], -0.90 to -0.53) in the 1200-mg group and -0.86 log10 copies per milliliter (95% CI, -1.00 to -0.72) in the 2400-mg group. Serious adverse events occurred more frequently in the placebo group (4.0%) than in the 1200-mg group (1.1%) and the 2400-mg group (1.3%); infusion-related reactions of grade 2 or higher occurred in less than 0.3% of the patients in all groups.REGEN-COV reduced the risk of Covid-19-related hospitalization or death from any cause, and it resolved symptoms and reduced the SARS-CoV-2 viral load more rapidly than placebo. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04425629.).

  View details for DOI 10.1056/NEJMoa2108163

  View details for PubMedID 34587383

  View details for PubMedCentralID PMC8522800

• Comparison of Strategies for Typhoid Conjugate Vaccine Introduction in India: A Cost-Effectiveness Modeling Study. The Journal of infectious diseases Ryckman, T., Karthikeyan, A. S., Kumar, D., Cao, Y., Kang, G., Goldhaber-Fiebert, J. D., John, J., Lo, N. C., Andrews, J. R. 2021; 224 (Supplement_5): S612-S624

  Abstract

  Typhoid fever causes substantial global mortality, with almost half occurring in India. New typhoid vaccines are highly effective and recommended by the World Health Organization for high-burden settings. There is a need to determine whether and which typhoid vaccine strategies should be implemented in India.We assessed typhoid vaccination using a dynamic compartmental model, parameterized by and calibrated to disease and costing data from a recent multisite surveillance study in India. We modeled routine and 1-time campaign strategies that target different ages and settings. The primary outcome was cost-effectiveness, measured by incremental cost-effectiveness ratios (ICERs) benchmarked against India's gross national income per capita (US$2130).Both routine and campaign vaccination strategies were cost-saving compared to the status quo, due to averted costs of illness. The preferred strategy was a nationwide community-based catchup campaign targeting children aged 1-15 years alongside routine vaccination, with an ICER of $929 per disability-adjusted life-year averted. Over the first 10 years of implementation, vaccination could avert 21-39 million cases and save $1.6-$2.2 billion. These findings were broadly consistent across willingness-to-pay thresholds, epidemiologic settings, and model input distributions.Despite high initial costs, routine and campaign typhoid vaccination in India could substantially reduce mortality and was highly cost-effective.

  View details for DOI 10.1093/infdis/jiab150

  View details for PubMedID 35238367

• Case-Fatality Ratio of Enteric Fever: Estimates From Multitiered Surveillance in India. The Journal of infectious diseases Samuel, P., Njarekkattuvalappil, S. K., Kumar, D., Raju, R., Andrews, J. R., Kang, G., John, J. 2021; 224 (Supplement_5): S517-S521

  Abstract

  The case-fatality ratio (CFR) for enteric fever is essential for estimating disease burden and calibrating measures that balance the likely health gains from interventions against social and economic costs.We aimed to estimate the CFR for enteric fever using multiple data sources within the National Surveillance System for Enteric Fever in India. This surveillance (2017-2020) was established as a multitiered surveillance system including community cohorts (tier 1), facility-based (tier 2), and tertiary care surveillance (tier 3) for estimating the burden of enteric fever in India. The CFR was calculated after accounting for healthcare-seeking behavior for enteric fever and deaths occurring outside the hospital.A total of 1236 hospitalized patients with blood culture-confirmed enteric fever were enrolled, of which 9 fatal cases were identified, for an estimated hospitalized CFR of 0.73% (95% confidence interval [CI], .33%-1.38%). After adjusting for severity, healthcare-seeking behavior, and deaths occurring out-of-hospital, the CFR was estimated to be 0.16% (95% CI, .07%-.29%) for all enteric fevers.Our estimates of the CFR are relatively lower than previously estimated, accounting for care-seeking behavior and deaths outside the hospital.

  View details for DOI 10.1093/infdis/jiab388

  View details for PubMedID 35238359

• Geographic Pattern of Typhoid Fever in India: A Model-Based Estimate of Cohort and Surveillance Data. The Journal of infectious diseases Cao, Y., Karthikeyan, A. S., Ramanujam, K., Raju, R., Krishna, S., Kumar, D., Ryckman, T., Mohan, V. R., Kang, G., John, J., Andrews, J. R., Lo, N. C. 2021; 224 (Supplement_5): S475-S483

  Abstract

  Typhoid fever remains a major public health problem in India. Recently, the Surveillance for Enteric Fever in India program completed a multisite surveillance study. However, data on subnational variation in typhoid fever are needed to guide the introduction of the new typhoid conjugate vaccine in India.We applied a geospatial statistical model to estimate typhoid fever incidence across India, using data from 4 cohort studies and 6 hybrid surveillance sites from October 2017 to March 2020. We collected geocoded data from the Demographic and Health Survey in India as predictors of typhoid fever incidence. We used a log linear regression model to predict a primary outcome of typhoid incidence.We estimated a national incidence of typhoid fever in India of 360 cases (95% confidence interval [CI], 297-494) per 100 000 person-years, with an annual estimate of 4.5 million cases (95% CI, 3.7-6.1 million) and 8930 deaths (95% CI, 7360-12 260), assuming a 0.2% case-fatality rate. We found substantial geographic variation of typhoid incidence across the country, with higher incidence in southwestern states and urban centers in the north.There is a large burden of typhoid fever in India with substantial heterogeneity across the country, with higher burden in urban centers.

  View details for DOI 10.1093/infdis/jiab187

  View details for PubMedID 35238365

• Subcutaneous REGEN-COV Antibody Combination to Prevent Covid-19. The New England journal of medicine O'Brien, M. P., Forleo-Neto, E., Musser, B. J., Isa, F., Chan, K. C., Sarkar, N., Bar, K. J., Barnabas, R. V., Barouch, D. H., Cohen, M. S., Hurt, C. B., Burwen, D. R., Marovich, M. A., Hou, P., Heirman, I., Davis, J. D., Turner, K. C., Ramesh, D., Mahmood, A., Hooper, A. T., Hamilton, J. D., Kim, Y., Purcell, L. A., Baum, A., Kyratsous, C. A., Krainson, J., Perez-Perez, R., Mohseni, R., Kowal, B., DiCioccio, A. T., Stahl, N., Lipsich, L., Braunstein, N., Herman, G., Yancopoulos, G. D., Weinreich, D. M. 2021; 385 (13): 1184-1195

  Abstract

  REGEN-COV (previously known as REGN-COV2), a combination of the monoclonal antibodies casirivimab and imdevimab, has been shown to markedly reduce the risk of hospitalization or death among high-risk persons with coronavirus disease 2019 (Covid-19). Whether subcutaneous REGEN-COV prevents severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent Covid-19 in persons at high risk for infection because of household exposure to a person with SARS-CoV-2 infection is unknown.We randomly assigned, in a 1:1 ratio, participants (≥12 years of age) who were enrolled within 96 hours after a household contact received a diagnosis of SARS-CoV-2 infection to receive a total dose of 1200 mg of REGEN-COV or matching placebo administered by means of subcutaneous injection. At the time of randomization, participants were stratified according to the results of the local diagnostic assay for SARS-CoV-2 and according to age. The primary efficacy end point was the development of symptomatic SARS-CoV-2 infection through day 28 in participants who did not have SARS-CoV-2 infection (as measured by reverse-transcriptase-quantitative polymerase-chain-reaction assay) or previous immunity (seronegativity).Symptomatic SARS-CoV-2 infection developed in 11 of 753 participants in the REGEN-COV group (1.5%) and in 59 of 752 participants in the placebo group (7.8%) (relative risk reduction [1 minus the relative risk], 81.4%; P<0.001). In weeks 2 to 4, a total of 2 of 753 participants in the REGEN-COV group (0.3%) and 27 of 752 participants in the placebo group (3.6%) had symptomatic SARS-CoV-2 infection (relative risk reduction, 92.6%). REGEN-COV also prevented symptomatic and asymptomatic infections overall (relative risk reduction, 66.4%). Among symptomatic infected participants, the median time to resolution of symptoms was 2 weeks shorter with REGEN-COV than with placebo (1.2 weeks and 3.2 weeks, respectively), and the duration of a high viral load (>104 copies per milliliter) was shorter (0.4 weeks and 1.3 weeks, respectively). No dose-limiting toxic effects of REGEN-COV were noted.Subcutaneous REGEN-COV prevented symptomatic Covid-19 and asymptomatic SARS-CoV-2 infection in previously uninfected household contacts of infected persons. Among the participants who became infected, REGEN-COV reduced the duration of symptomatic disease and the duration of a high viral load. (Funded by Regeneron Pharmaceuticals and others; ClinicalTrials.gov number, NCT04452318.).

  View details for DOI 10.1056/NEJMoa2109682

  View details for PubMedID 34347950

  View details for PubMedCentralID PMC8362593

• SARS-CoV-2 Subgenomic RNA Kinetics in Longitudinal Clinical Samples. Open forum infectious diseases Verma, R., Kim, E., Martínez-Colón, G. J., Jagannathan, P., Rustagi, A., Parsonnet, J., Bonilla, H., Khosla, C., Holubar, M., Subramanian, A., Singh, U., Maldonado, Y., Blish, C. A., Andrews, J. R. 2021; 8 (7): ofab310

  Abstract

  Given the persistence of viral RNA in clinically recovered coronavirus disease 2019 (COVID-19) patients, subgenomic RNAs (sgRNAs) have been reported as potential molecular viability markers for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). However, few data are available on their longitudinal kinetics, compared with genomic RNA (gRNA), in clinical samples.We analyzed 536 samples from 205 patients with COVID-19 from placebo-controlled, outpatient trials of peginterferon Lambda-1a (Lambda; n = 177) and favipiravir (n = 359). Nasal swabs were collected at 3 time points in the Lambda (days 1, 4, and 6) and favipiravir (days 1, 5, and 10) trials. N-gene gRNA and sgRNA were quantified by quantitative reverse transcription polymerase chain reaction. To investigate the decay kinetics in vitro, we measured gRNA and sgRNA in A549ACE2+ cells infected with SARS-CoV-2, following treatment with remdesivir or dimethylsulfoxide control.At 6 days in the Lambda trial and 10 days in the favipiravir trial, sgRNA remained detectable in 51.6% (32/62) and 49.5% (51/106) of the samples, respectively. Cycle threshold (Ct) values for gRNA and sgRNA were highly linearly correlated (marginal R 2 = 0.83), and the rate of increase did not differ significantly in the Lambda trial (1.36 cycles/d vs 1.36 cycles/d; P = .97) or the favipiravir trial (1.03 cycles/d vs 0.94 cycles/d; P = .26). From samples collected 15-21 days after symptom onset, sgRNA was detectable in 48.1% (40/83) of participants. In SARS-CoV-2-infected A549ACE2+ cells treated with remdesivir, the rate of Ct increase did not differ between gRNA and sgRNA.In clinical samples and in vitro, sgRNA was highly correlated with gRNA and did not demonstrate different decay patterns to support its application as a viability marker.

  View details for DOI 10.1093/ofid/ofab310

  View details for PubMedID 34295944

  View details for PubMedCentralID PMC8291522

• Blood-based host biomarker diagnostics in active case finding for pulmonary tuberculosis: A diagnostic case-control study. EClinicalMedicine Moreira, F. M., Verma, R., Pereira Dos Santos, P. C., Leite, A., da Silva Santos, A., de Araujo, R. C., da Silva, B. O., de Sá Queiroz, J. H., Persing, D. H., Södersten, E., Gnanashanmugam, D., Khatri, P., Croda, J., Andrews, J. R. 2021; 33: 100776

  Abstract

  There is a need to identify scalable tuberculosis screening strategies among high burden populations. The WHO has identified a non-sputum-based triage test as a development priority.We performed a diagnostic case-control study of point-of-care C-reactive protein (CRP) and Prototype-Xpert-MTB-Host-Response (Xpert-MTB-HR) assays in the context of a mass screening program for tuberculosis in two prisons in Brazil. All incarcerated individuals irrespective of symptoms were screened by sputum Xpert MTB/RIF and sputum culture. Among consecutive, Xpert MTB/RIF or culture-confirmed cases and Xpert MTB/RIF and culture-negative controls, CRP was quantified in serum by a point-of-care assay (iChroma-II) and a 3-gene expression score was quantified from whole blood using the Xpert-MTB-HR cartridge. We evaluated receiver operating characteristic area under the curve (AUC) and assessed specificity at 90% sensitivity and sensitivity at 70% specificity, consistent with WHO target product profile (TPP) benchmarks.Two hundred controls (no TB) and 100 culture- or Xpert MTB/RIF-positive tuberculosis cases were included. Half of tuberculosis cases and 11% of controls reported any tuberculosis symptoms. AUC for CRP was 0·79 (95% CI: 0·73-0·84) and for Xpert-MTB-HR was 0·84 (95% CI: 0·79-0·89). At 90% sensitivity, Xpert-MTB-HR had significantly higher specificity (53·0%, 95% CI: 45·0-69·0%) than CRP (28·1%, 95% CI: 20·2-41·8%) (p = 0·003), both well below the TPP benchmark of 70%. Among individuals with medium or high sputum Xpert MTB/RIF semi-quantitative load, sensitivity (at 70% specificity) of CRP (90·3%, 95% CI: 74·2-98·0) and Xpert-MTB-HR (96·8%, 95% CI: 83·3-99·9%) was higher.For active case finding in this high tuberculosis-burden setting, CRP and Xpert-MTB-HR did not meet TPP benchmarks for a triage test. However, Xpert-MTB-HR was highly sensitive in detecting individuals with medium or high sputum bacillary burden.National Institutes of Health (R01 AI130058 and R01 AI149620) and Brazilian National Council for Scientific and Technological Development (CNPq-404182/2019-4).

  View details for DOI 10.1016/j.eclinm.2021.100776

  View details for PubMedID 33842866

  View details for PubMedCentralID PMC8020164

• Local and Travel-Associated Transmission of Tuberculosis at Central Western Border of Brazil, 2014-2017. Emerging infectious diseases Walter, K. S., Tatara, M. B., Esther da Silva, K. n., Moreira, F. M., Dos Santos, P. C., de Melo Ferrari, D. D., Cunha, E. A., Andrews, J. R., Croda, J. n. 2021; 27 (3): 905–14

  Abstract

  International migrants are at heightened risk for tuberculosis (TB) disease. Intensified incarceration at international borders may compound population-wide TB risk. However, few studies have investigated the contributions of migration, local transmission, or prisons in driving incident TB at international borders. We conducted prospective population-based genomic surveillance in 3 cities along Brazil's central western border from 2014-2017. Although most isolates (89/132; 67%) fell within genomic transmission clusters, genetically unique isolates disproportionately occurred among participants with recent international travel (17/42; 40.5%), suggesting that both local transmission and migration contribute to incident TB. Isolates from 40 participants with and 76 without an incarceration history clustered together throughout a maximum-likelihood phylogeny, indicating the close interrelatedness of prison and community epidemics. Our findings highlight the need for ongoing surveillance to control continued introductions of TB and reduce the disproportionate burden of TB in prisons at Brazil's international borders.

  View details for DOI 10.3201/eid2703.203839

  View details for PubMedID 33622493

• COVID-19 in the California State Prison System: an Observational Study of Decarceration, Ongoing Risks, and Risk Factors. Journal of general internal medicine Chin, E. T., Ryckman, T., Prince, L., Leidner, D., Alarid-Escudero, F., Andrews, J. R., Salomon, J. A., Studdert, D. M., Goldhaber-Fiebert, J. D. 2021

  Abstract

  Correctional institutions nationwide are seeking to mitigate COVID-19-related risks.To quantify changes to California's prison population since the pandemic began and identify risk factors for COVID-19 infection.For California state prisons (March 1-October 10, 2020), we described residents' demographic characteristics, health status, COVID-19 risk scores, room occupancy, and labor participation. We used Cox proportional hazard models to estimate the association between rates of COVID-19 infection and room occupancy and out-of-room labor, respectively.Residents of California state prisons.Changes in the incarcerated population's size, composition, housing, and activities. For the risk factor analysis, the exposure variables were room type (cells vs. dormitories) and labor participation (any room occupant participating in the prior 2 weeks) and the outcome variable was incident COVID-19 case rates.The incarcerated population decreased 19.1% (119,401 to 96,623) during the study period. On October 10, 2020, 11.5% of residents were aged ≥60, 18.3% had high COVID-19 risk scores, 31.0% participated in out-of-room labor, and 14.8% lived in rooms with ≥10 occupants. Nearly 40% of residents with high COVID-19 risk scores lived in dormitories. In 9 prisons with major outbreaks (6,928 rooms; 21,750 residents), dormitory residents had higher infection rates than cell residents (adjusted hazard ratio [AHR], 2.51 95% CI, 2.25-2.80) and residents of rooms with labor participation had higher rates than residents of other rooms (AHR, 1.56; 95% CI, 1.39-1.74).Despite reductions in room occupancy and mixing, California prisons still house many medically vulnerable residents in risky settings. Reducing risks further requires a combination of strategies, including rehousing, decarceration, and vaccination.

  View details for DOI 10.1007/s11606-021-07022-x

  View details for PubMedID 34291377

• Effectiveness of CoronaVac among healthcare workers in the setting of high SARS-CoV-2 Gamma variant transmission in Manaus, Brazil: A test-negative case-control study. Lancet Regional Health. Americas Hitchings, M. D., Ranzani, O. T., Torres, M. S., de Oliveira, S. B., Almiron, M., Said, R., Borg, R., Schulz, W. L., de Oliveira, R. D., da Silva, P. V., de Castro, D. B., Sampaio, V. d., de Albuquerque, B. C., Ramos, T. C., Fraxe, S. H., da Costa, C. F., Naveca, F. G., Siqueira, A. M., de Araújo, W. N., Andrews, J. R., Cummings, D. A., Ko, A. I., Croda, J. 2021: 100025

  Abstract

  Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variant, Gamma, emerged in the city of Manaus in late 2020 during a large resurgence of coronavirus disease (COVID-19), and has spread throughout Brazil. The effectiveness of vaccines in settings with widespread Gamma variant transmission has not been reported.We performed a matched test-negative case-control study to estimate the effectiveness of an inactivated vaccine, CoronaVac, in healthcare workers (HCWs) in Manaus, where the Gamma variant accounted for 86% of genotyped SARS-CoV-2 samples at the peak of its epidemic. We performed an early analysis of effectiveness following administration of at least one vaccine dose and an analysis of effectiveness of the two-dose schedule. The primary outcome was symptomatic SARS-CoV-2 infection.For the early at-least-one-dose and two-dose analyses the study population was, respectively, 53,176 and 53,153 HCWs residing in Manaus and aged 18 years or older, with complete information on age, residence, and vaccination status. Among 53,153 HCWs eligible for the two-dose analysis, 47,170 (89%) received at least one dose of CoronaVac and 2,656 individuals (5%) underwent RT-PCR testing from 19 January, 2021 to 13 April, 2021. Of 3,195 RT-PCR tests, 885 (28%) were positive. 393 and 418 case-control pairs were selected for the early and two-dose analyses, respectively, matched on calendar time, age, and neighbourhood. Among those who had received both vaccine doses before the RT-PCR sample collection date, the average time from second dose to sample collection date was 14 days (IQR 7-24). In the early analysis, vaccination with at least one dose was associated with a 0.50-fold reduction (adjusted vaccine effectiveness (VE), 49.6%, 95% CI 11.3 to 71.4) in the odds of symptomatic SARS-CoV-2 infection during the period 14 days or more after receiving the first dose. However, we estimated low effectiveness (adjusted VE 36.8%, 95% CI -54.9 to 74.2) of the two-dose schedule against symptomatic SARS-CoV-2 infection during the period 14 days or more after receiving the second dose. A finding that vaccinated individuals were much more likely to be infected than unvaccinated individuals in the period 0-13 days after first dose (aOR 2.11, 95% CI 1.36-3.27) suggests that unmeasured confounding led to downward bias in the vaccine effectiveness estimate.Evidence from this test-negative study of the effectiveness of CoronaVac was mixed, and likely affected by bias in this setting. Administration of at least one vaccine dose showed effectiveness against symptomatic SARS-CoV-2 infection in the setting of epidemic Gamma variant transmission. However, the low estimated effectiveness of the two-dose schedule underscores the need to maintain non-pharmaceutical interventions while vaccination campaigns with CoronaVac are being implemented.Fundação Oswaldo Cruz (Fiocruz); Municipal Health Secretary of Manaus; Fundação de Vigilância em Saúde do Amazonas.

  View details for DOI 10.1016/j.lana.2021.100025

  View details for PubMedID 34386791

  View details for PubMedCentralID PMC8310555

• Pooling Sputum Samples for Efficient Mass Tuberculosis Screening in Prisons. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Dos Santos, P. C., da Silva Santos, A., de Oliveira, R. D., da Silva, B. O., Soares, T. R., Martinez, L., Andrews, J. R., Croda, J. 2021

  Abstract

  Although systematic tuberculosis screening in high-risk groups is recommended by WHO, implementation in prisons has been limited due to resource constraints. Whether Xpert Ultra sputum pooling could be a sensitive and efficient approach to mass screening in prisons is unknown.1,280 sputum samples were collected from inmates in Brazil during mass screening and tested using Xpert G4. We selected samples for mixing in pools of 4, 8, 12, and 16, which were then tested using Ultra. In each pool, a single positive sample of differing Xpert mycobacterial loads was used. Additionally, 10 pools of 16 negative samples each were analyzed as controls. We then simulated tuberculosis screening at prevalences of 0.5-5% and calculated the cost per tuberculosis case detected at different sputum pooling sizes.The sensitivity and specificity of sputum pooling were high (sensitivity: 94%; 95% CI: 88-98; specificity: 100%, 95% CI: 84-100). Sensitivity was greater in pools in which the positive sample had a high mycobacterial load compared to those that were very low (100% vs 88%). In settings with a higher tuberculosis prevalence, pools of 4 and 8 were more efficient than larger pool sizes. Larger pools decreased the costs by 87% at low prevalences whereas smaller pools fitted greater at higher prevalences (57%).Sputum pooling using Ultra was a sensitive strategy for tuberculosis screening. This approach was more efficient than individual testing across a broad range of simulated tuberculosis prevalence settings and could enable active case finding to be scaled while containing costs.

  View details for DOI 10.1093/cid/ciab847

  View details for PubMedID 34718459

• Effectiveness of ChAdOx1 vaccine in older adults during SARS-CoV-2 Gamma variant circulation in São Paulo. Nature communications Hitchings, M. D., Ranzani, O. T., Dorion, M., D'Agostini, T. L., de Paula, R. C., de Paula, O. F., de Moura Villela, E. F., Torres, M. S., de Oliveira, S. B., Schulz, W., Almiron, M., Said, R., de Oliveira, R. D., Silva, P. V., de Araújo, W. N., Gorinchteyn, J. C., Andrews, J. R., Cummings, D. A., Ko, A. I., Croda, J. 2021; 12 (1): 6220

  Abstract

  A two-dose regimen of the Oxford-AstraZeneca (ChAdOx1) Covid-19 vaccine with an inter-dose interval of three months has been implemented in many countries with restricted vaccine supply. However, there is limited evidence for the effectiveness of ChAdOx1 by dose in elderly populations in countries with high prevalence of the Gamma variant of SARS-CoV-2. Here, we estimate ChAdOx1 effectiveness by dose against the primary endpoint of RT-PCR-confirmed Covid-19, and secondary endpoints of Covid-19 hospitalization and Covid-19-related death, in adults aged ≥60 years during an epidemic with high Gamma variant prevalence in São Paulo state, Brazil using a matched, test-negative case-control study. Starting 28 days after the first dose, effectiveness of a single dose of ChAdOx1 is 33.4% (95% CI, 26.4-39.7) against Covid-19, 55.1% (95% CI, 46.6-62.2) against hospitalization, and 61.8% (95% CI, 48.9-71.4) against death. Starting 14 days after the second dose, effectiveness of the two-dose schedule is 77.9% (95% CI, 69.2-84.2) against Covid-19, 87.6% (95% CI, 78.2-92.9) against hospitalization, and 93.6% (95% CI, 81.9-97.7) against death. Completion of the ChAdOx1 vaccine schedule affords significantly increased protection over a single dose against mild and severe Covid-19 outcomes in elderly individuals during widespread Gamma variant circulation.

  View details for DOI 10.1038/s41467-021-26459-6

  View details for PubMedID 34711813

• Effectiveness of the CoronaVac vaccine in older adults during a gamma variant associated epidemic of covid-19 in Brazil: test negative case-control study. BMJ (Clinical research ed.) Ranzani, O. T., Hitchings, M. D., Dorion, M., D'Agostini, T. L., de Paula, R. C., de Paula, O. F., Villela, E. d., Torres, M. S., de Oliveira, S. B., Schulz, W., Almiron, M., Said, R., de Oliveira, R. D., Vieira da Silva, P., de Araújo, W. N., Gorinchteyn, J. C., Andrews, J. R., Cummings, D. A., Ko, A. I., Croda, J. 2021; 374: n2015

  Abstract

  To estimate the effectiveness of the inactivated whole virus vaccine, CoronaVac (Sinovac Biotech), against symptomatic covid-19 in the elderly population of São Paulo state, Brazil during widespread circulation of the gamma variant.Test negative case-control study.Community testing for covid-19 in São Paulo state, Brazil.43 774 adults aged ≥70 years who were residents of São Paulo state and underwent reverse transcription polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 from 17 January to 29 April 2021. 26 433 cases with symptomatic covid-19 and 17 622 test negative controls with covid-19 symptoms were formed into 13 283 matched sets, one case with to up to five controls, according to age, sex, self-reported race, municipality of residence, previous covid-19 status, and date of RT-PCR test (±3 days).Vaccination with a two dose regimen of CoronaVac.RT-PCR confirmed symptomatic covid-19 and associated hospital admissions and deaths.Adjusted vaccine effectiveness against symptomatic covid-19 was 24.7% (95% confidence interval 14.7% to 33.4%) at 0-13 days and 46.8% (38.7% to 53.8%) at ≥14 days after the second dose. Adjusted vaccine effectiveness against hospital admissions was 55.5% (46.5% to 62.9%) and against deaths was 61.2% (48.9% to 70.5%) at ≥14 days after the second dose. Vaccine effectiveness ≥14 days after the second dose was highest for the youngest age group (70-74 years)-59.0% (43.7% to 70.2%) against symptomatic disease, 77.6% (62.5% to 86.7%) against hospital admissions, and 83.9% (59.2% to 93.7%) against deaths-and declined with increasing age.Vaccination with CoronaVac was associated with a reduction in symptomatic covid-19, hospital admissions, and deaths in adults aged ≥70 years in a setting with extensive transmission of the gamma variant. Vaccine protection was, however, low until completion of the two dose regimen, and vaccine effectiveness was observe to decline with increasing age among this elderly population.

  View details for DOI 10.1136/bmj.n2015

  View details for PubMedID 34417194

• Mycobacterium tuberculosis-Specific T Cell Functional, Memory, and Activation Profiles in QuantiFERON-Reverters Are Consistent With Controlled Infection. Frontiers in immunology Mpande, C. A., Steigler, P., Lloyd, T., Rozot, V., Mosito, B., Schreuder, C., Reid, T. D., Bilek, N., Ruhwald, M., Andrews, J. R., Hatherill, M., Little, F., Scriba, T. J., Nemes, E. 2021; 12: 712480

  Abstract

  Reversion of immune sensitization tests for Mycobacterium tuberculosis (M.tb) infection, such as interferon-gamma release assays or tuberculin skin test, has been reported in multiple studies. We hypothesized that QuantiFERON-TB Gold (QFT) reversion is associated with a decline of M.tb-specific functional T cell responses, and a distinct pattern of T cell and innate responses compared to persistent QFT+ and QFT- individuals. We compared groups of healthy adolescents (n=~30 each), defined by four, 6-monthly QFT tests: reverters (QFT+/+/-/-), non-converters (QFT-/-/-/-) and persistent positives (QFT+/+/+/+). We stimulated peripheral blood mononuclear cells with M.tb antigens (M.tb lysate; CFP-10/ESAT-6 and EspC/EspF/Rv2348 peptide pools) and measured M.tb-specific adaptive T cell memory, activation, and functional profiles; as well as functional innate (monocytes, natural killer cells), donor-unrestricted T cells (DURT: gammadelta T cells, mucosal-associated invariant T and natural killer T-like cells) and B cells by flow cytometry. Projection to latent space discriminant analysis was applied to determine features that best distinguished between QFT reverters, non-converters and persistent positives. No longitudinal changes in immune responses to M.tb were observed upon QFT reversion. M.tb-specific Th1 responses detected in reverters were of intermediate magnitude, higher than responses in QFT non-converters and lower than responses in persistent positives. About one third of reverters had a robust response to CFP-10/ESAT-6. Among those with measurable responses, lower proportions of TSCM (CD45RA+CCR7+CD27+) and early differentiated (CD45RA-) IFN-gamma-TNF+IL-2- M.tb lysate-specific CD4+ cells were observed in reverters compared with non-converters. Conversely, higher proportions of early differentiated and lower proportions of effector (CD45RA-CCR7-) CFP10/ESAT6-specific Th1 cells were observed in reverters compared to persistent-positives. No differences in M.tb-specific innate, DURT or B cell functional responses were observed between the groups. Statistical modelling misclassified the majority of reverters as non-converters more frequently than they were correctly classified as reverters or misclassified as persistent positives. These findings suggest that QFT reversion occurs in a heterogeneous group of individuals with low M.tb-specific T cell responses. In some individuals QFT reversion may result from assay variability, while in others the magnitude and differentiation status of M.tb-specific Th1 cells are consistent with well-controlled M.tb infection.

  View details for DOI 10.3389/fimmu.2021.712480

  View details for PubMedID 34526988

• Inflammatory but not respiratory symptoms are associated with ongoing upper airway viral shedding in outpatients with uncomplicated COVID-19. Diagnostic microbiology and infectious disease Jacobson, K. B., Purington, N., Parsonnet, J., Andrews, J., Balasubramanian, V., Bonilla, H., Edwards, K., Desai, M., Singh, U., Hedlin, H., Jagannathan, P. 2021; 102 (3): 115612

  Abstract

  Although the vast majority of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infections are uncomplicated, our understanding of predictors of symptom resolution and viral shedding cessation remains limited. We characterized symptom trajectories and oropharyngeal viral shedding among 120 outpatients with uncomplicated Coronavirus Disease of 2019 (COVID-19) enrolled in a clinical trial of Peginterferon Lambda, which demonstrated no clinical or virologic benefit compared with placebo. In the combined trial cohort, objective fever was uncommon, inflammatory symptoms (myalgias, fatigue) peaked at 4 to 5 days postsymptom onset, and cough peaked at 9 days. The median time to symptom resolution from earliest symptom onset was 17 days (95% confidence interval 14-18). SARS-CoV-2 IgG seropositivity at enrollment was associated with hastened resolution of viral shedding (hazard ratio 1.80, 95% confidence interval 1.05-3.1, P = 0.03), but not with symptom resolution. Inflammatory symptoms were associated with a significantly greater odds of oropharyngeal SARS-CoV-2 RNA detection; respiratory symptoms were not. These findings have important implications for COVID-19 screening approaches and trial design.

  View details for DOI 10.1016/j.diagmicrobio.2021.115612

  View details for PubMedID 34974350

• Effectiveness of the mRNA-1273 Vaccine during a SARS-CoV-2 Delta Outbreak in a Prison. The New England journal of medicine Chin, E. T., Leidner, D., Zhang, Y., Long, E., Prince, L., Li, Y., Andrews, J. R., Studdert, D. M., Goldhaber-Fiebert, J. D., Salomon, J. A. 2021

  View details for DOI 10.1056/NEJMc2114089

  View details for PubMedID 34670040

• Dependence of COVID-19 Policies on End-of-Year Holiday Contacts in Mexico City Metropolitan Area: A Modeling Study. MDM policy & practice Alarid-Escudero, F., Gracia, V., Luviano, A., Roa, J., Peralta, Y., Reitsma, M. B., Claypool, A. L., Salomon, J. A., Studdert, D. M., Andrews, J. R., Goldhaber-Fiebert, J. D. 2021; 6 (2): 23814683211049249

  Abstract

  Background. Mexico City Metropolitan Area (MCMA) has the largest number of COVID-19 (coronavirus disease 2019) cases in Mexico and is at risk of exceeding its hospital capacity in early 2021. Methods. We used the Stanford-CIDE Coronavirus Simulation Model (SC-COSMO), a dynamic transmission model of COVID-19, to evaluate the effect of policies considering increased contacts during the end-of-year holidays, intensification of physical distancing, and school reopening on projected confirmed cases and deaths, hospital demand, and hospital capacity exceedance. Model parameters were derived from primary data, literature, and calibrated. Results. Following high levels of holiday contacts even with no in-person schooling, MCMA will have 0.9 million (95% prediction interval 0.3-1.6) additional COVID-19 cases between December 7, 2020, and March 7, 2021, and hospitalizations will peak at 26,000 (8,300-54,500) on January 25, 2021, with a 97% chance of exceeding COVID-19-specific capacity (9,667 beds). If MCMA were to control holiday contacts, the city could reopen in-person schools, provided they increase physical distancing with 0.5 million (0.2-0.9) additional cases and hospitalizations peaking at 12,000 (3,700-27,000) on January 19, 2021 (60% chance of exceedance). Conclusion. MCMA must increase COVID-19 hospital capacity under all scenarios considered. MCMA's ability to reopen schools in early 2021 depends on sustaining physical distancing and on controlling contacts during the end-of-year holiday.

  View details for DOI 10.1177/23814683211049249

  View details for PubMedID 34660906

  View details for PubMedCentralID PMC8512280

• Outbreaks of COVID-19 variants in US prisons: a mathematical modelling analysis of vaccination and reopening policies. The Lancet. Public health Ryckman, T., Chin, E. T., Prince, L., Leidner, D., Long, E., Studdert, D. M., Salomon, J. A., Alarid-Escudero, F., Andrews, J. R., Goldhaber-Fiebert, J. D. 2021

  Abstract

  Residents of prisons have experienced disproportionate COVID-19-related health harms. To control outbreaks, many prisons in the USA restricted in-person activities, which are now resuming even as viral variants proliferate. This study aims to use mathematical modelling to assess the risks and harms of COVID-19 outbreaks in prisons under a range of policies, including resumption of activities.We obtained daily resident-level data for all California state prisons from Jan 1, 2020, to May 15, 2021, describing prison layouts, housing status, sociodemographic and health characteristics, participation in activities, and COVID-19 testing, infection, and vaccination status. We developed a transmission-dynamic stochastic microsimulation parameterised by the California data and published literature. After an initial infection is introduced to a prison, the model evaluates the effect of various policy scenarios on infections and hospitalisations over 200 days. Scenarios vary by vaccine coverage, baseline immunity (0%, 25%, or 50%), resumption of activities, and use of non-pharmaceutical interventions (NPIs) that reduce transmission by 75%. We simulated five prison types that differ by residential layout and demographics, and estimated outcomes with and without repeated infection introductions over the 200 days.If a viral variant is introduced into a prison that has resumed pre-2020 contact levels, has moderate vaccine coverage (ranging from 36% to 76% among residents, dependent on age, with 40% coverage for staff), and has no baseline immunity, 23-74% of residents are expected to be infected over 200 days. High vaccination coverage (90%) coupled with NPIs reduces cumulative infections to 2-54%. Even in prisons with low room occupancies (ie, no more than two occupants) and low levels of cumulative infections (ie, <10%), hospitalisation risks are substantial when these prisons house medically vulnerable populations. Risks of large outbreaks (>20% of residents infected) are substantially higher if infections are repeatedly introduced.Balancing benefits of resuming activities against risks of outbreaks presents challenging trade-offs. After achieving high vaccine coverage, prisons with mostly one-to-two-person cells that have higher baseline immunity from previous outbreaks can resume in-person activities with low risk of a widespread new outbreak, provided they maintain widespread NPIs, continue testing, and take measures to protect the medically vulnerable.Horowitz Family Foundation, National Institute on Drug Abuse, Centers for Disease Control and Prevention, National Science Foundation, Open Society Foundation, Advanced Micro Devices.

  View details for DOI 10.1016/S2468-2667(21)00162-6

  View details for PubMedID 34364404

• Peginterferon Lambda-1a for treatment of outpatients with uncomplicated COVID-19: a randomized placebo-controlled trial. Nature communications Jagannathan, P. n., Andrews, J. R., Bonilla, H. n., Hedlin, H. n., Jacobson, K. B., Balasubramanian, V. n., Purington, N. n., Kamble, S. n., de Vries, C. R., Quintero, O. n., Feng, K. n., Ley, C. n., Winslow, D. n., Newberry, J. n., Edwards, K. n., Hislop, C. n., Choong, I. n., Maldonado, Y. n., Glenn, J. n., Bhatt, A. n., Blish, C. n., Wang, T. n., Khosla, C. n., Pinsky, B. A., Desai, M. n., Parsonnet, J. n., Singh, U. n. 2021; 12 (1): 1967

  Abstract

  Type III interferons have been touted as promising therapeutics in outpatients with coronavirus disease 2019 (COVID-19). We conducted a randomized, single-blind, placebo-controlled trial (NCT04331899) in 120 outpatients with mild to moderate COVID-19 to determine whether a single, 180 mcg subcutaneous dose of Peginterferon Lambda-1a (Lambda) within 72 hours of diagnosis could shorten the duration of viral shedding (primary endpoint) or symptoms (secondary endpoint). In both the 60 patients receiving Lambda and 60 receiving placebo, the median time to cessation of viral shedding was 7 days (hazard ratio [HR] = 0.81; 95% confidence interval [CI] 0.56 to 1.19). Symptoms resolved in 8 and 9 days in Lambda and placebo, respectively, and symptom duration did not differ significantly between groups (HR 0.94; 95% CI 0.64 to 1.39). Both Lambda and placebo were well-tolerated, though liver transaminase elevations were more common in the Lambda vs. placebo arm (15/60 vs 5/60; p = 0.027). In this study, a single dose of subcutaneous Peginterferon Lambda-1a neither shortened the duration of SARS-CoV-2 viral shedding nor improved symptoms in outpatients with uncomplicated COVID-19.

  View details for DOI 10.1038/s41467-021-22177-1

  View details for PubMedID 33785743

• Covid-19 Vaccine Acceptance in California State Prisons. The New England journal of medicine Chin, E. T., Leidner, D. n., Ryckman, T. n., Liu, Y. E., Prince, L. n., Alarid-Escudero, F. n., Andrews, J. R., Salomon, J. A., Goldhaber-Fiebert, J. D., Studdert, D. M. 2021

  View details for DOI 10.1056/NEJMc2105282

  View details for PubMedID 33979505

• Covid-19 in the California State Prison System: An Observational Study of Decarceration, Ongoing Risks, and Risk Factors. medRxiv : the preprint server for health sciences Chin, E. T., Ryckman, T. n., Prince, L. n., Leidner, D. n., Alarid-Escudero, F. n., Andrews, J. R., Salomon, J. A., Studdert, D. M., Goldhaber-Fiebert, J. D. 2021

  Abstract

  Correctional institutions nationwide are seeking to mitigate Covid-19-related risks.To quantify changes to California's prison population since the pandemic began and identify risk factors for Covid-19 infection.We described residents' demographic characteristics, health status, Covid-19 risk scores, room occupancy, and labor participation. We used Cox proportional hazard models to estimate the association between rates of Covid-19 infection and room occupancy and out-of-room labor, respectively.California state prisons (March 1-October 10, 2020).Residents of California state prisons.Changes in the incarcerated population's size, composition, housing, and activities. For the risk factor analysis, the exposure variables were room type (cells vs dormitories) and labor participation (any room occupant participating in the prior 2 weeks) and the outcome variable was incident Covid-19 case rates.The incarcerated population decreased 19.1% (119,401 to 96,623) during the study period.On October 10, 2020, 11.5% of residents were aged ≥60, 18.3% had high Covid-19 risk scores, 31.0% participated in out-of-room labor, and 14.8% lived in rooms with ≥10 occupants. Nearly 40% of residents with high Covid-19 risk scores lived in dormitories. In 9 prisons with major outbreaks (6,928 rooms; 21,750 residents), dormitory residents had higher infection rates than cell residents (adjusted hazard ratio [AHR], 2.51 95%CI, 2.25-2.80) and residents of rooms with labor participation had higher rates than residents of other rooms (AHR, 1.56; 95%CI, 1.39-1.74).Inability to measure density of residents' living conditions or contact networks among residents and staff.Despite reductions in room occupancy and mixing, California prisons still house many medically vulnerable residents in risky settings. Reducing risks further requires a combination of strategies, including rehousing, decarceration, and vaccination.Horowitz Family Foundation; National Institute on Drug Abuse; National Science Foundation Graduate Research Fellowship; Open Society Foundations.

  View details for DOI 10.1101/2021.03.04.21252942

  View details for PubMedID 33758868

  View details for PubMedCentralID PMC7987024

• Blood-based host biomarker diagnostics in active case finding for pulmonary tuberculosis: EClinicalMedicine, published by The Lancet Martinez, F., Verma, R., Cesar, P., Leite, A., Santos, ., Rafaele, Bruna, Persing, D., Södersten, E., Gnanashanmugam, D., Khatri, P., Croda, J., Andrews, J., et al 2021

  View details for DOI 10.1016/j.eclinm.2021.100776

• Tracking the Emergence of Azithromycin Resistance in Multiple Genotypes of Typhoidal Salmonella. mBio Sajib, M. S., Tanmoy, A. M., Hooda, Y. n., Rahman, H. n., Andrews, J. R., Garrett, D. O., Endtz, H. P., Saha, S. K., Saha, S. n. 2021; 12 (1)

  Abstract

  The rising prevalence of antimicrobial resistance in Salmonella enterica serovars Typhi and Paratyphi A, causative agents of typhoid and paratyphoid, have led to fears of untreatable infections. Of specific concern is the emerging resistance against azithromycin, the only remaining oral drug to treat extensively drug resistant (XDR) typhoid. Since the first report of azithromycin resistance from Bangladesh in 2019, cases have been reported from Nepal, India, and Pakistan. The genetic basis of this resistance is a single point mutation in the efflux pump AcrB (R717Q/L). Here, we report 38 additional cases of azithromycin-resistant (AzmR) Salmonella Typhi and Paratyphi A isolated in Bangladesh between 2016 and 2018. Using genomic analysis of 56 AzmR isolates from South Asia with AcrB-R717Q/L, we confirm that this mutation has spontaneously emerged in different Salmonella Typhi and Paratyphi A genotypes. The largest cluster of AzmR Typhi belonged to genotype 4.3.1.1; Bayesian analysis predicts the mutation to have emerged sometime in 2010. A travel-related Typhi isolate with AcrB-R717Q belonging to 4.3.1.1 was isolated in the United Kingdom, increasing fears of global spread. For real-time detection of AcrB-R717Q/L, we developed an extraction-free, rapid, and low-cost mismatch amplification mutation assay (MAMA). Validation of MAMA using 113 AzmR and non-AzmR isolates yielded >98% specificity and sensitivity versus phenotypic and whole-genome sequencing assays currently used for azithromycin resistance detection. With increasing azithromycin use, AcrB-R717Q/L is likely to be acquired by XDR strains. The proposed tool for active detection and surveillance of this mutation may detect pan-oral drug resistance early, giving us a window to intervene.IMPORTANCE In the early 1900s, with mortality of ∼30%, typhoid and paratyphoid ravaged parts of the world; with improved water, sanitation, and hygiene in resource-rich countries and the advent of antimicrobials, mortality dwindled to <1%. Today, the burden rests disproportionately on South Asia, where the primary means for combatting the disease is antimicrobials. However, prevalence of antimicrobial resistance is rising and, in 2016, an extensively drug resistant Typhi strain triggered an ongoing outbreak in Pakistan, leaving only one oral drug, azithromycin, to treat it. Since the description of emergence of azithromycin resistance, conferred by a point mutation in acrB (AcrB-R717Q/L) in 2019, there have been increasing numbers of reports. Using genomics and Bayesian analysis, we illustrate that this mutation emerged in approximately 2010 and has spontaneously arisen multiple times. Emergence of pan-oral drug resistant Salmonella Typhi is imminent. We developed a low-cost, rapid PCR tool to facilitate real-time detection and prevention policies.

  View details for DOI 10.1128/mBio.03481-20

  View details for PubMedID 33593966

• Molecular Detection of Airborne Mycobacterium tuberculosis in South African High Schools. American journal of respiratory and critical care medicine Bunyasi, E. W., Middelkoop, K., Koch, A., Hoosen, Z., Mulenga, H., Luabeya, A. K., Shenje, J., Mendelsohn, S. C., Tameris, M., Scriba, T. J., Warner, D. F., Wood, R., Andrews, J. R., Hatherill, M. 2021

  Abstract

  Rationale South African adolescents carry a high tuberculosis disease burden. It is not known if schools are high-risk settings for Mycobacterium tuberculosis (MTB) transmission. Objectives To detect airborne MTB genomic DNA in classrooms. Methods We studied 72 classrooms occupied by 1,836 students in two South African schools. High-volume air filtration was performed for median 40 minutes (interquartile range 35-54) and assayed by droplet digital PCR (ddPCR) targeting MTB Region of Difference 9 (RD9), with concurrent CO2 concentration measurement. Classroom data were benchmarked against public health clinics. Students who consented to individual TB screening completed a questionnaire and sputum collection (Xpert MTB/RIF Ultra) if symptom-positive. Poisson statistics were used for MTB RD9 copy quantification. Measurements and Main Results ddPCR assays were positive in 13/72 (18.1%) classroom and 4/39 (10.3%) clinic measurements (p=0.276). Median ambient CO2 concentration was 886 ppm (IQR 747-1223) in classrooms vs. 490 ppm (IQR 405-587) in clinics (p<0.001). Average airborne concentration of MTB RD9 was 3.61 copies per 180,000 litres in classrooms vs. 1.74 copies per 180,000 litres in clinics (p=0.280). Across all classrooms, the average risk of an occupant inhaling one MTB RD9 copy was estimated as 0.71% during one standard lesson of 35 minutes. Among 1,836/2,262 (81.2%) students who consented to screening, 21/90 symptomatic students produced a sputum sample (36.2%), of which one was Xpert MTB/RIF Ultra positive. Conclusions Airborne MTB genomic DNA was detected frequently in high school classrooms. Instantaneous risk of classroom exposure was similar to the risk in public health clinics.

  View details for DOI 10.1164/rccm.202102-0405OC

  View details for PubMedID 34752730

• Proinflammatory IgG Fc structures in patients with severe COVID-19. Nature immunology Chakraborty, S., Gonzalez, J., Edwards, K., Mallajosyula, V., Buzzanco, A. S., Sherwood, R., Buffone, C., Kathale, N., Providenza, S., Xie, M. M., Andrews, J. R., Blish, C. A., Singh, U., Dugan, H., Wilson, P. C., Pham, T. D., Boyd, S. D., Nadeau, K. C., Pinsky, B. A., Zhang, S., Memoli, M. J., Taubenberger, J. K., Morales, T., Schapiro, J. M., Tan, G. S., Jagannathan, P., Wang, T. T. 2020

  Abstract

  Severe acute respiratory syndrome coronavirus 2 infections can cause coronavirus disease 2019 (COVID-19), which manifests with a range of severities from mild illness to life-threatening pneumonia and multi-organ failure. Severe COVID-19 is characterized by an inflammatory signature, including high levels of inflammatory cytokines, alveolar inflammatory infiltrates and vascular microthrombi. Here we show that patients with severe COVID-19 produced a unique serologic signature, including an increased likelihood of IgG1 with afucosylated Fc glycans. This Fc modification on severe acute respiratory syndrome coronavirus 2 IgGs enhanced interactions with the activating Fcγ receptor FcγRIIIa; when incorporated into immune complexes, Fc afucosylation enhanced production of inflammatory cytokines by monocytes, including interleukin-6 and tumor necrosis factor. These results show that disease severity in COVID-19 correlates with the presence of proinflammatory IgG Fc structures, including afucosylated IgG1.

  View details for DOI 10.1038/s41590-020-00828-7

  View details for PubMedID 33169014

• Gold-standard cholera diagnostics are tarnished by lytic bacteriophage and antibiotics. Journal of clinical microbiology Nelson, E. J., Grembi, J. A., Chao, D. L., Andrews, J. R., Alexandrova, L., Rodriguez, P. H., Ramachandran, V. V., Sayeed, M. A., Wamala, J. F., Debes, A. K., Sack, D. A., Hryckowian, A. J., Haque, F., Khatun, S., Rahman, M., Chien, A., Spormann, A. M., Schoolnik, G. K. 2020

  Abstract

  A fundamental, clinical and scientific concern is how lytic bacteriophage, as well as antibiotics, impact diagnostic positivity. Cholera was chosen as a model disease to investigate this important question because cholera outbreaks enable large enrollment, field methods are well established, and the predatory relationship between lytic bacteriophage and the etiologic agent Vibrio cholerae share commonalities across bacterial taxa. Patients with diarrheal disease were enrolled at two remote hospitals in Bangladesh. Diagnostic performance was assessed as a function of lytic bacteriophage detection and exposure to the first-line antibiotic azithromycin detected in stool samples by mass spectrometry. Among diarrheal samples positive by nanoliter quantitative PCR for V. cholerae (n=78/849), the odds that a rapid diagnostic test (RDT) or qPCR was positive was reduced by 89% (OR 0.108; 95%CI 0.002-0.872) and 87% (OR 0.130; 95%CI 0.022-0.649) when lytic bacteriophage were detected, respectively. The odds that a rapid diagnostic test (RDT) or qPCR was positive was reduced by more than 99% (OR 0.00; 95% CI: 0.00-0.28) and 89% (OR 0.11; 95% CI: 0.03-0.44) when azithromycin was detected, respectively. Analysis of additional samples from South Sudan found similar phage effects on RDTs; antibiotics were not assayed. Cholera burden estimates may improve by accommodating for the negative effects of lytic bacteriophage and antibiotic exposure on diagnostic positivity. One accommodation is using bacteriophage detection as proxy for pathogen detection. These findings have relevance for other diagnostic settings where bacterial pathogens are vulnerable to lytic bacteriophage predation.

  View details for DOI 10.1128/JCM.00412-20

  View details for PubMedID 32611794

• Primary Prophylaxis to Prevent Tuberculosis Infection in Prison Inmates: A Randomized, Double-Blind, Placebo-Controlled Trial. The American journal of tropical medicine and hygiene Dias de Oliveira, R. n., da Silva Santos, A. n., Reis, C. B., de Cássia Leite, A. n., Correia Sacchi, F. P., Araujo, R. P., Dos Santos, P. P., Rolla, V. C., Martinez, L. n., Andrews, J. n., Croda, J. n. 2020

  Abstract

  In many low- and middle-income countries, tuberculosis (TB) incidence in prisons is high, exposing incarcerated populations to an elevated risk of TB infection. We conducted a randomized, double-blind, placebo-controlled trial among HIV-negative male inmates of a high TB burden prison to determine whether isoniazid given twice weekly (900 mg) for 12 months prevents TB infection. The primary outcome was QuantiFERON-TB Gold in Plus (QFT) conversion to ≥ 0.35 international units per milliliter (IU/mL) at 6 months; secondary outcomes included alternative QFT thresholds (≥ 0.7, ≥ 2.0, and ≥ 4.0 IU/mL). In total, 467 participants were randomly assigned to intervention (N = 258) or control (N = 209). In an interim analysis of participants who had completed 6 months of follow-up (N = 170), QFT conversion occurred in 20.8% (19/91) and 21.5% (17/79) of participants in intervention and control arms (efficacy: 2.9%, P = 0.91), respectively. The trial was then stopped according to the trial protocol, and the remaining participants prematurely discontinued. In an analysis of secondary outcomes, the intervention arm had significantly lower rates of conversion at a cutoff of ≥ 2.0 IU/mL (efficacy: 82.6%, P < 0.01). In conclusion, 900 mg of isoniazid, administered twice a week, did not effectively prevent QFT conversion at a cutoff point ≥ 0.35 IU/mL in a trial of QFT-negative inmates. Higher QFT cutoffs are associated with sustained conversion and greater protection. Future clinical trials that evaluate protection for latent infection should use the highest cutoff than that recommended by the manufacturer.

  View details for DOI 10.4269/ajtmh.20-0110

  View details for PubMedID 32876010

• Oral swab testing by Xpert® MTB/RIF Ultra for mass tuberculosis screening in prisons. Journal of clinical tuberculosis and other mycobacterial diseases Lima, F. n., Santos, A. S., Oliveira, R. D., Silva, C. C., Gonçalves, C. C., Andrews, J. R., Croda, J. n. 2020; 19: 100148

  Abstract

  Diagnosis of pulmonary tuberculosis is usually achieved by testing sputum for presence of Mycobacterium tuberculosis by microscopy, culture or nucleic acid amplification tests. However, many individuals are unable to produce sputum, particularly early in the course of illness. Studies have reported that oral swabs, assayed by nucleic acid amplification tests, may be a suitable substitute or complement to sputum testing. To determine whether this method could be useful of case finding, in which bacillary load is often lower, we evaluated it in the setting of a mass tuberculosis screening study in prison inmates in Brazil. For this sub-study, we enrolled 128 individuals with pulmonary tuberculosis confirmed by sputum Xpert testing, and 128 controls who tested negative by sputum culture and Xpert. We collected two oral swabs by participant, prior to starting treatment. Swabs were collected from the tongue by brushing along the surface for 10 times. The sensitivity of a single oral swab was 43% (N = 55/128; 95% CI: 34-52%). Using two consecutive oral swabs the sensitivity increased to 51% (N = 66/128; 95% CI: 43-60%). The specificity was 100% (128/128). In participants with high mycobaterial load in the sputum, the combined sensitivity was 90% (N = 9/10). In the participants with medium mycobaterial load in the sputum, the combined sensitivity was 79% (N = 23/29). In the participants with low or very low mycobaterial load in the sputum, the combined sensitivity was 38% (N = 34/89). Our data suggest that oral swab sampling, assayed by Xpert, has comparable sensitivity to sputum in participants with high and medium mycobacterial load in the sputum. However, 70% (89/128) of individuals identified through our mass screening study (Carbone et al.) had detection number low or very low in their sputum. In this population, oral swab testing may not have sufficient sensitivity as currently performed. Further studies are needed to identify alternative non-sputum sampling strategies in this population.

  View details for DOI 10.1016/j.jctube.2020.100148

  View details for PubMedID 32099908

  View details for PubMedCentralID PMC7031315

• Burden of Ileal Perforations Among Surgical Patients Admitted in Tertiary Care Hospitals of Three Asian countries: Surveillance of Enteric Fever in Asia Project (SEAP), September 2016-September 2019. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Qazi, S. H., Yousafzai, M. T., Saddal, N. S., Dehraj, I. F., Thobani, R. S., Akhtar, A. n., Syed, J. R., Kazi, A. M., Hotwani, A. n., Rahman, N. n., Mehmood, J. n., Andrews, J. R., Luby, S. P., Garrett, D. O., Qamar, F. N. 2020; 71 (Supplement_3): S232–S238

  Abstract

  Typhoid fever is caused by Salmonella enterica subspecies enterica serovar Typhi (S. Typhi) and can lead to systemic illness and complications. We aimed to characterize typhoid-related ileal perforation in the context of the population-based Surveillance of Enteric Fever in Asia Project (SEAP) in Bangladesh, Nepal and Pakistan.Between September 2016 and September 2019, all cases of nontraumatic ileal perforation with a clinical diagnosis of typhoid were enrolled from 4 tertiary care hospitals in Karachi, 2 pediatric hospitals in Bangladesh, and 2 hospitals in Nepal. Sociodemographic data were collected from patients or their caregivers, and clinical and outcome data were retrieved from medical records. Tissue samples were collected for histopathology and blood cultures where available.Of the 249 enrolled cases, 2 from Bangladesh, 5 from Nepal and 242 from Pakistan. In Pakistan, most of the cases were in the 0-15 (117/242; 48%) and 16-30 (89/242; 37%) age groups. In all countries, males were most affected: Pakistan 74.9% (180/242), Nepal 80% (4/5), and Bangladesh 100% (2/2). Blood culture was done on 76 cases; 8 (11%) were positive for S. Typhi, and all were extensively drug resistant (XDR) S. Typhi. Tissue cultures was done on 86 patients; 3 (3%) were positive for S. Typhi, and all were XDR S. Typhi, out of 86 samples tested for histopathology 4 (5%) revealed ileal perforation with necrosis. Culture or histopathology confirmed total 15 (11%) enteric fever cases with ileal perforation are similar to the clinically diagnosed cases. There were 16/242 (7%) deaths from Pakistan. Cases of ileal perforation who survived were more likely to have sought care before visiting the sentinel hospital (P = .009), visited any hospital for treatment (P = .013) compared to those who survived.Although surveillance differed substantially by country, one reason for the higher number of ileal perforation cases in Pakistan could be the circulation of XDR strain of S. Typhi in Karachi.

  View details for DOI 10.1093/cid/ciaa1309

  View details for PubMedID 33258928

• Illness Severity and Outcomes Among Enteric Fever Cases From Bangladesh, Nepal, and Pakistan: Data From the Surveillance for Enteric Fever in Asia Project, 2016-2019. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Longley, A. T., Hemlock, C. n., Date, K. n., Luby, S. P., Andrews, J. R., Saha, S. K., Bogoch, I. I., Yousafzai, M. T., Garrett, D. O., Qamar, F. N. 2020; 71 (Supplement_3): S222–S231

  Abstract

  Enteric fever can lead to prolonged hospital stays, clinical complications, and death. The Surveillance for Enteric Fever in Asia Project (SEAP), a prospective surveillance study, characterized the burden of enteric fever, including illness severity, in selected settings in Bangladesh, Nepal, and Pakistan. We assessed disease severity, including hospitalization, clinical complications, and death among SEAP participants.We analyzed clinical and laboratory data from blood culture-confirmed enteric fever cases enrolled in SEAP hospitals and associated network laboratories from September 2016 to September 2019. We used hospitalization and duration of hospital stay as proxies for severity. We conducted a follow-up interview 6 weeks after enrollment to ascertain final outcomes.Of the 8705 blood culture-confirmed enteric fever cases enrolled, we identified 6 deaths (case-fatality ratio, .07%; 95% CI, .01-.13%), 2 from Nepal, 4 from Pakistan, and none from Bangladesh. Overall, 1.7% (90/5205) of patients recruited from SEAP hospitals experienced a clinical complication (Bangladesh, 0.6% [18/3032]; Nepal, 2.3% [12/531]; Pakistan, 3.7% [60/1642]). The most identified complications were hepatitis (n = 36), septic shock (n = 22), and pulmonary complications/pneumonia (n = 13). Across countries, 32% (2804/8669) of patients with hospitalization data available were hospitalized (Bangladesh, 27% [1295/4868]; Nepal, 29% [455/1595]; Pakistan, 48% [1054/2206]), with a median hospital stay of 5 days (IQR, 3-7).While defined clinical complications and deaths were uncommon at the SEAP sites, the high proportion of hospitalizations and prolonged hospital stays highlight illness severity and the need for enteric fever control measures, including the use of typhoid conjugate vaccines.

  View details for DOI 10.1093/cid/ciaa1320

  View details for PubMedID 33258929

• Burden of Culture Confirmed Enteric Fever Cases in Karachi, Pakistan: Surveillance For Enteric Fever in Asia Project (SEAP), 2016-2019. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Yousafzai, M. T., Irfan, S. n., Thobani, R. S., Kazi, A. M., Hotwani, A. n., Memon, A. M., Iqbal, K. n., Qazi, S. H., Saddal, N. S., Rahman, N. n., Dehraj, I. F., Hunzai, M. J., Mehmood, J. n., Garrett, D. O., Saha, S. K., Andrews, J. R., Luby, S. P., Qamar, F. N. 2020; 71 (Supplement_3): S214–S221

  Abstract

  The Surveillance for Enteric Fever in Asia Project (SEAP) is a multicenter, multicountry study conducted in Pakistan, Nepal, and Bangladesh. The objectives of the study were to characterize disease incidence among patients with enteric fever. We report the burden of enteric fever at selected sites of Karachi, Pakistan.During September 2016 to September 2019, prospective surveillance was conducted at inpatient, outpatient, surgical departments, and laboratory networks of Aga Khan University Hospital, Kharadar General Hospital, and surgery units of National Institute of Child Health and Jinnah Postgraduate Medical Centre. Socio-demographic, clinical, and laboratory data were obtained from all suspected or confirmed enteric fever cases.Overall, 22% (2230/10 094) of patients enrolled were culture-positive for enteric fever. 94% (2093/2230) of isolates were Salmonella Typhi and 6% (137/2230) were S. Paratyphi. 15% of isolates multi-drug resistant (MDR) to first-line antibiotics and 60% were extensively drug-resistant (XDR), resistant to first-line antibiotics, fluoroquinolones and third generation cephalosporin.Enteric fever cases have increased during the last 3 years with large proportion of drug resistant S. Typhi cases. However, the burden of paratyphoid is still relatively low. Strengthening the existing surveillance system for enteric fever and antimicrobial resistance at the national level is recommended in Pakistan to inform prevention measures. While typhoid vaccination can significantly decrease the burden of typhoid and may also impact antimicrobial resistance, water, sanitation, and hygiene improvement is highly recommended to prevent the spread of enteric fever.

  View details for DOI 10.1093/cid/ciaa1308

  View details for PubMedID 33258931

• Spatial Heterogeneity of Enteric Fever in 2 Diverse Communities in Nepal. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Tamrakar, D. n., Vaidya, K. n., Yu, A. T., Aiemjoy, K. n., Naga, S. R., Cao, Y. n., Bern, C. n., Shrestha, R. n., Karmacharya, B. M., Pradhan, S. n., Qamar, F. N., Saha, S. n., Date, K. n., Longley, A. T., Hemlock, C. n., Luby, S. n., Garrett, D. O., Bogoch, I. I., Andrews, J. R. 2020; 71 (Supplement_3): S205–S213

  Abstract

  Typhoid fever is endemic in the urban Kathmandu Valley of Nepal; however, there have been no population-based studies of typhoid outside of this community in the past 3 decades. Whether typhoid immunization should be prioritized in periurban and rural communities has been unclear.We performed population-based surveillance for enteric fever in 1 urban catchment (Kathmandu) and 1 periurban and rural catchment (Kavrepalanchok) as part of the Surveillance for Enteric Fever in Asia Project (SEAP). We recruited individuals presenting to outpatient and emergency departments at 2 study hospitals with suspected enteric fever and performed blood cultures. Additionally, we conducted a household survey in each catchment area to characterize care seeking for febrile illness. We evaluated spatial heterogeneity in febrile illness, care seeking, and enteric fever incidence.Between September 2016 and September 2019, we enrolled 5736 participants with suspected enteric fever at 2 study hospitals. Among these, 304 (5.3%) were culture positive for Salmonella Typhi (249 [81.9%]) or Paratyphi A (55 [18.1%]). Adjusted typhoid incidence in Kathmandu was 484 per 100 000 person-years and in Kavrepalanchok was 615 per 100 000 person-years. While all geographic areas for which estimates could be made had incidence >200 per 100 000 person-years, we observed spatial heterogeneity with up to 10-fold variation in incidence between communities.In urban, periurban, and rural communities in and around Kathmandu, we measured a high but heterogenous incidence of typhoid. These findings provide some support for the introduction of conjugate vaccines in Nepal, including outside urban areas, alongside other measures to prevent enteric fever.

  View details for DOI 10.1093/cid/ciaa1319

  View details for PubMedID 33258932

• A Cluster-based, Spatial-sampling Method for Assessing Household Healthcare Utilization Patterns in Resource-limited Settings. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Yu, A. T., Shakya, R. n., Adhikari, B. n., Tamrakar, D. n., Vaidya, K. n., Maples, S. n., Date, K. n., Bogoch, I. I., Bern, C. n., Qamar, F. n., Yousafzai, M. T., Garrett, D. O., Longley, A. T., Hemlock, C. n., Luby, S. n., Aiemjoy, K. n., Andrews, J. R. 2020; 71 (Supplement_3): S239–S247

  Abstract

  Implementation of population-based surveys is resource intensive and logistically demanding, especially in areas with rapidly changing demographics and incomplete or no enumeration of the underlying population and their residences. To remove the need for pre-enumeration and to simplify field logistics for the population healthcare utilization survey used for the Surveillance for Enteric Fever in Asia Project in Nepal, we incorporated a geographic information system-based geosurvey and field mapping system into a single-stage cluster sampling approach.A survey was administered to ascertain healthcare-seeking behavior in individuals with recent suspected enteric fever. Catchment areas were based on residential addresses of enteric fever patients using study facilities; clusters were randomly selected from digitally created grids using available satellite images and all households within clusters were offered enrollment. A tablet-compatible geosurvey and mapping system that allowed for data-syncing and use in areas without cellular data was created using the ArcGIS suite of software.Between January 2017 and November 2018, we surveyed 25 521 households in Nepal (16 769 in urban Kathmandu and 8752 in periurban Kavrepalanchok), representing 84 202 individuals. Overall, the survey participation rate was 90.9%, with geographic heterogeneity in participation rates within each catchment area. Areas with higher average household wealth had lower participation rates.A geographic information system-based geosurvey and field mapping system allowed creation of a virtual household map at the same time as survey administration, enabling a single-stage cluster sampling method to assess healthcare utilization in Nepal for the Surveillance for Enteric Fever in Asia Project . This system removed the need for pre-enumeration of households in sampling areas, simplified logistics and could be replicated in future community surveys.

  View details for DOI 10.1093/cid/ciaa1310

  View details for PubMedID 33258933

• Antimicrobial Resistance in Typhoidal Salmonella: Surveillance for Enteric Fever in Asia Project, 2016-2019. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Qamar, F. N., Yousafzai, M. T., Dehraj, I. F., Shakoor, S. n., Irfan, S. n., Hotwani, A. n., Hunzai, M. J., Thobani, R. S., Rahman, N. n., Mehmood, J. n., Hemlock, C. n., Memon, A. M., Andrews, J. R., Luby, S. P., Garrett, D. O., Longley, A. T., Date, K. n., Saha, S. K. 2020; 71 (Supplement_3): S276–S284

  Abstract

  Clinicians have limited therapeutic options for enteric as a result of increasing antimicrobial resistance, and therefore typhoid vaccination is recommended as a preventive measure. As a part of the Surveillance for Enteric Fever in Asia Project (SEAP), we investigated the extent measured the burden of antimicrobial resistance (AMR) among confirmed enteric fever cases in Bangladesh, Nepal, and Pakistan.From September 2016-September 2019, SEAP recruited study participants of all age groups from its outpatient, inpatient, hospital laboratory, laboratory network, and surgical sites who had a diagnosis of febrile illness that was either suspected or blood culture confirmed for enteric fever. Antimicrobial resistance of isolates was determined by disc diffusion using Clinical and Laboratory Standard Institute cut-off points. We reported the frequency of multidrug resistance (MDR)(resistance to ampicillin, cotrimoxazole, and chloramphenicol), extensive drug resistance (XDR) (MDR plus non-susceptible to fluoroquinolone and any 3rd generation cephalosporins), and fluoroquinolone (FQ) and azithromycin non-susceptibility.We enrolled 8,705 blood culture confirmed enteric fever cases: 4,873 (56%) from Bangladesh, 1,602 (18%) from Nepal and 2,230 (26%) from Pakistan. Of these, 7,591 (87%) were Salmonella Typhi and 1114 (13%) were S. Paratyphi. MDR S. Typhi was identified in 17% (701/4065) of isolates in Bangladesh, and 1% (19/1342) in Nepal. In Pakistan, 16 % (331/2084) of S. Typhi isolates were MDR, and 64% (1319/2074) were XDR. FQ nonsusceptibility among S. Typhi isolates was 98% in Bangladesh, 87% in Nepal, and 95% in Pakistan. Azithromycin non-susceptibility was detected in 77 (2%) in Bangladesh, 9 (.67%) in Nepal and 9 (.59%) isolates in Pakistan. In Pakistan, three (2%) S. Paratyphi isolates were MDR; no MDR S. Paratyphi was reported from Bangladesh or Nepal.Although AMR against S. Paratyphi was low across the three countries, there was widespread drug resistance among S. Typhi, including FQ non-susceptibility and the emergence of XDR S. Typhi in Pakistan, limiting treatment options. As typhoid conjugate vaccine (TCV) is rolled out, surveillance should continue to monitor changes in AMR to inform policies and to monitor drug resistance in S. Paratyphi, for which there is no vaccine.

  View details for DOI 10.1093/cid/ciaa1323

  View details for PubMedID 33258934

• Antibiotic Use Prior to Hospital Presentation Among Individuals With Suspected Enteric Fever in Nepal, Bangladesh, and Pakistan. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Vaidya, K. n., Aiemjoy, K. n., Qamar, F. N., Saha, S. K., Tamrakar, D. n., Naga, S. R., Saha, S. n., Hemlock, C. n., Longley, A. T., Date, K. n., Bogoch, I. I., Garrett, D. O., Luby, S. P., Andrews, J. R. 2020; 71 (Supplement_3): S285–S292

  Abstract

  Antibiotic use prior to seeking care at a hospital may reduce the sensitivity of blood culture for enteric fever, with implications for both clinical care and surveillance. The Surveillance for Enteric Fever in Asia Project (SEAP) is a prospective study of enteric fever incidence in Nepal, Bangladesh, and Pakistan. Nested within SEAP, we evaluated the accuracy of self-reported antibiotic use and investigated the association between antibiotic use and blood culture positivity.Between November 2016 and April 2019, we collected urine samples among a subset of SEAP participants to test for antibiotic use prior to the hospital visit using an antibacterial activity assay. All participants were asked about recent antibiotic use and had a blood culture performed. We used mixed-effect logit models to evaluate the effect of antimicrobial use on blood culture positivity, adjusted for markers of disease severity.We enrolled 2939 patients with suspected enteric fever. Antibiotics were detected in 39% (1145/2939) of urine samples. The correlation between measured and reported antibiotic use was modest (κ = 0.72). After adjusting for disease severity, patients with antibiotics in their urine were slightly more likely to be blood culture positive for enteric fever; however, the effect was not statistically significant (prevalence ratio, 1.22 [95% confidence interval, .99-1.50]).The reliability of self-reported prior antibiotic use was modest among individuals presenting with fever to tertiary hospitals. While antibiotics are likely to reduce the sensitivity of blood culture, our findings indicate that there is still considerable value in performing blood culture for individuals reporting antibiotic use.

  View details for DOI 10.1093/cid/ciaa1333

  View details for PubMedID 33258935

• Diagnostic Value of Clinical Features to Distinguish Enteric Fever From Other Febrile Illnesses in Bangladesh, Nepal, and Pakistan. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Aiemjoy, K. n., Tamrakar, D. n., Saha, S. n., Naga, S. R., Yu, A. T., Longley, A. n., Date, K. n., Hemlock, C. n., Qamar, F. N., Saha, S. K., Luby, S. P., Garrett, D. O., Andrews, J. R., Bogoch, I. I. 2020; 71 (Supplement_3): S257–S265

  Abstract

  Enteric fever, a bacterial infection caused by Salmonella enterica serotypes Typhi and Paratyphi A, frequently presents as a nonlocalizing febrile illness that is difficult to distinguish from other infectious causes of fever. Blood culture is not widely available in endemic settings and, even when available, results can take up to 5 days. We evaluated the diagnostic performance of clinical features, including both reported symptoms and clinical signs, of enteric fever among patients participating in the Surveillance for Enteric Fever in Asia Project (SEAP), a 3-year surveillance study in Bangladesh, Nepal, and Pakistan.Outpatients presenting with ≥3 consecutive days of reported fever and inpatients with clinically suspected enteric fever from all 6 SEAP study hospitals were eligible to participate. We evaluated the diagnostic performance of select clinical features against blood culture results among outpatients using mixed-effect regression models with a random effect for study site hospital. We also compared the clinical features of S. Typhi to S. Paratyphi A among both outpatients and inpatients.We enrolled 20 899 outpatients, of whom 2116 (10.1%) had positive blood cultures for S. Typhi and 297 (1.4%) had positive cultures for S. Paratyphi A. The sensitivity of absence of cough was the highest among all evaluated features, at 65.5% (95% confidence interval [CI], 55.0-74.7), followed by measured fever at presentation at 59.0% (95% CI, 51.6-65.9) and being unable to complete normal activities for 3 or more days at 51.0% (95% CI, 23.8-77.6). A combined case definition of 3 or more consecutive days of reported fever and 1 or more of the following (a) either the absence of cough, (b) fever at presentation, or (c) 3 or more consecutive days of being unable to conduct usual activity--yielded a sensitivity of 94.6% (95% CI, 93.4-95.5) and specificity of 13.6% (95% CI, 9.8-17.5).Clinical features do not accurately distinguish blood culture-confirmed enteric fever from other febrile syndromes. Rapid, affordable, and accurate diagnostics are urgently needed, particularly in settings with limited or no blood culture capacity.

  View details for DOI 10.1093/cid/ciaa1297

  View details for PubMedID 33258936

• Healthcare Utilization Patterns for Acute Febrile Illness in Bangladesh, Nepal, and Pakistan: Results from the Surveillance for Enteric Fever in Asia Project. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Andrews, J. R., Vaidya, K. n., Saha, S. n., Yousafzai, M. T., Hemlock, C. n., Longley, A. n., Aiemjoy, K. n., Yu, A. T., Bogoch, I. I., Tamrakar, D. n., Date, K. n., Saha, S. K., Garrett, D. O., Luby, S. P., Qamar, F. n. 2020; 71 (Supplement_3): S248–S256

  Abstract

  Characterizing healthcare-seeking patterns for acute febrile illness is critical for generating population-based enteric fever incidence estimates from facility-based surveillance data.We used a hybrid model in the Surveillance for Enteric Fever in Asia Project (SEAP) to assess incidence of enteric fever at 6 study hospitals in 3 countries. We recruited individuals presenting to the hospitals and obtained blood cultures to evaluate for enteric fever. For this analysis, we undertook cluster random household surveys in Dhaka, Bangladesh (2 sites); Karachi, Pakistan; Kathmandu, Nepal; and Kavrepalanchok, Nepal between January 2017 and February 2019, to ascertain care-seeking behavior for individuals with 1) fever for ≥3 consecutive days within the past 8 weeks; or 2) fever resulting in hospitalization within the past year. We also collected data about disease severity and household demographics and assets. We used mixed-effect multivariable logistic regression models to identify determinants of healthcare seeking at study hospitals and determinants of culture-confirmed enteric fever.We enrolled 31 841 households (53 926 children) in Bangladesh, 25 510 households (84 196 children and adults) in Nepal, and 21 310 households (108 031 children and adults) in Pakistan. Children <5 years were most likely to be taken to the study hospitals for febrile illness at all sites. Household wealth was positively correlated with healthcare seeking in 4 of 5 study sites, and at least one marker of disease severity was positively associated with healthcare seeking in 3 of 5 catchment areas. Wealth and disease severity were variably predictive of blood culture-confirmed enteric fever.Age, household wealth, and disease severity are important determinants of healthcare seeking for acute febrile illness and enteric fever risk in these communities, and should be incorporated into estimation models for enteric fever incidence.

  View details for DOI 10.1093/cid/ciaa1321

  View details for PubMedID 33258937

• Typhoid and Paratyphoid Cost of Illness in Nepal: Patient and Health Facility Costs From the Surveillance for Enteric Fever in Asia Project II. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Mejia, N. n., Abimbola, T. n., Andrews, J. R., Vaidya, K. n., Tamrakar, D. n., Pradhan, S. n., Shakya, R. n., Garrett, D. O., Date, K. n., Pallas, S. W. 2020; 71 (Supplement_3): S306–S318

  Abstract

  Enteric fever is endemic in Nepal and its economic burden is unknown. The objective of this study was to estimate the cost of illness due to enteric fever (typhoid and paratyphoid) at selected sites in Nepal.We implemented a study at 2 hospitals in Nepal to estimate the cost per case of enteric fever from the perspectives of patients, caregivers, and healthcare providers. We collected direct medical, nonmedical, and indirect costs per blood culture-confirmed case incurred by patients and their caregivers from illness onset until after enrollment and 6 weeks later. We estimated healthcare provider direct medical economic costs based on quantities and prices of resources used to diagnose and treat enteric fever, and procedure frequencies received at these facilities by enrolled patients. We collected costs in Nepalese rupees and converted them into 2018 US dollars.We collected patient and caregiver cost of illness information for 395 patients, with a median cost of illness per case of $59.99 (IQR, $24.04-$151.23). Median direct medical and nonmedical costs per case represented ~3.5% of annual individual labor income. From the healthcare provider perspective, the average direct medical economic cost per case was $79.80 (range, $71.54 [hospital B], $93.43 [hospital A]).Enteric fever can impose a considerable economic burden on patients, caregivers, and health facilities in Nepal. These new estimates of enteric fever cost of illness can improve evaluation and modeling of the costs and benefits of enteric fever-prevention measures.

  View details for DOI 10.1093/cid/ciaa1335

  View details for PubMedID 33258938

• Utilization of Blood Culture in South Asia for the Diagnosis and Treatment of Febrile Illness. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Hemlock, C. n., Luby, S. P., Saha, S. n., Qamar, F. n., Andrews, J. R., Saha, S. K., Tamrakar, D. n., Date, K. n., Longley, A. T., Garrett, D. O., Bogoch, I. I. 2020; 71 (Supplement_3): S266–S275

  Abstract

  Blood culture is the current standard for diagnosing bacteremic illnesses, yet it is not clear how physicians in many low- and middle-income countries utilize blood culture for diagnostic purposes and to inform treatment decisions.We screened suspected enteric fever cases from 6 hospitals in Bangladesh, Nepal, and Pakistan, and enrolled patients if blood culture was prescribed by the treating physician. We used generalized additive regression models to analyze the probability of receiving blood culture by age, and linear regression models to analyze changes by month to the proportion of febrile cases prescribed a blood culture compared with the burden of febrile illness, stratified by hospital. We used logistic regression to analyze predictors for receiving antibiotics empirically. We descriptively reviewed changes in antibiotic therapy by susceptibility patterns and coverage, stratified by country.We screened 30 809 outpatients resulting in 1819 enteric fever cases; 1935 additional cases were enrolled from other hospital locations. Younger outpatients were less likely to receive a blood culture. The association between the number of febrile outpatients and the proportion prescribed blood culture varied by hospital. Antibiotics prescribed empirically were associated with severity and provisional diagnoses, but 31% (1147/3754) of enteric fever cases were not covered by initial therapy; this was highest in Pakistan (50%) as many isolates were resistant to cephalosporins, which were commonly prescribed empirically.Understanding hospital-level communication between laboratories and physicians may improve patient care and timeliness of appropriate antibiotics, which is important considering the rise of antimicrobial resistance.

  View details for DOI 10.1093/cid/ciaa1322

  View details for PubMedID 33258939

• Hospitalization of Pediatric Enteric Fever Cases, Dhaka, Bangladesh, 2017-2019: Incidence and Risk Factors. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Saha, S. n., Sayeed, K. M., Saha, S. n., Islam, M. S., Rahaman, A. n., Islam, M. n., Rahman, H. n., Das, R. n., Hasan, M. M., Uddin, M. J., Tanmoy, A. M., Ahmed, A. S., Luby, S. P., Andrews, J. R., Garrett, D. O., Saha, S. K. 2020; 71 (Supplement_3): S196–S204

  Abstract

  Enteric fever causes substantial morbidity and mortality in low- and middle-income countries. Here, we analyzed Surveillance for Enteric Fever in Asia Project (SEAP) data to estimate the burden of enteric fever hospitalization among children aged <15 years and identify risk factors for hospitalization in Bangladesh.SEAP used hospital surveillance paired with a community-based health-care utilization assessment. In SEAP hospital surveillance, blood was obtained for culture from children aged <15 years with ≥3 days of fever. In the hospital catchment area, a health-care utilization survey (HCUS) was conducted to estimate the proportion of febrile children hospitalized at the study hospitals. We analyzed hospital surveillance and HCUS data to estimate the health care-adjusted incidence of enteric fever hospitalization, and conducted univariable and multivariable logistic regressions.From July 2017 through June 2019, 2243 laboratory-confirmed enteric fever cases were detected in 2 study hospitals; 673 (30%) were hospitalized. The health care-adjusted incidence of enteric fever hospitalization among children <15 years old was 303/100 000 children/year (95% confidence interval [CI], 293-313). Salmonella Typhi contributed most to the enteric fever hospitalization incidence (277/100 000 children/year; 95% CI, 267-287). The incidence was highest among children aged 2 to <5 years (552/100 000 children/year; 95% CI, 522-583), followed by those aged <2 years (316/100 000 children/year; 95% CI, 288-344). Factors independently associated with enteric fever hospitalization included fever duration, diarrhea, vomiting, abdominal pain, and leukocytopenia.We estimated a high burden of hospitalization due to enteric fever among children aged <5 years in Bangladesh. The introduction of a typhoid conjugate vaccine would protect children from typhoid and avert typhoid hospitalizations.

  View details for DOI 10.1093/cid/ciaa1356

  View details for PubMedID 33258942

• Cost-Effectiveness of a Pharmacogenomic Test for Stratified Isoniazid Dosing in Treatment of Active Tuberculosis. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Rens, N. E., Uyl-de Groot, C. A., Goldhaber-Fiebert, J. D., Croda, J. n., Andrews, J. R. 2020

  Abstract

  There is marked interindividual variability in metabolism and resulting toxicity and effectiveness of drugs used for tuberculosis treatment. For isoniazid, mutations in the N-acetyltransferase-2 (NAT2) gene explain over 88% of pharmacokinetic variability. However, weight-based dosing remains the norm globally. The potential clinical impact and cost-effectiveness of pharmacogenomic-guided therapy (PGT) is unknown.We constructed a decision tree model to project lifetime costs and benefits of isoniazid PGT for drug-susceptible tuberculosis in Brazil, South Africa, and India. PGT was modeled to reduce isoniazid toxicity among slow NAT2 acetylators and reduce treatment failure among rapid acetylators. The genotyping test was assumed to cost the same as the GeneXpert test. The main outcomes were costs (2018 USD), quality adjusted life years (QALYs), and incremental cost-effectiveness ratios.In Brazil, PGT gained 19 discounted life years (23 QALYs) and cost $11,064 per 1,000 patients, a value of $476 per QALY gained. In South Africa, PGT gained 15 life years (19 QALYs) and cost $33,182 per 1,000 patients, a value of $1,780 per QALY gained. In India, PGT gained 20 life years (24 QALYs) and cost $13,195 per 1,000 patients, a value of $546 per QALY gained. One-way sensitivity analyses showed the cost-effectiveness to be robust to all input parameters. Probabilistic sensitivity analyses were below per capita GDP in all three countries in 99% of simulations.Isoniazid PGT improves health outcomes and would be cost-effective in the treatment of drug-susceptible tuberculosis in Brazil, South Africa, and India.

  View details for DOI 10.1093/cid/ciz1212

  View details for PubMedID 31905381

• Clinical Validation of a Deep Learning Algorithm for Detection of Pneumonia on Chest Radiographs in Emergency Department Patients with Acute Febrile Respiratory Illness. Journal of clinical medicine Kim, J. H., Kim, J. Y., Kim, G. H., Kang, D. n., Kim, I. J., Seo, J. n., Andrews, J. R., Park, C. M. 2020; 9 (6)

  Abstract

  Early identification of pneumonia is essential in patients with acute febrile respiratory illness (FRI). We evaluated the performance and added value of a commercial deep learning (DL) algorithm in detecting pneumonia on chest radiographs (CRs) of patients visiting the emergency department (ED) with acute FRI. This single-centre, retrospective study included 377 consecutive patients who visited the ED and the resulting 387 CRs in August 2018-January 2019. The performance of a DL algorithm in detection of pneumonia on CRs was evaluated based on area under the receiver operating characteristics (AUROC) curves, sensitivity, specificity, negative predictive values (NPVs), and positive predictive values (PPVs). Three ED physicians independently reviewed CRs with observer performance test to detect pneumonia, which was re-evaluated with the algorithm eight weeks later. AUROC, sensitivity, and specificity measurements were compared between "DL algorithm" vs. "physicians-only" and between "physicians-only" vs. "physicians aided with the algorithm". Among 377 patients, 83 (22.0%) had pneumonia. AUROC, sensitivity, specificity, PPV, and NPV of the algorithm for detection of pneumonia on CRs were 0.861, 58.3%, 94.4%, 74.2%, and 89.1%, respectively. For the detection of 'visible pneumonia on CR' (60 CRs from 59 patients), AUROC, sensitivity, specificity, PPV, and NPV were 0.940, 81.7%, 94.4%, 74.2%, and 96.3%, respectively. In the observer performance test, the algorithm performed better than the physicians for pneumonia (AUROC, 0.861 vs. 0.788, p = 0.017; specificity, 94.4% vs. 88.7%, p < 0.0001) and visible pneumonia (AUROC, 0.940 vs. 0.871, p = 0.007; sensitivity, 81.7% vs. 73.9%, p = 0.034; specificity, 94.4% vs. 88.7%, p < 0.0001). Detection of pneumonia (sensitivity, 82.2% vs. 53.2%, p = 0.008; specificity, 98.1% vs. 88.7%; p < 0.0001) and 'visible pneumonia' (sensitivity, 82.2% vs. 73.9%, p = 0.014; specificity, 98.1% vs. 88.7%, p < 0.0001) significantly improved when the algorithm was used by the physicians. Mean reading time for the physicians decreased from 165 to 101 min with the assistance of the algorithm. Thus, the DL algorithm showed a better diagnosis of pneumonia, particularly visible pneumonia on CR, and improved diagnosis by ED physicians in patients with acute FRI.

  View details for DOI 10.3390/jcm9061981

  View details for PubMedID 32599874

• The household secondary attack rate of SARS-CoV-2: A rapid review. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Fung, H. F., Martinez, L. n., Alarid-Escudero, F. n., Salomon, J. A., Studdert, D. M., Andrews, J. R., Goldhaber-Fiebert, J. D. 2020

  Abstract

  Although much of the public health effort to combat COVID-19 has focused on disease control strategies in public settings, transmission of SARS-CoV-2 within households remains an important problem. The nature and determinants of household transmission are poorly understood.To address this gap, we gathered and analyzed data from 22 published and pre-published studies from 10 countries (20,291 household contacts) that were available through September 2, 2020. Our goal was to combine estimates of the SARS-CoV-2 household secondary attack rate (SAR) and explore variation in estimates of the household SAR.The overall pooled random-effects estimate of the household SAR was 17.1% (95% CI: 13.7-21.2%). In study-level, random-effects meta-regressions stratified by testing frequency (1 test, 2 tests, >2 tests), SAR estimates were 9.2% (95% CI: 6.7-12.3%), 17.5% (95% CI: 13.9-21.8%), and 21.3% (95% CI: 13.8-31.3%), respectively. Household SAR tended to be higher among older adult contacts and among contacts of symptomatic cases.These findings suggest that SAR reported using a single follow-up test may be underestimated and that testing household contacts of COVID-19 cases on multiple occasions may increase the yield for identifying secondary cases.

  View details for DOI 10.1093/cid/ciaa1558

  View details for PubMedID 33045075

• Interferon-gamma release assay for accurate detection of SARS-CoV-2 T cell response. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Murugesan, K. n., Jagannathan, P. n., Pham, T. D., Pandey, S. n., Bonilla, H. F., Jacobson, K. n., Parsonnet, J. n., Andrews, J. R., Weiskopf, D. n., Sette, A. n., Pinsky, B. A., Singh, U. n., Banaei, N. n. 2020

  Abstract

  We investigated feasibility and accuracy of an interferon-gamma release assay (IGRA) for detection of T cell responses to SARS-CoV-2. Whole blood IGRA accurately distinguished between convalescents and uninfected healthy blood donors with a predominantly CD4+ T cell response. SARS-CoV-2 IGRA may serve as a useful diagnostic tool in managing the COVID-19 pandemic.

  View details for DOI 10.1093/cid/ciaa1537

  View details for PubMedID 33035306

• Proinflammatory IgG Fc structures in patients with severe COVID-19 Nature Immunology Chakraborty, S., Gonzales, J., Edwards, K., Mallajosyulla, V., Buzzanco, A. S., Sherwood, R., Buffone, C., Kathale, N., Providenza, S., Xie, M. M., Andrews, J. R., Blish, C. A., Singh, U., Dugan, H., Wilson, P. C., Pham, T. D., Boyd, S. D., Nadeau, K. C., Pinsky, B. A., Zhang, S., Memoli, M. J., Taubenberger, J. K., Morales, T., Schapiro, J. M., Tan, G. S., et al 2020

  View details for DOI 10.1038/s41590-020-00828-7

• Deep learning-based automated detection algorithm for active pulmonary tuberculosis on chest radiographs: diagnostic performance in systematic screening of asymptomatic individuals. European radiology Lee, J. H., Park, S. n., Hwang, E. J., Goo, J. M., Lee, W. Y., Lee, S. n., Kim, H. n., Andrews, J. R., Park, C. M. 2020

  Abstract

  Performance of deep learning-based automated detection (DLAD) algorithms in systematic screening for active pulmonary tuberculosis is unknown. We aimed to validate DLAD algorithm for detection of active pulmonary tuberculosis and any radiologically identifiable relevant abnormality on chest radiographs (CRs) in this setting.We performed out-of-sample testing of a pre-trained DLAD algorithm, using CRs from 19.686 asymptomatic individuals (ages, 21.3 ± 1.9 years) as part of systematic screening for tuberculosis between January 2013 and July 2018. Area under the receiver operating characteristic curves (AUC) for diagnosis of tuberculosis and any relevant abnormalities were measured. Accuracy measures including sensitivities, specificities, positive predictive values (PPVs), and negative predictive values (NPVs) were calculated at pre-defined operating thresholds (high sensitivity threshold, 0.16; high specificity threshold, 0.46).All five CRs from four individuals with active pulmonary tuberculosis were correctly classified as having abnormal findings by DLAD with specificities of 0.959 and 0.997, PPVs of 0.006 and 0.068, and NPVs of both 1.000 at high sensitivity and high specificity thresholds, respectively. With high specificity thresholds, DLAD showed comparable diagnostic measures with the pooled radiologists (p values > 0.05). For the radiologically identifiable relevant abnormality (n = 28), DLAD showed an AUC value of 0.967 (95% confidence interval, 0.938-0.996) with sensitivities of 0.821 and 0.679, specificities of 0.960 and 0.997, PPVs of 0.028 and 0.257, and NPVs of both 0.999 at high sensitivity and high specificity thresholds, respectively.In systematic screening for tuberculosis in a low-prevalence setting, DLAD algorithm demonstrated excellent diagnostic performance, comparable with the radiologists in the detection of active pulmonary tuberculosis.• Deep learning-based automated detection algorithm detected all chest radiographs with active pulmonary tuberculosis with high specificities and negative predictive values in systematic screening. • Deep learning-based automated detection algorithm had comparable diagnostic measures with the radiologists for detection of active pulmonary tuberculosis on chest radiographs. • For the detection of radiologically identifiable relevant abnormalities on chest radiographs, deep learning-based automated detection algorithm showed excellent diagnostic performance in systematic screening.

  View details for DOI 10.1007/s00330-020-07219-4

  View details for PubMedID 32857202

• Increased incarceration rates drive growing tuberculosis burden in prisons and jeopardize overall tuberculosis control in Paraguay. Scientific reports Sequera, V. G., Aguirre, S. n., Estigarribia, G. n., Cellamare, M. n., Croda, J. n., Andrews, J. R., Martinez, L. n., García-Basteiro, A. L. 2020; 10 (1): 21247

  Abstract

  Incarcerated populations are at high-risk to develop tuberculosis (TB), however their impact on the population-level tuberculosis epidemic has been scarcely studied. We aimed to describe the burden and trends of TB among incarcerated populations over time in Paraguay, its clinical and epidemiological differences and the population attributable fraction. This is an observational, descriptive study including all TB cases notified to the National TB control Program in Paraguay during the period 2009-2018. We also used case registries of prisoners diagnosed with tuberculosis from the Minister of Justice. The population attributable fraction of TB in the community due to incarcerated cases was estimated through Levin's formula. The characteristics of TB cases in and outside of prison were compared as well as the characteristics of TB in prisons were modified over time. During 2009-2018, 2764 (9.7%) of the 28,534 TB reported cases in Paraguay occurred in prisons. The number of prisoners in Paraguay increased from 6258 in 2009 to 14,627 in 2018 (incarceration rate, 101 to 207 per 100,000 persons) while the number of TB cases among prisoners increased by 250% (n = 192 in 2009 versus n = 480 in 2018). The annual TB notification rate among male prisoners was 3218 and 3459 per 100,000 inmates in 2009 and 2018, respectively. The percentage of all TB cases occurring among prisoners increased from 7.1% in 2009 to 14.5% in 2018. The relative risk of TB in prisons compared to community was 70.3 (95% CI, 67.7-73.1); the overall population attributable risk was 9.5%. Among the 16 penitentiary centers in the country, two of them-Tacumbú (39.0%) and Ciudad del Este (23.3%)-represent two thirds of all TB cases in prisons. TB among inmates is predominantly concentrated in those 20-34 years old (77.3% of all), twice the percentage of cases for the same age group outside of prison. Our findings show that the TB epidemic in prisons represents one of the most important challenges for TB control in Paraguay, especially in the country's largest cities. Appropriate TB control measures among incarcerated populations are needed and may have substantial impact on the overall TB burden in the country.

  View details for DOI 10.1038/s41598-020-77504-1

  View details for PubMedID 33277515

• The Surveillance for Enteric Fever in Asia Project (SEAP), Severe Typhoid Fever Surveillance in Africa (SETA), Surveillance of Enteric Fever in India (SEFI), and Strategic Typhoid Alliance Across Africa and Asia (STRATAA) Population-based Enteric Fever Studies: A Review of Methodological Similarities and Differences. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Carey, M. E., MacWright, W. R., Im, J. n., Meiring, J. E., Gibani, M. M., Park, S. E., Longley, A. n., Jeon, H. J., Hemlock, C. n., Yu, A. T., Soura, A. n., Aiemjoy, K. n., Owusu-Dabo, E. n., Terferi, M. n., Islam, S. n., Lunguya, O. n., Jacobs, J. n., Gordon, M. n., Dolecek, C. n., Baker, S. n., Pitzer, V. E., Yousafzai, M. T., Tonks, S. n., Clemens, J. D., Date, K. n., Qadri, F. n., Heyderman, R. S., Saha, S. K., Basnyat, B. n., Okeke, I. N., Qamar, F. N., Voysey, M. n., Luby, S. n., Kang, G. n., Andrews, J. n., Pollard, A. J., John, J. n., Garrett, D. n., Marks, F. n. 2020; 71 (Supplement_2): S102–S110

  Abstract

  Building on previous multicountry surveillance studies of typhoid and others salmonelloses such as the Diseases of the Most Impoverished program and the Typhoid Surveillance in Africa Project, several ongoing blood culture surveillance studies are generating important data about incidence, severity, transmission, and clinical features of invasive Salmonella infections in sub-Saharan Africa and South Asia. These studies are also characterizing drug resistance patterns in their respective study sites. Each study answers a different set of research questions and employs slightly different methodologies, and the geographies under surveillance differ in size, population density, physician practices, access to healthcare facilities, and access to microbiologically safe water and improved sanitation. These differences in part reflect the heterogeneity of the epidemiology of invasive salmonellosis globally, and thus enable generation of data that are useful to policymakers in decision-making for the introduction of typhoid conjugate vaccines (TCVs). Moreover, each study is evaluating the large-scale deployment of TCVs, and may ultimately be used to assess post-introduction vaccine impact. The data generated by these studies will also be used to refine global disease burden estimates. It is important to ensure that lessons learned from these studies not only inform vaccination policy, but also are incorporated into sustainable, low-cost, integrated vaccine-preventable disease surveillance systems.

  View details for DOI 10.1093/cid/ciaa367

  View details for PubMedID 32725221

• Environmental Surveillance as a Tool for Identifying High-risk Settings for Typhoid Transmission. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Andrews, J. R., Yu, A. T., Saha, S. n., Shakya, J. n., Aiemjoy, K. n., Horng, L. n., Qamar, F. n., Garrett, D. n., Baker, S. n., Saha, S. n., Luby, S. P. 2020; 71 (Supplement_2): S71–S78

  Abstract

  Enteric fever remains a major cause of morbidity in developing countries with poor sanitation conditions that enable fecal contamination of water distribution systems. Historical evidence has shown that contamination of water systems used for household consumption or agriculture are key transmission routes for Salmonella Typhi and Salmonella Paratyphi A. The World Health Organization now recommends that typhoid conjugate vaccines (TCV) be used in settings with high typhoid incidence; consequently, governments face a challenge regarding how to prioritize typhoid against other emerging diseases. A key issue is the lack of typhoid burden data in many low- and middle-income countries where TCV could be deployed. Here we present an argument for utilizing environmental sampling for the surveillance of enteric fever organisms to provide data on community-level typhoid risk. Such an approach could complement traditional blood culture-based surveillance or even replace it in settings where population-based clinical surveillance is not feasible. We review historical studies characterizing the transmission of enteric fever organisms through sewage and water, discuss recent advances in the molecular detection of typhoidal Salmonella in the environment, and outline challenges and knowledge gaps that need to be addressed to establish environmental sampling as a tool for generating actionable data that can inform public health responses to enteric fever.

  View details for DOI 10.1093/cid/ciaa513

  View details for PubMedID 32725227

• Genomic variant-identification methods may alter Mycobacterium tuberculosis transmission inferences. Microbial genomics Walter, K. S., Colijn, C. n., Cohen, T. n., Mathema, B. n., Liu, Q. n., Bowers, J. n., Engelthaler, D. M., Narechania, A. n., Lemmer, D. n., Croda, J. n., Andrews, J. R. 2020

  Abstract

  Pathogen genomic data are increasingly used to characterize global and local transmission patterns of important human pathogens and to inform public health interventions. Yet, there is no current consensus on how to measure genomic variation. To test the effect of the variant-identification approach on transmission inferences for Mycobacterium tuberculosis, we conducted an experiment in which five genomic epidemiology groups applied variant-identification pipelines to the same outbreak sequence data. We compared the variants identified by each group in addition to transmission and phylogenetic inferences made with each variant set. To measure the performance of commonly used variant-identification tools, we simulated an outbreak. We compared the performance of three mapping algorithms, five variant callers and two variant filters in recovering true outbreak variants. Finally, we investigated the effect of applying increasingly stringent filters on transmission inferences and phylogenies. We found that variant-calling approaches used by different groups do not recover consistent sets of variants, which can lead to conflicting transmission inferences. Further, performance in recovering true variation varied widely across approaches. While no single variant-identification approach outperforms others in both recovering true genome-wide and outbreak-level variation, variant-identification algorithms calibrated upon real sequence data or that incorporate local reassembly outperform others in recovering true pairwise differences between isolates. The choice of variant filters contributed to extensive differences across pipelines, and applying increasingly stringent filters rapidly eroded the accuracy of transmission inferences and quality of phylogenies reconstructed from outbreak variation. Commonly used approaches to identify M. tuberculosis genomic variation have variable performance, particularly when predicting potential transmission links from pairwise genetic distances. Phylogenetic reconstruction may be improved by less stringent variant filtering. Approaches that improve variant identification in repetitive, hypervariable regions, such as long-read assemblies, may improve transmission inference.

  View details for DOI 10.1099/mgen.0.000418

  View details for PubMedID 32735210

• Yield, Efficiency and Costs of Mass Screening Algorithms for Tuberculosis in Brazilian Prisons. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Santos, A. d., Oliveira, R. D., Lemos, E. F., Lima, F. n., Cohen, T. n., Cords, O. n., Martinez, L. n., Gonçalves, C. n., Ko, A. n., Andrews, J. R., Croda, J. n. 2020

  Abstract

  Tuberculosis is a major cause of morbidity and mortality among incarcerated populations globally. We performed mass tuberculosis screening in three prisons and assessed yield, efficiency, and costs associated with various screening algorithms.Between 2017 and 2018, inmates from the three prisons in Brazil were screened for tuberculosis by symptom assessment, chest radiography, sputum testing by Xpert MTB/RIF 4th generation and culture. Chest radiographs were scored by an automated interpretation algorithm (CAD4TB) that was locally calibrated to establish a positivity threshold. Four diagnostic algorithms were evaluated. We assessed the yield (percent of total cases found) and efficiency (prevalence among those screened) for each algorithm. We performed unit costing to estimate the costs of each screening or diagnostic test and calculated the cost per case detected for each algorithm.We screened 5,387 prisoners, of whom 214 (3.9%) were diagnosed with tuberculosis. Compared to other screening strategies initiated with radiography or chest symptoms, the trial of all participants with a single Xpert MTB / RIF sputum test detected 74% of all tuberculosis cases at a cost of $ 249. Performing Xpert MTB/RIF screening tests only on those with symptoms had a similar cost per case diagnosed (US$ 255) but missed as many cases (73 vs 54) as screening all inmates.In this prospective study in three with prisons in high tuberculosis burden countries Brazilian prisons, we found that testing all participants with sputum Xpert MTB/RIF was sensitive approach, while remaining cost-efficient. These results support use of Xpert MTB/RIF for mass screening in tuberculosis-endemic prisons.

  View details for DOI 10.1093/cid/ciaa135

  View details for PubMedID 32064514

• Seasonal drivers of tuberculosis: evidence from over 100 years of notifications in Cape Town. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease Andrews, J. R., Cobelens, F. n., Horsburgh, C. R., Hatherill, M. n., Basu, S. n., Hermans, S. n., Wood, R. n. 2020; 24 (5): 477–84

  Abstract

  BACKGROUND: Tuberculosis incidence varies seasonally in many settings. However, the role of seasonal variation in reactivation vs. transmission is unclear.METHODS: We reviewed data on TB notifications in Cape Town, South Africa, from 1903 to 2017 (exclusive of 1995-2002, which were unavailable). Data from 2003 onward were stratified by HIV status, age and notification status (new vs. retreatment). We performed seasonal decomposition and time-dependent spectral analysis using wavelets to assess periodicity over time. We estimated monthly peak-to-peak seasonal amplitude of notifications as a percentage of the annual notification rate.RESULTS: A seasonal trend was intermittently detected between 1904 and 1994, particularly during periods of high notification rates, but was consistently and strongly evident between 2003 and 2017, with peaks in September through November, following winter. Among young children, a second, higher seasonal peak was observed in March. Seasonal variation was greater in children (<5 years, 54%, 95% CI 47-61; 5-14 years, 63%, 95% CI 58-69) than in adults (36%, 95% CI 33-39).CONCLUSIONS: Stronger seasonal effects were seen in children, in whom progression following recent infection is known to be the predominant driver of disease. These findings may support increased transmission in the winter as an important driver of TB in Cape Town.

  View details for DOI 10.5588/ijtld.19.0274

  View details for PubMedID 32398196

• Identifying priorities for testing and treatment of latent tuberculosis infection in the United States. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Martinez, L. n., Andrews, J. R. 2020

  View details for DOI 10.1093/cid/ciaa850

  View details for PubMedID 32588882

• Evaluation of a Rapid Point-of-Care Multiplex Immunochromatographic Assay for the Diagnosis of Enteric Fever. mSphere Kumar, S. n., Nodoushani, A. n., Khanam, F. n., DeCruz, A. T., Lambotte, P. n., Scott, R. n., Bogoch, I. I., Vaidya, K. n., Calderwood, S. B., Bhuiyan, T. R., Esfandiari, J. n., Ryan, E. T., Qadri, F. n., Andrews, J. R., Charles, R. C. 2020; 5 (3)

  Abstract

  There is a critical need for an improved rapid diagnostic for enteric fever. We have previously demonstrated that serum IgA responses targeting Salmonella enterica serovar Typhi hemolysin E (HlyE) and lipopolysaccharide (LPS) are able to discriminate patients with acute typhoid from healthy controls in areas where enteric fever is endemic (healthy endemic controls) and from patients with other bacterial infections. We now have data demonstrating that IgA antibody responses against these antigens also work well for identifying patients with acute S. Paratyphi A infection. To develop a test for acute enteric fever detection, we have adapted a point-of-care immunochromatographic dual-path platform technology (DPP), which improves on the traditional lateral flow technology by using separate sample and conjugate paths and a compact, portable reader, resulting in diagnostics with higher sensitivity and multiplexing abilities. In this analysis, we have compared our standard enzyme-linked immunosorbent assay (ELISA) method to the DPP method in detecting acute phase plasma/serum anti-HlyE and anti-LPS IgA antibodies in a cohort of patients with culture-confirmed S. Typhi (n = 30) and Paratyphi A infection (n = 20), healthy endemic controls (n = 25), and febrile endemic controls (n = 25). We found that the DPP measurements highly correlated with ELISA results, and both antigens had an area under the curve (AUC) of 0.98 (sensitivity of 92%, specificity of 94%) with all controls and an AUC of 0.98 (sensitivity of 90%, specificity of 96%) with febrile endemic controls. Our results suggest that the point-of-care DPP Typhoid System has high diagnostic accuracy for the rapid detection of enteric fever and warrants further evaluation.IMPORTANCE Enteric fever remains a significant global problem, and control programs are significantly limited by the lack of an optimal assay for identifying individuals with acute infection. This is especially critical considering the recently released World Health Organization (WHO) position paper endorsing the role of the typhoid conjugate vaccine in communities where enteric fever is endemic. A reliable diagnostic test is needed to assess and evaluate typhoid intervention strategies and determine which high-burden areas may benefit most from a vaccine intervention. Our collaborative team has developed and evaluated a point-of-care serodiagnostic assay based on detection of anti-HlyE and LPS IgA. Our finding of the high diagnostic accuracy of the DPP Typhoid System for the rapid detection of enteric fever has the potential to have significant public health impact by allowing for improved surveillance and for control and prevention programs in areas with limited laboratory capacity.

  View details for DOI 10.1128/mSphere.00253-20

  View details for PubMedID 32522777

• Temporal trends in the prevalence of Mycobacterium tuberculosis infection in South African adolescents. The international journal of tuberculosis and lung disease : the official journal of the International Union against Tuberculosis and Lung Disease Bunyasi, E. W., Geldenhuys, H., Mulenga, H., Shenje, J., Luabeya, A. K., Tameris, M., Nemes, E., Mahomed, H., Rozot, V., Wood, R., Scriba, T., Andrews, J. R., Hatherill, M. 2019; 23 (5): 571-578

  Abstract

  South Africa. 1) To measure changes in the adolescent prevalence of latent tuberculous infection (LTBI) between 2005 and 2015, and 2) to evaluate medium-term impact of TB control measures on LTBI prevalence. We compared baseline data from a cohort study (2005-2007) and a vaccine trial (2014-2015) which enrolled adolescents from the same eight South African high schools. LTBI was defined based on QuantiFERON®-TB Gold In-Tube test positivity. We analysed data from 4880 adolescents between 2005 and 2007, and 1968 adolescents between 2014 and 2015, when the average LTBI prevalence was respectively 43.8% (95%CI 28.4-59.1) vs. 48.5% (95%CI 41.1-55.8). Age-specific LTBI prevalence increased between the ages 12 and 18 years by 13% only in lower socio-economic quintile schools, where the average LTBI prevalence was unchanged between the two periods (54% vs. 53%). In the highest socio-economic quintile schools, LTBI prevalence did not increase with age; however, the average LTBI prevalence increased from 20% to 38% between the two periods. Adolescent LTBI prevalence remained high and constant over a decade, suggesting that Mycobacterium tuberculosis transmission to children was not impacted in the medium term by effective TB control efforts. Trends in adolescent LTBI prevalence should be interpreted in the context of the sociodemographic factors that affect the risk of transmission before and during adolescence. .

  View details for DOI 10.5588/ijtld.18.0283

  View details for PubMedID 31097065

• Comparative accuracy of typhoid diagnostic tools: A Bayesian latent-class network analysis. PLoS neglected tropical diseases Arora, P. n., Thorlund, K. n., Brenner, D. R., Andrews, J. R. 2019; 13 (5): e0007303

  Abstract

  Typhoid fevers are infections caused by the bacteria Salmonella enterica serovar Typhi (Salmonella Typhi) and Paratyphi A, B and C (Salmonella Paratyphi). Approximately 17.8 million incident cases of typhoid fever occur annually, and incidence is highest in children. The accuracy of current diagnostic tests of typhoid fever is poorly understood. We aimed to determine the comparative accuracy of available tests for the pediatric population.We first conducted a systematic literature review to identify studies that compared diagnostic tests for typhoid fever in children (aged ≤15 years) to blood culture results. We applied a Bayesian latent-class extension to a network meta-analysis model. We modelled known diagnostic properties of bone marrow culture and the relationship between bone marrow and blood culture as informative priors in a Bayesian framework. We tested sensitivities for the proportion of negative blood samples that were false as well as bone marrow sensitivity and specificity.We found 510 comparisons from 196 studies and 57 specific to the pediatric population. IgM-based tests outperformed their IgG-based counterparts for ELISA and Typhidot tests. The lateral flow IgG test performed comparatively well with 92% sensitivity (72% to 98% across scenario analyses) and 94% specificity. The most sensitive test of those investigated for the South Asian pediatric population was the Reverse Passive Hemagglutination Assay with 96% sensitivity (98% - 100% across scenario analyses). Adding a Widal slide test to other typhoid diagnostics did not substantially improve diagnostic performance beyond the single test alone, however, a lateral flow-based IgG rapid test combined with the typhoid/paratyphoid (TPT) assay yielded improvements in sensitivity without substantial declines in specificity and was the best performing combination test in this setting.In the pediatric population, lateral-flow IgG, TPT and Reverse Passive Hemagglutination tests had high diagnostic accuracy compared to other diagnostics. Combinations of tests may provide a feasible option to increase diagnostic sensitivity. South Asia has the most informed set of data on typhoid diagnostic testing accuracy, and the evidence base in other important regions needs to be expanded.

  View details for PubMedID 31067228

• How Can the Typhoid Fever Surveillance in Africa and the Severe Typhoid Fever in Africa Programs Contribute to the Introduction of Typhoid Conjugate Vaccines? Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Jeon, H. J., Im, J. n., Haselbeck, A. n., Holm, M. n., Rakotozandrindrainy, R. n., Bassiahi, A. S., Panzner, U. n., Mogeni, O. D., Seo, H. J., Lunguya, O. n., Jacobs, J. n., Okeke, I. N., Terferi, M. n., Owusu-Dabo, E. n., Dougan, G. n., Carey, M. n., Steele, A. D., Kim, J. H., Clemens, J. D., Andrews, J. R., Park, S. E., Baker, S. n., Marks, F. n. 2019; 69 (Supplement_6): S417–S421

  Abstract

  The World Health Organization now recommends the use of typhoid conjugate vaccines (TCVs) in typhoid-endemic countries, and Gavi, the Vaccine Alliance, added TCVs into the portfolio of subsidized vaccines. Data from the Severe Typhoid Fever in Africa (SETA) program were used to contribute to TCV introduction decision-making processes, exemplified for Ghana and Madagascar.Data collected from both countries were evaluated, and barriers to and benefits of introduction scenarios are discussed. No standardized methodological framework was applied.The Ghanaian healthcare system differs from its Malagasy counterpart: Ghana features a functioning insurance system, antimicrobials are available nationwide, and several sites in Ghana deploy blood culture-based typhoid diagnosis. A higher incidence of antimicrobial-resistant Salmonella Typhi is reported in Ghana, which has not been identified as an issue in Madagascar. The Malagasy people have a low expectation of provided healthcare and experience frequent unavailability of medicines, resulting in limited healthcare-seeking behavior and extended consequences of untreated disease.For Ghana, high typhoid fever incidence coupled with spatiotemporal heterogeneity was observed. A phased TCV introduction through an initial mass campaign in high-risk areas followed by inclusion into routine national immunizations prior to expansion to other areas of the country can be considered. For Madagascar, a national mass campaign followed by routine introduction would be the introduction scenario of choice as it would protect the population, reduce transmission, and prevent an often-deadly disease in a setting characterized by lack of access to healthcare infrastructure. New, easy-to-use diagnostic tools, potentially including environmental surveillance, should be explored and improved to facilitate identification of high-risk areas.

  View details for DOI 10.1093/cid/ciz629

  View details for PubMedID 31665772

• Investigation of preanalytical variables impacting pathogen cell-free DNA in blood and urine. Journal of clinical microbiology Murugesan, K. n., Hogan, C. A., Palmer, Z. n., Reeve, B. n., Theron, G. n., Andama, A. n., Somoskovi, A. n., Steadman, A. n., Madan, D. n., Andrews, J. n., Croda, J. n., Sahoo, M. K., Cattamanchi, A. n., Pinsky, B. A., Banaei, N. n. 2019

  Abstract

  Pathogen cell-free DNA (pcfDNA) in blood and urine is an attractive biomarker; however, the impact of preanalytical factors is not well understood.Blood and urine samples from healthy donors spiked with cfDNA from Mycobacterium tuberculosis, Salmonella enterica, Aspergillus fumigatus and EBV, and samples from tuberculosis patients were used to evaluate the impact of blood collection tube, urine preservative, processing delay, processing method, freezing and thawing, and sample volume on pcfDNA. PCR cycle threshold (CT) was used to measure amplifiable cfDNA.In spiked samples, median CT for M. tuberculosis, S. enterica, and EBV cfDNA was significantly lower in blood collected in K2EDTA than Streck and PAXgene blood collection tubes, and significantly lower in EDTA-urine than Streck-urine. Blood and urine samples from TB patients preserved with K2EDTA and Tris-EDTA, respectively, showed significantly lower median M. tuberculosis CT compared with Streck blood collection tube and urine preservative. Processing delay increased median pathogen CT for Streck and PAXgene but not K2EDTA blood samples, and for urine preserved with Streck reagent but not EDTA. Double spin compared with single spin plasma separation increased median pathogen CT regardless of blood collection tube. No differences were observed between whole urine and supernatant, and between fresh and thawed plasma and urine after 24 weeks at -80 °C. Larger plasma and urine volume in contrived and patient samples showed a significantly lower median M. tuberculosis CT. These findings suggest large volume single spin K2EDTA-plasma and EDTA-whole urine with up to 24-hour processing delay may optimize pcfDNA detection.

  View details for DOI 10.1128/JCM.00782-19

  View details for PubMedID 31511335

• Detection, survival and infectious potential of Mycobacterium tuberculosis in the environment: A review of the evidence and epidemiological implications. The European respiratory journal Martinez, L. n., Verma, R. n., Croda, J. n., Horsburgh, C. R., Walter, K. S., Degner, N. n., Middelkoop, K. n., Koch, A. n., Hermans, S. n., Warner, D. n., Wood, R. n., Cobelens, F. n., Andrews, J. R. 2019

  Abstract

  Much remains unknown about Mycobacterium tuberculosis transmission. Seminal experimental studies from the 1950s demonstrated that airborne expulsion of droplet nuclei from an infectious tuberculosis patient is the primary route of transmission. However, these findings did not rule out other routes of M. tuberculosis transmission. We reviewed historical scientific evidence from the late 19th and early 20th century and contemporary studies investigating the presence, persistence, and infectiousness of environmental M. tuberculosis We found evidence - both experimental and epidemiological - supporting the presence and viability of M. tuberculosis in multiple natural and built environments for months to years, presumably following contamination by a human source. Further, several studies confirm M. tuberculosis viability and virulence in the environment using guinea pig and mouse models. Most of this evidence was historical; however, several recent studies have reported consistent findings of M. tuberculosis detection and viability in the environment using modern methods. Whether or not M. tuberculosis in environments represents an infectious threat to humans, it may represent an untapped source of data with which to further understand M. tuberculosis transmission. We discuss potential opportunities for harnessing these data to generate new insights into tuberculosis transmission in congregate settings.

  View details for PubMedID 31048345

• Epidemiology of Typhoid and Paratyphoid: Implications for Vaccine Policy. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Saha, S. n., Islam, M. S., Sajib, M. S., Saha, S. n., Uddin, M. J., Hooda, Y. n., Hasan, M. n., Amin, M. R., Hanif, M. n., Shahidullah, M. n., Islam, M. n., Luby, S. P., Andrews, J. R., Saha, S. K. 2019; 68 (Supplement_2): S117–S123

  Abstract

  Typhoid and paratyphoid remain the most common bloodstream infections in many resource-poor settings. The World Health Organization recommends typhoid conjugate vaccines for country-specific introduction, but questions regarding typhoid and paratyphoid epidemiology persist, especially regarding their severity in young children.We conducted enteric fever surveillance in Bangladesh from 2004 through 2016 in the inpatient departments of 2 pediatric hospitals and the outpatient departments of 1 pediatric hospital and 1 private consultation clinic. Blood cultures were conducted at the discretion of the treating physicians; cases of culture-confirmed typhoid/paratyphoid were included. Hospitalizations and durations of hospitalizations were used as proxies for severity in children <12 years old.We identified 7072 typhoid and 1810 paratyphoid culture-confirmed cases. There was no increasing trend in the proportion of paratyphoid over the 13 years. The median age in the typhoid cases was 60 months, and 15% of the cases occurred in children <24 months old. The median age of the paratyphoid cases was significantly higher, at 90 months (P < .001); 9.4% were in children <24 months old. The proportion of children (<12 years old) hospitalized with typhoid and paratyphoid (32% and 21%, respectively) decreased with age; there was no significant difference in durations of hospitalizations between age groups. However, children with typhoid were hospitalized for longer than those with paratyphoid.Typhoid and paratyphoid fever are common in Dhaka, including among children under 2 years old, who have equivalent disease severity as older children. Early immunization with typhoid conjugate vaccines could avert substantial morbidity, but broader efforts are required to reduce the paratyphoid burden.

  View details for PubMedID 30845325

• Building a tuberculosis-free world: The Lancet Commission on tuberculosis. Lancet (London, England) Reid, M. J., Arinaminpathy, N. n., Bloom, A. n., Bloom, B. R., Boehme, C. n., Chaisson, R. n., Chin, D. P., Churchyard, G. n., Cox, H. n., Ditiu, L. n., Dybul, M. n., Farrar, J. n., Fauci, A. S., Fekadu, E. n., Fujiwara, P. I., Hallett, T. B., Hanson, C. L., Harrington, M. n., Herbert, N. n., Hopewell, P. C., Ikeda, C. n., Jamison, D. T., Khan, A. J., Koek, I. n., Krishnan, N. n., Motsoaledi, A. n., Pai, M. n., Raviglione, M. C., Sharman, A. n., Small, P. M., Swaminathan, S. n., Temesgen, Z. n., Vassall, A. n., Venkatesan, N. n., van Weezenbeek, K. n., Yamey, G. n., Agins, B. D., Alexandru, S. n., Andrews, J. R., Beyeler, N. n., Bivol, S. n., Brigden, G. n., Cattamanchi, A. n., Cazabon, D. n., Crudu, V. n., Daftary, A. n., Dewan, P. n., Doepel, L. K., Eisinger, R. W., Fan, V. n., Fewer, S. n., Furin, J. n., Goldhaber-Fiebert, J. D., Gomez, G. B., Graham, S. M., Gupta, D. n., Kamene, M. n., Khaparde, S. n., Mailu, E. W., Masini, E. O., McHugh, L. n., Mitchell, E. n., Moon, S. n., Osberg, M. n., Pande, T. n., Prince, L. n., Rade, K. n., Rao, R. n., Remme, M. n., Seddon, J. A., Selwyn, C. n., Shete, P. n., Sachdeva, K. S., Stallworthy, G. n., Vesga, J. F., Vilc, V. n., Goosby, E. P. 2019

  View details for PubMedID 30904263

• Antibacterial mass drug administration for child mortality reduction: Opportunities, concerns, and possible next steps. PLoS neglected tropical diseases Bogoch, I. I., Utzinger, J. n., Lo, N. C., Andrews, J. R. 2019; 13 (5): e0007315

  View details for DOI 10.1371/journal.pntd.0007315

  View details for PubMedID 31120903

• Identification of widespread antibiotic exposure in cholera patients correlates with clinically relevant microbiota changes. The Journal of infectious diseases Alexandrova, L. n., Haque, F. n., Rodriguez, P. n., Marrazzo, A. C., Grembi, J. A., Ramachandran, V. n., Hryckowian, A. J., Adams, C. M., Siddique, M. S., Khan, A. I., Qadri, F. n., Andrews, J. R., Rahman, M. n., Spormann, A. M., Schoolnik, G. K., Chien, A. n., Nelson, E. J. 2019

  Abstract

  A first step to combating antimicrobial resistance in enteric pathogens is to establish an objective assessment of antibiotic exposure. Our goal was to develop and evaluate a liquid chromatography-ion trap mass spectrometry (LC/MS) method to determine antibiotic exposure in cholera patients.A priority list for targeted LC/MS was generated from medication vendor surveys in Bangladesh. A study of cholera and non-cholera patients was conducted to collect and analyze paired urine and stool samples.Among 845 patients, 11% (n=90) were Vibrio cholerae positive; at least one antibiotic was detected in 86% and at least two in 52% of cholera stools. Among paired urine and stool (n=44), at least one antibiotic was detected in 98% and at least two in 84%, despite 55% self-reporting medication use. Compared to LC/MS, a low-cost antimicrobial detection bio-assay lacked sufficient negative predictive value (10%; 95% CI 6-16). Detection of guideline-recommended antibiotics in stool did (azithromycin; p=0.040) and did not (ciprofloxacin) correlate with V. cholerae suppression. A non-recommended antibiotic (metronidazole) was associated with decreases in anaerobes (Prevotella; p<0.001).The findings suggest there may be no true negative control group when attempting to account for antibiotic exposure in settings like those in this study.

  View details for DOI 10.1093/infdis/jiz299

  View details for PubMedID 31192364

• Clinical evaluation for morbidity associated with soil-transmitted helminth infection in school-age children on Pemba Island, Tanzania. PLoS neglected tropical diseases Bogoch, I. I., Speich, B. n., Lo, N. C., Moser, W. n., Croll, D. n., Ali, S. M., Ame, S. M., Utzinger, J. n., Andrews, J. R., Keiser, J. n. 2019; 13 (7): e0007581

  Abstract

  More than 1.5 billion people are infected with soil-transmitted helminths (Ascaris lumbricoides, hookworm, Strongyloides stercoralis, and Trichuris trichiura), causing an estimated global burden in excess of 3 million disability-adjusted life years. However, the relationship between soil-transmitted helminth infection, adverse health consequences, and beneficial effects of deworming are not well understood.We pursued a detailed longitudinal clinical evaluation of school-age children to evaluate morbidity associated with soil-transmitted helminth infection and responses to treatment. This exploratory study was embedded into a randomized controlled trial. Overall, 434 children, aged 7-14 years, underwent a detailed medical history, physical examination, stool microscopy for soil-transmitted helminths, and hemoglobin (Hb) measurement at baseline. Medical history and stool examination were repeated at 3 and 18 weeks posttreatment. Additionally, Hb measurement was performed at the 18-week treatment follow-up. Logistic regression was employed to assess clinical factors associated with soil-transmitted helminth infection at baseline, and longitudinal data analysis to examine change in health outcomes following treatment over time.All enrolled children were infected with T. trichiura, and randomized into four different treatment interventions. None of the medical history, physical examination, and laboratory (i.e., Hb) findings were associated with A. lumbricoides, hookworm, or S. stercoralis infection at baseline. A composite of physical exam findings for anemia, including pallor of the conjunctiva, nail beds, and palmar creases predicted lower Hb values (-3.8 g/dl, 95% confidence interval (CI): -6.9, -0.6 g/dl). When examining longitudinal trends, we did not find improvements to Hb or face Wong-Baker Likert scale among children with soil-transmitted helminth infection compared to those without infection, although there was a slight trend toward improving Hb values after treating hookworm infection.Our study demonstrates the challenges of measuring morbidity in the context of soil-transmitted helminth infection and treatment, thus confirming the mainly subtle morbidity effects of infection.

  View details for DOI 10.1371/journal.pntd.0007581

  View details for PubMedID 31306433

• Paediatric tuberculosis transmission outside the household: challenging historical paradigms to inform future public health strategies. The Lancet. Respiratory medicine Martinez, L. n., Lo, N. C., Cords, O. n., Hill, P. C., Khan, P. n., Hatherill, M. n., Mandalakas, A. n., Kay, A. n., Croda, J. n., Horsburgh, C. R., Zar, H. J., Andrews, J. R. 2019

  Abstract

  Tuberculosis is a major cause of death and disability among children globally, yet children have been neglected in global tuberculosis control efforts. Historically, tuberculosis in children has been thought of as a family disease, and because of this, household contact tracing of children after identification of an adult tuberculosis case has been emphasised as the principal public health intervention. However, the population-level effect of household contact tracing is predicated on the assumption that most paediatric tuberculosis infections are acquired within the household. In this Personal View, we focus on accumulating scientific evidence indicating that the majority of Mycobacterium tuberculosis transmission to children in high-burden settings occurs in the community, outside of households in which a person has tuberculosis. We estimate the population-attributable fraction of M tuberculosis transmission to children due to household exposures to be between 10% and 30%. M tuberculosis transmission from the household was low (<30%) even in children younger than age 5 years. We propose that an effective public health response to childhood tuberculosis requires comprehensive, community-based interventions, such as active surveillance in select settings, rather than contact tracing alone. Importantly, the historical paradigm that most paediatric transmission occurs in households should be reconsidered on the basis of the scientific knowledge presented.

  View details for PubMedID 31078497

• The global burden of typhoid and paratyphoid fevers: a systematic analysis for the Global Burden of Disease Study 2017. The Lancet. Infectious diseases 2019

  Abstract

  Efforts to quantify the global burden of enteric fever are valuable for understanding the health lost and the large-scale spatial distribution of the disease. We present the estimates of typhoid and paratyphoid fever burden from the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2017, and the approach taken to produce them.For this systematic analysis we broke down the relative contributions of typhoid and paratyphoid fevers by country, year, and age, and analysed trends in incidence and mortality. We modelled the combined incidence of typhoid and paratyphoid fevers and split these total cases proportionally between typhoid and paratyphoid fevers using aetiological proportion models. We estimated deaths using vital registration data for countries with sufficiently high data completeness and using a natural history approach for other locations. We also estimated disability-adjusted life-years (DALYs) for typhoid and paratyphoid fevers.Globally, 14·3 million (95% uncertainty interval [UI] 12·5-16·3) cases of typhoid and paratyphoid fevers occurred in 2017, a 44·6% (42·2-47·0) decline from 25·9 million (22·0-29·9) in 1990. Age-standardised incidence rates declined by 54·9% (53·4-56·5), from 439·2 (376·7-507·7) per 100 000 person-years in 1990, to 197·8 (172·0-226·2) per 100 000 person-years in 2017. In 2017, Salmonella enterica serotype Typhi caused 76·3% (71·8-80·5) of cases of enteric fever. We estimated a global case fatality of 0·95% (0·54-1·53) in 2017, with higher case fatality estimates among children and older adults, and among those living in lower-income countries. We therefore estimated 135·9 thousand (76·9-218·9) deaths from typhoid and paratyphoid fever globally in 2017, a 41·0% (33·6-48·3) decline from 230·5 thousand (131·2-372·6) in 1990. Overall, typhoid and paratyphoid fevers were responsible for 9·8 million (5·6-15·8) DALYs in 2017, down 43·0% (35·5-50·6) from 17·2 million (9·9-27·8) DALYs in 1990.Despite notable progress, typhoid and paratyphoid fevers remain major causes of disability and death, with billions of people likely to be exposed to the pathogens. Although improvements in water and sanitation remain essential, increased vaccine use (including with typhoid conjugate vaccines that are effective in infants and young children and protective for longer periods) and improved data and surveillance to inform vaccine rollout are likely to drive the greatest improvements in the global burden of the disease.Bill & Melinda Gates Foundation.

  View details for DOI 10.1016/S1473-3099(18)30685-6

  View details for PubMedID 30792131

• Molecular mechanism of azithromycin resistance among typhoidal Salmonella stains in Bangladesh identified through passive pediatric surveillance. PLoS neglected tropical diseases Hooda, Y. n., Sajib, M. S., Rahman, H. n., Luby, S. P., Bondy-Denomy, J. n., Santosham, M. n., Andrews, J. R., Saha, S. K., Saha, S. n. 2019; 13 (11): e0007868

  Abstract

  With the rise in fluoroquinolone-resistant Salmonella Typhi and the recent emergence of ceftriaxone resistance, azithromycin is one of the last oral drugs available against typhoid for which resistance is uncommon. Its increasing use, specifically in light of the ongoing outbreak of extensively drug-resistant (XDR) Salmonella Typhi (resistant to chloramphenicol, ampicillin, cotrimoxazole, streptomycin, fluoroquinolones and third-generation cephalosporins) in Pakistan, places selective pressure for the emergence and spread of azithromycin-resistant isolates. However, little is known about azithromycin resistance in Salmonella, and no molecular data are available on its mechanism.We conducted typhoid surveillance in the two largest pediatric hospitals of Bangladesh from 2009-2016. All typhoidal Salmonella strains were screened for azithromycin resistance using disc diffusion and resistance was confirmed using E-tests. In total, we identified 1,082 Salmonella Typhi and Paratyphi A strains; among these, 13 strains (12 Typhi, 1 Paratyphi A) were azithromycin-resistant (MIC range: 32-64 μg/ml) with the first case observed in 2013. We sequenced the resistant strains, but no molecular basis of macrolide resistance was identified by the currently available antimicrobial resistance prediction tools. A whole genome SNP tree, made using RAxML, showed that the 12 Typhi resistant strains clustered together within the 4.3.1.1 sub-clade (H58 lineage 1). We found a non-synonymous single-point mutation exclusively in these 12 strains in the gene encoding AcrB, an efflux pump that removes small molecules from bacterial cells. The mutation changed the conserved amino acid arginine (R) at position 717 to a glutamine (Q). To test the role of R717Q present in azithromycin-resistant strains, we cloned acrB from azithromycin-resistant and sensitive strains, expressed them in E. coli, Typhi and Paratyphi A strains and tested their azithromycin susceptibility. Expression of AcrB-R717Q in E. coli and Typhi strains increased the minimum inhibitory concentration (MIC) for azithromycin by 11- and 3-fold respectively. The azithromycin-resistant Paratyphi A strain also contained a mutation at R717 (R717L), whose introduction in E. coli and Paratyphi A strains increased MIC by 7- and 3-fold respectively, confirming the role of R717 mutations in conferring azithromycin resistance.This report confirms 12 azithromycin-resistant Salmonella Typhi strains and one Paratyphi A strain. The molecular basis of this resistance is one mutation in the AcrB protein at position 717. This is the first report demonstrating the impact of this non-synonymous mutation in conferring macrolide resistance in a clinical setting. With increasing azithromycin use, strains with R717 mutations may spread and be acquired by XDR strains. An azithromycin-resistant XDR strain would shift enteric fever treatment from outpatient departments, where patients are currently treated with oral azithromycin, to inpatient departments to be treated with injectable antibiotics like carbapenems, thereby further burdening already struggling health systems in endemic regions. Moreover, with the dearth of novel antimicrobials in the horizon, we risk losing our primary defense against widespread mortality from typhoid. In addition to rolling out the WHO prequalified typhoid conjugate vaccine in endemic areas to decrease the risk of pan-resistant Salmonella Typhi strains, it is also imperative to implement antimicrobial stewardship and water sanitation and hygiene intervention to decrease the overall burden of enteric fever.

  View details for DOI 10.1371/journal.pntd.0007868

  View details for PubMedID 31730615

• Global, regional, and national burden of tuberculosis, 1990-2016: results from the Global Burden of Diseases, Injuries, and Risk Factors 2016 Study LANCET INFECTIOUS DISEASES Kyu, H., Maddison, E. R., Henry, N. J., Ledesma, J. R., Wiens, K. E., Reiner, R., Biehl, M. H., Shields, C., Osgood-Zimmerman, A., Ross, J. M., Carter, A., Frank, T. D., Wang, H., Srinivasan, V., Abebe, Z., Agarwal, S., Alahdab, F., Alene, K., Ali, B., Alvis-Guzman, N., Andrews, J. R., Antonio, C. T., Atique, S., Atre, S. R., Awasthi, A., Ayele, H., Badali, H., Badawi, A., Barac, A., Bedi, N., Behzadifar, M., Behzadifar, M., Bekele, B., Belay, S., Bensenor, I. M., Butt, Z. A., Carvalho, F., Cercy, K., Christopher, D. J., Daba, A., Dandona, L., Dandona, R., Daryani, A., Demeke, F., Deribe, K., Dharmaratne, S., Doku, D., Dubey, M., Edessa, D., El-Khatib, Z., Enany, S., Fernandes, E., Fischer, F., Garcia-Basteiro, A. L., Gebre, A., Gebregergs, G., Gebremichael, T., Gelano, T., Geremew, D., Gona, P. N., Goodridge, A., Gupta, R., Bidgoli, H., Hailu, G., Hassen, H., Hedayati, M., Henok, A., Hostiuc, S., Hussen, M., Ilesanmi, O., Irvani, S., Jacobsen, K. H., Johnson, S. C., Jonas, J. B., Kahsay, A., Kant, S., Kasaeian, A., Kassa, T., Khader, Y., Khafaie, M., Khalil, I., Khan, E., Khang, Y., Kim, Y., Kochhar, S., Koyanagi, A., Krohn, K. J., Kumar, G., Lakew, A., Leshargie, C., Lodha, R., Macarayan, E., Majdzadeh, R., Martins-Melo, F., Melese, A., Memish, Z. A., Mendoza, W., Mengistu, D., Mengistu, G., Mestrovic, T., Moazen, B., Mohammad, K., Mohammed, S., Mokdad, A. H., Moosazadeh, M., Mousavi, S., Mustafa, G., Nachega, J. B., Long Hoang Nguyen, Son Hoang Nguyen, Trang Huyen Nguyen, Ningrum, D., Nirayo, Y., Vuong Minh Nong, Ofori-Asenso, R., Ogbo, F., Oh, I., Oladimeji, O., Olagunju, A. T., Oren, E., Pereira, D. M., Prakash, S., Qorbani, M., Rafay, A., Rai, R., Ram, U., Rubino, S., Safiri, S., Salomon, J. A., Samy, A. M., Sartorius, B., Satpathy, M., Seyedmousavi, S., Sharif, M., Silva, J., Silveira, D., Singh, J. A., Sreeramareddy, C. T., Tran, B., Tsadik, A., Ukwaja, K., Ullah, I., Uthman, O. A., Vlassov, V., Vollset, S., Vu, G., Weldegebreal, F., Werdecker, A., Yimer, E. M., Yonemoto, N., Yotebieng, M., Naghavi, M., Theo Vos, Hay, S. I., Murray, C. L., GBD TB Collaborators 2018; 18 (12): 1329–49

  Abstract

  Although a preventable and treatable disease, tuberculosis causes more than a million deaths each year. As countries work towards achieving the Sustainable Development Goal (SDG) target to end the tuberculosis epidemic by 2030, robust assessments of the levels and trends of the burden of tuberculosis are crucial to inform policy and programme decision making. We assessed the levels and trends in the fatal and non-fatal burden of tuberculosis by drug resistance and HIV status for 195 countries and territories from 1990 to 2016.We analysed 15 943 site-years of vital registration data, 1710 site-years of verbal autopsy data, 764 site-years of sample-based vital registration data, and 361 site-years of mortality surveillance data to estimate mortality due to tuberculosis using the Cause of Death Ensemble model. We analysed all available data sources, including annual case notifications, prevalence surveys, population-based tuberculin surveys, and estimated tuberculosis cause-specific mortality to generate internally consistent estimates of incidence, prevalence, and mortality using DisMod-MR 2.1, a Bayesian meta-regression tool. We assessed how the burden of tuberculosis differed from the burden predicted by the Socio-demographic Index (SDI), a composite indicator of income per capita, average years of schooling, and total fertility rate.Globally in 2016, among HIV-negative individuals, the number of incident cases of tuberculosis was 9·02 million (95% uncertainty interval [UI] 8·05-10·16) and the number of tuberculosis deaths was 1·21 million (1·16-1·27). Among HIV-positive individuals, the number of incident cases was 1·40 million (1·01-1·89) and the number of tuberculosis deaths was 0·24 million (0·16-0·31). Globally, among HIV-negative individuals the age-standardised incidence of tuberculosis decreased annually at a slower rate (-1·3% [-1·5 to -1·2]) than mortality did (-4·5% [-5·0 to -4·1]) from 2006 to 2016. Among HIV-positive individuals during the same period, the rate of change in annualised age-standardised incidence was -4·0% (-4·5 to -3·7) and mortality was -8·9% (-9·5 to -8·4). Several regions had higher rates of age-standardised incidence and mortality than expected on the basis of their SDI levels in 2016. For drug-susceptible tuberculosis, the highest observed-to-expected ratios were in southern sub-Saharan Africa (13·7 for incidence and 14·9 for mortality), and the lowest ratios were in high-income North America (0·4 for incidence) and Oceania (0·3 for mortality). For multidrug-resistant tuberculosis, eastern Europe had the highest observed-to-expected ratios (67·3 for incidence and 73·0 for mortality), and high-income North America had the lowest ratios (0·4 for incidence and 0·5 for mortality).If current trends in tuberculosis incidence continue, few countries are likely to meet the SDG target to end the tuberculosis epidemic by 2030. Progress needs to be accelerated by improving the quality of and access to tuberculosis diagnosis and care, by developing new tools, scaling up interventions to prevent risk factors for tuberculosis, and integrating control programmes for tuberculosis and HIV.Bill & Melinda Gates Foundation.

  View details for DOI 10.1016/S1473-3099(18)30625-X

  View details for Web of Science ID 000450899900030

  View details for PubMedID 30507459

• Extensively Drug-Resistant Typhoid - Are Conjugate Vaccines Arriving Just in Time? The New England journal of medicine Andrews, J. R., Qamar, F. N., Charles, R. C., Ryan, E. T. 2018; 379 (16): 1493–95

  View details for PubMedID 30332569

• Phenotyping antibiotic resistance with single-cell resolution for the detection of heteroresistance SENSORS AND ACTUATORS B-CHEMICAL Lyu, F., Pan, M., Patil, S., Wang, J., Matin, A. C., Andrews, J. R., Tang, S. Y. 2018; 270: 396–404

  View details for DOI 10.10196/j.snb.2018.05.047

  View details for Web of Science ID 000434011500048

• Improving Tuberculosis Case Finding in Persons Living with Advanced HIV through New Diagnostic Algorithms. American journal of respiratory and critical care medicine Martinez, L., Andrews, J. R. 2018

  View details for PubMedID 30273498

• Integrating Facility-Based Surveillance With Healthcare Utilization Surveys to Estimate Enteric Fever Incidence: Methods and Challenges. The Journal of infectious diseases Andrews, J. R., Barkume, C., Yu, A. T., Saha, S. K., Qamar, F. N., Garrett, D., Luby, S. P. 2018

  Abstract

  Cohort studies and facility-based sentinel surveillance are common approaches to characterizing infectious disease burden, but present trade-offs; cohort studies are resource-intensive and may alter disease natural history, while sentinel surveillance underestimates incidence in the population. Hybrid surveillance, whereby facility-based surveillance is paired with a community-based healthcare utilization assessment, represents an alternative approach to generating population-based disease incidence estimates with moderate resource investments. Here, we discuss this method in the context of the Surveillance for Enteric Fever in Asia Project (SEAP) study. We describe how data are collected and utilized to adjust enteric fever incidence for blood culture sensitivity, facility-based enrollment, and healthcare seeking, incorporating uncertainty in these parameters in the uncertainty around incidence estimates. We illustrate how selection of surveillance sites and their coverage may influence precision and bias, and we identify approaches in the study design and analysis to minimize and control for these biases. Rigorously designed hybrid surveillance systems can be an efficient approach to generating population-based incidence estimates for infectious diseases.

  View details for PubMedID 30184162

• Typhoid conjugate vaccines: a new tool in the fight against antimicrobial resistance. The Lancet. Infectious diseases Andrews, J. R., Baker, S., Marks, F., Alsan, M., Garrett, D., Gellin, B. G., Saha, S. K., Qamar, F. N., Yousafzai, M. T., Bogoch, I. I., Antillon, M., Pitzer, V. E., Kim, J., John, J., Gauld, J., Mogasale, V., Ryan, E. T., Luby, S. P., Lo, N. C. 2018

  Abstract

  Typhoid fever is an acute systemic infectious disease responsible for an estimated 12-20 million illnesses and over 150 000 deaths annually. In March, 2018, a new recommendation was issued by WHO for the programmatic use of typhoid conjugate vaccines in endemic countries. Health economic analyses of typhoid vaccines have informed funding decisions and national policies regarding vaccine rollout. However, by focusing only on averted typhoid cases and their associated costs, traditional cost-effectiveness analyses might underestimate crucial benefits of typhoid vaccination programmes, because the potential effect of typhoid vaccines on the treatment of patients with non-specific acute febrile illnesses is not considered. For every true case of typhoid fever, three to 25 patients without typhoid disease are treated with antimicrobials unnecessarily, conservatively amounting to more than 50 million prescriptions per year. Antimicrobials for suspected typhoid might therefore be an important selective pressure for the emergence and spread of antimicrobial resistance globally. We propose that large-scale, more aggressive typhoid vaccination programmes-including catch-up campaigns in children up to 15 years of age, and vaccination in lower incidence settings-have the potential to reduce the overuse of antimicrobials and thereby reduce antimicrobial resistance in many bacterial pathogens. Funding bodies and national governments must therefore consider the potential for broad reductions in antimicrobial use and resistance in decisions related to the rollout of typhoid conjugate vaccines.

  View details for PubMedID 30170987

• Impact and cost-effectiveness of snail control to achieve disease control targets for schistosomiasis. Proceedings of the National Academy of Sciences of the United States of America Lo, N. C., Gurarie, D. n., Yoon, N. n., Coulibaly, J. T., Bendavid, E. n., Andrews, J. R., King, C. H. 2018

  Abstract

  Schistosomiasis is a parasitic disease that affects over 240 million people globally. To improve population-level disease control, there is growing interest in adding chemical-based snail control interventions to interrupt the lifecycle of Schistosoma in its snail host to reduce parasite transmission. However, this approach is not widely implemented, and given environmental concerns, the optimal conditions for when snail control is appropriate are unclear. We assessed the potential impact and cost-effectiveness of various snail control strategies. We extended previously published dynamic, age-structured transmission and cost-effectiveness models to simulate mass drug administration (MDA) and focal snail control interventions against Schistosoma haematobium across a range of low-prevalence (5-20%) and high-prevalence (25-50%) rural Kenyan communities. We simulated strategies over a 10-year period of MDA targeting school children or entire communities, snail control, and combined strategies. We measured incremental cost-effectiveness in 2016 US dollars per disability-adjusted life year and defined a strategy as optimally cost-effective when maximizing health gains (averted disability-adjusted life years) with an incremental cost-effectiveness below a Kenya-specific economic threshold. In both low- and high-prevalence settings, community-wide MDA with additional snail control reduced total disability by an additional 40% compared with school-based MDA alone. The optimally cost-effective scenario included the addition of snail control to MDA in over 95% of simulations. These results support inclusion of snail control in global guidelines and national schistosomiasis control strategies for optimal disease control, especially in settings with high prevalence, "hot spots" of transmission, and noncompliance to MDA.

  View details for PubMedID 29301964

• Building capacity for advances in tuberculosis research; proceedings of the third RePORT international meeting. Tuberculosis (Edinburgh, Scotland) van der Heijden, Y. F., Abdullah, F. n., Andrade, B. B., Andrews, J. R., Christopher, D. J., Croda, J. n., Ewing, H. n., Haas, D. W., Hatherill, M. n., Horsburgh, C. R., Mave, V. n., Nakaya, H. I., Rolla, V. n., Srinivasan, S. n., Sugiyono, R. I., Ugarte-Gil, C. n., Hamilton, C. n. 2018; 113: 153–62

  Abstract

  RePORT International is a global network of research sites in India, Brazil, Indonesia, South Africa, China, and the Philippines dedicated to collaborative tuberculosis research in the context of HIV. A standardized research protocol (the Common Protocol) guides the enrollment of participants with active pulmonary tuberculosis and contacts into observational cohorts. The establishment of harmonized clinical data and bio-repositories will allow cutting-edge, large-scale advances in the understanding of tuberculosis, including identification of novel biomarkers for progression to active tuberculosis and relapse after treatment. The RePORT International infrastructure aims to support research capacity development through enabling globally-diverse collaborations. To that end, representatives from the RePORT International network sites, funding agencies, and other stakeholders gathered together in Brazil in September 2017 to present updates on relevant research findings and discuss ideas for collaboration. Presenters emphasized research involving biomarker identification for incipient tuberculosis, host immunity and pharmacogenomics, co-morbidities such as HIV and type 2 diabetes mellitus, and tuberculosis transmission in vulnerable and high-risk populations. Currently, 962 active TB participants and 670 household contacts have contributed blood, sputum, urine and microbes to in-country biorepositories. Cross-consortium collaborations have begun sharing data and specimens to analyze molecular and cytokine predictive patterns.

  View details for PubMedID 30514497

• Phase I of the Surveillance for Enteric Fever in Asia Project (SEAP): An Overview and Lessons Learned. The Journal of infectious diseases Barkume, C. n., Date, K. n., Saha, S. K., Qamar, F. N., Sur, D. n., Andrews, J. R., Luby, S. P., Khan, M. I., Freeman, A. n., Yousafzai, M. T., Garrett, D. n. 2018

  Abstract

  The objective of Phase I of the Surveillance for Enteric Fever in Asia Project (SEAP), a multiphase surveillance study characterizing the burden of disease in South Asia, was to inform data collection for prospective surveillance and to capture clinical aspects of disease.Through a retrospective record review conducted at hospitals in Bangladesh, India, Nepal, and Pakistan, we examined laboratory and clinical records to assess the culture positivity rate for Salmonella Typhi and Salmonella Paratyphi, age and sex distribution, and antimicrobial susceptability in each country.Of all blood cultures performed in Bangladesh, India, Nepal, and Pakistan, 1.5%, 0.43%, 2%, and 1.49%, respectively, were positive for S. Typhi and 0.24%, 0.1%, 0.5%, and 0.67%, respectively, were positive for S. Paratyphi. A higher proportion of laboratory-confirmed infections in Bangladesh and Pakistan were aged ≤5 years, while India and Nepal had a higher proportion of participants aged 15-25 years. In all countries, the sex of the majority of participants was male. The majority of isolates in all countries were resistant to fluoroquinolones, with a high proportion also resistant to ampicillin, chloramphenicol, and trimethoprim-sulfamethoxazole.Enteric fever remains endemic in South Asia. Data generated by this study can help inform strategies for implementation and evaluation of prevention and control measures.

  View details for PubMedID 30304505

• Evaluating PCR-Based Detection of Salmonella Typhi and Paratyphi A in the Environment as an Enteric Fever Surveillance Tool. The American journal of tropical medicine and hygiene Saha, S. n., Tanmoy, A. M., Andrews, J. R., Sajib, M. S., Yu, A. T., Baker, S. n., Luby, S. P., Saha, S. K. 2018

  Abstract

  With prequalification of a typhoid conjugate vaccine by the World Health Organization, countries are deciding whether and at what geographic scale to provide the vaccine. Optimal local data to clarify typhoid risk are expensive and often unavailable. To determine whether quantitative real-time PCR can be used as a tool to detect typhoidal Salmonella DNA in the environment and approximate the burden of enteric fever, we tested water samples from urban Dhaka, where enteric fever burden is high, and rural Mirzapur, where enteric fever burden is low and sporadic. Sixty-six percent (38/59) of the water sources of Dhaka were contaminated with typhoidal Salmonella DNA, in contrast to none of 33 samples of Mirzapur. If these results can be replicated in larger scale in Bangladesh and other enteric fever endemic areas, drinking water testing could become a low-cost approach to determine the presence of typhoidal Salmonella in the environment that can, in turn, guide informed-design of blood culture-based surveillance and thus assist policy decisions on investing to control typhoid.

  View details for PubMedID 30426919

• Assessing the Risk of Vaccine-derived Outbreaks After Reintroduction of Oral Poliovirus Vaccine in Postcessation Settings. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Fu, R. n., Altamirano, J. n., Sarnquist, C. C., Maldonado, Y. A., Andrews, J. R. 2018; 67 (suppl_1): S26–S34

  Abstract

  The Polio Eradication and Endgame Strategic Plan 2013-2018 calls for the gradual withdrawal of oral poliovirus vaccine (OPV) from routine immunization. We aimed to quantify the transmission potential of Sabin strains from OPV when it is reintroduced, accidentally or deliberately, in a community vaccinated with inactivated poliovirus vaccine alone.We built an individual-based stochastic epidemiological model that allows independent spread of 3 Sabin serotypes and differential transmission rates within versus between households. Model parameters were estimated by fitting to data from a prospective cohort in Mexico. We calculated the effective reproductive number for the Mexico cohort and simulated scenarios of Sabin strain resurgence under postcessation conditions, projecting the risk of prolonged circulation, which could lead to circulating vaccine-derived poliovirus (cVDPV).The estimated effective reproductive number for naturally infected individuals was about 1 for Sabin 2 and Sabin 3 (OPV2 and OPV3) in a postcessation setting. Most transmission events occurred between households. We estimated the probability of circulation for >9 months to be (1) <1% for all 3 serotypes when 90% of children <5 years of age were vaccinated in a hypothetical outbreak control campaign; (2) 45% and 24% for Sabin 2 and Sabin 3, respectively, when vaccine coverage dropped to 10%; (3) 37% and 8% for Sabin 2 and Sabin 3, respectively, when a single active shedder appeared in a community.Critical factors determining the risk of cVDPV emergence are the scale at which OPV is reintroduced and the between-household transmission rate for poliovirus, with intermediate values posing the greatest risk.

  View details for PubMedID 30376087

• Assessment of Validity of a Blood-Based 3-Gene Signature Score for Progression and Diagnosis of Tuberculosis, Disease Severity, and Treatment Response JAMA Network Open Warsinske, H. C., Rao, A. M., Moreira, F. M., Santos, P. M., Liu, A. B., Scott, M., Malherbe, S. T., Ronacher, K., Walzl, G., Winter, J., Sweeney, T. E., Croda, J., Andrews, J. R., Khatri, P. 2018; 1 (6): e183779
• Spatially targeted screening to reduce tuberculosis transmission in high-incidence settings. The Lancet. Infectious diseases Cudahy, P. G., Andrews, J. R., Bilinski, A. n., Dowdy, D. W., Mathema, B. n., Menzies, N. A., Salomon, J. A., Shrestha, S. n., Cohen, T. n. 2018

  Abstract

  As the leading infectious cause of death worldwide and the primary proximal cause of death in individuals living with HIV, tuberculosis remains a global concern. Existing tuberculosis control strategies that rely on passive case-finding appear insufficient to achieve targets for reductions in tuberculosis incidence and mortality. Active case-finding strategies aim to detect infectious individuals earlier in their infectious period to reduce onward transmission and improve treatment outcomes. Empirical studies of active case-finding have produced mixed results and determining how to direct active screening to those most at risk remains a topic of intense research. Our systematic review of literature evaluating the effects of geographically targeted tuberculosis screening interventions found three studies in low tuberculosis incidence settings, but none conducted in high tuberculosis incidence countries. We discuss open questions related to the use of spatially targeted approaches for active screening in countries where tuberculosis incidence is highest.

  View details for PubMedID 30554997

• Advances in the understanding of Mycobacterium tuberculosis transmission in HIV-endemic settings. The Lancet. Infectious diseases Peters, J. S., Andrews, J. R., Hatherill, M. n., Hermans, S. n., Martinez, L. n., Schurr, E. n., van der Heijden, Y. n., Wood, R. n., Rustomjee, R. n., Kana, B. D. 2018

  Abstract

  Tuberculosis claims more human lives than any other infectious disease. This alarming epidemic has fuelled the development of novel antimicrobials and diagnostics. However, public health interventions that interrupt transmission have been slow to emerge, particularly in HIV-endemic settings. Transmission of tuberculosis is complex, involving various environmental, bacteriological, and host factors, among which concomitant HIV infection is important. Preventing person-to-person spread is central to halting the epidemic and, consequently, tuberculosis transmission is now being studied with renewed interest. In this Series paper, we review recent advances in the understanding of tuberculosis transmission, from the view of source-case infectiousness, inherent susceptibility of exposed individuals, appending tools for predicting risk of disease progression, the biophysical nature of the contagion, and the environments in which transmission occurs and is sustained in populations. We focus specifically on how HIV infection affects these features with a view to describing novel transmission blocking strategies in HIV-endemic settings.

  View details for PubMedID 30554995

• Investigating spillover of multidrug-resistant tuberculosis from a prison: a spatial and molecular epidemiological analysis. BMC medicine Warren, J. L., Grandjean, L. n., Moore, D. A., Lithgow, A. n., Coronel, J. n., Sheen, P. n., Zelner, J. L., Andrews, J. R., Cohen, T. n. 2018; 16 (1): 122

  Abstract

  Congregate settings may serve as institutional amplifiers of tuberculosis (TB) and multidrug-resistant tuberculosis (MDR-TB). We analyze spatial, epidemiological, and pathogen genetic data prospectively collected from neighborhoods surrounding a prison in Lima, Peru, where inmates experience a high risk of MDR-TB, to investigate the risk of spillover into the surrounding community.Using hierarchical Bayesian statistical modeling, we address three questions regarding the MDR-TB risk: (i) Does the excess risk observed among prisoners also extend outside the prison? (ii) If so, what is the magnitude, shape, and spatial range of this spillover effect? (iii) Is there evidence of additional transmission across the region?The region of spillover risk extends for 5.47 km outside of the prison (95% credible interval: 1.38, 9.63 km). Within this spillover region, we find that nine of the 467 non-inmate patients (35 with MDR-TB) have MDR-TB strains that are genetic matches to strains collected from current inmates with MDR-TB, compared to seven out of 1080 patients (89 with MDR-TB) outside the spillover region (p values: 0.022 and 0.008). We also identify eight spatially aggregated genetic clusters of MDR-TB, four within the spillover region, consistent with local transmission among individuals living close to the prison.We demonstrate a clear prison spillover effect in this population, which suggests that interventions in the prison may have benefits that extend to the surrounding community.

  View details for PubMedID 30071850

• Plasma IgA responses against two Salmonella Typhi antigens identify patients with typhoid fever. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Andrews, J. R., Khanam, F. n., Rahman, N. n., Hossain, M. n., Bogoch, I. I., Vaidya, K. n., Kelly, M. n., Calderwood, S. B., Bhuiyan, T. R., Ryan, E. T., Qadri, F. n., Charles, R. C. 2018

  Abstract

  There is a need for a reliable, simple diagnostic assay for typhoid fever. Available commercial serologic assays for typhoid fever have limited sensitivity and specificity. Using high-throughput immuno-screening technologies, we previously identified several immuno-reactive Salmonella Typhi antigens that appear promising for possible inclusion in a new diagnostic assay: hemolysin E (HlyE); cytolethal distending toxin (CdtB), S. Typhi LPS, and S. Typhi membrane preparation (MP).We assessed plasma antibody responses (IgM, IgA, and IgG) to these antigens via ELISA in patients with suspected enteric fever, controls with other febrile illnesses, and healthy controls in Dhaka, Bangladesh and performed Tubex, Typhidot, Widal and the Typhoid/Paratyphoid test (TPTest) on each patient. Using machine learning methods, we identified a parsimonious serology signature to distinguish acute typhoid cases from controls and then validated our findings in an independent test cohort from Nepal of culture-confirmed S. Typhi patients and controls with other bacteremic illnesses.We identified anti-MP IgG and IgA plasma responses to HlyE, LPS, and MP as important predictors of acute typhoid in the Bangladesh cohort. Using our Nepalese validation cohort, we demonstrated that the use of two antigens (HlyE and LPS) with one antibody isotype (IgA) could distinguish typhoid from other invasive bacterial infections (AUC 0.95; sensitivity 90%, specificity 92%). Use of a single antigen (HlyE) and isotype (IgA) had an AUC of 0.93.Our results suggest that development of a diagnostic assay for acute typhoid fever focused on detecting IgA responses against HlyE, with or without LPS, is warranted.

  View details for PubMedID 30020426

• Suicide in Brazilian indigenous communities: clustering of cases in children and adolescents by household. Revista de saude publica Lazzarini, T. A., Gonçalves, C. C., Benites, W. M., Silva, L. F., Tsuha, D. H., Ko, A. I., Rohrbaugh, R. n., Andrews, J. R., Croda, J. n. 2018; 52: 56

  Abstract

  OBJECTIVE To estimate age and sex-specific suicide rates, compare suicide rates between indigenous communities, and quantify the frequency of intrafamilial suicide clustering. METHODS We performed a retrospective cohort study involving 14,666 indigenous individuals in reservations in Dourados, state of Mato Grosso do Sul, Brazil, from 2003 through 2013 using national and local census. RESULTS The overall suicide rate was 73.4 per 100,000 person-years. Adolescent males aged 15-19 and girls aged 10-14 had the highest rates for each sex at 289.3 (95%CI 187.5-391.2) and 85.3 (95%CI 34.9-135.7), respectively. Comparing the largest reservations, Bororo had a higher suicide rate than Jaguapiru (RR = 4.83, 95%CI 2.85-8.16) and had significantly lower socioeconomic indicators including income and access to electricity. Nine of 19 suicides among children under 15 occurred in household clusters. Compared with adult suicides, a greater proportion of child (OR = 5.12, 95%CI 1.89-13.86, p = 0.001) and adolescent (OR = 3.48, 95%CI 1.29-9.44, p = 0.017) suicides occurred within household clusters. CONCLUSIONS High rates of suicide occur among children and adolescents in these indigenous reservations, particularly in poor communities. Nearly half of child suicides occur within household clusters. These findings underscore the need for broad public health interventions and focused mental health interventions in households following a suicide.

  View details for PubMedID 29791676

• What is the best immunization strategy for protecting African children against invasive Salmonella disease? Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Jeon, H. J., Pak, G. D., Im, J. n., Owusu-Dabo, E. n., Adu-Sarkodie, Y. n., Gassama Sow, A. n., Bassiahi, A. S., Gasmelseed, N. n., Keddy, K. H., Bjerregaard-Andersen, M. n., Konings, F. n., Aseffa, A. n., Crump, J. A., Chon, Y. n., Breiman, R. F., Park, S. E., Cruz Espinoza, L. M., Seo, H. J., May, J. n., Meyer, C. G., Andrews, J. R., Panzner, U. n., von Kalckreuth, V. n., Wierzba, T. F., Rakotozandrindrainy, R. n., Dougan, G. n., Levine, M. M., Hombach, J. n., Kim, J. H., Clemens, J. D., Baker, S. n., Marks, F. n. 2018

  Abstract

  The WHO recently prequalified a typhoid conjugate vaccine (TCV), recommending its use in persons aged ≥6 months to 45 years residing in typhoid fever (TF)-endemic areas. We now need to consider how TCVs can have the greatest impact in the most vulnerable populations in Africa.The Typhoid Fever Surveillance in Africa Program (TSAP) in 10 sub-Saharan African countries included blood culture-based surveillance in febrile people presenting at healthcare-facilities originating from defined catchment areas. The TF/invasive non-typhoidal Salmonella (iNTS) disease incidences were estimated for 0-10 year-old children in yearly increments.Salmonella Typhi and iNTS were the most frequently isolated pathogens, 135 and 94 cases were identified, respectively. Isolates (12 and 4, respectively) from Ethiopia, Senegal and South Africa were excluded due to person-years of observation (PYO) data absence. 37/123 (30.1%) TF and 71/90 (78.9%) iNTS disease cases occurred among individuals aged <5 years. No TF and 8/90 (8.9%) iNTS-infections were observed in children aged <9 months. The TF incidences (/100,000 PYO) for children aged <1 year and 1-<2 years were 5 and 39, respectively; the highest incidence was 304/100,000 PYO in 4-<5 year-old children. The iNTS incidence in the defined age groups ranged between 81 and 233/100,000 PYO, with the highest incidence in 1-<2 year-old children. Higher TF/iNTS disease incidences were observed in West Africa.The high TF burden observed in TSAP merits TCV introductions. Considering the additional iNTS disease burden, a trivalent vaccine targeting S. Typhi, S. Typhimurium, and S. Enteritidis may be a future solution.

  View details for PubMedID 29746615

• Drivers of seasonal variation in tuberculosis incidence: insights from a systematic review and mathematical model. Epidemiology (Cambridge, Mass.) Tedijanto, C. n., Hermans, S. n., Cobelens, F. n., Wood, R. n., Andrews, J. R. 2018

  Abstract

  Seasonality in tuberculosis incidence has been widely observed across countries and populations; however, its drivers are poorly understood. We conducted a systematic review of studies reporting seasonal patterns in tuberculosis to identify demographic and ecologic factors associated with timing and magnitude of seasonal variation.We identified studies reporting seasonal variation in tuberculosis incidence through PubMed and EMBASE and extracted incidence data and population metadata. We described key factors relating to seasonality and, when data permitted, quantified seasonal variation and its association with metadata. We developed a dynamic tuberculosis natural history and transmission model incorporating seasonal differences in disease progression and/or transmission rates to examine magnitude of variation required to produce observed seasonality in incidence.Fifty-seven studies met inclusion criteria. In the majority of studies (n=49), tuberculosis incidence peaked in spring or summer and reached a trough in late fall or winter. A standardized seasonal amplitude was calculated for 34 of the studies, resulting in a mean of 17.1% (range: 2.7-85.5%) after weighting by sample size. Across multiple studies, stronger seasonality was associated with younger patients, extrapulmonary disease, and latitudes farther from the Equator. The mathematical model was generally able to reproduce observed levels of seasonal case variation; however, substantial variation in transmission and/or disease progression risk was required to replicate several extreme values.We observed seasonal variation in tuberculosis, with consistent peaks occurring in spring, across countries with varying tuberculosis burden. Future research is needed to explore and quantify potential gains from strategically conducting mass screening interventions in the spring.

  View details for PubMedID 29870427

• Deworming in pre-school age children: A global empirical analysis of health outcomes. PLoS neglected tropical diseases Lo, N. C., Snyder, J. n., Addiss, D. G., Heft-Neal, S. n., Andrews, J. R., Bendavid, E. n. 2018; 12 (5): e0006500

  Abstract

  There is debate over the effectiveness of deworming children against soil-transmitted helminthiasis (STH) to improve health outcomes, and current evidence may be limited in study design and generalizability. However, programmatic deworming continues throughout low and middle-income countries.We performed an empirical evaluation of the relationship between deworming in pre-school age children (ages 1-4 years) within the previous 6 months, as proxy-reported by the mother, and health outcomes of weight, height, and hemoglobin. We used nationally representative cross-sectional data from 45 countries using the Demographic and Health Surveys (DHS) during the period 2005-2016. We used logistic regression with coarsened exact matching, fixed effects for survey and year, and person-level covariates. We included data on 325,115 children in 45 STH-endemic countries from 66 DHS surveys. Globally in STH-endemic countries, children who received deworming treatment were less likely to be stunted (1.2 percentage point decline from mean of 36%; 95% CI [-1.9, -0.5%]; p<0.001), but we did not detect consistent associations between deworming and anemia or weight. In sub-Saharan Africa, we found that children who received deworming treatment were less likely to be stunted (1.1 percentage point decline from mean of 36%; 95% CI [-2.1, -0.2%]; p = 0.01) and less likely to have anemia (1.8 percentage point decline from mean of 58%; 95% CI [-2.8, -0.7%]; p<0.001), but we did not detect consistent associations between deworming and weight. These findings were robust across multiple statistical models, and we did not find consistently measurable associations with data from non-endemic settings.Among pre-school age children, we detected a robust and consistent association between deworming and reduced stunting, with additional evidence for reduced anemia in sub-Saharan Africa. We did not find a consistent relationship between deworming and improved weight. This global empirical analysis provides evidence to support the deworming of pre-school age children.

  View details for PubMedID 29852012

• Serum vitamin D levels and risk of prevalent tuberculosis, incident tuberculosis and tuberculin skin test conversion among prisoners. Scientific reports Maceda, E. B., Gonçalves, C. C., Andrews, J. R., Ko, A. I., Yeckel, C. W., Croda, J. n. 2018; 8 (1): 997

  Abstract

  Poor vitamin D status has been associated with tuberculosis (TB); whether poor status is cause or consequence of disease is uncertain. We conducted a case-control study and two nested case-control studies to determine whether vitamin D levels were associated with active TB, tuberculin skin test (TST) conversion, and risk of progression to the active TB in prisoners in Brazil. In multivariable conditional logistic regression, subnormal vitamin D levels (OR, 3.77; 95% CI, 1.04-13.64) were more likely in prisoners with active TB. In contrast, vitamin D was not found to be a risk factor for either TST conversion (OR, 2.49; 95% CI, 0.64-9.66) or progression to active disease (OR, 0.59; 95% CI, 0.13-2.62). Black race (OR, 11.52; 95% CI, 2.01-63.36), less than 4 years of schooling (OR, 2.70; 95% CI, 0.90-8.16), cigarette smoking (OR, 0.23; 95% CI, 0.06-0.79) were identified as risk factors for TST conversion. Risk of progression to active TB was found to be associated with cigarette smoking (OR, 7.42; 95% CI, 1.23-44.70). Our findings in the prison population show that poor vitamin D status is more common in individuals with active TB, but is not a risk factor for acquisition of latent TB or progression to active TB.

  View details for PubMedID 29343733

• Invasive Pomacea snails as important intermediate hosts of Angiostrongylus cantonensis in Laos, Cambodia and Vietnam: implications for outbreaks of eosinophilic meningitis. Acta tropica Lv, S. n., Guo, Y. H., Nguyen, H. M., Sinuon, M. n., Sayasone, S. n., Lo, N. C., Zhou, X. N., Andrews, J. R. 2018

  Abstract

  The rat lungworm Angiostrongylus cantonensis causes human eosinophilic meningitis and it is endemic in Southeast Asia, but little is known about its distribution in Laos, Cambodia and Vietnam. We conducted a multi-country survey for A. cantonensis in these countries to estimate its prevalence in snails along the Mekong River and the east coast of Vietnam. We identified Angiostrongylus species by morphological and molecular analysis. We found A. cantonensis in the invasive snail, Pomacea spp. The wide accessibility of Pomacea snails, along with their infection by A. cantonensis, indicates that this snail species could be used in surveillance for preventing outbreaks of eosinophilic meningitis.

  View details for PubMedID 29574000

• Comparison of Strategies and Incidence Thresholds for Vi Conjugate Vaccines Against Typhoid Fever: A Cost-effectiveness Modeling Study. The Journal of infectious diseases Lo, N. C., Gupta, R. n., Stanaway, J. D., Garrett, D. O., Bogoch, I. I., Luby, S. P., Andrews, J. R. 2018

  Abstract

  Typhoid fever remains a major public health problem globally. While new Vi conjugate vaccines hold promise for averting disease, the optimal programmatic delivery remains unclear. We aimed to identify the strategies and associated epidemiologic conditions under which Vi conjugate vaccines would be cost-effective.We developed a dynamic, age-structured transmission and cost-effectiveness model that simulated multiple vaccination strategies with a typhoid Vi conjugate vaccine from a societal perspective. We simulated 10-year vaccination programs with (1) routine immunization of infants (aged <1 year) through the Expanded Program on Immunization (EPI) and (2) routine immunization of infants through the EPI plus a 1-time catch-up campaign in school-aged children (aged 5-14 years). In the base case analysis, we assumed a 0.5% case-fatality rate for all cases of clinically symptomatic typhoid fever and defined strategies as highly cost-effective by using the definition of a low-income country (defined as a country with a gross domestic product of $1045 per capita). We defined incidence as the true number of clinically symptomatic people in the population per year.Vi conjugate typhoid vaccines were highly cost-effective when administered by routine immunization activities through the EPI in settings with an annual incidence of >50 cases/100000 (95% uncertainty interval, 40-75 cases) and when administered through the EPI plus a catch-up campaign in settings with an annual incidence of >130 cases/100000 (95% uncertainty interval, 50-395 cases). The incidence threshold was sensitive to the typhoid-related case-fatality rate, carrier contribution to transmission, vaccine characteristics, and country-specific economic threshold for cost-effectiveness.Typhoid Vi conjugate vaccines would be highly cost-effective in low-income countries in settings of moderate typhoid incidence (50 cases/100000 annually). These results were sensitive to case-fatality rates, underscoring the need to consider factors contributing to typhoid mortality (eg, healthcare access and antimicrobial resistance) in the global vaccination strategy.

  View details for PubMedID 29444257

• Development of a new dipstick (Cholkit) for rapid detection of Vibrio cholerae O1 in acute watery diarrheal stools. PLoS neglected tropical diseases Sayeed, M. A., Islam, K. n., Hossain, M. n., Akter, N. J., Alam, M. N., Sultana, N. n., Khanam, F. n., Kelly, M. n., Charles, R. C., Kováč, P. n., Xu, P. n., Andrews, J. R., Calderwood, S. B., Amin, J. n., Ryan, E. T., Qadri, F. n. 2018; 12 (3): e0006286

  Abstract

  Recognizing cholera cases early, especially in the initial phase of an outbreak and in areas where cholera has not previously circulated, is a high public health priority. Laboratory capacity in such settings is often limited. To address this, we have developed a rapid diagnostic test (RDT) termed Cholkit that is based on an immunochromatographic lateral flow assay for the diagnosis of cholera cases using stool. Cholkit contains a monoclonal antibody (ICL-33) to the O-specific polysaccharide (OSP) component of V. cholerae O1 lipopolysaccharide, and recognizes both Inaba and Ogawa serotypes. We tested the Cholkit dipstick using fresh stool specimens of 76 adults and children presenting with acute watery diarrhea at the icddr,b hospital in Dhaka, Bangladesh. We compared Cholkit's performance with those of microbial culture, PCR (targeting the rfb and ctxA genes of V. cholerae) and the commercially available RDT, Crystal VC (Span Diagnostics; Surat, India). We found that all stool specimens with a positive culture for V. cholerae O1 (n = 19) were positive by Cholkit as well as Crystal VC. We then used Bayesian latent class modeling to estimate the sensitivity and specificity of each diagnostic assay. The sensitivity of Cholkit, microbiological culture, PCR and Crystal VC was 98% (95% CI: 88-100), 71% (95% CI: 59-81), 74% (95% CI: 59-86) and 98% (95% CI: 88-100), respectively. The specificity for V. cholerae O1 was 97% (95% CI: 89-100), 100%, 97% (95% CI: 93-99) and 98% (95% CI: 92-100), respectively. Of note, two Crystal VC dipsticks were positive for V. cholerae O139 but negative by culture and PCR in this area without known circulating epidemic V. cholerae O139. In conclusion, the Cholkit dipstick is simple to use, requires no dedicated laboratory capacity, and has a sensitivity and specificity for V. cholerae O1 of 98% and 97%, respectively. Cholkit warrants further evaluation in other settings.

  View details for PubMedID 29538377

• Eosinophilic Meningitis Caused by Angiostrongylus cantonensis. ACS chemical neuroscience Lv, S., Zhou, X. N., Andrews, J. R. 2017

  Abstract

  Rat lungworm, Angiostrongylus cantonensis, is one major cause of human eosinophilic meningitis. This helminth is endemic in Southeast Asia, Pacific Islands, and the Caribbean and has recently expanded to South America. The infection is characterized by an elevated eosinophil count in cerebrospinal fluid. Common symptoms and signs include headache, neck stiffness, paresthesia and nausea/vomiting. The unique history of eating freshwater and land snails or slugs within 2 weeks before onset is helpful for diagnosis. Antihelminthic agents have not shown efficacy in human infection; treatment involves supportive care with management of inflammation and intracranial pressure.

  View details for DOI 10.1021/acschemneuro.7b00233

  View details for PubMedID 28704038

• Disease ecology, health and the environment: a framework to account for ecological and socio-economic drivers in the control of neglected tropical diseases PHILOSOPHICAL TRANSACTIONS OF THE ROYAL SOCIETY B-BIOLOGICAL SCIENCES Garchitorena, A., Sokolow, S. H., Roche, B., Ngonghala, C. N., Jocque, M., Lund, A., Barry, M., MORDECAI, E. A., Daily, G. C., Jones, J. H., Andrews, J. R., Bendavid, E., Luby, S. P., LaBeaud, A. D., Seetah, K., Guegan, J. F., Bonds, M. H., De Leo, G. A. 2017; 372 (1722)

  Abstract

  Reducing the burden of neglected tropical diseases (NTDs) is one of the key strategic targets advanced by the Sustainable Development Goals. Despite the unprecedented effort deployed for NTD elimination in the past decade, their control, mainly through drug administration, remains particularly challenging: persistent poverty and repeated exposure to pathogens embedded in the environment limit the efficacy of strategies focused exclusively on human treatment or medical care. Here, we present a simple modelling framework to illustrate the relative role of ecological and socio-economic drivers of environmentally transmitted parasites and pathogens. Through the analysis of system dynamics, we show that periodic drug treatments that lead to the elimination of directly transmitted diseases may fail to do so in the case of human pathogens with an environmental reservoir. Control of environmentally transmitted diseases can be more effective when human treatment is complemented with interventions targeting the environmental reservoir of the pathogen. We present mechanisms through which the environment can influence the dynamics of poverty via disease feedbacks. For illustration, we present the case studies of Buruli ulcer and schistosomiasis, two devastating waterborne NTDs for which control is particularly challenging.This article is part of the themed issue 'Conservation, biodiversity and infectious disease: scientific evidence and policy implications'.

  View details for DOI 10.1098/rstb.2016.0128

  View details for PubMedID 28438917

• Evaluation of a Mobile Phone-Based Microscope for Screening of Schistosoma haematobium Infection in Rural Ghana. The American journal of tropical medicine and hygiene Bogoch, I. I., Koydemir, H. C., Tseng, D., Ephraim, R. K., Duah, E., Tee, J., Andrews, J. R., Ozcan, A. 2017; 96 (6): 1468-1471

  Abstract

  AbstractSchistosomiasis affects over 170 million people in Africa. Here we compare a novel, low-cost mobile phone microscope to a conventional light microscope for the label-free diagnosis of Schistosoma haematobium infections in a rural Ghanaian school setting. We tested the performance of our handheld microscope using 60 slides that were randomly chosen from an ongoing epidemiologic study in school-aged children. The mobile phone microscope had a sensitivity of 72.1% (95% confidence interval [CI]: 56.1-84.2), specificity of 100% (95% CI: 75.9-100), positive predictive value of 100% (95% CI: 86.3-100), and a negative predictive value of 57.1% (95% CI: 37.4-75.0). With its modest sensitivity and high specificity, this handheld and cost-effective mobile phone-based microscope is a stepping-stone toward developing a powerful tool in clinical and public health settings where there is limited access to conventional laboratory diagnostic support.

  View details for DOI 10.4269/ajtmh.16-0912

  View details for PubMedID 28719262

• Determinants of severe dehydration from diarrheal disease at hospital presentation: Evidence from 22 years of admissions in Bangladesh. PLoS neglected tropical diseases Andrews, J. R., Leung, D. T., Ahmed, S., Malek, M. A., Ahmed, D., Begum, Y. A., Qadri, F., Ahmed, T., Faruque, A. S., Nelson, E. J. 2017; 11 (4)

  Abstract

  To take advantage of emerging opportunities to reduce morbidity and mortality from diarrheal disease, we need to better understand the determinants of life-threatening severe dehydration (SD) in resource-poor settings.We analyzed records of patients admitted with acute diarrheal disease over twenty-two years at the International Centre for Diarrhoeal Disease Research, Bangladesh (1993-2014). Patients presenting with and without SD were compared by multivariable logistic regression models, which included socio-demographic factors and pathogens isolated. Generalized additive models evaluated non-linearities between age or household income and SD. Among 55,956 admitted patients, 13,457 (24%) presented with SD. Vibrio cholerae was the most common pathogen isolated (12,405 patients; 22%), and had the strongest association with SD (AOR 4.77; 95% CI: 4.41-5.51); detection of multiple pathogens did not exacerbate SD risk. The highest proportion of severely dehydrated patients presented in a narrow window only 4-12 hours after symptom onset. Risk of presenting with SD increased sharply from zero to ten years of age and remained high throughout adolescence and adulthood. Adult women had a 38% increased odds (AOR 1.38; 95% CI: 1.30-1.46) of SD compared to adult men. The probability of SD increased sharply at low incomes. These findings were consistent across pathogens.There remain underappreciated populations vulnerable to life-threatening diarrheal disease that include adult women and the very poor. In addition to efforts that address diarrheal disease in young children, there is a need to develop interventions for these other high-risk populations that are accessible within 4 hours of symptom onset.

  View details for DOI 10.1371/journal.pntd.0005512

  View details for PubMedID 28448489

• Increase in Tuberculosis Cases among Prisoners, Brazil, 2009-2014(1). Emerging infectious diseases Bourdillon, P. M., Gonçalves, C. C., Pelissari, D. M., Arakaki-Sanchez, D., Ko, A. I., Croda, J., Andrews, J. R. 2017; 23 (3): 496-499

  Abstract

  During 2009-2014, incarceration rates in Brazil rose 34%, and tuberculosis (TB) cases among prisoners rose 28.8%. The proportion of national TB cases that occurred among prisoners increased from 6.2% to 8.4% overall and from 19.3% to 25.6% among men 20-29 years of age.

  View details for DOI 10.3201/eid2303.161006

  View details for PubMedID 28221118

• A call to strengthen the global strategy against schistosomiasis and soil-transmitted helminthiasis: the time is now. The Lancet. Infectious diseases Lo, N. C., Addiss, D. G., Hotez, P. J., King, C. H., Stothard, J. R., Evans, D. S., Colley, D. G., Lin, W., Coulibaly, J. T., Bustinduy, A. L., Raso, G., Bendavid, E., Bogoch, I. I., Fenwick, A., Savioli, L., Molyneux, D., Utzinger, J., Andrews, J. R. 2017; 17 (2): e64-e69

  Abstract

  In 2001, the World Health Assembly (WHA) passed the landmark WHA 54.19 resolution for global scale-up of mass administration of anthelmintic drugs for morbidity control of schistosomiasis and soil-transmitted helminthiasis, which affect more than 1·5 billion of the world's poorest people. Since then, more than a decade of research and experience has yielded crucial knowledge on the control and elimination of these helminthiases. However, the global strategy has remained largely unchanged since the original 2001 WHA resolution and associated WHO guidelines on preventive chemotherapy. In this Personal View, we highlight recent advances that, taken together, support a call to revise the global strategy and guidelines for preventive chemotherapy and complementary interventions against schistosomiasis and soil-transmitted helminthiasis. These advances include the development of guidance that is specific to goals of morbidity control and elimination of transmission. We quantify the result of forgoing this opportunity by computing the yearly disease burden, mortality, and lost economic productivity associated with maintaining the status quo. Without change, we estimate that the population of sub-Saharan Africa will probably lose 2·3 million disability-adjusted life-years and US$3·5 billion of economic productivity every year, which is comparable to recent acute epidemics, including the 2014 Ebola and 2015 Zika epidemics. We propose that the time is now to strengthen the global strategy to address the substantial disease burden of schistosomiasis and soil-transmitted helminthiasis.

  View details for DOI 10.1016/S1473-3099(16)30535-7

  View details for PubMedID 27914852

  View details for PubMedCentralID PMC5280090

• The benefits of mass deworming on health outcomes: new evidence synthesis, the debate persists. The Lancet. Global health Andrews, J. R., Bogoch, I. I., Utzinger, J. 2017; 5 (1): e4-e5

  View details for DOI 10.1016/S2214-109X(16)30333-3

  View details for PubMedID 27955787

• High Rates of Enteric Fever Diagnosis and Lower Burden of Culture-Confirmed Disease in Peri-urban and Rural Nepal. The Journal of infectious diseases Andrews, J. R., Vaidya, K. n., Bern, C. n., Tamrakar, D. n., Wen, S. n., Madhup, S. n., Shrestha, R. n., Karmacharya, B. n., Amatya, B. n., Koju, R. n., Adhikari, S. R., Hohmann, E. n., Ryan, E. T., Bogoch, I. I. 2017

  Abstract

  In South Asia, data on enteric fever are sparse outside of urban areas. We characterized enteric fever diagnosis patterns and the burden of culture-confirmed cases in peri-urban and rural Nepal.We used national reports to estimate enteric fever diagnosis rates over 20 years (1994-2014) and conducted a prospective study of patients presenting with a >72-hour history of fever to 4 peri-urban and rural healthcare facilities (during August 2013-June 2016). We compared clinical characteristics of patients with culture-confirmed Salmonella Typhi or Paratyphi infection to those of patients without enteric fever. We used generalized additive models with logistic link functions to evaluate associations of age and population density with culture positivity.National rates of enteric fever diagnosis were high, reaching 18.8 cases per 1000 during 2009-2014. We enrolled 4309 participants with acute febrile illness. Among those with a provisional clinical diagnosis, 55% (1334 of 2412) received a diagnosis of enteric fever; however, only 4.1% of these had culture-confirmed typhoidal Salmonella infection. Culture positivity was highest among young adults and was strongly associated with higher population density (P < .001).Enteric fever diagnosis rates were very high throughout Nepal, but in rural settings, few patients had culture-confirmed disease. Expanded surveillance may inform local enteric fever treatment and prevention strategies.

  View details for PubMedID 28961918

• Mobile phone and handheld microscopes for public health applications Lancet Public Health Bogoch, I. I., Lundin, J., Lo, N. C., Andrews, J. R. 2017; 2 (8): e355

  View details for DOI 10.1016/S2468-2667(17)30120-2

• The global burden of tuberculosis: results from the Global Burden of Disease Study 2015. The Lancet. Infectious diseases 2017

  Abstract

  An understanding of the trends in tuberculosis incidence, prevalence, and mortality is crucial to tracking of the success of tuberculosis control programmes and identification of remaining challenges. We assessed trends in the fatal and non-fatal burden of tuberculosis over the past 25 years for 195 countries and territories.We analysed 10 691 site-years of vital registration data, 768 site-years of verbal autopsy data, and 361 site-years of mortality surveillance data using the Cause of Death Ensemble model to estimate tuberculosis mortality rates. We analysed all available age-specific and sex-specific data sources, including annual case notifications, prevalence surveys, and estimated cause-specific mortality, to generate internally consistent estimates of incidence, prevalence, and mortality using DisMod-MR 2.1, a Bayesian meta-regression tool. We assessed how observed tuberculosis incidence, prevalence, and mortality differed from expected trends as predicted by the Socio-demographic Index (SDI), a composite indicator based on income per capita, average years of schooling, and total fertility rate. We also estimated tuberculosis mortality and disability-adjusted life-years attributable to the independent effects of risk factors including smoking, alcohol use, and diabetes.Globally, in 2015, the number of tuberculosis incident cases (including new and relapse cases) was 10·2 million (95% uncertainty interval 9·2 million to 11·5 million), the number of prevalent cases was 10·1 million (9·2 million to 11·1 million), and the number of deaths was 1·3 million (1·1 million to 1·6 million). Among individuals who were HIV negative, the number of incident cases was 8·8 million (8·0 million to 9·9 million), the number of prevalent cases was 8·9 million (8·1 million to 9·7 million), and the number of deaths was 1·1 million (0·9 million to 1·4 million). Annualised rates of change from 2005 to 2015 showed a faster decline in mortality (-4·1% [-5·0 to -3·4]) than in incidence (-1·6% [-1·9 to -1·2]) and prevalence (-0·7% [-1·0 to -0·5]) among HIV-negative individuals. The SDI was inversely associated with HIV-negative mortality rates but did not show a clear gradient for incidence and prevalence. Most of Asia, eastern Europe, and sub-Saharan Africa had higher rates of HIV-negative tuberculosis burden than expected given their SDI. Alcohol use accounted for 11·4% (9·3-13·0) of global tuberculosis deaths among HIV-negative individuals in 2015, diabetes accounted for 10·6% (6·8-14·8), and smoking accounted for 7·8% (3·8-12·0).Despite a concerted global effort to reduce the burden of tuberculosis, it still causes a large disease burden globally. Strengthening of health systems for early detection of tuberculosis and improvement of the quality of tuberculosis care, including prompt and accurate diagnosis, early initiation of treatment, and regular follow-up, are priorities. Countries with higher than expected tuberculosis rates for their level of sociodemographic development should investigate the reasons for lagging behind and take remedial action. Efforts to prevent smoking, alcohol use, and diabetes could also substantially reduce the burden of tuberculosis.Bill & Melinda Gates Foundation.

  View details for DOI 10.1016/S1473-3099(17)30703-X

  View details for PubMedID 29223583

• Genetic Clustering of Tuberculosis in an Indigenous Community of Brazil. The American journal of tropical medicine and hygiene Correia Sacchi, F. P., Tatara, M. B., Camioli de Lima, C. n., Ferreia da Silva, L. n., Cunha, E. A., Simonsen, V. n., Ferrazoli, L. n., Gomes, H. M., Gonçalves Vasconcellos, S. E., Suffys, P. N., Andrews, J. R., Croda, J. n. 2017

  Abstract

  We conducted a population-based study of tuberculosis (TB) from 2009 to 2015 in an indigenous community of Brazil, the largest in the country, to investigate risk factors associated with recent TB transmission. The clinical isolates of Mycobacterium tuberculosis were genotyped by IS6110-RFLP (restriction fragment length polymorphism) and spoligotyping analysis. Among 67 isolates typed by RFLP, 69% fell into fifteen clusters, and 91% of TB cases with shared IS6110-RFLP pattern were diagnosed within 2 years of another case in the cluster. Individual risk factors associated with genetic clustering were domestic overcrowding (odds ratio [OR]: 6.10; 95% confidence interval [CI]: 1.50-24.88) and low social class (OR: 3.72; 95% CI: 1.00-13.98). Most reported contacts (76%) were identified within the household of the index TB case, but most of the genetic clustering of M. tuberculosis occurred outside of household (79%). Expanded contacts investigation and prophylaxis outside of household should be considered as a priority for TB control programs in this population.

  View details for PubMedID 29210353

• Schistosoma haematobium Egg Excretion does not Increase after Exercise: Implications for Diagnostic Testing. The American journal of tropical medicine and hygiene Coulibaly, J. T., Andrews, J. R., Lo, N. C., N'Goran, E. K., Utzinger, J. n., Keiser, J. n., Bogoch, I. I. 2017

  Abstract

  Children are frequently invited to exercise before micturition, as it is believed that this will result in higher Schistosoma haematobium egg excretion, and hence, increases sensitivity of microscopic diagnoses. However, the evidence of this recommendation is scant. In the study presented here, 257 children, aged 2-15 years from south Côte d'Ivoire, provided urine samples for microscopy on consecutive days; one sample without prior exercise and one sample after exercise. Comparing the same individuals without and with prior exercise, sample positivity for S. haematobium (25.7% versus 23.0%, P = 0.31) and mean egg counts (10.2 eggs/10 mL versus 8.5 eggs/10 mL, P = 0.45) did not differ. Exercise before urine collection does not appear to increase S. haematobium egg excretion.

  View details for PubMedID 29260647

• Drivers of Tuberculosis Transmission. The Journal of infectious diseases Mathema, B. n., Andrews, J. R., Cohen, T. n., Borgdorff, M. W., Behr, M. n., Glynn, J. R., Rustomjee, R. n., Silk, B. J., Wood, R. n. 2017; 216 (suppl_6): S644–S653

  Abstract

  Measuring tuberculosis transmission is exceedingly difficult, given the remarkable variability in the timing of clinical disease after Mycobacterium tuberculosis infection; incident disease can result from either a recent (ie, weeks to months) or a remote (ie, several years to decades) infection event. Although we cannot identify with certainty the timing and location of tuberculosis transmission for individuals, approaches for estimating the individual probability of recent transmission and for estimating the fraction of tuberculosis cases due to recent transmission in populations have been developed. Data used to estimate the probable burden of recent transmission include tuberculosis case notifications in young children and trends in tuberculin skin test and interferon γ-release assays. More recently, M. tuberculosis whole-genome sequencing has been used to estimate population levels of recent transmission, identify the distribution of specific strains within communities, and decipher chains of transmission among culture-positive tuberculosis cases. The factors that drive the transmission of tuberculosis in communities depend on the burden of prevalent tuberculosis; the ways in which individuals live, work, and interact (eg, congregate settings); and the capacity of healthcare and public health systems to identify and effectively treat individuals with infectious forms of tuberculosis. Here we provide an overview of these factors, describe tools for measurement of ongoing transmission, and highlight knowledge gaps that must be addressed.

  View details for PubMedID 29112745

• Identification of Novel Serodiagnostic Signatures of Typhoid Fever Using a Salmonella Proteome Array. Frontiers in microbiology Darton, T. C., Baker, S. n., Randall, A. n., Dongol, S. n., Karkey, A. n., Voysey, M. n., Carter, M. J., Jones, C. n., Trappl, K. n., Pablo, J. n., Hung, C. n., Teng, A. n., Shandling, A. n., Le, T. n., Walker, C. n., Molina, D. n., Andrews, J. n., Arjyal, A. n., Basnyat, B. n., Pollard, A. J., Blohmke, C. J. 2017; 8: 1794

  Abstract

  Current diagnostic tests for typhoid fever, the disease caused by Salmonella Typhi, are poor. We aimed to identify serodiagnostic signatures of typhoid fever by assessing microarray signals to 4,445 S. Typhi antigens in sera from 41 participants challenged with oral S. Typhi. We found broad, heterogeneous antibody responses with increasing IgM/IgA signals at diagnosis. In down-selected 250-antigen arrays we validated responses in a second challenge cohort (n = 30), and selected diagnostic signatures using machine learning and multivariable modeling. In four models containing responses to antigens including flagellin, OmpA, HlyE, sipC, and LPS, multi-antigen signatures discriminated typhoid (n = 100) from other febrile bacteremia (n = 52) in Nepal. These models contained combinatorial IgM, IgA, and IgG responses to 5 antigens (ROC AUC, 0.67 and 0.71) or 3 antigens (0.87), although IgA responses to LPS also performed well (0.88). Using a novel systematic approach we have identified and validated optimal serological diagnostic signatures of typhoid fever.

  View details for PubMedID 28970824

  View details for PubMedCentralID PMC5609549

• Optimization and Interpretation of Serial QuantiFERON Testing to Measure Acquisition of M. tuberculosis Infection. American journal of respiratory and critical care medicine Nemes, E. n., Rozot, V. n., Geldenhuys, H. n., Bilek, N. n., Mabwe, S. n., Abrahams, D. n., Makhethe, L. n., Erasmus, M. n., Keyser, A. n., Toefy, A. n., Cloete, Y. n., Ratangee, F. n., Blauenfeldt, T. n., Ruhwald, M. n., Walzl, G. n., Smith, B. n., Loxton, A. G., Hanekom, W. A., Andrews, J. R., Lempicki, M. D., Ellis, R. n., Ginsberg, A. M., Hatherill, M. n., Scriba, T. J. 2017

  Abstract

  Conversion from a negative to positive QuantiFERON-TB test is indicative of Mycobacterium tuberculosis (M.tb) infection, which predisposes to tuberculosis disease. Interpretation of serial tests is confounded by immunological and technical variability.To improve consistency of serial QuantiFERON-TB testing algorithms and provide a data-driven definition of conversion.Sources of QuantiFERON-TB variability were assessed and optimal procedures identified. Distributions of IFNγ response levels were analysed in healthy adolescents, M.tb-unexposed controls, and pulmonary tuberculosis patients.Individuals with no known M.tb exposure had IFNγ values <0.2 IU/mL. Among individuals with IFNγ values <0.2, 0.2-0.34, 0.35-0.7, and >0.7 IU/mL, tuberculin skin test positivity was 15%, 53%, 66% and 91% (p<0.005), respectively. Together, these findings suggest that values <0.2 IU/mL were true negatives. In short-term serial testing, "uncertain" conversions, with at least one value within the uncertainty zone (0.2-0.7 IU/mL), were partly explained by technical assay variability. Individuals who had a change in QuantiFERON-TB IFNγ values from <0.2 to >0.7 IU/mL had 10-fold higher tuberculosis incidence rates than those who maintained values <0.2 IU/mL over 2 years (p=0.0003). By contrast, "uncertain" converters were not at higher risk than non-converters (p=0.229). Eighty-seven percent of active TB patients had IFNγ values >0.7 IU/mL, suggesting that these values are consistent with established M.tb infection.Implementation of optimized procedures and a more rigorous QuantiFERON-TB conversion definition, an increase from IFNγ <0.2 to >0.7 IU/mL, would allow more definitive detection of recent M.tb infection and potentially improve identification of those more likely to develop disease.

  View details for PubMedID 28737960

• Mobile-phone and handheld microscopy for neglected tropical diseases. PLoS neglected tropical diseases Rajchgot, J. n., Coulibaly, J. T., Keiser, J. n., Utzinger, J. n., Lo, N. C., Mondry, M. K., Andrews, J. R., Bogoch, I. I. 2017; 11 (7): e0005550

  View details for PubMedID 28683127

• Evaluation of a Smartphone Decision-Support Tool for Diarrheal Disease Management in a Resource-Limited Setting. PLoS neglected tropical diseases Haque, F., Ball, R. L., Khatun, S., Ahmed, M., Kache, S., Chisti, M. J., Sarker, S. A., Maples, S. D., Pieri, D., Vardhan Korrapati, T., Sarnquist, C., Federspiel, N., Rahman, M. W., Andrews, J. R., Rahman, M., Nelson, E. J. 2017; 11 (1)

  Abstract

  The emergence of mobile technology offers new opportunities to improve clinical guideline adherence in resource-limited settings. We conducted a clinical pilot study in rural Bangladesh to evaluate the impact of a smartphone adaptation of the World Health Organization (WHO) diarrheal disease management guidelines, including a modality for age-based weight estimation. Software development was guided by end-user input and evaluated in a resource-limited district and sub-district hospital during the fall 2015 cholera season; both hospitals lacked scales which necessitated weight estimation. The study consisted of a 6 week pre-intervention and 6 week intervention period with a 10-day post-discharge follow-up. Standard of care was maintained throughout the study with the exception that admitting clinicians used the tool during the intervention. Inclusion criteria were patients two months of age and older with uncomplicated diarrheal disease. The primary outcome was adherence to guidelines for prescriptions of intravenous (IV) fluids, antibiotics and zinc. A total of 841 patients were enrolled (325 pre-intervention; 516 intervention). During the intervention, the proportion of prescriptions for IV fluids decreased at the district and sub-district hospitals (both p < 0.001) with risk ratios (RRs) of 0.5 and 0.2, respectively. However, when IV fluids were prescribed, the volume better adhered to recommendations. The proportion of prescriptions for the recommended antibiotic azithromycin increased (p < 0.001 district; p = 0.035 sub-district) with RRs of 6.9 (district) and 1.6 (sub-district) while prescriptions for other antibiotics decreased; zinc adherence increased. Limitations included an absence of a concurrent control group and no independent dehydration assessment during the pre-intervention. Despite limitations, opportunities were identified to improve clinical care, including better assessment, weight estimation, and fluid/ antibiotic selection. These findings demonstrate that a smartphone-based tool can improve guideline adherence. This study should serve as a catalyst for a randomized controlled trial to expand on the findings and address limitations.

  View details for DOI 10.1371/journal.pntd.0005290

  View details for PubMedID 28103233

• Poor Validity of Noninvasive Hemoglobin Measurements by Pulse Oximetry Compared with Conventional Absorptiometry in Children in Cote d'Ivoire AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE Bogoch, I. I., Coulibaly, J. T., Rajchgot, J., Andrews, J. R., Kovac, J., Utzinger, J., Panic, G., Keiser, J. 2017; 96 (1): 217-220

  Abstract

  Anemia remains a major public health issue in many African communities. We compared a novel, commercially available noninvasive hemoglobin (Hb)-measuring device to direct Hb measurements by finger-prick samples in a pediatric cohort in rural Côte d'Ivoire. Noninvasive Hb measurements were attempted in 191 children 2-15 years of age and obtained in 102 (53.5%) children. The median Hb for the 102 children was 12.0 g/dL (interquartile range [IQR] = 11.3-12.7 g/dL) for conventional absorptiometry and 13.3 g/dL (IQR = 12.1-14.2 g/dL) for noninvasive measurements. A Bland-Altman analysis demonstrated a median bias of +1.1 g/dL (IQR = 0.4-2.0 g/dL), with greater overestimation of Hb by noninvasive testing occurring at low Hb values. This overestimation of the noninvasive Hb-measuring device to direct Hb measurements persisted across preschool- and school-aged children, and both sexes. The Pearson correlation coefficient was 0.50 for children 4-9 years of age, and 0.33 for children 10-15 years of age. Further study and development of noninvasive Hb devices is necessary prior to implementation in African pediatric populations.

  View details for DOI 10.4269/ajtmh.16-0505

  View details for Web of Science ID 000397822900040

  View details for PubMedID 28077748

• Efficacy and safety of praziquantel against light infections of Opisthorchis viverrini: a randomised parallel single blind dose-ranging trial. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America Sayasone, S., Meister, I., Andrews, J. R., Odermatt, P., Vonghachack, Y., Xayavong, S., Senggnam, K., Phongluxa, K., Hattendorf, J., Bogoch, I. I., Keiser, J. 2016

  Abstract

  The liver fluke Opisthorchis viverrini, highly prevalent in Southeast Asia, is an important public health burden, including a risk factor for developing an aggressive bile duct cancer, cholangiocarcinoma, in chronically infected patients. Praziquantel, administered at single 40 mg/kg in preventive chemotherapy programs and 3 x 25 mg/kg for individual treatment is the drug of choice, yet information on the nature of the dose-response relationship is lacking.We performed a randomized, parallel, single blind dose-ranging Phase 2 trial in Lao PDR in O. viverrini-infected adults. Patients were randomly assigned to 30, 40, 50, 3 x 25 mg/kg praziquantel or placebo. Adverse events were recorded at baseline, 3 and 24 hours post-treatment. Cure rates and egg reduction rates were estimated 3 weeks after drug administration using available case analysis. Dose-response curves were predicted using Emax models.Two-hundred and seventeen O. viverrini-infected patients were assigned to the five treatment arms. The majority (94.3%) of patients harbored light infections. The Emax model predicted a high efficacy among the observed dose range. We observed cure rates ranging from 92.7-93.3% and egg reduction rates above 99.5% for all praziquantel-treatment groups. Adverse events were mild but higher in the standard treatment group (3x25 mg/kg) than in the single dose treatment arms.Single dose praziquantel appear to be as efficacious as the standard 3x25 mg/kg regimen for the treatment of O. viverrini infections, while presenting fewer adverse events. Further studies are necessary in moderate and heavy O. viverrini infections.

  View details for DOI 10.1093/cid/ciw785

  View details for PubMedID 27927864

• The mass miniature chest radiography programme in Cape Town, South Africa, 1948 - 1994: The impact of active tuberculosis case finding. South African medical journal = Suid-Afrikaanse tydskrif vir geneeskunde Hermans, S. M., Andrews, J. R., Bekker, L. G., Wood, R. 2016; 106 (12): 1263-1269

  Abstract

  Tuberculosis (TB) control programmes rely mainly on passive detection of symptomatic individuals. The resurgence of TB has rekindled interest in active case finding. Cape Town (South Africa) had a mass miniature radiography (MMR) screening programme from 1948 to 1994.To evaluate screening coverage, yield and secular trends in TB notifications during the MMR programme.We performed an ecological analysis of the MMR programme and TB notification data from the City of Cape Town Medical Officer of Health reports for 1948 - 1994.Between 1948 and 1962, MMR screening increased to 12% of the population per annum with yields of 14 cases per 1 000 X-rays performed, accounting for >20% of total annual TB notifications. Concurrent with increasing coverage (1948 - 1965), TB case notification decreased in the most heavily TB-burdened non-European population from 844/100 000 population to 415/100 000. After 1966, coverage declined and TB notifications that initially remained stable (1967 - 1978) subsequently increased to 525/100 000. MMR yields remained low in the European population but declined rapidly in the non-European population after 1966, coincidental with forced removals from District 6. An inverse relationship between screening coverage and TB notification rates was observed in the non-European adult population. Similar secular trends occurred in infants and young children who were not part of the MMR screening programme.MMR of a high-burdened population may have significantly contributed to TB control and was temporally associated with decreased transmission to infants and children. These historical findings emphasise the importance of re-exploring targeted active case finding strategies as part of population TB control.

  View details for DOI 10.7196/SAMJ.2016.v106.i12.10744

  View details for PubMedID 27917775

• Impact of mass-screening on tuberculosis incidence in a prospective cohort of Brazilian prisoners. BMC infectious diseases Paião, D. S., Lemos, E. F., Carbone, A. d., Sgarbi, R. V., Junior, A. L., da Silva, F. M., Brandão, L. M., Dos Santos, L. S., Martins, V. S., Simionatto, S., Motta-Castro, A. R., Pompílio, M. A., Urrego, J., Ko, A. I., Andrews, J. R., Croda, J. 2016; 16 (1): 533

  Abstract

  Globally, prison inmates are a high-risk population for tuberculosis (TB), but the specific drivers of disease and impact of mass screening interventions are poorly understood.We performed a prospective cohort study to characterize the incidence and risk factors for tuberculosis infection and disease in 12 Brazilian prisons, and to investigate the effect of mass screening on subsequent disease risk. After recruiting a stratified random sample of inmates, we administered a questionnaire to ascertain symptoms and potential risk factors for tuberculosis; performed tuberculin skin testing (TST); collected sera for HIV testing; and obtained two sputum samples for smear microscopy and culture, from participants reporting a cough of any duration. We repeated the questionnaire and all tests for inmates who remained incarcerated after 1 year. TST conversion was defined as TST ≥10 mm and an induration increase of at least 6 mm in an individual with a baseline TST <10 mm. Cox proportional hazard models were performed to identify risk factors associated with active TB. To evaluate the impact of screening on subsequent risk of disease, we compared TB notifications over one year among individuals randomized to screening for active TB with those not randomized to screening.Among 3,771 inmates recruited, 3,380 (89.6 %) were enrolled in the study, and 1,422 remained incarcerated after one year. Among 1,350 inmates (94.9 %) with paired TSTs at baseline and one-year follow-up, 25.7 % (272/1060) converted to positive. Among those incarcerated for the year, 10 (0.7 %) had TB at baseline and 25 (1.8 %) were diagnosed with TB over the subsequent year. Cases identified through active screening were less likely to be smear-positive than passively detected cases (10.0 % vs 50.9 %; p < 0.01), suggesting early case detection. However, there was no reduction in subsequent disease among individuals actively screened versus those not screened (1.3 % vs 1.7 %; p = 0.88). Drug use during the year (AHR 3.22; 95 % CI 1.05-9.89) and knows somebody with TB were (AHR 2.86; 95 % CI 1.01-8.10) associated with active TB during one year of follow up CONCLUSIONS: Mass screening in twelve Brazilian prisons did not reduce risk of subsequent disease in twelve Brazilian prisons, likely due to an extremely high force of infection. New approaches are needed to control TB in this high-transmission setting.

  View details for DOI 10.1186/s12879-016-1868-5

  View details for PubMedID 27716170

• Evaluation of Malaria Diagnoses Using a Handheld Light Microscope in a Community-Based Setting in Rural Cote d'Ivoire AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE Coulibaly, J. T., Ouattara, M., Keiser, J., Bonfoh, B., N'Goran, E. K., Andrews, J. R., Bogoch, I. I. 2016; 95 (4): 831-834

  Abstract

  Portable microscopy may facilitate quality diagnostic care in resource-constrained settings. We compared a handheld light microscope (Newton Nm1) with a mobile phone attachment to conventional light microscopy for the detection of Plasmodium falciparum in a cross-sectional study in rural Côte d'Ivoire. Single Giemsa-stained thick blood film from 223 individuals were prepared and read by local laboratory technicians on both microscopes under 1,000× magnification with oil. Of the 223 samples, 162 (72.6%) were P. falciparum positive, and the overall mean parasite count was 1,392/μL of blood. Sensitivity and specificity of the handheld microscope was 80.2% (95% confidence interval [CI]: 73.1-85.9%) and 100.0% (95% CI: 92.6-100.0%), respectively, with a positive and negative predictive value of 100.0% (95% CI: 96.4-100.0%) and 65.6% (95% CI: 54.9-74.9%), respectively. If sensitivity can be improved, handheld light microscopy may become a valuable public health tool for P. falciparum diagnosis.

  View details for DOI 10.4269/ajtmh.16-0328

  View details for Web of Science ID 000400206500021

  View details for PubMedID 27527637

• Risk of self-reported symptoms or diagnosis of active tuberculosis in relationship to low body mass index, diabetes and their co-occurrence. Tropical medicine & international health Prince, L., Andrews, J. R., Basu, S., Goldhaber-Fiebert, J. D. 2016; 21 (10): 1272-1281

  Abstract

  Globally, tuberculosis prevalence has declined, but its risk factors have varied across place and time - low body mass index (BMI) has persisted while diabetes has increased. Using India's National Family Health Survey (NFHS), wave 3 and World Health Survey (WHS) data, we examined their relationships to support projection of future trends and targeted control efforts.Multivariate logistic regressions at the individual level with and without diabetes/BMI interactions assessed the relationship between tuberculosis, diabetes and low BMI and the importance of risk factor co-occurrence. Population-level analyses examined how tuberculosis incidence and prevalence varied with diabetes/low BMI co-occurrence.In NFHS, diabetic individuals had higher predicted tuberculosis risks (diabetic vs. non-diabetic: 2.50% vs. 0.63% at low BMI; 0.81% vs. 0.20% at normal BMI; 0.37% vs. 0.09% at high BMI), which were not significantly different when modelled independently or allowing for risk modification with diabetes/low BMI co-occurrence. WHS findings were generally consistent. Population-level analysis found that diabetes/low BMI co-occurrence may be associated with elevated tuberculosis risk, although its predicted effect on tuberculosis incidence/prevalence was generally ≤0.2 percentage points and not robustly statistically significant.Concerns about the additional elevation of tuberculosis risk from diabetes/low BMI co-occurrence and hence the need to coordinate tuberculosis control efforts around the nexus of co-occurring diabetes and low BMI may be premature. However, study findings robustly support the importance of individually targeting low BMI and diabetes as part of ongoing tuberculosis control efforts.

  View details for DOI 10.1111/tmi.12763

  View details for PubMedID 27495971

• Advances in diagnosis, treatment, and prevention of invasive Salmonella infections. Current opinion in infectious diseases MacFadden, D. R., Bogoch, I. I., Andrews, J. R. 2016; 29 (5): 453-458

  Abstract

  Typhoidal and nontyphoidal Salmonella enterica serotypes are among the most common bacterial causes of acute febrile illnesses in the developing world. In this review, we discuss new advances in understanding of the burden, diagnostic approaches, treatment and vaccines for invasive Salmonella infections.Recent estimates of the global burden of typhoidal and nontyphoidal Salmonella not only affirm the importance of these infections but also highlight the paucity of systematic incidence data from many regions. New data from Africa indicate that typhoidal Salmonella may be more common than previously considered. Novel diagnostic techniques for Salmonella include new serologic, molecular and metabolomic approaches, but blood culture - although slow and insensitive - remains the primary means of establishing a diagnosis. Antibiotic resistance, particularly to fluoroquinolones, continues to emerge and threatens to undermine treatment success for these infections. New vaccines for typhoid, including conjugate vaccines with longer duration of immunity than prior vaccines, represent a promising tool for prevention of enteric fever.Invasive Salmonella infections are a major cause of morbidity and mortality worldwide. Increasing antibiotic resistance in Salmonella is concerning, and empiric oral options are being rapidly eroded. Where new effective antimicrobials are lacking, developments in vaccines offer hope for reducing the burden of Salmonella infections globally.

  View details for DOI 10.1097/QCO.0000000000000302

  View details for PubMedID 27479027

• Evaluation of a Urine Pooling Strategy for the Rapid and Cost-Efficient Prevalence Classification of Schistosomiasis. PLoS neglected tropical diseases Lo, N. C., Coulibaly, J. T., Bendavid, E., N'Goran, E. K., Utzinger, J., Keiser, J., Bogoch, I. I., Andrews, J. R. 2016; 10 (8)

  Abstract

  A key epidemiologic feature of schistosomiasis is its focal distribution, which has important implications for the spatial targeting of preventive chemotherapy programs. We evaluated the diagnostic accuracy of a urine pooling strategy using a point-of-care circulating cathodic antigen (POC-CCA) cassette test for detection of Schistosoma mansoni, and employed simulation modeling to test the classification accuracy and efficiency of this strategy in determining where preventive chemotherapy is needed in low-endemicity settings.We performed a cross-sectional study involving 114 children aged 6-15 years in six neighborhoods in Azaguié Ahoua, south Côte d'Ivoire to characterize the sensitivity and specificity of the POC-CCA cassette test with urine samples that were tested individually and in pools of 4, 8, and 12. We used a Bayesian latent class model to estimate test characteristics for individual POC-CCA and quadruplicate Kato-Katz thick smears on stool samples. We then developed a microsimulation model and used lot quality assurance sampling to test the performance, number of tests, and total cost per school for each pooled testing strategy to predict the binary need for school-based preventive chemotherapy using a 10% prevalence threshold for treatment.The sensitivity of the urine pooling strategy for S. mansoni diagnosis using pool sizes of 4, 8, and 12 was 85.9%, 79.5%, and 65.4%, respectively, when POC-CCA trace results were considered positive, and 61.5%, 47.4%, and 30.8% when POC-CCA trace results were considered negative. The modeled specificity ranged from 94.0-97.7% for the urine pooling strategies (when POC-CCA trace results were considered negative). The urine pooling strategy, regardless of the pool size, gave comparable and often superior classification performance to stool microscopy for the same number of tests. The urine pooling strategy with a pool size of 4 reduced the number of tests and total cost compared to classical stool microscopy.This study introduces a method for rapid and efficient S. mansoni prevalence estimation through examining pooled urine samples with POC-CCA as an alternative to widely used stool microscopy.

  View details for DOI 10.1371/journal.pntd.0004894

  View details for PubMedID 27504954

  View details for PubMedCentralID PMC4978437

• Improving helminth treatment access: costs and opportunities. The Lancet. Infectious diseases Lo, N. C., Andrews, J. R., Bogoch, I. I. 2016; 16 (7): 762-4

  View details for DOI 10.1016/S1473-3099(16)30049-4

  View details for PubMedID 27352742

• Accuracy of Mobile Phone and Handheld Light Microscopy for the Diagnosis of Schistosomiasis and Intestinal Protozoa Infections in Cote d'Ivoire PLOS NEGLECTED TROPICAL DISEASES Coulibaly, J. T., Ouattara, M., D'Ambrosio, M. V., Fletcher, D. A., Keiser, J., Utzinger, J., N'Goran, E. K., Andrews, J. R., Bogoch, I. I. 2016; 10 (6)

  Abstract

  Handheld light microscopy using compact optics and mobile phones may improve the quality of health care in resource-constrained settings by enabling access to prompt and accurate diagnosis.Laboratory technicians were trained to operate two handheld diagnostic devices (Newton Nm1 microscope and a clip-on version of the mobile phone-based CellScope). The accuracy of these devices was compared to conventional light microscopy for the diagnosis of Schistosoma haematobium, S. mansoni, and intestinal protozoa infection in a community-based survey in rural Côte d'Ivoire. One slide of 10 ml filtered urine and a single Kato-Katz thick smear from 226 individuals were subjected to the Newton Nm1 microscope and CellScope for detection of Schistosoma eggs and compared to conventional microscopy. Additionally, 121 sodium acetate-acetic acid-formalin (SAF)-fixed stool samples were examined by the Newton Nm1 microscope and compared to conventional microscopy for the diagnosis of intestinal protozoa.The prevalence of S. haematobium, S. mansoni, Giardia intestinalis, and Entamoeba histolytica/E. dispar, as determined by conventional microscopy, was 39.8%, 5.3%, 20.7%, and 4.9%, respectively. The Newton Nm1 microscope had diagnostic sensitivities for S. mansoni and S. haematobium infection of 91.7% (95% confidence interval (CI) 59.8-99.6%) and 81.1% (95% CI 71.2-88.3%), respectively, and specificities of 99.5% (95% CI 97.0-100%) and 97.1% (95% CI 92.2-99.1%), respectively. The CellScope demonstrated sensitivities for S. mansoni and S. haematobium of 50.0% (95% CI 25.4-74.6%) and 35.6% (95% CI 25.9-46.4%), respectively, and specificities of 99.5% (95% CI 97.0-100%) and 100% (95% CI 86.7-100%), respectively. For G. intestinalis and E. histolytica/E. dispar, the Newton Nm1 microscope had sensitivity of 84.0% (95% CI 63.1-94.7%) and 83.3% (95% CI 36.5-99.1%), respectively, and 100% specificity.Handheld diagnostic devices can be employed in community-based surveys in resource-constrained settings after minimal training of laboratory technicians to diagnose intestinal parasites.

  View details for DOI 10.1371/journal.pntd.0004768

  View details for Web of Science ID 000379346200031

  View details for PubMedID 27348755

• Comparison of the Performance of the TPTest, Tubex, Typhidot and Widal Immunodiagnostic Assays and Blood Cultures in Detecting Patients with Typhoid Fever in Bangladesh, Including Using a Bayesian Latent Class Modeling Approach. PLoS neglected tropical diseases Islam, K., Sayeed, M. A., Hossen, E., Khanam, F., Charles, R. C., Andrews, J., Ryan, E. T., Qadri, F. 2016; 10 (4): e0004558

  Abstract

  There is an urgent need for an improved diagnostic assay for typhoid fever. In this current study, we compared the recently developed TPTest (Typhoid and Paratyphoid Test) with the Widal test, blood culture, and two commonly used commercially available kits, Tubex and Typhidot.For analysis, we categorized 92 Bangladeshi patients with suspected enteric fever into four groups: S. Typhi bacteremic patients (n = 28); patients with a fourfold change in Widal test from day 0 to convalescent period (n = 7); patients with Widal titer ≥1:320 (n = 13) at either acute or convalescent stage of disease; and patients suspected with enteric fever, but with a negative blood culture and Widal titer (n = 44). We also tested healthy endemic zone controls (n = 20) and Bangladeshi patients with other febrile illnesses (n = 15). Sample size was based on convenience to facilitate preliminary analysis.Of 28 S. Typhi bacteremic patients, 28 (100%), 21 (75%) and 18 (64%) patients were positive by TPTest, Tubex and Typhidot, respectively. In healthy endemic zone controls, the TPTest method was negative in all, whereas Tubex and Typhidot were positive in 3 (15%) and 5 (25%), respectively. We then estimated sensitivity and specificity of all diagnostic tests using Bayesian latent class modeling. The sensitivity of TPTest, Tubex and Typhidot were estimated at 96.0% (95% CI: 87.1%-99.8%), 60.2% (95% CI: 49.3%-71.2%), and 59.6% (95% CI: 50.1%-69.3%), respectively. Specificity was estimated at 96.6% (90.7%-99.2%) for TPTest, 89.9% (79.6%-96.8%) for Tubex, and 80.0% (67.7%-89.7%) for Typhidot.These results suggest that the TPTest is highly sensitive and specific in diagnosing individuals with typhoid fever in a typhoid endemic setting, outperforming currently available and commonly used alternatives.

  View details for DOI 10.1371/journal.pntd.0004558

  View details for PubMedID 27058877

• Diagnosis of Opisthorchis viverrini Infection with Handheld Microscopy in Lao People's Democratic Republic. American journal of tropical medicine and hygiene Bogoch, I. I., Sayasone, S., Vonghachack, Y., Meister, I., Utzinger, J., Odermatt, P., Andrews, J. R., Keiser, J. 2016; 94 (1): 158-160

  Abstract

  Opisthorchis viverrini infection is a neglected tropical disease, yet it is of considerable public health importance in southeast Asia given the predilection for chronically infected persons to develop cholangiocarcinoma. We evaluated a handheld microscope for the diagnosis of O. viverrini in a community-based setting in Lao People's Democratic Republic compared with conventional light microscopy. In stool samples collected from 104 individuals, handheld microscopy revealed a sensitivity of 70.6% and a specificity of 89.5% for O. viverrini infection. Pearson's correlation for quantitative fecal egg counts between the two devices was 0.98 (95% confidence interval: 0.98-0.99). With small adjustments to further increase diagnostic sensitivity, a handheld microscope may become a helpful tool to screen for O. viverrini and other helminth infections in public health settings.

  View details for DOI 10.4269/ajtmh.15-0525

  View details for PubMedID 26526923

• Achieving high treatment success for multidrug-resistant TB in Africa: initiation and scale-up of MDR TB care in Ethiopia-an observational cohort study. Thorax Meressa, D., Hurtado, R. M., Andrews, J. R., Diro, E., Abato, K., Daniel, T., Prasad, P., Prasad, R., Fekade, B., Tedla, Y., Yusuf, H., Tadesse, M., Tefera, D., Ashenafi, A., Desta, G., Aderaye, G., Olson, K., Thim, S., Goldfeld, A. E. 2015; 70 (12): 1181-1188

  Abstract

  In Africa, fewer than half of patients receiving therapy for multidrug-resistant TB (MDR TB) are successfully treated, with poor outcomes reported for HIV-coinfected patients.A standardised second-line drug (SLD) regimen was used in a non-governmental organisation-Ministry of Health (NGO-MOH) collaborative community and hospital-based programme in Ethiopia that included intensive side effect monitoring, adherence strategies and nutritional supplementation. Clinical outcomes for patients with at least 24 months of follow-up were reviewed and predictors of treatment failure or death were evaluated by Cox proportional hazards models.From February 2009 to December 2014, 1044 patients were initiated on SLD. 612 patients with confirmed or presumed MDR TB had ≥24 months of follow-up, 551 (90.0%) were confirmed and 61 (10.0%) were suspected MDR TB cases. 603 (98.5%) had prior TB treatment, 133 (21.7%) were HIV coinfected and median body mass index (BMI) was 16.6. Composite treatment success was 78.6% with 396 (64.7%) cured, 85 (13.9%) who completed treatment, 10 (1.6%) who failed, 85 (13.9%) who died and 36 (5.9%) who were lost to follow-up. HIV coinfection (adjusted HR (AHR): 2.60, p<0.001), BMI (AHR 0.88/kg/m(2), p=0.006) and cor pulmonale (AHR 3.61, p=0.003) and confirmed MDR TB (AHR 0.50, p=0.026) were predictive of treatment failure or death.We report from Ethiopia the highest MDR TB treatment success outcomes so far achieved in Africa, in a setting with severe resource constraints and patients with advanced disease. Intensive treatment of adverse effects, nutritional supplementation, adherence interventions and NGO-MOH collaboration were key strategies contributing to success. We argue these approaches should be routinely incorporated into programmes.

  View details for DOI 10.1136/thoraxjnl-2015-207374

  View details for PubMedID 26506854

• A Cross-Sectional Survey of HIV Testing and Prevalence in Twelve Brazilian Correctional Facilities. PloS one Sgarbi, R. V., Carbone, A. d., Paião, D. S., Lemos, E. F., Simionatto, S., Puga, M. A., Motta-Castro, A. R., Pompilio, M. A., Urrego, J., Ko, A. I., Andrews, J. R., Croda, J. 2015; 10 (10): e0139487

  Abstract

  Prior studies have reported higher HIV prevalence among prisoners than the general population in Brazil, but data have been derived from single prisons. The aim of this study was to evaluate HIV testing practices, prevalence and linkage to care among inmates in a network of 12 prisons.We administered a questionnaire to a population-based sample of inmates from 12 prisons in Central-West Brazil and collected sera for HIV and syphilis testing from January to December 2013. We evaluated factors associated with HIV testing and infection using multivariable logistic regression models. Six months after HIV testing, we assessed whether each HIV-infected prisoner was engaged in clinical care and whether they had started antiretroviral therapy.We recruited 3,362 inmates, of whom 2,843 (85%) were men from 8 prisons, and 519 (15%) were women from 4 prisons. Forty-five percent of participants reported never having been tested for HIV previously. In multivariable analysis, the variables associated with previous HIV testing were lack of a stable partner (adjusted odds ratio [AOR]: 1.38; 95% CI: 1.18-1.60), completed more than four years of schooling (AOR 1.40; 95% CI: 1.20-1.64), history of previous incarceration (AOR: 1.68; 95% CI: 1.43-1.98), history of mental illness (AOR 1.52; 95% CI: 1.31-1.78) and previous surgery (AOR 1.31; 95% CI: 1.12-1.52). Fifty-four (1.6%) of all participants tested positive for HIV; this included 44 (1.54%) men and 10 (1.92%) women. Among male inmates, HIV infection was associated with homosexuality (AOR 6.20, 95% CI: 1.73-22.22), self-report of mental illness (AOR 2.18, 95% CI: 1.13-4.18), history of sexually transmitted infections (AOR 3.28, 95% CI: 1.64-6.56), and syphilis sero-positivity (AOR 2.54, 95% CI: 1.20-5.39). Among HIV-infected individuals, 34 (63%) were unaware of their HIV status; only 23 of these 34 (68%) newly diagnosed participants could be reached at six month follow-up, and 21 of 23 (91%) were engaged in HIV care.HIV testing rates among prison inmates are low, and the majority of HIV-infected inmates were unaware of their HIV diagnosis. Incarceration can be an opportunity for diagnosis and treatment of HIV among vulnerable populations who have poor access to health services, but further work is needed on transitional HIV care for released inmates.

  View details for DOI 10.1371/journal.pone.0139487

  View details for PubMedID 26466312

• The Impact of Ventilation and Early Diagnosis on Tuberculosis Transmission in Brazilian Prisons AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE Urrego, J., Ko, A. I., Santos Carbone, A. d., Guimaraes Paiao, D. S., Enne Sgarbi, R. V., Yeckel, C. W., Andrews, J. R., Crodat, J. 2015; 93 (4): 739-746

  Abstract

  Prisoners have among the highest incidence of tuberculosis (TB) globally. However, the contribution of the prison environment on transmission is not well understood and structural characteristics have received little attention as effective epidemiological interventions in TB control. We evaluated architectural characteristics and estimated ventilation rates in 141 cells in three prisons in central west Brazil using steady-state exhaled carbon dioxide (CO2) levels. We used a modified Wells-Riley equation to estimate the probability of infection for inmates sharing a cell with an infectious case and projected the impact of interventions, including early diagnosis and improved ventilation. Overall, prison cells were densely populated (mean 2.1 m(2) per occupant) and poorly ventilated, with only three cells meeting World Health Organization (WHO) standards for per-person ventilation (60 L/s) applied in infection control settings. In the absence of interventions, projected median risk of infection was 78.0% during a 6-month period. Decreasing time-to-diagnosis by 25% reduced transmission risk by 8.3%. Improving ventilation to WHO standards decreased transmission by 38.2%, whereas optimizing cross-ventilation reduced transmission by 64.4%. Prison environments promote high infection risk over short-time intervals. In this context, enhanced diagnostics have a limited impact on reducing transmission. Improving natural ventilation may be required to effectively control TB in prisons.

  View details for DOI 10.4269/ajtmh.15-0166

  View details for Web of Science ID 000362311800014

  View details for PubMedID 26195459

• Changes to Initial Postexposure Prophylaxis Regimens Between the Emergency Department and Clinic. Journal of acquired immune deficiency syndromes (1999) Bogoch, I. I., Siemieniuk, R. A., Andrews, J. R., Scully, E. P., Mayer, K. H., Bell, C. M., Zachary, K. C., Yawetz, S. 2015; 69 (5): e182-4

  View details for DOI 10.1097/QAI.0000000000000680

  View details for PubMedID 25967272

• Is a Cholera Outbreak Preventable in Post-earthquake Nepal? PLoS neglected tropical diseases Nelson, E. J., Andrews, J. R., Maples, S., Barry, M., Clemens, J. D. 2015; 9 (8)

  View details for DOI 10.1371/journal.pntd.0003961

  View details for PubMedID 26270343

• Diagnostics for invasive Salmonella infections: Current challenges and future directions. Vaccine Andrews, J. R., Ryan, E. T. 2015; 33: C8-15

  Abstract

  Invasive Salmonellosis caused by Salmonella enterica serotype Typhi or Paratyphi A, B, C, or invasive non-typhoidal Salmonella serotypes, is an immensely important disease cluster for which reliable, rapid diagnostic tests are not available. Blood culture remains the gold standard but is insensitive, slow, and resource-intensive. Existing molecular diagnostics have poor sensitivity due to the low organism burden in bodily fluids. Commercially available serologic tests for typhoidal Salmonella have had limited sensitivity and specificity. In high burden, resource-limited settings, reliance on clinical diagnosis or inaccurate tests often results in frequent, unnecessary treatment, which contributes selective pressure for the emergence of antimicrobial resistance. This practice also results in inadequate therapy for other etiologies of acute febrile illnesses, including leptospirosis and rickettsial infections. A number of novel serologic, molecular, transcriptomic and metabolomic approaches to diagnostics are under development. Target product profiles that outline specific needs may focus development and investment, and establish benchmarks for accuracy, cost, speed, and portability of new diagnostics. Of note, a critical barrier to diagnostic assay rollout will be the low cost and low perceived harm of empiric therapy on behalf of providers and patients, which leaves few perceived incentives to utilize diagnostics. Approaches that align incentives with societal goals of limiting inappropriate antimicrobial use, such as subsidizing diagnostics, may be essential for stimulating development and uptake of such assays in resource-limited settings. New diagnostics for invasive Salmonellosis should be developed and deployed alongside diagnostics for alternative etiologies of acute febrile illnesses to improve targeted use of antibiotics.

  View details for DOI 10.1016/j.vaccine.2015.02.030

  View details for PubMedID 25937611

• Towards sustainable public health surveillance for enteric fever. Vaccine Luby, S. P., Saha, S., Andrews, J. R. 2015; 33: C3-7

  Abstract

  Enteric fever that results from infection by the typhoidal Salmonellas (Salmonella Typhi and Salmonella Paratyphi A, B and C) is a life-threatening preventable illness. Surveillance of enteric fever is important to understand current burden of disease, to track changes in human health burden from increasing antimicrobial resistance and to assess the impact of efforts to reduce disease burden. Since enteric fever occurs predominantly in low income communities, expensive surveillance is not sustainable. Traditional hospital-based surveillance does not estimate population burden and intensive community-based cohort studies do not capture the severe disease that is crucial to policy decisions. While cohort studies have been considered the gold standard for incidence estimates, the resources required to conduct them are great; as a consequence, estimates of enteric fever burden have been highly geographically and temporally restricted. A hybrid approach combining laboratory diagnosis that is already being conducted in healthcare centers with community-based surveillance of health care facility use offers a low-cost, sustainable approach to generate policy relevant data.

  View details for DOI 10.1016/j.vaccine.2015.02.054

  View details for PubMedID 25912287

• Diagnosis of Schistosoma haematobium Infection with a Mobile Phone-Mounted Foldscope and a Reversed-Lens CellScope in Ghana AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE Ephraim, R. K., Duah, E., Cybulski, J. S., Prakash, M., D'Ambrosio, M. V., Fletcher, D. A., Keiser, J., Andrews, J. R., Bogoch, I. I. 2015; 92 (6): 1253-1256

  Abstract

  We evaluated two novel, portable microscopes and locally acquired, single-ply, paper towels as filter paper for the diagnosis of Schistosoma haematobium infection. The mobile phone-mounted Foldscope and reversed-lens CellScope had sensitivities of 55.9% and 67.6%, and specificities of 93.3% and 100.0%, respectively, compared with conventional light microscopy for diagnosing S. haematobium infection. With conventional light microscopy, urine filtration using single-ply paper towels as filter paper showed a sensitivity of 67.6% and specificity of 80.0% compared with centrifugation for the diagnosis of S. haematobium infection. With future improvements to diagnostic sensitivity, newer generation handheld and mobile phone microscopes may be valuable tools for global health applications.

  View details for DOI 10.4269/ajtmh.14-0741

  View details for Web of Science ID 000355785400028

  View details for PubMedID 25918211

• The epidemiological advantage of preferential targeting of tuberculosis control at the poor INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE Andrews, J. R., Basu, S., Dowdy, D. W., Murray, M. B. 2015; 19 (4): 375-380

  Abstract

  Tuberculosis (TB) remains disproportionately concentrated among the poor, yet known determinants of TB reactivation may fail to explain observed disparities in disease rates according to wealth. Reviewing data on TB disparities in India and the wealth distribution of known TB risk factors, we describe how social mixing patterns could be contributing to TB disparities. Wealth-assortative mixing, whereby individuals are more likely to be in contact with others from similar socio-economic backgrounds, amplifies smaller differences in risk of TB, resulting in large population-level disparities. As disparities and assortativeness increase, TB becomes more difficult to control, an effect that is obscured by looking at population averages of epidemiological parameters, such as case detection rates. We illustrate how TB control efforts may benefit from preferential targeting toward the poor. In India, an equivalent-scale intervention could have a substantially greater impact if targeted at those living below the poverty line than with a population-wide strategy. In addition to potential efficiencies in targeting higher-risk populations, TB control efforts would lead to a greater reduction in secondary TB cases per primary case diagnosed if they were preferentially targeted at the poor. We highlight the need to collect programmatic data on TB disparities and explicitly incorporate equity considerations into TB control plans.

  View details for DOI 10.5588/ijtld.14.0423

  View details for Web of Science ID 000351967800004

  View details for PubMedID 25859990

• The Dynamics of QuantiFERON-TB Gold In-Tube Conversion and Reversion in a Cohort of South African Adolescents. American journal of respiratory and critical care medicine Andrews, J. R., Hatherill, M., Mahomed, H., Hanekom, W. A., Campo, M., Hawn, T. R., Wood, R., Scriba, T. J. 2015; 191 (5): 584-591

  Abstract

  Rationale: Interferon-gamma release assays are used to diagnose tuberculosis infection. In developed countries, high rates of reversion following conversion have been described. Objectives: Assess QuantiFERON® TB Gold In-tube (QFT) conversion and reversion dynamics in a tuberculosis-endemic setting. Methods. Adolescents aged 12-18 residing near Cape Town were recruited. Tuberculin skin testing (TST) and QFT were performed at baseline and after 2 years of follow-up; half also had TST and QFT performed at additional time points. Participants were observed for incident tuberculosis disease for up to five years. Measurements and Main Results. Among 5,357 participants, 2,751 (51.4%) and 2,987 (55.8%) were positive by QFT and TST at baseline. Annualized QFT and TST conversion risks were 14.0% and 13.0%, respectively; reversion risks were 5.1% and 4.1%. Concordance was excellent for conversions (κ = 0.74), but poor for reversions (κ = 0.12). Among recent QFT converters, magnitude of QFT value was strongly inversely associated with risk of reversion (p<0.0001). When longitudinal QFT data were analyzed in a cross-sectional manner, the annual risk of infection was 7.3%, whereas inclusion of reversions in the analysis showed that the actual risk of infection was 14.0%. Incident tuberculosis was 8-fold higher among QFT reverters, compared with persons with all negative QFT results (1.47 vs. 0.18 cases/100 person-years, p=0.011). Conclusions. In this tuberculosis-endemic setting, annual risk of infection was extremely high, while QFT and TST conversion concordance were higher and QFT reversion rates were lower than reported from low-burden settings.

  View details for DOI 10.1164/rccm.201409-1704OC

  View details for PubMedID 25562578

• Prisons as Reservoir for Community Transmission of Tuberculosis, Brazil EMERGING INFECTIOUS DISEASES Sacchi, F. P., Praca, R. M., Tatara, M. B., Simonsen, V., Ferrazoli, L., Croda, M. G., Suffys, P. N., Ko, A. I., Andrews, J. R., Croda, J. 2015; 21 (3): 452-455

  Abstract

  We conducted a population-based study of tuberculosis (TB) cases in Dourados, Brazil, to assess the relationship between incarceration and TB in the general population. Incarceration was associated with TB in an urban population; 54% of Mycobacterium tuberculosis strains were related to strains from persons in prisons. TB control in prisons is critical for reducing disease prevalence.

  View details for DOI 10.3201/eid2103.140896

  View details for Web of Science ID 000350269300009

  View details for PubMedID 25642998

• Treating multidrug-resistant tuberculosis in community settings: a wise investment. international journal of tuberculosis and lung disease Andrews, J. R., Stout, J. E. 2015; 19 (2): 127-?

  View details for DOI 10.5588/ijtld.14.0761

  View details for PubMedID 25574906

• Active and latent tuberculosis in Brazilian correctional facilities: a cross-sectional study. BMC infectious diseases Carbone, A. d., Paião, D. S., Sgarbi, R. V., Lemos, E. F., Cazanti, R. F., Ota, M. M., Junior, A. L., Bampi, J. V., Elias, V. P., Simionatto, S., Motta-Castro, A. R., Pompílio, M. A., de Oliveira, S. M., Ko, A. I., Andrews, J. R., Croda, J. 2015; 15: 24-?

  Abstract

  BackgroundTuberculosis (TB) rates among prisoners are more than 20 times that of the general population in Brazil, yet there are limited data available to facilitate the development of effective interventions in this high-transmission setting. We aimed to assess risk factors for TB infection and evaluate the yield of mass screening for active disease among inmates.MethodsWe administered a questionnaire and tuberculin skin test (TST) to a population-based sample of inmates from 12 prisons in Central-West Brazil and collected sera for HIV testing and two sputum samples for smear microscopy and culture from participants reporting a cough of any duration. Hierarchical Poisson regression models were used to evaluate factors associated with latent tuberculosis infection (LTBI).ResultsWe recruited 3,380 inmates, of which 2,861 (84.6%) were males from 8 prisons, and 519 (15.4%) were females from 4 prisons. Among the 1,020 (30%) subjects who reported a cough, we obtained sputum from 691 (68%) and identified 31 cases of active TB for a point prevalence of 917 (95% CI, 623¿1302) per 100,000 prisoners. Evaluation of the two sputum smear samples failed to identify 74% of the TB cases, and 29% of the cases reported less than 2 weeks of symptoms. Obtaining a second culture identified an additional 7 (24%) cases. The prevalences of LTBI were 22.5% and 11.7% for male and female prisoners, respectively and duration of incarceration (in years) was associated with LTBI in male and female in the multivariable model (1.04, 95% CI, 1.01-1.07 and 1.34, 95% CI, 1.06-1.70, respectively). The prevalence of LTBI is 8.6% among newly incarcerated inmates, among whom LTBI prevalence significantly increased by 5% with each year of incarceration.ConclusionsAlthough the overall LTBI prevalence among inmates in Central-West Brazil is low, tuberculosis incidence is high (>1,800/100,00), likely due to the high force of infection among a largely susceptible inmate population. Efforts to reduce transmission in prisons may require mass screening for active TB, utilizing sputum culture in case-detection protocols.

  View details for DOI 10.1186/s12879-015-0764-8

  View details for PubMedID 25608746

• Comparison of community-wide, integrated mass drug administration strategies for schistosomiasis and soil-transmitted helminthiasis: a cost-effectiveness modelling study Lancet Global Health Lo, N. C., Bogoch, I. I., Blackburn, B. G., Raso, G., N’Goran, E. K., Coulibaly, J. T., Becker, S. L., Abrams, H. B., Utzinger, J., Andrews, J. R. 2015: e629-38

  Abstract

  More than 1·5 billion people are affected by schistosomiasis or soil-transmitted helminthiasis. WHO's recommendations for mass drug administration (MDA) against these parasitic infections emphasise treatment of school-aged children, using separate treatment guidelines for these two helminthiases groups. We aimed to evaluate the cost-effectiveness of expanding integrated MDA to the entire community in four settings in Côte d'Ivoire.We extended previously published, dynamic, age-structured models of helminthiases transmission to simulate costs and disability averted with integrated MDA (of praziquantel and albendazole) for schistosomiasis and soil-transmitted helminthiasis. We calibrated the model to data for prevalence and intensity of species-specific helminth infection from surveys undertaken in four communities in Côte d'Ivoire between March, 1997, and September, 2010. We simulated a 15-year treatment programme with 75% coverage in only school-aged children; school-aged children and preschool-aged children; adults; and the entire community. Treatment costs were estimated at US$0·74 for school-aged children and $1·74 for preschool-aged children and adults. The incremental cost-effectiveness ratio (ICER) was calculated in 2014 US dollars per disability-adjusted life-year (DALY) averted.Expanded community-wide treatment was highly cost effective compared with treatment of only school-aged children (ICER $167 per DALY averted) and WHO guidelines (ICER $127 per DALY averted), and remained highly cost effective even if treatment costs for preschool-aged children and adults were ten times greater than those for school-aged children. Community-wide treatment remained highly cost effective even when elimination of helminth infections was not achieved. These findings were robust across the four diverse communities in Côte d'Ivoire, only one of which would have received annual MDA for both schistosomiasis and soil-transmitted helminthiasis under the latest WHO guidelines. Treatment every 6 months was also highly cost effective in three out of four communities.Integrated, community-wide MDA programmes for schistosomiasis and soil-transmitted helminthiasis can be highly cost effective, even in communities with low disease burden in any helminth group. These results support an urgent need to re-evaluate current global guidelines for helminthiases control programmes to include community-wide treatment, increased treatment frequency, and consideration for lowered prevalence thresholds for integrated treatment.Stanford University Medical Scholars Programme, Mount Sinai Hospital-University Health Network AMO Innovation Fund.

  View details for DOI 10.1016/S2214-109X(15)00047-9

• Quantitative evaluation of a handheld light microscope for field diagnosis of soil-transmitted helminth infection. The American journal of tropical medicine and hygiene Bogoch, I. I., Andrews, J. R., Speich, B., Ame, S. M., Ali, S. M., Stothard, J. R., Utzinger, J., Keiser, J. 2014; 91 (6): 1138-1141

  Abstract

  We evaluated the Newton Nm1, a commercially available handheld light microscope and compared it with conventional light microscopy for the diagnosis of soil-transmitted helminth infections. A total of 91 Kato-Katz thick smears were examined by experienced microscopists and helminth eggs were counted and expressed as eggs per gram of stool (EPG). Mean egg counts were significantly higher with the conventional light microscope (5,190.0 EPG versus 2,385.8 EPG for Ascaris lumbricoides; 826.3 versus 455.7 for Trichuris trichiura; both P < 0.05). Using regression coefficients and accounting for intensity of infection, we found that the agreement between the two devices was excellent for both species (κ = 0.90, 95% confidence interval = 0.82-0.99 for A. lumbricoides and κ = 0.96, 95% CI = 0.91-1.00 for T. trichiura). The Newton Nm1 microscope may be a useful tool for the detection and quantification of soil-transmitted helminth infection in clinical, epidemiologic, and public health settings.

  View details for DOI 10.4269/ajtmh.14-0253

  View details for PubMedID 25246697

• Evaluation of portable microscopic devices for the diagnosis of Schistosoma and soil-transmitted helminth infection PARASITOLOGY Bogoch, I. I., Coulibaly, J. T., Andrews, J. R., Speich, B., Keiser, J., Stothard, J. R., N'Goran, E. K., Utzinger, J. 2014; 141 (14): 1811-1818

  Abstract

  SUMMARY The diagnosis of parasitic worm (helminth) infections requires specialized laboratory settings, but most affected individuals reside in locations without access to such facilities. We tested two portable microscopic devices for the diagnosis of helminth infections in a cross-sectional survey in rural Côte d'Ivoire. We examined 164 stool samples under a light microscope and then re-examined with a commercial portable light microscope and an experimental mobile phone microscope for the diagnosis of Schistosoma mansoni and soil-transmitted helminths. Additionally, 180 filtered urine samples were examined by standard microscopy and compared with the portable light microscope for detection of Schistosoma haematobium eggs. Conventional microscopy was considered the diagnostic reference standard. For S. mansoni, S. haematobium and Trichuris trichiura, the portable light microscope showed sensitivities of 84·8%, 78·6% and 81·5%, respectively, and specificities of 85·7%, 91·0% and 93·0%, respectively. For S. mansoni and T. trichiura, we found sensitivities for the mobile phone microscope of 68·2% and 30·8%, respectively, and specificities of 64·3% and 71·0%, respectively. We conclude that the portable light microscope has sufficient diagnostic yield for Schistosoma and T. trichiura infections, while the mobile phone microscope has only modest sensitivity in its current experimental set-up. Development of portable diagnostic technologies that can be used at point-of-sample collection will enhance diagnostic coverage in clinical and epidemiological settings.

  View details for DOI 10.1017/S0031182014000432

  View details for Web of Science ID 000346740700005

  View details for PubMedID 24776232

• Isoniazid preventive therapy in medium-incidence settings: the price is right. international journal of tuberculosis and lung disease Stout, J. E., Andrews, J. R. 2014; 18 (12): 1388-?

  View details for DOI 10.5588/ijtld.14.0760

  View details for PubMedID 25517800

• Strengthening Nepal's Female Community Health Volunteer network: a qualitative study of experiences at two years BMC HEALTH SERVICES RESEARCH Schwarz, D., Sharma, R., Bashyal, C., Schwarz, R., Baruwal, A., Karelas, G., Basnet, B., Khadka, N., Brady, J., Silver, Z., Mukherjee, J., Andrews, J., Maru, D. S. 2014; 14

  Abstract

  Nepal's Female Community Health Volunteer (FCHV) program has been described as an exemplary public-sector community health worker program. However, despite its merits, the program still struggles to provide high-quality, accessible services nation-wide. Both in Nepal and globally, best practices for community health worker program implementation are not yet known: there is a dearth of empiric research, and the research that has been done has shown inconsistent results.Here we evaluate a pilot program designed to strengthen the Nepali government's FCHV network. The program was structured with five core components: 1) improve local FCHV leadership; 2) facilitate structured weekly FCHV meetings and 3) weekly FCHV trainings at the village level; 4) implement a monitoring and evaluation system for FCHV patient encounters; and 5) provide financial compensation for FCHV work. Following twenty-four months of program implementation, a retrospective programmatic evaluation was conducted, including qualitative analysis of focus group discussions and semi-structured interviews.Qualitative data analysis demonstrated that the program was well-received by program participants and community members, and suggests that the five core components of this program were valuable additions to the pre-existing FCHV network. Analysis also revealed key challenges to program implementation including geographic limitations, literacy limitations, and limitations of professional respect from healthcare workers to FCHVs. Descriptive statistics are presented for programmatic process metrics and costs throughout the first twenty four months of implementation.The five components of this pilot program were well-received as a mechanism for strengthening Nepal's FCHV program. To our knowledge, this is the first study to present such data, specifically informing programmatic design and management of the FCHV program. Despite limitations in its scope, this study offers tangible steps forward for further research and community health worker program improvement, both within Nepal and globally.

  View details for DOI 10.1186/1472-6963-14-473

  View details for Web of Science ID 000349638000001

  View details for PubMedID 25301105

• Ultra-Low-Cost Urine Filtration for Schistosoma haematobium Diagnosis: A Proof-of-Concept Study. American journal of tropical medicine and hygiene Ephraim, R. K., Duah, E., Andrews, J. R., Bogoch, I. I. 2014; 91 (3): 544-546

  Abstract

  Simple, efficient, and cost-effective strategies are needed for urine sample preparation in the field diagnosis of infection with Schistosoma haematobium. In this proof-of-concept study, we evaluated inexpensive and widely available paper products (paper towels, school workbook paper, and newspaper) to gravity-filter urine containing 60 eggs/mL of Schistosoma haematobium. Eggs were reliably visualized by light microscopy by using single-ply paper towels as urine filters. This filtration method has broad applicability in clinical and public health settings in resource-constrained environments.

  View details for DOI 10.4269/ajtmh.14-0221

  View details for PubMedID 24980496

• Integrating Social Contact and Environmental Data in Evaluating Tuberculosis Transmission in a South African Township JOURNAL OF INFECTIOUS DISEASES Andrews, J. R., Morrow, C., Walensky, R. P., Wood, R. 2014; 210 (4): 597-603

  Abstract

  Background. Population models of tuberculosis transmission have not accounted for social contact structure and the role of the environment in which tuberculosis is transmitted.Methods. We utilized extensions to the Wells-Riley model of tuberculosis transmission, using exhaled carbon dioxide as a tracer gas, to describe transmission patterns in an endemic community. Drawing upon social interaction data and carbon dioxide measurements from a South African township, we created an age-structured model of tuberculosis transmission in households, public transit, schools and workplaces. We fit the model to local data on latent tuberculosis prevalence by age.Results. Most tuberculosis infections (84%) were estimated to occur outside of one's own household. 50% of infections among young adults (ages 15-19) occurred in schools, due to high contact rates and poor ventilation. Despite lower numbers of contacts in workplaces, assortative mixing among adults with high rates of smear-positive tuberculosis contributed to transmission in this environment. Households and public transit were important sites of transmission between age groups.Conclusions. Consistent with molecular epidemiologic estimates, a minority of tuberculosis transmission was estimated to occur within households, which may limit the impact of contact investigations. Further work is needed to investigate the role of schools in tuberculosis transmission.

  View details for DOI 10.1093/infdis/jiu138

  View details for Web of Science ID 000340243500013

  View details for PubMedID 24610874

• The Importance of Implementation Strategy in Scaling Up Xpert MTB/RIF for Diagnosis of Tuberculosis in the Indian Health-Care System: A Transmission Model PLOS MEDICINE Salje, H., Andrews, J. R., Deo, S., Satyanarayana, S., Sun, A. Y., Pai, M., Dowdy, D. W. 2014; 11 (7)

  Abstract

  India has announced a goal of universal access to quality tuberculosis (TB) diagnosis and treatment. A number of novel diagnostics could help meet this important goal. The rollout of one such diagnostic, Xpert MTB/RIF (Xpert) is being considered, but if Xpert is used mainly for people with HIV or high risk of multidrug-resistant TB (MDR-TB) in the public sector, population-level impact may be limited.We developed a model of TB transmission, care-seeking behavior, and diagnostic/treatment practices in India and explored the impact of six different rollout strategies. Providing Xpert to 40% of public-sector patients with HIV or prior TB treatment (similar to current national strategy) reduced TB incidence by 0.2% (95% uncertainty range [UR]: -1.4%, 1.7%) and MDR-TB incidence by 2.4% (95% UR: -5.2%, 9.1%) relative to existing practice but required 2,500 additional MDR-TB treatments and 60 four-module GeneXpert systems at maximum capacity. Further including 20% of unselected symptomatic individuals in the public sector required 700 systems and reduced incidence by 2.1% (95% UR: 0.5%, 3.9%); a similar approach involving qualified private providers (providers who have received at least some training in allopathic or non-allopathic medicine) reduced incidence by 6.0% (95% UR: 3.9%, 7.9%) with similar resource outlay, but only if high treatment success was assured. Engaging 20% of all private-sector providers (qualified and informal [providers with no formal medical training]) had the greatest impact (14.1% reduction, 95% UR: 10.6%, 16.9%), but required >2,200 systems and reliable treatment referral. Improving referrals from informal providers for smear-based diagnosis in the public sector (without Xpert rollout) had substantially greater impact (6.3% reduction) than Xpert scale-up within the public sector. These findings are subject to substantial uncertainty regarding private-sector treatment patterns, patient care-seeking behavior, symptoms, and infectiousness over time; these uncertainties should be addressed by future research.The impact of new diagnostics for TB control in India depends on implementation within the complex, fragmented health-care system. Transformative strategies will require private/informal-sector engagement, adequate referral systems, improved treatment quality, and substantial resources. Please see later in the article for the Editors' Summary.

  View details for DOI 10.1371/journal.pmed.1001674

  View details for Web of Science ID 000340617400007

  View details for PubMedID 25025235

• A User-Friendly, Open-Source Tool to Project Impact and Cost of Diagnostic Tests for Tuberculosis ELIFE Dowdy, D. W., Andrews, J. R., Dodd, P. J., Gilman, R. H. 2014; 3

  Abstract

  Most existing models of infectious diseases, including tuberculosis (TB), do not allow end-users to customize results to local conditions. We created a dynamic transmission model to project TB incidence, TB mortality, multidrug-resistant (MDR) TB prevalence, and incremental costs over five years after scale-up of nine alternative diagnostic strategies including combinations of sputum smear microscopy, Xpert MTB/RIF, microcolony-based culture, and same-day diagnosis. We developed a corresponding web-based interface that allows users to specify local costs and epidemiology. Full model code - including the ability to change any input parameter - is also included. The impact of improved diagnostic testing was greater for mortality and MDR-TB prevalence than TB incidence, and was maximized in high-incidence, low-HIV settings. More costly interventions generally had greater impact. In settings with little capacity for up-front investment, same-day microscopy had greatest impact on TB incidence and became cost-saving within five years if feasible to deliver at $10/test. In settings where more initial investment was possible, population-level scale-up of either Xpert MTB/RIF or microcolony-based culture offered substantially greater benefits, often averting ten times more TB cases than narrowly-targeted diagnostic strategies at minimal incremental long-term cost. Where containing MDR-TB is the overriding concern, Xpert for smear-positives has reasonable impact on MDR-TB incidence, but at substantial price and little impact on overall TB incidence and mortality. This novel, user-friendly modeling framework improves decision-makers' ability to evaluate the impact of TB diagnostic strategies, accounting for local conditions.

  View details for DOI 10.7554/eLife.02565

  View details for Web of Science ID 000336837300004

  View details for PubMedID 24898755

• Patient Attrition Between the Emergency Department and Clinic Among Individuals Presenting for HIV Nonoccupational Postexposure Prophylaxis CLINICAL INFECTIOUS DISEASES Bogoch, I. I., Scully, E. P., Zachary, K. C., Yawetz, S., Mayer, K. H., Bell, C. M., Andrews, J. R. 2014; 58 (11): 1618-1624

  Abstract

  Background. Nonoccupational postexposure prophylaxis (nPEP) is recommended after a sexual or parenteral exposure to human immunodeficiency virus (HIV). Patients frequently seek care in an emergency department (ED) after an exposure and are usually referred to an HIV clinic for further management. There have been few data on determinants of attrition after presentation to EDs for nPEP. Methods. From July 2010 to June 2011, we prospectively recorded all referrals to nPEP programs from 2 large EDs at 2 academic medical centers in Boston, Massachusetts. Data were recorded on patient demographics, nature of potential HIV exposures, referrals to and attendance at HIV clinics, and reported completion of 28 days of antiretroviral therapy (ART). Multivariable logistic regression was used to evaluate risk factors for (1) patient attrition between the ED and HIV clinic follow-up and (2) documented completion of ART. Results. Of 180 individuals who were referred to clinic follow-up for nPEP care from the ED, 98 (54.4%) attended a first nPEP clinic visit and 43 (23.9%) had documented completion of a 28-day course of ART. Multivariable analysis revealed older age (adjusted odds ratio [aOR], 0.96; 95% confidence interval [CI], .93-.99) and self-payment (aOR, 0.32; 95% CI, .11-.97) were significant predictors for failing to attend an initial HIV clinic appointment. Women were less likely than men to complete a 28-day ART regimen (aOR, 0.34; 95% CI, .15-.79). Conclusions. Commonly used nPEP delivery models may not be effective for all patients who present with nonoccupational exposures to HIV. Interventions are needed to improve rates of follow-up and completion of nPEP to reduce the risk of preventable HIV infections.

  View details for DOI 10.1093/cid/ciu118

  View details for Web of Science ID 000337031200020

  View details for PubMedID 24723288

• Timing of Tuberculosis Transmission and the Impact of Household Contact Tracing An Agent-based Simulation Model AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Kasaie, P., Andrews, J. R., Kelton, W. D., Dowdy, D. W. 2014; 189 (7): 845-852

  Abstract

  Rationale: Household contact tracing has recently been endorsed for global tuberculosis (TB) control, but its potential population-level impact remains uncertain. Objectives: To project the maximum impact of household contact tracing for TB in a moderate-burden setting. Methods: We developed a stochastic, agent-based simulation model of a simplified TB epidemic, calibrated to a setting of moderate TB incidence. We used data from the literature to generate "community-driven" and "household-driven" scenarios in which 22% and 50% of TB transmission occurred within the household respectively. In each scenario, we simulated an intervention in which the household members are screened and treated for TB at the time of an index patient's active TB diagnosis. Measurements and Main Results: By the time of TB diagnosis, 75-95% of initial household infections had already occurred, but only 1.5-3.0% of contacts had sufficient time to progress to active TB. With 100% sensitive tracing of all contacts for five consecutive years, TB incidence declined by 10-15%: a mean year-over-year decline of 2%/year. Effects were sustained for many years after stopping the intervention. Providing preventive therapy with contact tracing nearly doubled this impact (17-27% decline in incidence). Impact was proportional to sensitivity and coverage; thus, if 50% of contacts were screened with a 50% sensitive test, TB incidence declined by only 0.5%/year. Conclusions: Household contact tracing is unlikely to transform TB epidemiology in isolation but has the potential - especially with provision of preventive therapy - to augment a comprehensive package of interventions that could substantially reduce the population-level burden of TB.

  View details for DOI 10.1164/rccm.201310-1846OC

  View details for Web of Science ID 000333565600014

  View details for PubMedID 24559425

• Quantification of shared air: a social and environmental determinant of airborne disease transmission. PloS one Wood, R., Morrow, C., Ginsberg, S., Piccoli, E., Kalil, D., Sassi, A., Walensky, R. P., Andrews, J. R. 2014; 9 (9)

  Abstract

  Tuberculosis is endemic in Cape Town, South Africa where a majority of the population become tuberculosis infected before adulthood. While social contact patterns impacting tuberculosis and other respiratory disease spread have been studied, the environmental determinants driving airborne transmission have not been quantified.Indoor carbon dioxide levels above outdoor levels reflect the balance of exhaled breath by room occupants and ventilation. We developed a portable monitor to continuously sample carbon dioxide levels, which were combined with social contact diary records to estimate daily rebreathed litres. A pilot study established the practicality of monitor use up to 48-hours. We then estimated the daily volumes of air rebreathed by adolescents living in a crowded township.One hundred eight daily records were obtained from 63 adolescents aged between 12- and 20-years. Forty-five lived in wooden shacks and 18 in brick-built homes with a median household of 4 members (range 2-9). Mean daily volume of rebreathed air was 120.6 (standard error: 8.0) litres/day, with location contributions from household (48%), school (44%), visited households (4%), transport (0.5%) and other locations (3.4%). Independent predictors of daily rebreathed volumes included household type (p = 0.002), number of household occupants (p = 0.021), number of sleeping space occupants (p = 0.022) and winter season (p<0.001).We demonstrated the practical measurement of carbon dioxide levels to which individuals are exposed in a sequence of non-steady state indoor environments. A novel metric of rebreathed air volume reflects social and environmental factors associated with airborne infection and can identify locations with high transmission potential.

  View details for DOI 10.1371/journal.pone.0106622

  View details for PubMedID 25181526

• Challenges in Evaluating the Cost-effectiveness of New Diagnostic Tests for HIV-Associated Tuberculosis CLINICAL INFECTIOUS DISEASES Andrews, J. R., Lawn, S. D., Dowdy, D. W., Walensky, R. P. 2013; 57 (7): 1021-1026

  Abstract

  With an emerging array of rapid diagnostic tests for tuberculosis, cost-effectiveness analyses are needed to inform scale-up in various populations and settings. Human immunodeficiency virus (HIV)-associated tuberculosis poses unique challenges in estimating and interpreting the cost-effectiveness of novel diagnostic tools. First, gains in sensitivity and specificity do not directly correlate with impact on clinical outcomes. Second, the cost-effectiveness of implementing tuberculosis diagnostics in HIV-infected populations is heavily influenced by downstream costs of HIV care. As a result, tuberculosis diagnostics may appear less cost-effective in this population than among HIV-uninfected individuals, raising important ethical and policy questions about the design and interpretation of cost-effectiveness analyses in this setting. Third, conventional cost-effectiveness benchmarks may be inadequate for making decisions about whether to adopt new diagnostics. If we are to appropriately deploy novel diagnostics for tuberculosis to people living with HIV in resource-constrained settings, these challenges in measuring cost-effectiveness must be more widely recognized and addressed.

  View details for DOI 10.1093/cid/cit412

  View details for Web of Science ID 000326027400015

  View details for PubMedID 23788239

• Complexity in mathematical models of public health policies: a guide for consumers of models. PLoS medicine Basu, S., Andrews, J. 2013; 10 (10)

  Abstract

  Sanjay Basu and colleagues explain how models are increasingly used to inform public health policy yet readers may struggle to evaluate the quality of models. All models require simplifying assumptions, and there are tradeoffs between creating models that are more "realistic" versus those that are grounded in more solid data. Indeed, complex models are not necessarily more accurate or reliable simply because they can more easily fit real-world data than simpler models can. Please see later in the article for the Editors' Summary.

  View details for DOI 10.1371/journal.pmed.1001540

  View details for PubMedID 24204214

  View details for PubMedCentralID PMC3812083

• Evaluation of an Electricity-free, Culture-based Approach for Detecting Typhoidal Salmonella Bacteremia during Enteric Fever in a High Burden, Resource-limited Setting PLOS NEGLECTED TROPICAL DISEASES Andrews, J. R., Prajapati, K. G., Eypper, E., Shrestha, P., Shakya, M., Pathak, K. R., Joshi, N., Tiwari, P., Risal, M., Koirala, S., Karkey, A., Dongol, S., Wen, S., Smith, A. B., Maru, D., Basnyat, B., Baker, S., Farrar, J., Ryan, E. T., Hohmann, E., Arjyal, A. 2013; 7 (6)

  Abstract

  In many rural areas at risk for enteric fever, there are few data on Salmonella enterica serotypes Typhi (S. Typhi) and Paratyphi (S. Paratyphi) incidence, due to limited laboratory capacity for microbiologic culture. Here, we describe an approach that permits recovery of the causative agents of enteric fever in such settings. This approach involves the use of an electricity-free incubator based upon use of phase-change materials. We compared this against conventional blood culture for detection of typhoidal Salmonella.Three hundred and four patients with undifferentiated fever attending the outpatient and emergency departments of a public hospital in the Kathmandu Valley of Nepal were recruited. Conventional blood culture was compared against an electricity-free culture approach. Blood from 66 (21.7%) patients tested positive for a Gram-negative bacterium by at least one of the two methods. Sixty-five (21.4%) patients tested blood culture positive for S. Typhi (30; 9.9%) or S. Paratyphi A (35; 11.5%). From the 65 individuals with culture-confirmed enteric fever, 55 (84.6%) were identified by the conventional blood culture and 60 (92.3%) were identified by the experimental method. Median time-to-positivity was 2 days for both procedures. The experimental approach was falsely positive due to probable skin contaminants in 2 of 239 individuals (0.8%). The percentages of positive and negative agreement for diagnosis of enteric fever were 90.9% (95% CI: 80.0%-97.0%) and 96.0% (92.7%-98.1%), respectively. After initial incubation, Salmonella isolates could be readily recovered from blood culture bottles maintained at room temperature for six months.A simple culture approach based upon a phase-change incubator can be used to isolate agents of enteric fever. This approach could be used as a surveillance tool to assess incidence and drug resistance of the etiologic agents of enteric fever in settings without reliable local access to electricity or local diagnostic microbiology laboratories.

  View details for DOI 10.1371/journal.pntd.0002292

  View details for Web of Science ID 000321201300043

  View details for PubMedID 23853696

  View details for PubMedCentralID PMC3694822

• Short Report: Mobile Phone Microscopy for the Diagnosis of Soil-Transmitted Helminth Infections: A Proof-of-Concept Study AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE Bogoch, I. I., Andrews, J. R., Speich, B., Utzinger, J., Ame, S. M., Ali, S. M., Keiser, J. 2013; 88 (4): 626-629

  Abstract

  We created a mobile phone microscope and assessed its accuracy for the diagnosis of soil-transmitted helminths compared with conventional microscopy. Mobile phone microscopy has a sensitivity of 69.4% for detecting any helminth egg and sensitivities of 81.0%, 54.4%, and 14.3% for the diagnosis of Ascaris lumbricoides, Trichuris trichiura and hookworm respectively.

  View details for DOI 10.4269/ajtmh.12-0742

  View details for Web of Science ID 000317024700005

• Modeling the Role of Public Transportation in Sustaining Tuberculosis Transmission in South Africa AMERICAN JOURNAL OF EPIDEMIOLOGY Andrews, J. R., Morrow, C., Wood, R. 2013; 177 (6): 556-561

  Abstract

  Current tuberculosis notification rates in South Africa are among the highest ever recorded. Although the human immunodeficiency virus epidemic has been a critical factor, the density of respiratory contacts in high-risk environments may be an important and underappreciated driver. Using a modified Wells-Riley model for airborne disease transmission, we estimated the risk of tuberculosis transmission on 3 modes of public transit (minibus taxis, buses, and trains) in Cape Town, South Africa, using exhaled carbon dioxide as a natural tracer gas to evaluate air exchange. Carbon dioxide measurements were performed between October and December of 2011. Environmental risk, reflected in the rebreathed fraction of air, was highest in minibus taxis and lowest in trains; however, the average number of passengers sharing an indoor space was highest in trains and lowest in minibus taxis. Among daily commuters, the annual risk of tuberculosis infection was projected to be 3.5%-5.0% and was highest among minibus taxi commuters. Assuming a duration of infectiousness of 1 year, the basic reproductive number attributable to transportation was more than 1 in all 3 modes of transportation. Given its poor ventilation and high respiratory contact rates, public transportation may play a critical role in sustaining tuberculosis transmission in South African cities.

  View details for DOI 10.1093/aje/kws331

  View details for Web of Science ID 000316374500009

  View details for PubMedID 23423215

• Is Passive Diagnosis Enough? The Impact of Subclinical Disease on Diagnostic Strategies for Tuberculosis AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Dowdy, D. W., Basu, S., Andrews, J. R. 2013; 187 (5): 543-551

  Abstract

  Tuberculosis (TB) is characterized by a subclinical phase (symptoms absent or not considered abnormal); prediagnostic phase (symptoms noticed but diagnosis not pursued); and clinical phase (care actively sought). Diagnostic capacity during these phases is limited.To estimate the population-level impact of TB case-finding strategies in the presence of subclinical and prediagnostic disease.We created a mathematical epidemic model of TB, calibrated to global incidence. We then introduced three prototypical diagnostic interventions: increased sensitivity of diagnosis in the clinical phase by 20% ("passive"); early diagnosis during the prediagnostic phase at a rate of 10% per year ("enhanced"); and population-based diagnosis of 5% of undiagnosed prevalent cases per year ("active").If the subclinical phase was ignored, as in most models, the passive strategy was projected to reduce TB incidence by 18% (90% uncertainty range [UR], 11-32%) by year 10, compared with 23% (90% UR, 14-35%) for the enhanced strategy and 18% (90% UR, 11-28%) for the active strategy. After incorporating a subclinical phase into the model, consistent with population-based prevalence surveys, the active strategy still reduced 10-year TB incidence by 16% (90% UR, 11-28%), but the passive and enhanced strategies' impact was attenuated to 11% (90% UR, 8-25%) and 6% (90% UR, 4-13%), respectively. The degree of attenuation depended strongly on the transmission rate during the subclinical phase.Subclinical disease may limit the impact of current diagnostic strategies for TB. Active detection of undiagnosed prevalent cases may achieve greater population-level TB control than increasing passive case detection.

  View details for DOI 10.1164/rccm.201207-1217OC

  View details for Web of Science ID 000315977200014

  View details for PubMedID 23262515

• Clinical predictors for the aetiology of peripheral lymphadenopathy in HIV-infected adults HIV MEDICINE Bogoch, I. I., Andrews, J. R., Nagami, E. H., Rivera, A. M., Gandhi, R. T., Stone, D. 2013; 14 (3): 182-186

  Abstract

  The aim of the study was to determine the aetiology and clinical predictors of peripheral lymphadenopathy in HIV-infected individuals during the antiretroviral (ARV) era in a nontuberculosis endemic setting.A multicentred, retrospective cohort study of peripheral lymph node biopsies in HIV-positive adults was carried out. A total of 107 charts were identified and reviewed for clinical features, lymphadenopathy size, and ARV use and duration. Biopsy results were categorized, and multivariate logistic regression determined independent predictors of lymphadenopathy aetiology.Evaluation of 107 peripheral lymph node biopsies revealed that 42.9% of peripheral lymphadenopathy was attributable to malignancy, 49.5% to reactive changes, and 7.5% to infections, with only 2.8% of all cases secondary to tuberculosis. Fevers, weight loss, ARV use, and lower viral loads are significantly associated with nonreactive lymphadenopathy.Lymphadenopathy is likely to be reactive or malignant in nontuberculosis endemic regions. Readily available clinical features can aid clinicians in predicting the underlying aetiology, those at risk for malignancy, and who to biopsy.

  View details for DOI 10.1111/j.1468-1293.2012.01035.x

  View details for Web of Science ID 000314469500008

  View details for PubMedID 22805116

• Diagnosis of influenza from lower respiratory tract sampling after negative upper respiratory tract sampling VIRULENCE Bogoch, I. I., Andrews, J. R., Zachary, K. C., Hohmann, E. L. 2013; 4 (1): 82-84

  Abstract

  In this retrospective cohort study, we demonstrate that PCR-confirmed diagnoses of influenza were made solely by lower respiratory sampling in 6.9% of cases, as traditional upper respiratory tract tests were negative, indeterminate or not performed. Clinical features of these cases are presented. Clinicians should consider lower respiratory tract sampling in select cases of influenza-like illness for diagnosis.

  View details for DOI 10.4161/viru.22466

  View details for Web of Science ID 000313566000005

  View details for PubMedID 23135351

• Crossing the quality chasm in resource-limited settings GLOBALIZATION AND HEALTH Maru, D. S., Andrews, J., Schwarz, D., Schwarz, R., Acharya, B., Ramaiya, A., Karelas, G., Rajbhandari, R., Mate, K., Shilpakar, S. 2012; 8

  Abstract

  Over the last decade, extensive scientific and policy innovations have begun to reduce the "quality chasm"--the gulf between best practices and actual implementation that exists in resource-rich medical settings. While limited data exist, this chasm is likely to be equally acute and deadly in resource-limited areas. While health systems have begun to be scaled up in impoverished areas, scale-up is just the foundation necessary to deliver effective healthcare to the poor. This perspective piece describes a vision for a global quality improvement movement in resource-limited areas. The following action items are a first step toward achieving this vision: 1) revise global health investment mechanisms to value quality; 2) enhance human resources for improving health systems quality; 3) scale up data capacity; 4) deepen community accountability and engagement initiatives; 5) implement evidence-based quality improvement programs; 6) develop an implementation science research agenda.

  View details for DOI 10.1186/1744-8603-8-41

  View details for Web of Science ID 000312600500001

  View details for PubMedID 23193968

• Simple questionnaire and urine reagent strips compared to microscopy for the diagnosis of Schistosoma haematobium in a community in northern Ghana TROPICAL MEDICINE & INTERNATIONAL HEALTH Bogoch, I. I., Andrews, J. R., Dadzie Ephraim, R. K., Utzinger, J. 2012; 17 (10): 1217-1221

  Abstract

  To evaluate the utility of a simple questionnaire and urine reagent strip testing for the rapid diagnosis of Schistosoma haematobium in rural northern Ghana.Cross-sectional parasitological and questionnaire survey in a community in northern Ghana. Participants provided two urine specimens that were examined under a microscope using a centrifugation method. The first urine sample was additionally subjected to reagent strip testing. A short questionnaire was administered to all participants.Microscopy of urine samples obtained from 208 individuals aged 1-77 years revealed an S. haematobium prevalence of 6.8%. The presence of any blood or protein on a urine reagent strip was 100% and 42% sensitive, and 93% and 80% specific for S. haematobium diagnosis. Questionnaires were completed by 198 individuals. Self-reported haematuria showed a sensitivity of 53% and a specificity of 85%. A dichotomous two-question panel was helpful in S. haematobium diagnosis, with working and playing near the river significantly associated with S. haematobium infection (P < 0.001).The use of urine reagent strips, coupled with questions pertaining to water contact patterns, might be considered for point-of-contact diagnosis of S. haematobium where microscopy is unavailable.

  View details for DOI 10.1111/j.1365-3156.2012.03054.x

  View details for Web of Science ID 000308714200007

  View details for PubMedID 22863035

• Projecting the Benefits of Antiretroviral Therapy for HIV Prevention: The Impact of Population Mobility and Linkage to Care JOURNAL OF INFECTIOUS DISEASES Andrews, J. R., Wood, R., Bekker, L., Middelkoop, K., Walensky, R. P. 2012; 206 (4): 543-551

  Abstract

  Recent mathematical models suggested that frequent human immunodeficiency virus (HIV) testing with immediate initiation of antiretroviral therapy (ART) to individuals with a positive test result could profoundly curb transmission. The debate about ART as prevention has focused largely on parameter values. We aimed to evaluate structural assumptions regarding linkage to care and population mobility, which have received less attention.We modified the linkage structure of published models of ART as prevention, such that individuals who decline initial testing or treatment do not link to care until late-stage HIV infection. We then added population mobility to the models. We populated the models with demographic, clinical, immigration, emigration, and linkage data from a South African township.In the refined linkage model, elimination of HIV transmission (defined as an incidence of <0.1%) did not occur by 30 years, even with optimistic assumptions about the linkage rate. Across a wide range of estimates, models were more sensitive to structural assumptions about linkage than to parameter values. Incorporating population mobility further attenuated the reduction in incidence conferred by ART as prevention.Linkage to care and population mobility are critical features of ART-as-prevention models. Clinical trials should incorporate relevant data on linkage to care and migration to evaluate the impact of this strategy.

  View details for DOI 10.1093/infdis/jis401

  View details for Web of Science ID 000306667000012

  View details for PubMedID 22711905

  View details for PubMedCentralID PMC3491737

• Comparative Performance of Private and Public Healthcare Systems in Low- and Middle-Income Countries: A Systematic Review PLOS MEDICINE Basu, S., Andrews, J., Kishore, S., Panjabi, R., Stuckler, D. 2012; 9 (6)

  Abstract

  Private sector healthcare delivery in low- and middle-income countries is sometimes argued to be more efficient, accountable, and sustainable than public sector delivery. Conversely, the public sector is often regarded as providing more equitable and evidence-based care. We performed a systematic review of research studies investigating the performance of private and public sector delivery in low- and middle-income countries.Peer-reviewed studies including case studies, meta-analyses, reviews, and case-control analyses, as well as reports published by non-governmental organizations and international agencies, were systematically collected through large database searches, filtered through methodological inclusion criteria, and organized into six World Health Organization health system themes: accessibility and responsiveness; quality; outcomes; accountability, transparency, and regulation; fairness and equity; and efficiency. Of 1,178 potentially relevant unique citations, data were obtained from 102 articles describing studies conducted in low- and middle-income countries. Comparative cohort and cross-sectional studies suggested that providers in the private sector more frequently violated medical standards of practice and had poorer patient outcomes, but had greater reported timeliness and hospitality to patients. Reported efficiency tended to be lower in the private than in the public sector, resulting in part from perverse incentives for unnecessary testing and treatment. Public sector services experienced more limited availability of equipment, medications, and trained healthcare workers. When the definition of "private sector" included unlicensed and uncertified providers such as drug shop owners, most patients appeared to access care in the private sector; however, when unlicensed healthcare providers were excluded from the analysis, the majority of people accessed public sector care. "Competitive dynamics" for funding appeared between the two sectors, such that public funds and personnel were redirected to private sector development, followed by reductions in public sector service budgets and staff.Studies evaluated in this systematic review do not support the claim that the private sector is usually more efficient, accountable, or medically effective than the public sector; however, the public sector appears frequently to lack timeliness and hospitality towards patients.

  View details for DOI 10.1371/journal.pmed.1001244

  View details for Web of Science ID 000305946200015

  View details for PubMedID 22723748

• The cost-effectiveness of routine tuberculosis screening with Xpert MTB/RIF prior to initiation of antiretroviral therapy: a model-based analysis AIDS Andrews, J. R., Lawn, S. D., Rusu, C., Wood, R., Noubary, F., Bender, M. A., Horsburgh, C. R., Losina, E., Freedberg, K. A., Walensky, R. P. 2012; 26 (8): 987-995

  Abstract

  In settings with high tuberculosis (TB) prevalence, 15-30% of HIV-infected individuals initiating antiretroviral therapy (ART) have undiagnosed TB. Such patients are usually screened by symptoms and sputum smear, which have poor sensitivity.To project the clinical and economic outcomes of using Xpert MTB/RIF(Xpert), a rapid TB/rifampicin-resistance diagnostic, to screen individuals initiating ART.We used a microsimulation model to evaluate the clinical impact and cost-effectiveness of alternative TB screening modalities - in all patients or only symptomatic patients - for hypothetical cohorts of individuals initiating ART in South Africa (mean CD4 cell count = 171 cells/μl; TB prevalence 22%). We simulated no active screening and four diagnostic strategies, smear microscopy (sensitivity 23%); smear and culture (sensitivity, 100%); one Xpert sample (sensitivity in smear-negative TB: 43%); two Xpert samples (sensitivity in smear-negative TB: 62%). Outcomes included projected life expectancy, lifetime costs (2010 US$), and incremental cost-effectiveness ratios (ICERs). Strategies with ICERs less than $7100 (South African gross domestic product per capita) were considered very cost-effective.Compared with no screening, life expectancy in TB-infected patients increased by 1.6 months using smear in symptomatic patients and by 6.6 months with two Xpert samples in all patients. At 22% TB prevalence, the ICER of smear for all patients was $2800 per year of life saved (YLS), and of Xpert (two samples) for all patients was $5100/YLS. Strategies involving one Xpert sample or symptom screening were less efficient.Model-based analysis suggests that screening all individuals initiating ART in South Africa with two Xpert samples is very cost-effective.

  View details for DOI 10.1097/QAD.0b013e3283522d47

  View details for Web of Science ID 000303656000010

  View details for PubMedID 22333751

• On partnership. Narrative inquiry in bioethics Schwarz, R., Maru, D. S., Schwarz, D., Acharya, B., Acharya, B., Rajbhandari, R., Andrews, J., Karelas, G., Sharma, R., Arnoldy, M. 2012; 2 (2): 101-106

  View details for DOI 10.1353/nib.2012.0036

  View details for PubMedID 24406829

• Social and News Media Enable Estimation of Epidemiological Patterns Early in the 2010 Haitian Cholera Outbreak AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE Chunara, R., Andrews, J. R., Brownstein, J. S. 2012; 86 (1): 39-45

  Abstract

  During infectious disease outbreaks, data collected through health institutions and official reporting structures may not be available for weeks, hindering early epidemiologic assessment. By contrast, data from informal media are typically available in near real-time and could provide earlier estimates of epidemic dynamics. We assessed correlation of volume of cholera-related HealthMap news media reports, Twitter postings, and government cholera cases reported in the first 100 days of the 2010 Haitian cholera outbreak. Trends in volume of informal sources significantly correlated in time with official case data and was available up to 2 weeks earlier. Estimates of the reproductive number ranged from 1.54 to 6.89 (informal sources) and 1.27 to 3.72 (official sources) during the initial outbreak growth period, and 1.04 to 1.51 (informal) and 1.06 to 1.73 (official) when Hurricane Tomas afflicted Haiti. Informal data can be used complementarily with official data in an outbreak setting to get timely estimates of disease dynamics.

  View details for DOI 10.4269/ajtmh.2012.11-0597

  View details for Web of Science ID 000299065200013

  View details for PubMedID 22232449

• Risk factors for mortality among MDR- and XDR-TB patients in a high HIV prevalence setting INTERNATIONAL JOURNAL OF TUBERCULOSIS AND LUNG DISEASE Gandhi, N. R., Andrews, J. R., Brust, J. C., Montreuil, R., Weissman, D., Heo, M., Moll, A. P., Friedland, G. H., Shah, N. S. 2012; 16 (1): 90-97

  Abstract

  Recent studies suggest that the prevalence of drug-resistant tuberculosis (TB) in sub-Saharan Africa may be rising. This is of concern, as human immunodeficiency virus (HIV) co-infection in multidrug-resistant (MDR) and extensively drug-resistant (XDR) TB has been associated with exceedingly high mortality rates.To identify risk factors associated with mortality in MDR- and XDR-TB patients co-infected with HIV in South Africa.Case-control study of patients who died of all causes within 2 years of diagnosis with MDR- or XDR-TB.Among 123 MDR-TB patients, 78 (63%) died following diagnosis. CD4 count ≤ 50 (HR 4.64, P = 0.01) and 51-200 cells/mm(3) (HR 4.17, P = 0.008) were the strongest independent risk factors for mortality. Among 139 XDR-TB patients, 111 (80%) died. CD4 count ≤ 50 cells/mm(3) (HR 4.46, P = 0.01) and resistance to all six drugs tested (HR 2.54, P = 0.04) were the principal risk factors. Use of antiretroviral therapy (ART) was protective (HR 0.34, P = 0.009).Mortality due to MDR- and XDR-TB was associated with greater degree of immunosuppression and drug resistance. Efforts to reduce mortality must focus on preventing the amplification of resistance by strengthening TB treatment programs, as well as reducing the pool of immunosuppressed HIV-infected patients through aggressive HIV testing and ART initiation.

  View details for DOI 10.5588/ijtld.11.0153

  View details for Web of Science ID 000298726700017

  View details for PubMedID 22236852

• Implementing a systems-oriented morbidity and mortality conference in remote rural Nepal for quality improvement BMJ QUALITY & SAFETY Schwarz, D., Schwarz, R., Gauchan, B., Andrews, J., Sharma, R., Karelas, G., Rajbhandari, R., Acharya, B., Mate, K., Bista, A., Bista, M. G., Sox, C., Maru, D. S. 2011; 20 (12): 1082-1088

  Abstract

  In hospitals in rural, resource-limited settings, there is an acute need for simple, practical strategies to improve healthcare quality.A district hospital in remote western Nepal.To provide a mechanism for systems-level reflection so that staff can identify targets for quality improvement in healthcare delivery. Strategies for change To develop a morbidity and mortality conference (M&M) quality improvement initiative that aims to facilitate structured analysis of patient care and identify barriers to providing quality care, which can subsequently be improved.The authors designed an M&M involving clinical and non-clinical staff in conducting root-cause analyses of healthcare delivery at their hospital. Weekly conferences focus on seven domains of causal analysis: operations, supply chain, equipment, personnel, outreach, societal, and structural. Each conference focuses on assessing the care provided, and identifying ways in which services can be improved in the future.Staff reception of the M&Ms was positive. In these M&Ms, staff identified problem areas in healthcare delivery and steps for improvement. Subsequently, changes were made in hospital workflow, supply procurement, and on-site training.While widely practiced throughout the world, M&Ms typically do not involve both clinical and non-clinical staff members and do not take a systems-level approach. The authors' experience suggests that the adapted M&M conference is a simple, feasible tool for quality improvement in resource-limited settings. Senior managerial commitment is crucial to ensure successful implementation of M&Ms, given the challenging logistics of implementing these programmes in resource-limited health facilities.

  View details for DOI 10.1136/bmjqs-2011-000273

  View details for Web of Science ID 000297619300013

  View details for PubMedID 21949441

• Pandemic H1N1 Influenza Infection in Adult Transplant Recipients TRANSPLANTATION Bogoch, I. I., Andrews, J. R., Hohmann, E. L., Kotton, C. N., Marty, F. M. 2011; 91 (12): E80-E81

  View details for DOI 10.1097/TP.0b013e31821c1eac

  View details for Web of Science ID 000291430500001

  View details for PubMedID 21654492

• HIV-1 and 2009 H1N1 Influenza A in Adults JAIDS-JOURNAL OF ACQUIRED IMMUNE DEFICIENCY SYNDROMES Bogoch, I. I., Andrews, J. R., Marty, F. M., Hohmann, E. L. 2011; 56 (4): E111-E113

  View details for DOI 10.1097/QAI.0b013e31820a9afb

  View details for Web of Science ID 000287740700003

  View details for PubMedID 21350357

• Visceral Leishmaniasis in Far Western Nepal: Another Case and Concerns about a New Area of Endemicity AMERICAN JOURNAL OF TROPICAL MEDICINE AND HYGIENE Schwarz, D., Andrews, J., Gauchan, B. 2011; 84 (3): 508-508

  View details for DOI 10.4269/ajtmh.2011.11-0021

  View details for Web of Science ID 000287995600027

  View details for PubMedID 21363996

• Tuberculosis and HIV Co-Infection Screening and Treatment Strategies DRUGS Venkatesh, K. K., Swaminathan, S., Andrews, J. R., Mayer, K. H. 2011; 71 (9): 1133-1152

  Abstract

  Globally, tuberculosis (TB) and HIV interact in deadly synergy. The high burden of TB among HIV-infected individuals underlies the importance of TB diagnosis, treatment and prevention for clinicians involved in HIV care. Despite expanding access to antiretroviral therapy (ART) to treat HIV infection in resource-limited settings, many individuals in need of therapy initiate ART too late and have already developed clinically significant TB by the time they present for care. Many co-infected individuals are in need of concurrent ART and anti-TB therapy, which dramatically improves survival, but also raises several management challenges, including drug interactions, shared drug toxicities and TB immune reconstitution inflammatory syndrome (IRIS). Due to the survival benefits of promptly initiating ART among all HIV-infected individuals, including those with TB, it is recommended that co-infected individuals receive treatment for both diseases, regardless of CD4+ cell count. We review current screening and treatment strategies for TB and HIV co-infection. Recent findings and ongoing studies will assist clinicians in managing the prevention and treatment of TB and HIV co-infection, which remains a major global health challenge.

  View details for Web of Science ID 000293101200003

  View details for PubMedID 21711060

• Kaposi's Sarcoma-Associated Herpesvirus-Related Solid Lymphoma Involving the Heart and Brain. AIDS research and treatment Andrews, J. R., Cho-Park, Y. A., Ferry, J., Abramson, J. S., Robbins, G. K. 2011; 2011: 729854-?

  Abstract

  Since its discovery in 1994, Kaposi's sarcoma-associated herpesvirus (KSHV) has been associated with lymphoproliferative disorders, particularly in patients infected with human immunodeficiency virus (HIV). The disorders most strongly linked to KSHV are multicentric Castleman's Disease (MCD), primary effusion lymphoma, and diffuse large B-cell lymphomas. We report an unusual case of KSHV-associated lymphoma in an HIV-infected patient manifesting with myocardial and central nervous system involvement. We discuss this case in the context of increasing array of KSHV-associated lymphomas. In the HIV-infected patient with a mass lesion, a history of cutaneous Kaposi's sarcoma and prolonged immunosuppression should alert clinicians as to the possibility of KSHV-associated lymphoproliferative disorders, in order to establish a timely diagnosis.

  View details for DOI 10.1155/2011/729854

  View details for PubMedID 21541215

• Predictors of Multidrug- and Extensively Drug-Resistant Tuberculosis in a High HIV Prevalence Community PLOS ONE Andrews, J. R., Shah, N. S., Weissman, D., Moll, A. P., Friedland, G., Gandhi, N. R. 2010; 5 (12)

  Abstract

  Multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) have emerged in high-HIV-prevalence settings, which generally lack laboratory infrastructure for diagnosing TB drug resistance. Even where available, inherent delays with current drug-susceptibility testing (DST) methods result in clinical deterioration and ongoing transmission of MDR and XDR-TB. Identifying clinical predictors of drug resistance may aid in risk stratification for earlier treatment and infection control.We performed a retrospective case-control study of patients with MDR (cases), XDR (cases) and drug-susceptible (controls) TB in a high-HIV-prevalence setting in South Africa to identify clinical and demographic risk factors for drug-resistant TB. Controls were selected in a 1:1:1 ratio and were not matched. We calculated odds ratios (OR) and performed multivariate logistic regression to identify independent predictors.We enrolled 116, 123 and 139 patients with drug-susceptible, MDR, and XDR-TB. More than 85% in all three patient groups were HIV-infected. In multivariate analysis, MDR and XDR-TB were each strongly associated with history of TB treatment failure (adjusted OR 51.7 [CI 6.6-403.7] and 51.5 [CI 6.4-414.0], respectively) and hospitalization more than 14 days (aOR 3.8 [CI 1.1-13.3] and 6.1 [CI 1.8-21.0], respectively). Prior default from TB treatment was not a risk factor for MDR or XDR-TB. HIV was a risk factor for XDR (aOR 8.2, CI 1.3-52.6), but not MDR-TB. Comparing XDR with MDR-TB patients, the only significant risk factor for XDR-TB was HIV infection (aOR 5.3, CI 1.0-27.6).In this high-HIV-prevalence and drug-resistant TB setting, a history of prolonged hospitalization and previous TB treatment failure were strong risk factors for both MDR and XDR-TB. Given high mortality observed among patients with HIV and drug-resistant TB co-infection, previously treated and hospitalized patients should be considered for empiric second-line TB therapy while awaiting confirmatory DST results in settings with a high-burden of MDR/XDR-TB.

  View details for DOI 10.1371/journal.pone.0015735

  View details for Web of Science ID 000285793200047

  View details for PubMedID 21209951

• Turning a blind eye: the mobilization of radiology services in resource-poor regions. Globalization and health Maru, D. S., Schwarz, R., Jason, A., Basu, S., Sharma, A., Moore, C. 2010; 6: 18-?

  Abstract

  While primary care, obstetrical, and surgical services have started to expand in the world's poorest regions, there is only sparse literature on the essential support systems that are required to make these operations function. Diagnostic imaging is critical to effective rural healthcare delivery, yet it has been severely neglected by the academic, public, and private sectors. Currently, a large portion of the world's population lacks access to any form of diagnostic imaging. In this paper we argue that two primary imaging modalities--diagnostic ultrasound and X-Ray--are ideal for rural healthcare services and should be scaled-up in a rapid and standardized manner. Such machines, if designed for resource-poor settings, should a) be robust in harsh environmental conditions, b) function reliably in environments with unstable electricity, c) minimize radiation dangers to staff and patients, d) be operable by non-specialist providers, and e) produce high-quality images required for accurate diagnosis. Few manufacturers are producing ultrasound and X-Ray machines that meet the specifications needed for rural healthcare delivery in resource-poor regions. A coordinated effort is required to create demand sufficient for manufacturers to produce the desired machines and to ensure that the programs operating them are safe, effective, and financially feasible.

  View details for DOI 10.1186/1744-8603-6-18

  View details for PubMedID 20946643

• HIV Coinfection in Multidrug- and Extensively Drug-Resistant Tuberculosis Results in High Early Mortality AMERICAN JOURNAL OF RESPIRATORY AND CRITICAL CARE MEDICINE Gandhi, N. R., Shah, N. S., Andrews, J. R., Vella, V., Moll, A. P., Scott, M., Weissman, D., Marra, C., Lalloo, U. G., Friedland, G. H. 2010; 181 (1): 80-86

  Abstract

  The multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis (TB) epidemics are rapidly expanding in South Africa. Our initial report of HIV-associated XDR TB in South Africa revealed rapid and near complete mortality. Lower mortality has been described in the literature, but few of these patients have been HIV coinfected.To characterize mortality from MDR and XDR TB in a setting with high HIV-coinfection rates.We conducted a retrospective observational study among 654 MDR and XDR TB cases diagnosed in Tugela Ferry, South Africa, from 2005 to 2007. Demographics and HIV status were abstracted from available medical records.Survival was determined from the date of sputum collection until October 2008 and correlated with year of diagnosis and drug-susceptibility test results. From 2005 to 2007, 272 MDR TB and 382 XDR TB cases were diagnosed; HIV-coinfection rates were 90 and 98%, respectively. One-year mortality was 71% for MDR and 83% for XDR TB patients; 40% of MDR TB and 51% of XDR TB cases died within 30 days of sputum collection. One-year mortality among both MDR and XDR TB patients improved from 2005 to 2007; however, the majority of deaths still occurred within the first 30 days. One-year and 30-day mortality rates were worse with greater degree of drug resistance (P < 0.001).Mortality from MDR and XDR TB in this high HIV-prevalence region is extraordinarily high, particularly within the first 30 days. Efforts to reduce mortality must focus on earlier diagnosis and early initiation of second-line TB and antiretroviral therapy.

  View details for DOI 10.1164/rccm.200907-0989OC

  View details for Web of Science ID 000273147100015

  View details for PubMedID 19833824

• Global Health Delivery 2.0: Using Open-Access Technologies for Transparency and Operations Research PLOS MEDICINE Maru, D. S., Sharma, A., Andrews, J., Basu, S., Thapa, J., Oza, S., Bashyal, C., Acharya, B., Schwarz, R. 2009; 6 (12)

  View details for DOI 10.1371/journal.pmed.1000158

  View details for Web of Science ID 000273060600001

  View details for PubMedID 19956665

• Averting epidemics of extensively drug-resistant tuberculosis PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA Basu, S., Friedland, G. H., Medlock, J., Andrews, J. R., Shah, N. S., Gandhi, N. R., Moll, A., Moodley, P., Sturm, A. W., Galvani, A. P. 2009; 106 (18): 7672-7677

  Abstract

  Extensively drug-resistant tuberculosis (XDR TB) has been detected in most provinces of South Africa, particularly in the KwaZulu-Natal province where several hundred cases have been reported since 2004. We analyzed the transmission dynamics of XDR TB in the region using mathematical models, and observed that nosocomial transmission clusters of XDR TB may emerge into community-based epidemics under the public health conditions of many South African communities. The effective reproductive number of XDR TB in KwaZulu-Natal may be around 2. Intensified community-based case finding and therapy appears critical to curtailing transmission. In the setting of delayed disease presentation and high system demand, improved diagnostic approaches may need to be employed in community-based programs rather than exclusively at tertiary hospitals. Using branching process mathematics, we observed that early, community-based drug-susceptibility testing and effective XDR therapy could help curtail ongoing transmission and reduce the probability of XDR TB epidemics in neighboring territories.

  View details for DOI 10.1073/pnas.0812472106

  View details for Web of Science ID 000265783600073

  View details for PubMedID 19365076

• Treatment outcomes among patients with multidrug-resistant tuberculosis: systematic review and meta-analysis LANCET INFECTIOUS DISEASES Orenstein, E. W., Basu, S., Shah, N. S., Andrews, J. R., Friedland, G. H., Moll, A. P., Gandhi, N. R., Galvani, A. P. 2009; 9 (3): 153-161

  Abstract

  Multidrug-resistant (MDR) tuberculosis is a growing clinical and public-health concern. To evaluate existing evidence regarding treatment regimens for MDR tuberculosis, we used a Bayesian random-effects meta-analysis of the available therapeutic studies to assess how the reported proportion of patients treated successfully is influenced by differences in treatment regimen design, study methodology, and patient population. Successful treatment outcome was defined as cure or treatment completion. 34 clinical reports with a mean of 250 patients per report met the inclusion criteria. Our analysis shows that the proportion of patients treated successfully improved when treatment duration was at least 18 months, and if patients received directly observed therapy throughout treatment. Studies that combined both factors had significantly higher pooled success proportions (69%, 95% credible interval [CI] 64-73%) than other studies of treatment outcomes (58%, 95% CI 52-64%). Individualised treatment regimens had higher treatment success (64%, 95% CI 59-68%) than standardised regimens (54%, 95% CI 43-68%), although the difference was not significant. Treatment approaches and study methodologies were heterogeneous across studies. Many important variables, including patients' HIV status, were inconsistently reported between studies. These results underscore the importance of strong patient support and treatment follow-up systems to develop successful MDR tuberculosis treatment programmes.

  View details for Web of Science ID 000263787500014

  View details for PubMedID 19246019

• Multidrug-resistant and extensively drug-resistant tuberculosis: Implications for the HIV epidemic and antiretroviral therapy rollout in South Africa JOURNAL OF INFECTIOUS DISEASES Andrews, J. R., Shah, N. S., Gandhi, N., Moll, T., Friedland, G. 2007; 196: S482-S490

  Abstract

  Drug-resistant tuberculosis (TB) is emerging as a major clinical and public health challenge in areas of sub-Saharan Africa where there is a high prevalence of human immunodeficiency virus (HIV) infection. TB drug-resistance surveillance in this region has been limited by laboratory capacity and the public health infrastructure; however, with the maturation of the HIV epidemic, the burden of drug-resistant TB is increasing rapidly. The recent discovery of large numbers of cases of multidrug-resistant (MDR) TB and extensively drug-resistant (XDR) TB in South Africa likely represents an unrecognized and evolving epidemic rather than sporadic, localized outbreaks. The combination of a large population of HIV-infected susceptible hosts with poor TB treatment success rates, a lack of airborne infection control, limited drug-resistance testing, and an overburdened MDR-TB treatment program provides ideal conditions for an MDR-TB and XDR-TB epidemic of unparalleled magnitude. In the present article, we review the history of drug-resistant TB in South Africa, describe its interaction with the HIV epidemic and the resultant consequences, and suggest measures necessary for controlling MDR-TB and XDR-TB in this context. A successful response to the emergence of MDR-TB and XDR-TB will necessitate increased resources for and collaboration between TB and HIV programs.

  View details for DOI 10.1086/521121

  View details for Web of Science ID 000251398100007

  View details for PubMedID 18181698

• Prevention of nosocomial transmission of extensively drug-resistant tuberculosis in rural South African district hospitals: an epidemiological modelling study LANCET Basu, S., Andrews, J. R., Poolman, E. M., Gandhi, N. R., Shah, N. S., Moll, A., Moodley, P., Galvani, A. P., Friedland, G. H. 2007; 370 (9597): 1500-1507

  Abstract

  Extensively drug-resistant (XDR) tuberculosis has spread among hospitalised patients in South Africa, but the epidemic-level effect of hospital-based infection control strategies remains unknown. We modelled the plausible effect of rapidly available infection control strategies on the overall course of the XDR tuberculosis epidemic in a rural area of South Africa.We investigated the effect of administrative, environmental, and personal infection control measures on the epidemic trajectory of XDR tuberculosis in the rural community of Tugela Ferry. Assessments were done with a mathematical model incorporating over 2 years of longitudinal inpatient and community-based data. The model simulated inpatient airborne tuberculosis transmission, community tuberculosis transmission, and the effect of HIV and antiretroviral therapy.If no new interventions are introduced, about 1300 cases of XDR tuberculosis are predicted to occur in the area of Tugela Ferry by the end of 2012, more than half of which are likely to be nosocomially transmitted. Mask use alone would avert fewer than 10% of cases in the overall epidemic, but could prevent a large proportion of cases of XDR tuberculosis in hospital staff. The combination of mask use with reduced hospitalisation time and a shift to outpatient therapy could prevent nearly a third of XDR tuberculosis cases. Supplementing this approach with improved ventilation, rapid drug resistance testing, HIV treatment, and tuberculosis isolation facilities could avert 48% of XDR tuberculosis cases (range 34-50%) by the end of 2012. However, involuntary detention could result in an unexpected rise in incidence due to restricted isolation capacity.A synergistic combination of available nosocomial infection control strategies could prevent nearly half of XDR tuberculosis cases, even in a resource-limited setting. XDR tuberculosis transmission will probably continue in the community, indicating the need to develop and implement parallel community-based programmes.

  View details for Web of Science ID 000250487000027

  View details for PubMedID 17964351

• XDR-TB in South Africa: Theory and practice PLOS MEDICINE Andrews, J., Basu, S., Scales, D., Maru, D. S., Subbaraman, R. 2007; 4 (4): 770-771

  View details for DOI 10.1371/journal.pmed.0040163

  View details for Web of Science ID 000245947000028

  View details for PubMedID 17455998

• Extensively drug-resistant tuberculosis as a cause of death in patients co-infected with tuberculosis and HIV in a rural area of South Africa LANCET Gandhi, N. R., Moll, A., Sturm, A. W., Pawinski, R., Govender, T., Lalloo, U., Zeller, K., Andrews, J., Friedland, G. 2006; 368 (9547): 1575-1580

  Abstract

  The epidemics of HIV-1 and tuberculosis in South Africa are closely related. High mortality rates in co-infected patients have improved with antiretroviral therapy, but drug-resistant tuberculosis has emerged as a major cause of death. We assessed the prevalence and consequences of multidrug-resistant (MDR) and extensively drug-resistant (XDR) tuberculosis in a rural area in KwaZulu Natal, South Africa.We undertook enhanced surveillance for drug-resistant tuberculosis with sputum culture and drug susceptibility testing in patients with known or suspected tuberculosis. Genotyping was done for isolates resistant to first-line and second-line drugs.From January, 2005, to March, 2006, sputum was obtained from 1539 patients. We detected MDR tuberculosis in 221 patients, of whom 53 had XDR tuberculosis. Prevalence among 475 patients with culture-confirmed tuberculosis was 39% (185 patients) for MDR and 6% (30) for XDR tuberculosis. Only 55% (26 of 47) of patients with XDR tuberculosis had never been previously treated for tuberculosis; 67% (28 of 42) had a recent hospital admission. All 44 patients with XDR tuberculosis who were tested for HIV were co-infected. 52 of 53 patients with XDR tuberculosis died, with median survival of 16 days from time of diagnosis (IQR 6-37) among the 42 patients with confirmed dates of death. Genotyping of isolates showed that 39 of 46 (85%, 95% CI 74-95) patients with XDR tuberculosis had similar strains.MDR tuberculosis is more prevalent than previously realised in this setting. XDR tuberculosis has been transmitted to HIV co-infected patients and is associated with high mortality. These observations warrant urgent intervention and threaten the success of treatment programmes for tuberculosis and HIV.

  View details for DOI 10.1016/S0140-6736(06)69573-1

  View details for Web of Science ID 000242180900026

  View details for PubMedID 17084757

• Populations who test drugs should benefit from them NATURE Basu, S., Andrews, J., Smith-Rohrberg, D. 2006; 440 (7084): 605-605

  View details for DOI 10.1038/440605d

  View details for Web of Science ID 000236350400021

  View details for PubMedID 16572144

• Research in the ranks - vulnerable subjects, coercible collaborotionl and the hepatitis E vaccine trial in Nepal PERSPECTIVES IN BIOLOGY AND MEDICINE Andrews, J. 2006; 49 (1): 35-51

  Abstract

  Concern over the diminished autonomy of members of the armed forces has resulted in the classification of these groups as "vulnerable" in many international codes of research ethics, a designation that places the onus on researchers to provide special justification for the inclusion of these persons in research. This paper examines the application of these ethical requirements to a recent trial carried out by U.S. Army researchers among soldiers of the Royal Nepal Army (RNA) and concludes that the requirements to justify conducting research in this population were not met. Furthermore, noting the human rights abuses rampant in the RNA, it is appropriate to question the choice of this institution as both a partner and a subject pool for U.S. state-sponsored research. This case study raises another important ethical question about the vulnerability to coerced collaboration of groups or institutions. In response, I propose the idea of "institutional vulnerability" as an extension of the idea of individual "juridic vulnerability." The recent military and financial assistance that the RNA received from the U.S. Army, in light of their partnership in this biomedical research trial, constitutes an appropriate and revealing context in which to ground this discussion.

  View details for Web of Science ID 000235107900004

  View details for PubMedID 16489275

• US military sponsored vaccine trials and La resistance in Nepal AMERICAN JOURNAL OF BIOETHICS Andrews, J. 2005; 5 (3): W1-W3

  View details for DOI 10.1080/15265160591002962

  View details for Web of Science ID 000231019400028

  View details for PubMedID 16006352

• How do international trade agreements influence the promotion of public health?--An introduction to the issue. Yale journal of health policy, law, and ethics Andrews, J., Chaifetz, S. 2004; 4 (2): 339-340

  View details for PubMedID 15536915