Meri Varkila

All Publications

• Acceptance of SARS-CoV-2 Surveillance Testing Among Patients Receiving Dialysis: A Cluster Randomized Trial. JAMA network open Montez-Rath, M., Varkila, M., Yu, X., Brillhart, S., Morgan, C., Leppink, A., Block, M. S., Mehta, S., Hunsader, P., Fountaine, A., Subramanian, N., Dittrich, M., Owens, D. K., Chertow, G. M., Parsonnet, J., Anand, S., Block, G. A. 2024; 7 (9): e2434159

  Abstract

  Integrating routine SARS-CoV-2 testing in dialysis facilities may benefit patients receiving dialysis by mitigating risks of serious illness and reducing transmission. Patient acceptance of nonmandatory testing is unknown.To evaluate the acceptance of 2 SARS-CoV-2 testing strategies among patients in hemodialysis facilities nationwide.This nationwide cluster (dialysis facility-level) randomized trial investigated the acceptance of SARS-CoV-2 testing among patients receiving maintenance hemodialysis at facilities located in 22 states.Anterior nares real-time reverse transcriptase-polymerase chain reaction tests offered once every 2 weeks (static testing facilities) vs offered once a week, once every 2 weeks, or once a month depending on county COVID-19 infection prevalence (dynamic testing facilities). Facilities were randomized by county, and tests were offered for 3 months between February 4 and July 24, 2023.The primary outcome was test acceptance. Secondary outcomes included the proportion of patients who accepted at least 1 test.In total, 62 hemodialysis facilities were randomized and 57 participated. Among 2389 participating patients, the median age was 64 (IQR, 54-74) years, 1341 (56%) were male, 138 (6%) were categorized as American Indian, 60 (3%) Asian, 885 (37%) Black, 75 (3%) Native Hawaiian or Pacific Islander, 338 (14%) Hispanic, and 876 (37%) White; and 1603 (67%) had diabetes. A median of 6 (IQR, 6-6) tests were offered per patient in the static arm and 4 (3-6) tests in the dynamic arm. Test acceptance was low: 8% of offered tests were accepted in each of the test arms. Among 503 patients who accepted at least 1 test, the median percentage of offered tests that were accepted was 16% (IQR, 17%-42%) using the static testing strategy and 50% (IQR, 33%-75%) using the dynamic testing strategy (P < .001). Older patients (odds ratio [OR], 1.08 [95% CI, 1.01-1.16] per 5-year age increment), patients with (vs without) diabetes (OR, 1.59 [95% CI, 1.18-2.16]), and women compared with men (OR, 1.30 [95% CI, 0.98-1.73]) were more likely to accept multiple tests. Patients designated in the electronic health record as Hispanic were more likely than patients designated as White (OR, 1.78 [95% CI, 1.15-2.76]) to accept at least 1 test, whereas patients living in zip codes electing Republican representatives to Congress were less likely than patients living in zip codes electing Democratic representatives (OR, 0.34 [95% CI, 0.17-0.69]) to accept multiple tests.In this cluster randomized trial evaluating 2 SARS-CoV-2 testing strategies in dialysis facilities, test acceptance was low, and a dynamic testing strategy anchored to COVID-19 infection prevalence did not outperform a static testing strategy of every 2 weeks.ClinicalTrials.gov Identifier: NCT05225298.

  View details for DOI 10.1001/jamanetworkopen.2024.34159

  View details for PubMedID 39298171

  View details for PubMedCentralID PMC11413714

• Observations of Respiratory Syncytial Virus (RSV) Nucleic Acids in Wastewater Solids Across the United States in the 2022-2023 Season: Relationships with RSV Infection Positivity and Hospitalization Rates. ACS ES&T water Zulli, A., Varkila, M. R., Parsonnet, J., Wolfe, M. K., Boehm, A. B. 2024; 4 (4): 1657-1667

  Abstract

  Respiratory syncytial virus (RSV) is a leading cause of respiratory illness and hospitalization, but clinical surveillance detects only a minority of cases. Wastewater surveillance could determine the onset and extent of RSV circulation in the absence of sensitive case detection, but to date, studies of RSV in wastewater are few. We measured RSV RNA concentrations in wastewater solids from 176 sites during the 2022-2023 RSV season and compared those to publicly available RSV infection positivity and hospitalization rates. Concentrations ranged from undetectable to 107 copies per gram. RSV RNA concentration aggregated at state and national levels correlated with infection positivity and hospitalization rates. RSV season onset was determined using both wastewater and clinical positivity rates using independent algorithms for 14 states where both data were available at the start of the RSV season. In 4 of 14 states, wastewater and clinical surveillance identified RSV season onset during the same week; in 3 states, wastewater onset preceded clinical onset, and in 7 states, wastewater onset occurred after clinical onset. Wastewater concentrations generally peaked in the same week as hospitalization rates but after case positivity rates peaked. Differences in onset and peaks in wastewater versus clinical data may reflect inherent differences in the surveillance approaches.

  View details for DOI 10.1021/acsestwater.3c00725

  View details for PubMedID 38633368

  View details for PubMedCentralID PMC11019535

• Use of Wastewater Metrics to Track COVID-19 in the US. JAMA network open Varkila, M. R., Montez-Rath, M. E., Salomon, J. A., Yu, X., Block, G. A., Owens, D. K., Chertow, G. M., Parsonnet, J., Anand, S. 2023; 6 (7): e2325591

  Abstract

  Importance: Widespread use of at-home COVID-19 tests hampers determination of community COVID-19 incidence.Objective: To examine the association of county-level wastewater metrics with high case and hospitalization rates nationwide both before and after widespread use of at-home tests.Design, Setting, and Participants: This observational cohort study with a time series analysis was conducted from January to September 2022 in 268 US counties in 22 states participating in the US Centers for Disease Control and Prevention's National Wastewater Surveillance System. Participants included the populations of those US counties.Exposures: County level of circulating SARS-CoV-2 as determined by metrics based on viral wastewater concentration relative to the county maximum (ie, wastewater percentile) and 15-day percentage change in SARS-CoV-2 (ie, percentage change).Main Outcomes and Measures: High county incidence of COVID-19 as evidenced by dichotomized reported cases (current cases ≥200 per 100 000 population) and hospitalization (≥10 per 100 000 population lagged by 2 weeks) rates, stratified by calendar quarter.Results: In the first quarter of 2022, use of the wastewater percentile detected high reported case (area under the curve [AUC], 0.95; 95% CI, 0.94-0.96) and hospitalization (AUC, 0.86; 95% CI, 0.84-0.88) rates. The percentage change metric performed poorly, with AUCs ranging from 0.51 (95% CI, 0.50-0.53) to 0.57 (95% CI, 0.55-0.59) for reported new cases, and from 0.50 (95% CI, 0.48-0.52) to 0.55 (95% CI, 0.53-0.57) for hospitalizations across the first 3 quarters of 2022. The Youden index for detecting high case rates was wastewater percentile of 51% (sensitivity, 0.82; 95% CI, 0.80-0.84; specificity, 0.93; 95% CI, 0.92-0.95). A model inclusive of both metrics performed no better than using wastewater percentile alone. The performance of wastewater percentile declined over time for cases in the second quarter (AUC, 0.84; 95% CI, 0.82-0.86) and third quarter (AUC, 0.72; 95% CI, 0.70-0.75) of 2022.Conclusions and Relevance: In this study, nationwide, county wastewater levels relative to the county maximum were associated with high COVID-19 case and hospitalization rates in the first quarter of 2022, but there was increasing dissociation between wastewater and clinical metrics in subsequent quarters, which may reflect increasing underreporting of cases, reduced testing, and possibly lower virulence of infection due to vaccines and treatments. This study offers a strategy to operationalize county wastewater percentile to improve the accurate assessment of community SARS-CoV-2 infection prevalence when reliability of conventional surveillance data is declining.

  View details for DOI 10.1001/jamanetworkopen.2023.25591

  View details for PubMedID 37494040

• Feasibility and Acceptability of SARS-CoV-2 Screening among Patients Receiving Hemodialysis: A Pilot Study. Clinical journal of the American Society of Nephrology : CJASN Anand, S., Montez-Rath, M., Varkila, M., Yu, X., Block, M., Brillhart, S., Leppink, A., Hunsader, P., Owens, D. K., Chertow, G. M., Parsonnet, J., Block, G. 2023

  View details for DOI 10.2215/CJN.0000000000000137

  View details for PubMedID 36976655

• Glycan-specific IgM is critical for human immunity to Staphylococcus aureus. Cell reports. Medicine Hendriks, A., Kerkman, P. F., Varkila, M. R., Haitsma Mulier, J. L., Ali, S., Ten Doesschate, T., van der Vaart, T. W., de Haas, C. J., Aerts, P. C., Cremer, O. L., Bonten, M. J., Nizet, V., Liu, G. Y., Codée, J. D., Rooijakkers, S. H., van Strijp, J. A., van Sorge, N. M. 2024; 5 (9): 101734

  Abstract

  Staphylococcus aureus is a major human pathogen, yet the immune factors that protect against infection remain elusive. High titers of opsonic IgG antibodies, achieved in preclinical animal immunization studies, have consistently failed to provide protection in humans. Here, we investigate antibody responses to the conserved S. aureus surface glycan wall teichoic acid (WTA) and detect the presence of WTA-specific IgM and IgG antibodies in the plasma of healthy individuals. Functionally, WTA-specific IgM outperforms IgG in opsonophagocytic killing of S. aureus and protects against disseminated S. aureus bacteremia through passive immunization. In a clinical setting, patients with S. aureus bacteremia have significantly lower WTA-specific IgM but similar IgG levels compared to healthy controls. Importantly, low WTA-IgM levels correlate with disease mortality and impaired bacterial opsonization. Our findings may guide risk stratification of hospitalized patients and inform future design of antibody-based therapies and vaccines against serious S. aureus infection.

  View details for DOI 10.1016/j.xcrm.2024.101734

  View details for PubMedID 39293400

• Two-step interpretable modeling of ICU-AIs ARTIFICIAL INTELLIGENCE IN MEDICINE Lancia, G., Varkila, M. J., Cremer, O. L., Spitoni, C. 2024; 151: 102862

  Abstract

  We present a novel methodology for integrating high resolution longitudinal data with the dynamic prediction capabilities of survival models. The aim is two-fold: to improve the predictive power while maintaining the interpretability of the models. To go beyond the black box paradigm of artificial neural networks, we propose a parsimonious and robust semi-parametric approach (i.e., a landmarking competing risks model) that combines routinely collected low-resolution data with predictive features extracted from a convolutional neural network, that was trained on high resolution time-dependent information. We then use saliency maps to analyze and explain the extra predictive power of this model. To illustrate our methodology, we focus on healthcare-associated infections in patients admitted to an intensive care unit.

  View details for DOI 10.1016/j.artmed.2024.102862

  View details for Web of Science ID 001224271200001

  View details for PubMedID 38579437

• Gut barrier dysfunction and the risk of ICU-acquired bacteremia- a case-control study. Annals of intensive care Varkila, M. R., Verboom, D. M., Derde, L. P., van der Poll, T., Bonten, M. J., Cremer, O. L. 2024; 14 (1): 42

  Abstract

  Impaired intestinal barrier function can enable passage of enteric microorganisms into the bloodstream and lead to nosocomial bloodstream infections during critical illness. We aimed to determine the relative importance of gut translocation as a source for ICU-acquired enterococcal bacteremia of unknown origin.We conducted a nested case-control study in two mixed medical-surgical tertiary ICUs in the Netherlands among patients enrolled between 2011 and 2018. We selected 72 cases with ICU-acquired bacteremia due to enterococci (which are known gastrointestinal tract commensals) and 137 matched controls with bacteremia due to coagulase-negative staphylococci (CoNS) (which are of non-intestinal origin). We measured intestinal fatty acid-binding protein, trefoil factor-3, and citrulline 48 h before bacteremia onset. A composite measure for Gut Barrier Injury (GBI) was calculated as the sum of standardized z-scores for each biomarker plus a clinical gastrointestinal failure score.No single biomarker yielded statistically significant differences between cases and controls. Median composite GBI was higher in cases than in controls (0.58, IQR - 0.36-1.69 vs. 0.32, IQR - 0.53-1.57, p = 0.33) and higher composite measures of GBI correlated with higher disease severity and ICU mortality (p < 0.001). In multivariable analysis, higher composite GBI was not significantly associated with increased occurrence of enterococcal bacteremia relative to CoNS bacteremia (adjusted OR 1.12 95% CI 0.93-1.34, p = 0.22).We could not demonstrate an association between biomarkers of gastrointestinal barrier dysfunction and an increased occurrence of bacteremia due to gut compared to skin flora during critical illness, suggesting against bacterial translocation as a major vector for acquisition of nosocomial bloodstream infections in the ICU.

  View details for DOI 10.1186/s13613-024-01280-8

  View details for PubMedID 38536623

  View details for PubMedCentralID PMC10973289

• Observations of Respiratory Syncytial Virus (RSV) Nucleic Acids in Wastewater Solids Across the United States in the 2022-2023 Season: Relationships with RSV Infection Positivity and Hospitalization Rates ACS ES&T WATER Zulli, A., Varkila, M. J., Parsonnet, J., Wolfe, M. K., Boehm, A. B. 2024

  View details for DOI 10.1021/acsestwater.3c00725

  View details for Web of Science ID 001178631400001

• Use of wastewater metrics to track COVID-19 in the U.S.: a national time-series analysis over the first three quarters of 2022. medRxiv : the preprint server for health sciences Varkila, M., Montez-Rath, M., Salomon, J., Yu, X., Block, G., Owens, D. K., Chertow, G. M., Parsonnet, J., Anand, S. 2023

  Abstract

  Widespread use of at-home COVID-19 tests hampers determination of community COVID-19 incidence. Using nationwide data available through the US National Wastewater Surveillance System, we examined the performance of two wastewater metrics in predicting high case and hospitalizations rates both before and after widespread use of at-home tests.We performed area under the receiver operating characteristic (ROC) curve analysis (AUC) for two wastewater metrics-viral concentration relative to the peak of January 2022 ("wastewater percentile") and 15-day percent change in SARS-CoV-2 ("percent change"). Dichotomized reported cases (≥ 200 or <200 cases per 100,000) and new hospitalizations (≥ 10 or <10 per 100,000) were our dependent variables, stratified by calendar quarter. Using logistic regression, we assessed the performance of combining wastewater metrics.Among 268 counties across 22 states, wastewater percentile detected high reported case and hospitalizations rates in the first quarter of 2022 (AUC 0.95 and 0.86 respectively) whereas the percent change did not (AUC 0.54 and 0.49 respectively). A wastewater percentile of 51% maximized sensitivity (0.93) and specificity (0.82) for detecting high case rates. A model inclusive of both metrics performed no better than using wastewater percentile alone. The predictive capability of wastewater percentile declined over time (AUC 0.84 and 0.72 for cases for second and third quarters of 2022).Nationwide, county wastewater levels above 51% relative to the historic peak predicted high COVID rates and hospitalization in the first quarter of 2022, but performed less well in subsequent quarters. Decline over time in predictive performance of this metric likely reflects underreporting of cases, reduced testing, and possibly lower virulence of infection due to vaccines and treatments.

  View details for DOI 10.1101/2023.02.06.23285542

  View details for PubMedID 36798337

  View details for PubMedCentralID PMC9934789

• Transportability and Implementation Challenges of Early Warning Scores for Septic Shock in the ICU: A Perspective on the TREWScore FRONTIERS IN MEDICINE Niemantsverdriet, M. A., Varkila, M. J., Vromen-Wijsman, J. P., Hoefer, I. E., Bellomo, D., van Vliet, M. H., van Solinge, W. W., Cremer, O. L., Haitjema, S. 2022; 8: 793815

  Abstract

  The increased use of electronic health records (EHRs) has improved the availability of routine care data for medical research. Combined with machine learning techniques this has spurred the development of early warning scores (EWSs) in hospitals worldwide. EWSs are commonly used in the hospital where they have been developed, yet few have been transported to external settings and/or internationally. In this perspective, we describe our experiences in implementing the TREWScore, a septic shock EWS, and the transportability challenges regarding domain, predictors, and clinical outcome we faced. We used data of 53,330 ICU stays from Medical Information Mart for Intensive Care-III (MIMIC-III) and 18,013 ICU stays from the University Medical Center (UMC) Utrecht, including 17,023 (31.9%) and 2,557 (14.2%) cases of sepsis, respectively. The MIMIC-III and UMC populations differed significantly regarding the length of stay (6.9 vs. 9.0 days) and hospital mortality (11.6% vs. 13.6%). We mapped all 54 TREWScore predictors to the UMC database: 31 were readily available, seven required unit conversion, 14 had to be engineered, one predictor required text mining, and one predictor could not be mapped. Lastly, we classified sepsis cases for septic shock using the sepsis-2 criteria. Septic shock populations (UMC 31.3% and MIMIC-III 23.3%) and time to shock events showed significant differences between the two cohorts. In conclusion, we identified challenges to transportability and implementation regarding domain, predictors, and clinical outcome when transporting EWS between hospitals across two continents. These challenges need to be systematically addressed to improve model transportability between centers and unlock the potential clinical utility of EWS.

  View details for DOI 10.3389/fmed.2021.793815

  View details for Web of Science ID 000760478800001

  View details for PubMedID 35211485

  View details for PubMedCentralID PMC8860834

• Human plasma IgG1 repertoires are simple, unique, and dynamic. Cell systems Bondt, A., Hoek, M., Tamara, S., de Graaf, B., Peng, W., Schulte, D., van Rijswijck, D. M., den Boer, M. A., Greisch, J. F., Varkila, M. R., Snijder, J., Cremer, O. L., Bonten, M. J., Heck, A. J. 2021; 12 (12): 1131-1143.e5

  Abstract

  Although humans can produce billions of IgG1 variants through recombination and hypermutation, the diversity of IgG1 clones circulating in human blood plasma has largely eluded direct characterization. Here, we combined several mass-spectrometry-based approaches to reveal that the circulating IgG1 repertoire in human plasma is dominated by a limited number of clones in healthy donors and septic patients. We observe that each individual donor exhibits a unique serological IgG1 repertoire, which remains stable over time but can adapt rapidly to changes in physiology. We introduce an integrative protein- and peptide-centric approach to obtain and validate a full sequence of an individual plasma IgG1 clone de novo. This IgG1 clone emerged at the onset of a septic episode and exhibited a high mutation rate (13%) compared with the closest matching germline DNA sequence, highlighting the importance of de novo sequencing at the protein level. A record of this paper's transparent peer review process is included in the supplemental information.

  View details for DOI 10.1016/j.cels.2021.08.008

  View details for PubMedID 34613904

  View details for PubMedCentralID PMC8691384

• Mortality review as a tool to assess the contribution of healthcare-associated infections to death: results of a multicentre validity and reproducibility study, 11 European Union countries, 2017 to 2018. Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin van der Kooi, T., Lepape, A., Astagneau, P., Suetens, C., Nicolaie, M. A., de Greeff, S., Lozoraitiene, I., Czepiel, J., Patyi, M., Plachouras, D. 2021; 26 (23)

  Abstract

  IntroductionThe contribution of healthcare-associated infections (HAI) to mortality can be estimated using statistical methods, but mortality review (MR) is better suited for routine use in clinical settings. The European Centre for Disease Prevention and Control recently introduced MR into its HAI surveillance.AimWe evaluate validity and reproducibility of three MR measures.MethodsThe on-site investigator, usually an infection prevention and control doctor, and the clinician in charge of the patient independently reviewed records of deceased patients with bloodstream infection (BSI), pneumonia, Clostridioides difficile infection (CDI) or surgical site infection (SSI), and assessed the contribution to death using 3CAT: definitely/possibly/no contribution to death; WHOCAT: sole cause/part of causal sequence but not sufficient on its own/contributory cause but unrelated to condition causing death/no contribution, based on the World Health Organization's death certificate; QUANT: Likert scale: 0 (no contribution) to 10 (definitely cause of death). Inter-rater reliability was assessed with weighted kappa (wk) and intra-cluster correlation coefficient (ICC). Reviewers rated the fit of the measures.ResultsFrom 2017 to 2018, 24 hospitals (11 countries) recorded 291 cases: 87 BSI, 113 pneumonia , 71 CDI and 20 SSI. The inter-rater reliability was: 3CAT wk 0.68 (95% confidence interval (CI): 0.61-0.75); WHOCAT wk 0.65 (95% CI: 0.58-0.73); QUANT ICC 0.76 (95% CI: 0.71-0.81). Inter-rater reliability ranged from 0.72 for pneumonia to 0.52 for CDI. All three measures fitted 'reasonably' or 'well' in > 88%.ConclusionFeasibility, validity and reproducibility of these MR measures was acceptable for use in HAI surveillance.

  View details for DOI 10.2807/1560-7917.ES.2021.26.23.2000052

  View details for PubMedID 34114542

  View details for PubMedCentralID PMC8193992

• Persistent Lymphocytopenia Does Not Increase Nosocomial Infection Risk in the ICU. American journal of respiratory and critical care medicine Varkila, M. R., Marrec, L., Daix, T., Hoefer, I. E., Haitjema, S., Bonten, M. J., Cremer, O. L. 2021; 203 (7): 913-916

  View details for DOI 10.1164/rccm.202007-2858LE

  View details for PubMedID 33332996

• O-serotype distribution of Escherichia coli bloodstream infection isolates in critically ill patients in The Netherlands. Vaccine Verboom, D. M., Varkila, M. R., Morrow, B., Davies, T., Ibarra de Palacios, P., Poolman, J., Hermans, P. W., Dudley, E. G., Roberts, E., Cremer, O. L., Bonten, M. J. 2021; 39 (12): 1670-1674

  Abstract

  Invasive infections by extra-intestinal pathogenic Escherichia coli (ExPEC) strains are increasing. We determined O-serogroups of E. coli isolates from ICU patients having bloodstream infections (BSI) and the potential coverage of a 10-valent O-polysaccharide conjugate vaccine currently in development for the prevention of invasive ExPEC disease.We studied E. coli BSI among patients admitted to a tertiary ICU in the Netherlands between April 2011 and November 2016. O-serogroups were determined in vitro by agglutination and whole genome sequencing.Among 714 ICU patients having BSI, 70 (10%) had an E. coli BSI. Among 68 (97%) isolates serogrouped, the most common serogroups were O25 (n = 11; 16%), O8 (n = 5; 7%), O2 (n = 4; 6%), O6 (n = 4; 6%), and O15 (n = 4; 6%). The theoretical coverage of a 10-valent ExPEC vaccine was 54% (n = 37).A multi-valent ExPEC O-polysaccharide conjugate vaccine in development could potentially aid in the prevention of E. coli BSI in Dutch ICU patients.

  View details for DOI 10.1016/j.vaccine.2021.02.031

  View details for PubMedID 33642161

• Glycoproteoform Profiles of Individual Patients' Plasma Alpha-1-Antichymotrypsin are Unique and Extensively Remodeled Following a Septic Episode. Frontiers in immunology Čaval, T., Lin, Y. H., Varkila, M., Reiding, K. R., Bonten, M. J., Cremer, O. L., Franc, V., Heck, A. J. 2020; 11: 608466

  Abstract

  Sepsis and septic shock remain the leading causes of death in intensive care units (ICUs), yet the pathogenesis originating from the inflammatory response during sepsis remains ambiguous. Acute-phase proteins are typically highly glycosylated, and the nature of the glycans have been linked to the incidence and severity of such inflammatory responses. To further build upon these findings we here monitored, the longitudinal changes in the plasma proteome and, in molecular detail, glycoproteoform profiles of alpha-1-antichymotrypsin (AACT) extracted from plasma of ten individual septic patients. For each patient we included four different time-points, including post-operative (before sepsis) and following discharge from the ICU. We isolated AACT from plasma depleted for albumin, IgG and serotransferrin and used high-resolution native mass spectrometry to qualitatively and quantitatively monitor the multifaceted glycan microheterogeneity of desialylated AACT, which allowed us to monitor how changes in the glycoproteoform profiles reflected the patient's physiological state. Although we observed a general trend in the remodeling of the AACT glycoproteoform profiles, e.g. increased fucosylation and branching/LacNAc elongation, each patient exhibited unique features and responses, providing a resilient proof-of-concept for the importance of personalized longitudinal glycoproteoform profiling. Importantly, we observed that the AACT glycoproteoform changes induced by sepsis did not readily subside after discharge from ICU.

  View details for DOI 10.3389/fimmu.2020.608466

  View details for PubMedID 33519818

  View details for PubMedCentralID PMC7840657

• Adverse prognosis of glioblastoma contacting the subventricular zone: Biological correlates. PloS one Berendsen, S., van Bodegraven, E., Seute, T., Spliet, W. G., Geurts, M., Hendrikse, J., Schoysman, L., Huiszoon, W. B., Varkila, M., Rouss, S., Bell, E. H., Kroonen, J., Chakravarti, A., Bours, V., Snijders, T. J., Robe, P. A. 2019; 14 (10): e0222717

  Abstract

  The subventricular zone (SVZ) in the brain is associated with gliomagenesis and resistance to treatment in glioblastoma. In this study, we investigate the prognostic role and biological characteristics of subventricular zone (SVZ) involvement in glioblastoma.We analyzed T1-weighted, gadolinium-enhanced MR images of a retrospective cohort of 647 primary glioblastoma patients diagnosed between 2005-2013, and performed a multivariable Cox regression analysis to adjust the prognostic effect of SVZ involvement for clinical patient- and tumor-related factors. Protein expression patterns of a.o. markers of neural stem cellness (CD133 and GFAP-δ) and (epithelial-) mesenchymal transition (NF-κB, C/EBP-β and STAT3) were determined with immunohistochemistry on tissue microarrays containing 220 of the tumors. Molecular classification and mRNA expression-based gene set enrichment analyses, miRNA expression and SNP copy number analyses were performed on fresh frozen tissue obtained from 76 tumors. Confirmatory analyses were performed on glioblastoma TCGA/TCIA data.Involvement of the SVZ was a significant adverse prognostic factor in glioblastoma, independent of age, KPS, surgery type and postoperative treatment. Tumor volume and postoperative complications did not explain this prognostic effect. SVZ contact was associated with increased nuclear expression of the (epithelial-) mesenchymal transition markers C/EBP-β and phospho-STAT3. SVZ contact was not associated with molecular subtype, distinct gene expression patterns, or markers of stem cellness. Our main findings were confirmed in a cohort of 229 TCGA/TCIA glioblastomas.In conclusion, involvement of the SVZ is an independent prognostic factor in glioblastoma, and associates with increased expression of key markers of (epithelial-) mesenchymal transformation, but does not correlate with stem cellness, molecular subtype, or specific (mi)RNA expression patterns.

  View details for DOI 10.1371/journal.pone.0222717

  View details for PubMedID 31603915

  View details for PubMedCentralID PMC6788733

• Moderate positive predictive value of a multiplex real-time PCR on whole blood for pathogen detection in critically ill patients with sepsis. European journal of clinical microbiology & infectious diseases : official publication of the European Society of Clinical Microbiology van de Groep, K., Bos, M. P., Varkila, M. R., Savelkoul, P. H., Ong, D. S., Derde, L. P., Juffermans, N. P., van der Poll, T., Bonten, M. J., Cremer, O. L. 2019; 38 (10): 1829-1836

  Abstract

  A novel multiplex real-time PCR for bloodstream infections (BSI-PCR) detects pathogens directly in blood. This study aimed at determining the positive predictive value (PPV) of BSI-PCR in critically ill patients with sepsis. We included consecutive patients with presumed sepsis upon admission to the intensive care unit (ICU). The multiplexed BSI-PCR included 17 individual PCRs for a broad panel of species- and genus-specific DNA targets. BSI-PCR results were compared with a reference diagnosis for which plausibility of infection and causative pathogen(s) had been prospectively assessed by trained observers, based on available clinical and microbiological evidence. PPV and false positive proportion (FPP) were calculated. Clinical plausibility of discordant positive results was adjudicated by an expert panel. Among 325 patients, infection likelihood was categorized as confirmed, uncertain, and ruled out in 210 (65%), 88 (27%), and 27 (8%) subjects, respectively. BSI-PCR identified one or more microorganisms in 169 (52%) patients, of whom 104 (61%) had at least one detection in accordance with the reference diagnosis. Discordant positive PCR results were observed in 95 patients, including 30 subjects categorized as having an "unknown" pathogen. Based on 5525 individual PCRs yielding 295 positive results, PPV was 167/295 (57%) and FPP was 128/5525 (2%). Expert adjudication of the 128 discordant PCR findings resulted in an adjusted PPV of 68% and FPP of 2%. BSI-PCR was all-negative in 156 patients, including 79 (51%) patients in whom infection was considered ruled out. BSI-PCR may complement conventional cultures and expedite the microbiological diagnosis of sepsis in ICU patients, but improvements in positive predictive value of the test are warranted before its implementation in clinical practice can be considered.

  View details for DOI 10.1007/s10096-019-03616-w

  View details for PubMedID 31243596

  View details for PubMedCentralID PMC6778535

• Profile of the SeptiCyte™ LAB gene expression assay to diagnose infection in critically ill patients. Expert review of molecular diagnostics Verboom, D. M., Koster-Brouwer, M. E., Varkila, M. R., Bonten, M. J., Cremer, O. L. 2019; 19 (2): 95-108

  Abstract

  Sepsis is a severe and frequently occurring clinical syndrome, caused by the inflammatory response to infections. Recent studies on the human transcriptome during sepsis have yielded several gene-expression assays that might assist physicians during clinical assessment of patients suspected of sepsis. SeptiCyte™ LAB (Immunexpress, Seattle, WA) is the first gene expression assay that was cleared by the FDA in the United States to distinguish infectious from non-infectious causes of systemic inflammation in critically ill patients. The test consists of the simultaneous amplification of four RNA transcripts (CEACAM4, LAMP1, PLAC8, and PLA2G7) in whole blood using a quantitative real-time PCR reaction. This review provides an overview of the challenges in the diagnosis of sepsis, the development of gene expression signatures, and a detailed description of available clinical performance studies evaluating SeptiCyte™ LAB.

  View details for DOI 10.1080/14737159.2019.1567333

  View details for PubMedID 30623693

• The association between HIV infection and pulmonary function in a rural African population. PloS one Varkila, M. R., Vos, A. G., Barth, R. E., Tempelman, H. A., Devillé, W. L., Coutinho, R. A., Grobbee, D. E., Klipstein-Grobusch, K. 2019; 14 (1): e0210573

  Abstract

  HIV infection has been associated with an impaired lung function in high-income countries, but the association between HIV infection and pulmonary function in Sub-Saharan Africa remains unclear. This study aims to investigate the relation between HIV infection and pulmonary function in a rural African population.A cross-sectional study was conducted among HIV-positive and HIV-negative adults in a rural area in South Africa, as part of the Ndlovu Cohort Study. A respiratory questionnaire and post-bronchodilator spirometry were performed. Multivariable regression analysis was used to investigate whether HIV was independently associated with a decrease in post-bronchodilator FEV1/FVC ratio considering age, sex, body mass index, respiratory risk factors and a history of a pulmonary infection (tuberculosis (TB) or a pneumonia). Possible mediation by a history of pulmonary infection was tested by removing this variable from the final model.Two hundred and one consecutive participants were enrolled in the study in 2016, 84 (41.8%) were HIV-positive (82.1% on ART). The median age was 38 (IQR 29-51) years. Following multivariable analysis HIV was not significantly associated to a decline in post-bronchodilator FEV1/FVC ratio (β -0.017, p 0.18). However, upon removal of a history of a pulmonary infection from the final model HIV was significantly related to post-bronchodilator FEV1/FVC ratio, β -0.026, p 0.03.Pulmonary function is affected by HIV infection which most likely results from co-infection with TB or other pneumonia. Further research should focus on the influence of a pulmonary infection, most notably TB, on pulmonary function, especially as the incidence of TB is high in HIV infection.

  View details for DOI 10.1371/journal.pone.0210573

  View details for PubMedID 30645622

  View details for PubMedCentralID PMC6333365

• Is research from databases reliable? Not sure. Intensive care medicine Varkila, M. R., Cremer, O. L. 2019; 45 (1): 122-124

  View details for DOI 10.1007/s00134-018-5498-9

  View details for PubMedID 30552460

• Prognostic relevance of epilepsy at presentation in glioblastoma patients. Neuro-oncology Berendsen, S., Varkila, M., Kroonen, J., Seute, T., Snijders, T. J., Kauw, F., Spliet, W. G., Willems, M., Poulet, C., Broekman, M. L., Bours, V., Robe, P. A. 2016; 18 (5): 700-6

  Abstract

  Epileptogenic glioblastomas are thought to convey a favorable prognosis, either due to early diagnosis or potential antitumor effects of antiepileptic drugs. We investigated the relationship between survival and epilepsy at presentation, early diagnosis, and antiepileptic drug therapy in glioblastoma patients.Multivariable Cox regression was applied to survival data of 647 consecutive patients diagnosed with de novo glioblastoma between 2005 and 2013 in order to investigate the association between epilepsy and survival in glioblastoma patients. In addition, we quantified the association between survival and valproic acid (VPA) treatment.Epilepsy correlated positively with survival (HR: 0.75 (95% CI: 0.61-0.92), P < .01). This effect is independent of age, sex, performance status, type of surgery, adjuvant therapy, tumor location, and tumor volume, suggesting that this positive correlation cannot be attributed solely to early diagnosis. For patients who presented with epilepsy, the use of the antiepileptic drug VPA did not associate with survival when compared with patients who did not receive VPA treatment.Epilepsy is an independent prognostic factor for longer survival in glioblastoma patients. This prognostic effect is not solely explained by early diagnosis, and survival is not associated with VPA treatment.

  View details for DOI 10.1093/neuonc/nov238

  View details for PubMedID 26420896

  View details for PubMedCentralID PMC4827038