Kanak Verma Kennedy

All Publications

• FOXM1 inhibition reduces IL-13-induced epithelial remodelling and inflammation in eosinophilic oesophagitis. Gut Sasaki, M., Wang, J. X., Teranishi, R., Itami, T., Zhou, Y., Kennedy, K. V., Semeao, A., Ishikawa, S., Hara, T., McMillan, E. A., Mahon, M., Golden, H., Dhakal, D., Baccarella, A., Winters, H., Umeweni, C. N., Wilkins, B. J., Karakasheva, T. A., Whelan, K. A., Shaffer, S. M., Ruffner, M. A., Muir, A. B. 2025

  Abstract

  Eosinophilic oesophagitis (EoE) is a chronic allergic disease characterised by oesophageal epithelial remodelling, barrier dysfunction and inflammation. The transcription factor forkhead box M1 (FOXM1) has been shown to be a key regulator of epithelial proliferation and inflammation in allergic asthma.To investigate the role of FOXM1 in epithelial disruption in EoE and to evaluate the therapeutic potential of FOXM1 inhibition.FOXM1 expression was analysed in human oesophageal biopsies, patient-derived organoids and murine EoE models. Interleukin (IL)-13 stimulation was used to model EoE in vitro. Using FOXM1 inhibition via the small molecule Robert Costa Memorial drug-1 (RCM-1), small interfering RNA-mediated knockdown or FOXM1 overexpression, the roles of FOXM1 were assessed by histology, gene expression profiling, organoid formation rates, barrier integrity and proliferation assays. RNA sequencing and chromatin immunoprecipitation were performed to elucidate molecular mechanisms.FOXM1 was significantly upregulated in patients with active EoE and localised to the basal epithelium. IL-13 increased FOXM1 expression in vitro. FOXM1 inhibition restored differentiation markers, reduced basal cell hyperplasia and proliferation, and improved barrier function. In a murine model, RCM-1 reduced epithelial changes and eosinophil infiltration. Conversely, FOXM1 overexpression promoted basal cell hyperplasia and proliferation. Mechanistically, FOXM1 directly regulated cell cycle gene, cyclin B1, which was upregulated in EoE and downregulated on FOXM1 inhibition. RCM-1 reduced phosphorylated STAT6 under IL-13 stimulation. FOXM1 expression was driven in part by an IL-13-PI3K/AKT axis.FOXM1 plays a pivotal role in epithelial disruption in EoE by driving proliferation and impairing differentiation. Targeting FOXM1 restores epithelial homeostasis, mitigates inflammation and offers a novel therapeutic approach for EoE.

  View details for DOI 10.1136/gutjnl-2025-335163

  View details for PubMedID 41266120

• Histologic response is associated with improved esophageal distensibility and symptom burden in pediatric eosinophilic esophagitis. Gastroenterology Kennedy, K., Burger, C., Pan, Z., Umeweni, C. N., Alston, M., Benitez, A., Furuta, G. T., Mahon, M., Ruffner, M. A., Quinn, L., Muir, A., Menard-Katcher, C. 2025

  Abstract

  Chronic eosinophilic esophagitis (EoE)-associated inflammation can lead to progressive tissue remodeling and fibrostenosis. Longitudinal studies are limited, and the impact of histologic disease control during childhood remains unknown. We aimed to evaluate the relationship between esophageal distensibility, histology, and fibrostenotic complications in a cohort of children with EoE.We conducted a prospective longitudinal study at two tertiary pediatric institutions to evaluate longitudinal changes in esophageal distensibility in pediatric subjects aged 3 to 18 years. Impedance planimetry was used to determine esophageal distensibility during the baseline endoscopy and all subsequent clinically necessary endoscopies. Symptomatic, endoscopic, and histologic data were collected at each visit.Three hundred endoscopies involving 112 EoE patients (mean age 12.8 years, 72.3% male) were included, with a median follow-up time of 11 months (range 2-54 months). Participants exhibiting a histologic response to treatment showed the most significant improvement in distensibility over time (1.41 vs 0.16-0.53 mm/year, p = 0.003). After adjusting for EREFS and age of symptom onset, lower esophageal distensibility was independently associated with increased odds of patient-reported dysphagia (OR 0.85, CI 0.75-0.96, p = 0.008). Patients who developed clinical features of fibrostenosis were older at diagnosis (9.9 vs 6.7 years, p = 0.032), experienced longer disease duration (4.4 vs 2.4 years, p = 0.046), and had lower baseline esophageal distensibility (13.0 vs 14.9 mm, p = 0.012). Baseline distensibility predicted the need for future stricture dilation (AUC 0.757, p = 0.0003).Histologic remission is associated with improved esophageal distensibility over time in pediatric EoE patients. Baseline esophageal distensibility provides a quantitative marker of tissue remodeling and may help predict disease severity and fibrostenotic progression.

  View details for DOI 10.1053/j.gastro.2025.07.042

  View details for PubMedID 40819800

• Prevalence and predictors of low bone mineral density in pediatric inflammatory bowel disease. Journal of pediatric gastroenterology and nutrition Rudra, S., Kennedy, K., Neukrug, S., Huang, J., Cousminer, D. L., Patel, A., Xu, Y., Grant, S. F., Baldassano, R. N., Albenberg, L., Zemel, B. S., Stein, R. 2025; 81 (1): 34-42

  Abstract

  Bone health is at risk in children with inflammatory bowel disease (IBD). This study examined the prevalence and predictors of low bone mineral density (BMD) in a cohort of children and young adults with IBD.This single-center retrospective study included patients with IBD, ages 3.5-22 years, with completed dual x-ray absorptiometry (DXA) scans from 2006 to 2019. Demographic, clinical, and laboratory data were collected. Logistic regression analysis identified predictors associated with low BMD (Z-scores ≤ -2 standard deviations [SDs]) for three outcomes. In an overlapping IBD cohort with available genetic data between 2002 and 2019 (n = 378), genetic risk for diminished bone health was calculated using published polygenic risk scores generated from genome-wide association studies based on DXA or heel ultrasound speed of sound (SOS). Linear regression analysis examined associations of low BMD and genetic risk.Low BMD prevalence was 7% in our cohort (n = 600) based on spine bone mineral apparent density (BMAD), which best accounts for growth delays. Median (interquartile range [IQR]) spine BMAD Z-score was -0.37 SD (-1.11 to 0.35). Predictors of low BMAD included lower BMI Z-score (odds ratio [OR]: 0.67, p value: 0.02) and decreased height Z-score (OR: 0.6, p value: 0.005). Of those with longitudinal data (n = 118), low BMI (OR: 0.44, p value: <0.001) and steroid use (OR: 3.42, p value: 0.01) were associated with suboptimal bone health (Z-scores ≤ -1SD). In the cohort with genetic data, heel genomic SOS (β [standard error] = 0.17 [0.35], p ≤ 0.01) was associated with BMD.Lower BMI should prompt DXA monitoring in pediatric IBD. Genetic predisposition may identify an at-risk subpopulation.

  View details for DOI 10.1002/jpn3.70047

  View details for PubMedID 40296588

• FOXM1 Modulation Alleviates Epithelial Remodeling and Inflammation in Eosinophilic Esophagitis. bioRxiv : the preprint server for biology Sasaki, M., Wang, J. X., Zhou, Y., Kennedy, K. V., Teranishi, R., Itami, T., Ishikawa, S., Hara, T., Winters, H., McMillan, E. A., Mahon, M., Golden, H., Dhakal, D., Bacarella, A., Umeweni, C. N., Wilkins, B. J., Karakasheva, T. A., Whelan, K. A., Shaffer, S. M., Ruffner, M. A., Muir, A. B. 2025

  Abstract

  Eosinophilic esophagitis (EoE) is a chronic allergic disease characterized by esophageal epithelial remodeling, barrier dysfunction, and inflammation. Despite histologic remission, molecular and structural changes in the epithelium persist, contributing to ongoing symptoms and relapse. The transcription factor FOXM1 has been shown to be a key regulator of epithelial proliferation and inflammation in allergic asthma.To investigate the role of FOXM1 in epithelial disruption in EoE and to evaluate the therapeutic potential of FOXM1 inhibition.FOXM1 expression was analyzed in human esophageal biopsies, patient-derived organoids, and murine EoE models. IL-13 stimulation was used to model EoE in vitro. The effects of FOXM1 inhibition via the small molecule RCM-1 and siRNA-mediated knockdown were assessed by histology, gene expression profiling, organoid formation rates, and barrier integrity assays. RNA sequencing and chromatin immunoprecipitation were performed to elucidate molecular mechanisms.FOXM1 was significantly upregulated in patients with active EoE and localized to the basal epithelium. IL-13 increased FOXM1 expression, which impaired epithelial differentiation and enhanced basal cell hyperplasia. FOXM1 inhibition restored differentiation markers, reduced basal hyperplasia, and improved barrier function. In murine models, RCM-1 ameliorated epithelial changes and decreased eosinophil infiltration. Mechanistically, FOXM1 directly regulated cell cycle gene, CCNB1, which was upregulated in EoE and downregulated upon FOXM1 inhibition. FOXM1 expression was driven by an IL-13-PI3K/AKT axis.FOXM1 plays a pivotal role in epithelial disruption in EoE by driving proliferation and impairing differentiation. Targeting FOXM1 restores epithelial homeostasis, mitigates inflammation, and offers a novel therapeutic approach for EoE.What is already known on this topic: Eosinophilic esophagitis is marked by epithelial remodeling and barrier dysfunction driven by Th2 inflammation. Despite remission, molecular and histologic changes in the esophageal epithelium persist, contributing to symptoms and relapse. The mechanisms underlying this epithelial dysregulation remain poorly understood. What this study adds: This study identifies FOXM1 as a key transcriptional regulator of epithelial disruption in EoE, demonstrating that FOXM1 inhibition restores epithelial differentiation, reduces basal cell hyperplasia, improves barrier integrity, and mitigates inflammation. How this study might affect research, practice, or policy: Targeting FOXM1 offers a novel therapeutic strategy to restore epithelial homeostasis and reduce inflammation in EoE. This dual approach, addressing both epithelial and immune dysregulation, may guide future therapeutic development and improve patient outcomes.

  View details for DOI 10.1101/2025.05.25.655133

  View details for PubMedID 40501685

  View details for PubMedCentralID PMC12154673

• SPNing our wheels-Pancreatic solid pseudopapillary neoplasm as an extraluminal etiology of persistent duodenal ulceration. JPGN reports Kennedy, K. V., Fawad, J. A., Neugut, Y. D., Valenzuela-Araujo, D., Coe, A., Bhatti, T. R., Acord, M., Manfredi, M. D., Mamula, P., Loomes, K. M., Brownell, J. N. 2025; 6 (2): 189-192

  Abstract

  Pediatric upper gastrointestinal (GI) bleeding secondary to duodenal ulceration is a potentially serious and life-threatening condition with a broad differential diagnosis. We present a pediatric case of a pancreatic head solid pseudopapillary neoplasm (SPN) presenting with duodenal ulceration and recurrent upper GI bleeding. This case highlights pancreatic SPNs as a rare extrinsic cause of duodenal ulceration. Recurrence and progression in size and extent of a duodenal ulceration in the absence of other inciting factors should raise suspicion for an extraluminal etiology.

  View details for DOI 10.1002/jpr3.70003

  View details for PubMedID 40386339

• Finding the Value: Identifying the Key Elements of Recorded Clinic Visits From the Perspective of Patients, Clinicians, and Caregivers. Health expectations : an international journal of public participation in health care and health policy Barr, P. J., Wasp, G. T., Dannenberg, M. D., Mistler, L. A., Verma, K., Bonasia, K., Haslett, W. R., Ganoe, C. H., Bratches, R. W., Schifferdecker, K. 2025; 28 (1): e70143

  Abstract

  We aimed to understand what patients, caregivers and clinicians identified as the most important information from their audio-recorded clinic visits and why.We recruited patients, caregivers and clinicians from primary and speciality care clinics at an academic medical centre in New Hampshire, U.S. Participants reviewed a recording or transcript of their visit, identifying meaningful moments and the reasons why. Two researchers performed a summative content analysis of the data.Sixteen patients, four with caregivers, from six clinicians participated. Patients, caregivers and clinicians identified a median of 7.5 (3-20), 12.5 (6-50) and 18 (4-31) meaningful visit moments, respectively. Moments identified were similar across stakeholders, including patient education, symptoms, recommendations and medications. Four themes emerged as a rationale for finding visit information meaningful: providing and receiving information, sharing the patient experience, forming a care plan, and providing emotional support. Clinicians rarely identified patient statements as important.There was considerable agreement between patients, clinicians and caregivers regarding visit information that is most valuable. Patient contributions may be undervalued by clinicians.These findings can be used to improve patient-centred visit communication by focusing visit summaries and decision support on information of the most value to participants.

  View details for DOI 10.1111/hex.70143

  View details for PubMedID 39776090

• Lysyl Oxidase Mediates Proliferation and Differentiation in the Esophageal Epithelium. Biomolecules Kennedy, K. V., Wang, J. X., McMillan, E., Zhou, Y., Teranishi, R., Semeao, A., Mirchandani, L., Umeweni, C. N., Dhakal, D., Baccarella, A., Ishikawa, S., Sasaki, M., Itami, T., Harman, A. C., Joannas, L., Karakasheva, T. A., Nakagawa, H., Muir, A. B. 2024; 14 (12)

  Abstract

  In homeostatic conditions, the basal progenitor cells of the esophagus differentiate into a stratified squamous epithelium. However, in the setting of acid exposure or inflammation, there is a marked failure of basal cell differentiation, leading to basal cell hyperplasia. We have previously shown that lysyl oxidase (LOX), a collagen crosslinking enzyme, is upregulated in the setting of allergic inflammation of the esophagus; however, its role beyond collagen crosslinking is unknown. Herein, we propose a non-canonical epithelial-specific role of LOX in the maintenance of epithelial homeostasis using 3D organoid and murine models. We performed quantitative reverse transcriptase PCR, Western blot, histologic analysis, and RNA sequencing on immortalized non-transformed human esophageal epithelial cells (EPC2-hTERT) with short-hairpin RNA (shRNA) targeting LOX mRNA in both monolayer and 3D organoid culture. A novel murine model with a tamoxifen-induced Lox knockout specific to the stratified epithelium (K5CreER; Loxfl/fl) was utilized to further define the role of epithelial LOX in vivo. We found that LOX knockdown decreased the proliferative capacity of the esophageal epithelial cells in monolayer culture, and dramatically reduced the organoid formation rate (OFR) in the shLOX organoids. LOX knockdown was associated with decreased expression of the differentiation markers filaggrin, loricrin, and involucrin, with RNA sequencing analysis revealing 1224 differentially expressed genes demonstrating downregulation of pathways involved in cell differentiation and epithelial development. Mice with Lox knockout in their stratified epithelium demonstrated increased basaloid content of their esophageal epithelium and decreased Ki-67 staining compared to the vehicle-treated mice, suggesting reduced differentiation and proliferation in the Lox-deficient epithelium in vivo. Our results demonstrate, both in vivo and in vitro, that LOX may regulate epithelial homeostasis in the esophagus through the modulation of epithelial proliferation and differentiation. Understanding the mechanisms of perturbation in epithelial proliferation and differentiation in an inflamed esophagus could lead to the development of novel treatments that could promote epithelial healing and restore homeostasis.

  View details for DOI 10.3390/biom14121560

  View details for PubMedID 39766266

• Proton pump inhibitors and esophageal atresia: Too early to change clinical practice. Journal of pediatric gastroenterology and nutrition Manfredi, M. A., Yasuda, J., Mahon, M., Kennedy, K. V., Menard-Katcher, C., Mitchel, E., Muir, A. B. 2024; 79 (6): 1216-1217

  View details for DOI 10.1002/jpn3.12373

  View details for PubMedID 39324371

• Granulomatous hyperinflammatory state induced by dupilumab treatment for eosinophilic esophagitis. The journal of allergy and clinical immunology. Global Kennedy, K. V., Costello, A., Lerman, M. A., Burnham, J. M., Corcoran, A., Piccione, J., Grier, A., Sullivan, K., Whitehorn-Brown, T., Alexander, C. J., Finn, L. S., Wilkins, B. J., Muir, A. B. 2024; 3 (4): 100314

  Abstract

  We present the first case of a dupilumab-induced hyperinflammatory state in the setting of underlying eosinophilic esophagitis characterized by multisystem granulomatous inflammation. Although clinical trial data and subsequent real-world experience support dupilumab as a highly effective therapy for eosinophilic esophagitis, close monitoring for development of adverse symptoms following initiation remains paramount.

  View details for DOI 10.1016/j.jacig.2024.100314

  View details for PubMedID 39253107

  View details for PubMedCentralID PMC11382170

• Esophageal Remodeling Correlates With Eating Behaviors in Pediatric Eosinophilic Esophagitis. The American journal of gastroenterology Kennedy, K. V., Umeweni, C. N., Alston, M., Dolinsky, L., McCormack, S. M., Taylor, L. A., Bendavid, A., Benitez, A., Mitchel, E., Karakasheva, T., Goh, V., Maqbool, A., Albenberg, L., Brown-Whitehorn, T., Cianferoni, A., Muir, A. B. 2024; 119 (6): 1167-1176

  Abstract

  There are limited data characterizing eating habits among pediatric patients with eosinophilic esophagitis (EoE). We compared eating behaviors in pediatric patients with EoE with healthy controls and assessed the degree of correlation with symptomatology, endoscopic and histologic findings, and esophageal distensibility.We conducted a prospective, observational study where subjects consumed 4 food textures (puree, soft solid, chewable, and hard solid) and were scored for eating behaviors including number of chews per bite, sips of fluid per food, and consumption time. Symptomatic, endoscopic, histologic, and esophageal distensibility data were collected for case subjects.Twenty-seven case subjects and 25 healthy controls were enrolled in our study (mean age 11.0 years, 63.5% male). Compared with healthy controls, pediatric patients with EoE demonstrated more chews per bite with soft solid (13.6 vs 9.1, P = 0.031), chewable (14.7 vs 10.7, P = 0.047), and hard solid foods (19.0 vs 12.8, P = 0.037). Patients with EoE also demonstrated increased consumption time with soft solid (94.7 vs 58.3 seconds, P = 0.002), chewable (90.0 vs 65.1 seconds, P = 0.005), and hard solid foods (114.1 vs 76.4 seconds, P = 0.034) when compared with healthy controls. Subgroup analysis based on disease status showed no statistically significant differences in eating behaviors between active and inactive EoE. Total endoscopic reference score positively correlated with consumption time ( r = 0.53, P = 0.008) and number of chews ( r = 0.45, P = 0.027) for chewable foods and with number of chews ( r = 0.44, P = 0.043) for hard solid foods. Increased consumption time correlated with increased eosinophil count ( r = 0.42, P = 0.050) and decreased esophageal distensibility ( r = -0.82, P < 0.0001).Altered eating behaviors including increased chewing and increased consumption time can be seen in pediatric patients with EoE, can persist despite histologic remission, and may be driven by changes in esophageal distensibility.

  View details for DOI 10.14309/ajg.0000000000002661

  View details for PubMedID 38235740

  View details for PubMedCentralID PMC11150094

• Endoscopic and histologic utility of transnasal endoscopy in pediatric eosinophilic esophagitis. Journal of pediatric gastroenterology and nutrition Shaul, E., Kennedy, K. V., Spergel, Z. C., Daneshdoost, S., Mahon, M., Thanawala, S., Spergel, J. M., Wilkins, B., Ryan, M. J., Muir, A. B. 2024; 78 (5): 1155-1160

  Abstract

  Unsedated transnasal endoscopy (TNE) is an alternative method of examining the esophageal mucosa in pediatric patients with eosinophilic esophagitis (EoE), reducing cost, time, and risk associated with frequent surveillance esophagogastroduodenoscopies (EGD). Adequacy of transnasal esophageal biopsies for the evaluation of eosinophilic esophagitis histologic scoring system (EoEHSS) has not yet been evaluated. We compared procedure times, endoscopic findings, and EoEHSS scoring for EoE patients undergoing TNE versus standard EGD. Sixty-six TNE patients and 132 EGD controls matched for age (mean age 14.0 years) and disease status (29.3% active) were included. Compared to patients undergoing standard EGD, patients undergoing TNE spent 1.94 h less in the GI suite (p < 0.0001), with comparable occurrence rates of all visual endoscopic findings and most EoEHSS components. TNE serves as a useful tool for long-term disease surveillance, and consideration should be given to its use in clinical trials for EoE.

  View details for DOI 10.1002/jpn3.12170

  View details for PubMedID 38482943

• Pathophysiology of Eosinophilic Esophagitis. Immunology and allergy clinics of North America Kennedy, K. V., Muir, A. B., Ruffner, M. A. 2024; 44 (2): 119-128

  Abstract

  Eosinophilic esophagitis (EoE) is a chronic, progressive immune-mediated disease associated with antigen-driven type 2 inflammation and symptoms of esophageal dysfunction. Research over the last 2 decades has dramatically furthered our understanding of the complex interplay between genetics, environmental exposures, and cellular and molecular interactions involved in EoE. This review provides an overview of our current understanding of EoE pathogenesis.

  View details for DOI 10.1016/j.iac.2023.12.001

  View details for PubMedID 38575212

• Lysyl Oxidase Regulates Epithelial Differentiation and Barrier Integrity in Eosinophilic Esophagitis. Cellular and molecular gastroenterology and hepatology Sasaki, M., Hara, T., Wang, J. X., Zhou, Y., Kennedy, K. V., Umeweni, C. N., Alston, M. A., Spergel, Z. C., Ishikawa, S., Teranishi, R., Nakagawa, R., Mcmillan, E. A., Whelan, K. A., Karakasheva, T. A., Hamilton, K. E., Ruffner, M. A., Muir, A. B. 2024; 17 (6): 923-937

  Abstract

  Epithelial disruption in eosinophilic esophagitis (EoE) encompasses both impaired differentiation and diminished barrier integrity. We have shown that lysyl oxidase (LOX), a collagen cross-linking enzyme, is up-regulated in the esophageal epithelium in EoE. However, the functional roles of LOX in the esophageal epithelium remains unknown.We investigated roles for LOX in the human esophageal epithelium using 3-dimensional organoid and air-liquid interface cultures stimulated with interleukin (IL)13 to recapitulate the EoE inflammatory milieu, followed by single-cell RNA sequencing, quantitative reverse-transcription polymerase chain reaction, Western blot, histology, and functional analyses of barrier integrity.Single-cell RNA sequencing analysis on patient-derived organoids revealed that LOX was induced by IL13 in differentiated cells. LOX-overexpressing organoids showed suppressed basal and up-regulated differentiation markers. In addition, LOX overexpression enhanced junctional protein genes and transepithelial electrical resistance. LOX overexpression restored the impaired differentiation and barrier function, including in the setting of IL13 stimulation. Transcriptome analyses on LOX-overexpressing organoids identified an enriched bone morphogenetic protein (BMP) signaling pathway compared with wild-type organoids. In particular, LOX overexpression increased BMP2 and decreased the BMP antagonist follistatin. Finally, we found that BMP2 treatment restored the balance of basal and differentiated cells.Our data support a model whereby LOX exhibits noncanonical roles as a signaling molecule important for epithelial homeostasis in the setting of inflammation via activation of the BMP pathway in the esophagus. The LOX/BMP axis may be integral in esophageal epithelial differentiation and a promising target for future therapies.

  View details for DOI 10.1016/j.jcmgh.2024.01.025

  View details for PubMedID 38340809

  View details for PubMedCentralID PMC11026689

• Lysyl oxidase regulates epithelial differentiation and barrier integrity in eosinophilic esophagitis. bioRxiv : the preprint server for biology Sasaki, M., Hara, T., Wang, J. X., Zhou, Y., Kennedy, K. V., Umeweni, N. N., Alston, M. A., Spergel, Z. C., Nakagawa, R., Mcmillan, E. A., Whelan, K. A., Karakasheva, T. A., Hamilton, K. E., Ruffner, M. A., Muir, A. B. 2023

  Abstract

  Epithelial disruption in eosinophilic esophagitis (EoE) encompasses both impaired differentiation and diminished barrier integrity. We have shown that lysyl oxidase (LOX), a collagen cross-linking enzyme, is upregulated in the esophageal epithelium in EoE. However, the functional roles of LOX in the esophageal epithelium remains unknown.We investigated roles for LOX in the human esophageal epithelium using 3-dimensional organoid and air-liquid interface cultures stimulated with interleukin (IL)-13 to recapitulate the EoE inflammatory milieu, followed by single-cell RNA sequencing, quantitative reverse transcription-polymerase chain reaction, western blot, histology, and functional analyses of barrier integrity.Single-cell RNA sequencing analysis on patient-derived organoids revealed that LOX was induced by IL-13 in differentiated cells. LOX-overexpressing organoids demonstrated suppressed basal and upregulated differentiation markers. Additionally, LOX overexpression enhanced junctional protein genes and transepithelial electrical resistance. LOX overexpression restored the impaired differentiation and barrier function, including in the setting of IL-13 stimulation. Transcriptome analyses on LOX-overexpressing organoids identified enriched bone morphogenetic protein (BMP) signaling pathway compared to wild type organoids. Particularly, LOX overexpression increased BMP2 and decreased BMP antagonist follistatin. Finally, we found that BMP2 treatment restored the balance of basal and differentiated cells.Our data support a model whereby LOX exhibits non-canonical roles as a signaling molecule important for epithelial homeostasis in the setting of inflammation via activation of BMP pathway in esophagus. The LOX/BMP axis may be integral in esophageal epithelial differentiation and a promising target for future therapies.

  View details for DOI 10.1101/2023.03.27.534387

  View details for PubMedID 37034590

  View details for PubMedCentralID PMC10081173

• Treatment goals in eosinophilic esophagitis: Looking beyond eosinophil count. Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology Kennedy, K. V., Umeweni, C. N., Ruffner, M., Muir, A. B. 2023; 130 (1): 11-12

  View details for DOI 10.1016/j.anai.2022.08.001

  View details for PubMedID 35973654

• Independent translation of ORFs in dicistronic operons, synthetic building blocks for polycistronic chloroplast gene expression. The Plant journal : for cell and molecular biology Yu, Q., Tungsuchat-Huang, T., Verma, K., Radler, M. R., Maliga, P. 2020; 103 (6): 2318-2329

  Abstract

  We designed a dicistronic plastid marker system that relies on the plastid's ability to translate polycistronic mRNAs. The identification of transplastomic clones is based on selection for antibiotic resistance encoded in the first open reading frame (ORF) and accumulation of the reporter gene product in tobacco chloroplasts encoded in the second ORF. The antibiotic resistance gene may encode spectinomycin or kanamycin resistance based on the expression of aadA or neo genes, respectively. The reporter gene used in the study is the green fluorescent protein (GFP). The mRNA level depends on the 5'-untranslated region of the first ORF. The protein output depends on the strengths of the ribosome binding, and is proportional with the level of translatable mRNA. Because the dicistronic mRNA is not processed, we could show that protein output from the second ORF is independent from the first ORF. High-level GFP accumulation from the second ORF facilitates identification of transplastomic events under ultraviolet light. Expression of multiple proteins from an unprocessed mRNA is an experimental design that enables predictable protein output from polycistronic mRNAs, expanding the toolkit of plant synthetic biology.

  View details for DOI 10.1111/tpj.14864

  View details for PubMedID 32497322

• The health and economic outcomes of early egg introduction strategies. Allergy Shaker, M., Verma, K., Greenhawt, M. 2018; 73 (11): 2214-2223

  Abstract

  Studies suggest early egg introduction (EEI) in the first year of life is associated with reduced risk of developing egg allergy. No US recommendations exist regarding optimally implementing EEI.Using simulation and Markov modelling over a 20-year horizon, we explored optimal EEI strategies applied to US, European and Canadian populations, comparing screening of high-risk infants (skin prick testing [SPT] or serum-specific IgE[sIgE]) before introducing cooked egg at 6 months of life vs egg introduction at home, without screening, for all infants.A no-screen approach dominated egg SPT screening of high-risk infants with early-onset eczema. Base model per-patient incremental costs of SPT were $6865 US dollars (USD), 6801 euros and $10 610 Canadian dollars (CAD). For egg sIgE screening in primary care settings, base model incremental costs were $16 722 USD, 18 072 euros and $28 193 CAD. As the simulation concluded 2.5% were egg allergic without screening vs 9.5%, 12% and 21.4% of children undergoing SPT, delayed introduction or sIgE screening. Incremental societal costs from screening reached $2 009 351 175 USD for SPT and $4 894 445 790 USD for sIgE testing. In sensitivity analyses, if the risk of reaction with initial egg ingestion was ≥22.5%, SPT before EEI became a preferred strategy. A no-screen approach dominated both EEI of raw pasteurized egg and delayed cooked egg introduction approaches.Assuming initial reaction rates < 22.5%, a no-screening EEI cooked egg approach has superior health and economic benefits in terms of number of egg allergy cases prevented and total healthcare costs vs screening testing.

  View details for DOI 10.1111/all.13565

  View details for PubMedID 30028905

• Audio-/Videorecording Clinic Visits for Patient's Personal Use in the United States: Cross-Sectional Survey. Journal of medical Internet research Barr, P. J., Bonasia, K., Verma, K., Dannenberg, M. D., Yi, C., Andrews, E., Palm, M., Cavanaugh, K. L., Masel, M., Durand, M. A. 2018; 20 (9): e11308

  Abstract

  Few clinics in the United States routinely offer patients audio or video recordings of their clinic visits. While interest in this practice has increased, to date, there are no data on the prevalence of recording clinic visits in the United States.Our objectives were to (1) determine the prevalence of audiorecording clinic visits for patients' personal use in the United States, (2) assess the attitudes of clinicians and public toward recording, and (3) identify whether policies exist to guide recording practices in 49 of the largest health systems in the United States.We administered 2 parallel cross-sectional surveys in July 2017 to the internet panels of US-based clinicians (SERMO Panel) and the US public (Qualtrics Panel). To ensure a diverse range of perspectives, we set quotas to capture clinicians from 8 specialties. Quotas were also applied to the public survey based on US census data (gender, race, ethnicity, and language other than English spoken at home) to approximate the US adult population. We contacted 49 of the largest health systems (by clinician number) in the United States by email and telephone to determine the existence, or absence, of policies to guide audiorecordings of clinic visits for patients' personal use. Multiple logistic regression models were used to determine factors associated with recording.In total, 456 clinicians and 524 public respondents completed the surveys. More than one-quarter of clinicians (129/456, 28.3%) reported that they had recorded a clinic visit for patients' personal use, while 18.7% (98/524) of the public reported doing so, including 2.7% (14/524) who recorded visits without the clinician's permission. Amongst clinicians who had not recorded a clinic visit, 49.5% (162/327) would be willing to do so in the future, while 66.0% (346/524) of the public would be willing to record in the future. Clinician specialty was associated with prior recording: specifically oncology (odds ratio [OR] 5.1, 95% CI 1.9-14.9; P=.002) and physical rehabilitation (OR 3.9, 95% CI 1.4-11.6; P=.01). Public respondents who were male (OR 2.11, 95% CI 1.26-3.61; P=.005), younger (OR 0.73 for a 10-year increase in age, 95% CI 0.60-0.89; P=.002), or spoke a language other than English at home (OR 1.99; 95% CI 1.09-3.59; P=.02) were more likely to have recorded a clinic visit. None of the large health systems we contacted reported a dedicated policy; however, 2 of the 49 health systems did report an existing policy that would cover the recording of clinic visits for patient use. The perceived benefits of recording included improved patient understanding and recall. Privacy and medicolegal concerns were raised.Policy guidance from health systems and further examination of the impact of recordings-positive or negative-on care delivery, clinician-related outcomes, and patients' behavioral and health-related outcomes is urgently required.

  View details for DOI 10.2196/11308

  View details for PubMedID 30209029

  View details for PubMedCentralID PMC6231772

• Association of Rooming-in With Outcomes for Neonatal Abstinence Syndrome: A Systematic Review and Meta-analysis. JAMA pediatrics MacMillan, K. D., Rendon, C. P., Verma, K., Riblet, N., Washer, D. B., Volpe Holmes, A. 2018; 172 (4): 345-351

  Abstract

  Rising incidence of neonatal abstinence syndrome (NAS) is straining perinatal care systems. Newborns with NAS traditionally receive care in neonatal intensive care units (NICUs), but rooming-in with mother and family has been proposed to reduce the use of pharmacotherapy, length of stay (LOS), and cost.To systematically review and meta-analyze if rooming-in is associated with improved outcomes for newborns with NAS.MEDLINE, CINAHL, The Cochrane Library, and clinicaltrials.gov were searched from inception through June 25, 2017.This investigation included randomized clinical trials, cohort studies, quasi-experimental studies, and before-and-after quality improvement investigations comparing rooming-in vs standard NICU care for newborns with NAS.Two independent investigators reviewed studies for inclusion. A random-effects model was used to pool dichotomous outcomes using risk ratio (RR) and 95% CI. The study evaluated continuous outcomes using weighted mean difference (WMD) and 95% CI.The primary outcome was newborn treatment with pharmacotherapy. Secondary outcomes included LOS, inpatient cost, and harms from treatment, including in-hospital adverse events and readmission rates.Of 413 publications, 6 studies (n = 549 [number of patients]) met inclusion criteria. In meta-analysis of 6 studies, there was consistent evidence that rooming-in is preferable to NICU care for reducing both the use of pharmacotherapy (RR, 0.37; 95% CI, 0.19-0.71; I2 = 85%) and LOS (WMD, -10.41 days; 95% CI, -16.84 to -3.98 days; I2 = 91%). Sensitivity analysis resolved the heterogeneity for the use of pharmacotherapy, significantly favoring rooming-in (RR, 0.32; 95% CI, 0.18-0.57; I2 = 13%). Three studies reported that inpatient costs were lower with rooming-in; however, significant heterogeneity precluded quantitative analysis. Qualitative analysis favored rooming-in over NICU care for increasing breastfeeding rates and discharge home in familial custody, but few studies reported on these outcomes. Rooming-in was not associated with higher rates of readmission or in-hospital adverse events.Opioid-exposed newborns rooming-in with mother or other family members appear to be significantly less likely to be treated with pharmacotherapy and have substantial reductions in LOS compared with those cared for in NICUs. Rooming-in should be recommended as a preferred inpatient care model for NAS.

  View details for DOI 10.1001/jamapediatrics.2017.5195

  View details for PubMedID 29404599

  View details for PubMedCentralID PMC5875350