Kanak Verma Kennedy

All Publications

• 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