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BACKGROUND AND AIMS: Colonic eosinophilia, an enigmatic finding often referred to as eosinophilic colitis (EoC), is a poorly understood condition. Whether EoC is a distinct disease or a colonic manifestation of eosinophilic gastrointestinal diseases (EGIDs) or inflammatory bowel disease (IBD) is undetermined. METHODS: Subjects with EoC (n=27) and controls (normal [NL, n=20], Crohn disease [CD, n=14]) were enrolled across sites associated with the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR). EoC was diagnosed as colonic eosinophilia (ascending ≥100, descending ≥85, sigmoid ≥65 eosinophils/high-power field) with related symptoms. Colon biopsies were subjected to RNA sequencing. Associations between gene expression and histologic features were analyzed with Spearman correlation; operational pathways and cellular constituents were computationally derived. RESULTS: We identified 987 differentially expressed genes (EoC transcriptome) between EoC and NL (>1.5-fold change, P < .05). Colonic eosinophil count correlated with 31% of EoC transcriptome, most notably with CCL11 and CLC (r=0.78 and 0.77, P < .001). Among EoC and other EGIDs, there was minimal transcriptomic overlap; and minimal evidence of a strong allergic type 2 immune response compared with other EGIDs. Decreased cell-cycle and increased apoptosis in EoC compared with NL were identified by functional enrichment analysis and immunostaining using Ki-67 and cleaved caspase-3. Pericryptal circumferential eosinophil collars were associated with the EoC transcriptome (P < .001). EoC transcriptome-based scores were reversible with disease remission and differentiated EoC from IBD, even after controlling for colonic eosinophil levels (P < .0001). CONCLUSION: We established EoC transcriptomic profiles, identified mechanistic pathways, and integrated findings with parallel IBD and EGID data. These findings establish EoC as a distinct disease compared with other EGIDs and IBD, thereby providing a basis for improving diagnosis and treatment.

Eosinophilic esophagitis (EoE) can progress to fibrostenosis by unclear mechanisms. Herein, we investigated gene dysregulation in fibrostenotic EoE, its association with clinical parameters and specific pathways, and the functional consequences.Esophageal biopsies from subjects with EoE were collected across 11 Consortium of Eosinophilic Gastrointestinal Disease Researchers sites (n = 311) and 2 independent replication cohorts (n = 83). Inclusion criteria for fibrostenotic EoE were endoscopic rings, stricture, and/or a history of dilation. Endoscopic, histologic, and molecular features were assessed by the EoE Endoscopic Reference Score, EoE Histology Scoring System, EoE Diagnostic Panel, and RNA sequencing. Esophageal endothelial TSPAN12 expression and functional effects on barrier integrity and gene expression were analyzed in vitro.TSPAN12 was the gene most correlated with fibrostenosis (r = -0.40, P.001). TSPAN12 was lower in fibrostenotic EoE and correlated with EoE Endoscopic Reference Score, EoE Diagnostic Panel, and EoE Histology Scoring System (r = 0.34-0.47, P.001). Lower TSPAN12 associated with smaller esophageal diameter (r = 0.44, P = .03), increased lamina propria fibrosis (r = -0.41, P.001), and genes enriched in cell cycle-related pathways. Interleukin (IL)-13 reduced TSPAN12 expression in endothelial cells. Conversely, anti-IL-13 therapy increased TSPAN12 expression. TSPAN12 gene silencing increased endothelial cell permeability and dysregulated genes associated with extracellular matrix pathways. Endothelial cell-fibroblast crosstalk induced extracellular matrix changes relevant to esophageal remodeling.Patients with fibrostenotic EoE express decreased levels of endothelial TSPAN12. We propose that IL-13 decreases TSPAN12, likely contributing to the chronicity of EoE by promoting tissue remodeling through fibroblast-endothelial cell crosstalk.

The aim of the study was to determine the mucosal microbiota associated with eosinophilic esophagitis and eosinophilic gastritis in a geographically diverse cohort of patients compared to controls.We conducted a prospective study of individuals with eosinophilic gastrointestinal disease in the Consortium of Eosinophilic Gastrointestinal Disease Researchers (CEGIR), including pediatric and adult tertiary care centers. Eligible individuals had clinical data, mucosal biopsies and stool collected. Total bacterial load was determined from mucosal biopsy samples by quantitative PCR. Community composition was determined by small subunit rRNA gene amplicons.139 mucosal biopsies were evaluated corresponding to 93 EoE, 17 EoG and 29 control specimens (18 esophageal) from 10 sites across the United States. Dominant community members across disease activity differed significantly. When comparing EoE and EoG with controls, the dominant taxa in individuals with EGIDs was increased (Streptococcus in esophagus; Prevotella in stomach). Specific taxa were associated with active disease for both EoE (Streptococcus, Gemella) and EoG (Leptotrichia), although highly individualized communities likely impacted statistical testing. Alpha diversity metrics were similar across groups, but with high variability amongst individuals. Stool analyses did not correlate with bacterial communities found in mucosal biopsy samples and was similar in patients and controls.Dominant community members (Streptococcus for EoE, Prevotella for EoG) were different in the mucosal biopsies but not stool of individuals with EGIDs compared to controls; taxa associated with EGIDs were highly variable across individuals. Further study is needed to determine if therapeutic interventions contribute to the observed community differences.

The Core Outcome Set for Therapeutic Studies in Eosinophilic Esophagitis (COREOS) collaborators are a group of more than 70 gastroenterologists, pathologists, allergists, researchers, dietitians, psychologists, and methodologists who convened in a series of in-person and virtual meetings between 2018 and 2020 with the aim of developing a core outcome set (COS) for use in therapeutic studies of pharmacologic and dietary therapies for the treatment of eosinophilic esophagitis (EoE). Given heterogeneity in reported outcomes and uncertainties regarding the most appropriate end points for use in both randomized controlled trials (RCTs) and observational studies involving EoE patients, the EoE experts launched the COREOS exercise in 2018 to standardize outcome definitions using methods established by the Core Outcome Measures in Effectiveness Trials (COMET) initiative.1,2 The COS was developed using a multiphase approach, which is summarized in Figure 1. In the first phase, systematic reviews of the literature and patient engagement surveys were conducted to identify candidate outcomes that have been previously measured and are important to patients with EoE. Next, this information was used to build a framework of different outcome domains, and working groups for each domain were assembled to review the literature for relevant end points.3–6 The relative importance of these domains was categorized in a Delphi survey as core, important, and research agenda domains, and discussed in a moderated in-person meeting on May 17, 2019 at Digestive Disease Week (San Diego, CA). In phase 3, a comprehensive list of outcome measures within each of the core domains was evaluated by the COREOS collaborators in a 2-round Delphi survey and, finally, outcomes were ratified in a virtual meeting on December 8, 2020. In this meeting summary, we highlight the major points of discussion that occurred during the development of the EoE COS.

Despite best practice recommendations for managing eosinophilic esophagitis (EoE), variation in care exists.We used established methodology for quality indicator development to identify metrics to define quality for the treatment of EoE.Among 29 proposed quality indicator statements, 9 (31%) were adopted as highly valid across all categories. Two (22%) of these statements were identified as having existing or suspected quality gaps.We identified highly valid EoE quality indicators for adult gastroenterologists, which can be used for quality improvement with resulting benefits for patient outcomes.

Eosinophilic esophagitis (EoE) is a chronic allergic inflammatory disease. Multiple genetic risk factors linked to EoE have been identified; however, these studies have been primarily focused on populations of European ancestry. There is a lack of studies leveraging the genetic architecture of Black or African American (AA) populations for the identification of loci involved in EoE susceptibility. Herein, we present admixture mapping (AM) and genome-wide association analysis (GWAS) of EoE using the participants of AA populations.We conducted AM and GWAS of EoE using 137 EoE cases and 1465 healthy controls from AA population. Samples were genotyped using the Multi-Ethnic Genotyping Array (MEGA). Genotype imputation was carried out with the CAAPA reference panel using the Michigan Imputation Server. Global and local ancestry inference was carried out using RFMix v2, followed by fine-mapping analysis based on imputed genotypes, and RNAseq analysis. After standard quality control filtering, over 6,000,000 variants were tested by logistic regression adjusted for sex, age, and global ancestry.Global African ancestry proportion was found to be significantly lower among cases than controls (0.751 vs. 0.786, p-value = 0.012). Case-only AM identified four significant loci (9p13.3, 12q24.22-23, and 15q11.2) associated with EoE, two of which (12q24.22-23 and 9p13.3) were further replicated in the case-control analysis. At the two loci (12q24.23 and 9p13.3), the associations were observed for excess African ancestry. Fine mapping and multi-omic functional annotations prioritized the variants rs11068264 (FBXW8) and rs7307331 (VSIG10) at 12q24.23 and rs2297879 (ARHGEF39) at 9p13.3. GWAS identified one genome-wide significant locus at chromosome 1p22.3 (rs17131726, p-value = 2.39e-27, DDAH1) and 10 other suggestive loci including FAM179A (rs145050353), SCAND3 (rs56100858), TBC1D13 (rs114834583), MT2 (rs34800257) and PCSK2 (rs75293413) associated with EoE at p-value1×10We have identified an African ancestry specific genetic susceptibility locus DDAH1 at 1p22.3, 1p22.3, 9p13.3, and 12q24.23, through GWAS and admixture mapping for EoE in AA, providing evidence of ancestral specific inheritance of EoE. These findings highlight the need of independent genetic studies of different ancestries for EoE.

Recent advances in rare disease research are accelerated by the work of consortia that have been supported by the National Institutes of Health. Development of such consortia rely on multidisciplinary relationships and engagement with patient advocacy groups, as well as the National Institutes of Health and industry and academic partners. In this rostrum we present the development of such a process that focuses on eosinophilic gastrointestinal diseases. Principal investigators, patient advocacy groups, research assistants, and trainees work together to perform natural history studies that promote clinical trial readiness tools, conduct clinical trials, train a new generation of investigators, and perform innovative pilot studies.

The US Food and Drug Administration hosted a workshop on July 21, 2021, to discuss the disease characteristics, natural history, and end points to assess treatment benefit in patients with eosinophilic gastrointestinal disorders (EGIDs) beyond eosinophilic esophagitis (EoE). Notably, EGIDs beyond EoE, such as eosinophilic gastritis, eosinophilic enteritis, and eosinophilic colitis, herein referred to as non-EoE EGIDs, are understudied relative to EoE. This workshop provided a forum for open discussion among stakeholders-medical professionals (including their societies and research groups), Food and Drug Administration representatives, an industry representative, and a patient representative-to facilitate drug development. Experts in many disciplines related to EGIDs, including allergy, immunology, epidemiology, gastroenterology, and pathology, and both adult and pediatric clinicians contributed. Herein, we discuss some of the insights of the material presented at the meeting and present perspectives on moving the field forward toward drug approval.

Background and Aims: Endoscopic outcomes have become important measures of eosinophilic esophagitis (EoE) disease activity, including as an endpoint in randomized controlled trials (RCTs). We evaluated the operating properties of endoscopic measures for use in EoE RCTs. Methods: Modified Research and Development/University of California Los Angeles appropriateness methods and a panel of 15 international EoE experts identified endoscopic items and definitions with face validity that were used in a 2-round voting process to define simplified (all items graded as absent or present) and expanded versions (additional grades for edema, furrows, and/or exudates) of the EoE Endoscopic Reference Score (EREFS). Inter- and intrarater reliability of these instruments (expressed as intraclass correlation coefficients [ICC]) were evaluated using paired endoscopy video assessments of 2 blinded central readers in patients before and after 8 weeks of proton pump inhibitors, swallowed topical corticosteroids, or dietary elimination. Responsiveness was measured using the standardized effect size (SES). Results: The appropriateness of 41 statements relevant to EoE endoscopic activity (endoscopic items, item definitions and grading, and other considerations relevant for endoscopy) was considered. The original and expanded EREFS demonstrated moderate-to-substantial inter-rater reliability (ICCs of.472-.736 and.469-.763, respectively) and moderate-to-almost perfect intrarater reliability (ICCs of.580-.828 and.581-.828, respectively). Strictures were least reliably assessed (ICC,.072-.385). The original EREFS was highly responsive (SES, 1.126 [95% confidence interval {CI},.757-1.534]), although both expanded versions of EREFS, scored based on worst affected area, were numerically most responsive to treatment (expanded furrows: SES, 1.229 [95% CI,.858-1.643]; all items expanded: SES, 1.252 [95% CI,.880-1.667]). The EREFS and its modifications were not more reliably scored by segment and also not more responsive when proximal and distal EREFSs were summed. Conclusions: EREFS and its modifications were reliable and responsive, and the original or expanded versions of the EREFS may be preferred in RCTs. Disease activity scored based on the worst affected area optimizes reliability and responsiveness.

The ongoing shortage of organs for transplant combined with Manitoba having the highest prevalence of end-stage renal disease (ESRD) in Canada has resulted in long wait times on the deceased donor waitlist. Therefore, the Transplant Manitoba Adult Kidney Program has ongoing quality improvement initiatives to expand the deceased donor pool. This clinical transplant protocol describes the use of prophylactic pan-genotypic direct-acting anti-viral agents (DAA) for transplanting hepatitis C (HCV)-viremic kidneys (HCV antibody positive/nucleic acid [nucleic acid amplification testing, NAT] positive) to HCV-naïve recipients as routine standard of care. We will evaluate the provincial implementation of this protocol as a prospective observational cohort study.Scoping literature review and key stakeholder engagement with interdisciplinary health care providers and health system leaders/decision markers.Patients will be screened pre-transplant for eligibility and undergo a multilevel education and consent process to participate in this expanded donor program. Incident adult HCV-naïve recipients of an HCV-viremic kidney transplant will be treated prophylactically with glecaprevir-pibrentasvir with the first dose administered on call to the operation. Glecaprevir-pibrentasvir will be used for 8 weeks with viral monitoring and hepatology follow-up. Primary outcomes are sustained virologic response (SVR) at 12 weeks and the tolerability of DAA therapy. Secondary outcomes within the first year post-transplant are patient and graft survival, graft function, biopsy-proven rejection, HCV transmission to recipient (HCV NAT positive), and HCV nonstructural protein 5A (NS5A) resistance. Safety outcomes within the first year post-transplant include fibrosing cholestatic hepatitis, acute liver failure, primary and secondary DAA treatment failure, HCV transmission to a recipient's partner, elevated liver enzymes ≥2-fold, abnormal international normalized ratio (INR), angioedema, anaphylaxis, cirrhosis, and hepatocellular carcinoma.This program successfully advocated for and obtained hospital formulary, provincial Exceptional Drug Status (EDS), and Non-Insured Health Benefits (NIHB) to provide prophylactic DAA therapy for this indication, and this information may be useful to other provincial transplant organizations seeking to establish an HCV-viremic kidney transplant program with prophylactic DAA drug coverage.(1) Patient engagement was not undertaken during the program design phase, but patient-reported experience measures will be obtained for continuous quality improvement. (2) Only standard criteria donors (optimal kidney donor profile index [KDPI] ≤60) will be used. If this approach is safe and feasible, then higher KDPI donors may be included.The goal of this quality improvement project is to improve access to kidney transplantation for Manitobans. This program will provide prophylactic DAA therapy for HCV-viremic kidney transplant to HCV-naïve recipients as routine standard of care outside a clinical trial protocol. We anticipate this program will be a safe and effective way to expand kidney transplantation from a previously unutilized donor pool.La pénurie actuelle d’organes à transplanter, combinée au fait que le Manitoba est la province qui présente la plus forte prévalence d’insuffisance rénale terminale au Canada, entraîne de longs délais sur la liste d’attente d’un organe provenant d’un donneur décédé. Le programme de transplantation rénale pour les adultes du Manitoba (Transplant Manitoba Adult Kidney Program) a mis en place des initiatives d’amélioration continue de la qualité afin d’élargir le bassin de donneurs décédés. Ce protocole clinique de transplantation décrit l’emploi, comme traitement habituel, d’agents antiviraux directs (AAD) pan-génotypiques prophylactiques pour la transplantation de reins provenant de donneurs infectés par le virus de l’hépatite C (VHC) (individus positifs pour les anticorps VHC et acides nucléiques [NAT]) à des receveurs naïfs pour VHC. La mise en œuvre provinciale de ce protocole sera évaluée en tant qu’étude de cohorte prospective et observationnelle.Examen de la documentation et évaluation de l’engagement des principaux intervenants avec les fournisseurs de soins de santé interdisciplinaires et les dirigeants/décideurs du système de santé.L’admissibilité au programme sera évaluée avant la greffe. Pour participer à ce programme élargi de donneurs, les patients devront se soumettre à un processus d’information et de consentement à plusieurs niveaux. Les adultes incidents naïfs pour VHC devant recevoir un rein virémique-VHC seront traités de façon prophylactique par glécaprévir+pibrentasvir; la première dose administrée au moment de l’appel pour l’opération. Le traitement par glécaprévir+pibrentasvir sera administré pendant 8 semaines avec surveillance virale et suivi hépatologique. Les principaux résultats évalués seront une réponse virologique prolongée (RVP) à 12 semaines et la tolérance au traitement par AAD. Les résultats secondaires mesurés dans la première année suivant la greffe seront la survie du patient et du greffon; la fonction du greffon; le rejet avéré par biopsie; la transmission du VHC au receveur (positif pour VHC et NAT) et la résistance aux protéines non structurelles 5A (NS5A) du VHC. Les résultats relatifs à l’innocuité dans la première année suivant la greffe comprennent la cholestase hépatique fibrosante; l’insuffisance hépatique aiguë; l’échec primaire et secondaire du traitement par AAD; la transmission du VHC au partenaire d’un receveur; une élévation supérieure à 2 fois du taux d’enzymes hépatiques; un INR anormal; un angio-œdème; l’anaphylaxie; une cirrhose ou un carcinome hépatocellulaire.Le programme a recommandé et obtenu l’inscription du traitement prophylactique par AAD sur la liste de médicaments des hôpitaux pour cette indication, en plus du statut de médicament d’exception provincial et de son ajout au Programme des services de santé non assurés (SSNA). Ces renseignements pourraient être utiles à d’autres organismes provinciaux de transplantation qui cherchent à mettre en œuvre un programme de transplantation rénale virémique-VHC avec un traitement prophylactique par AAD.(1) La participation des patients n’a pas été entreprise pendant la phase de conception du programme, mais des mesures de l’expérience des patients seront obtenues pour l’amélioration continue de la qualité. (2) Seuls les donneurs satisfaisant aux critères standards (Kidney Donor Profile Index [KDPI] ≤ 60) seront inclus. Si cette approche est sécuritaire et faisable, des donneurs de KDPI plus élevés pourront être inclus.L’objectif de ce projet d’amélioration de la qualité est d’améliorer l’accès aux transplantations rénales pour les Manitobains. Ce programme offrira un traitement prophylactique aux AAD pour les greffes de reins virémiques-VHC à des receveurs naïfs pour VHC comme traitement de référence habituel en dehors d’un protocole d’essai clinique. Nous pensons que ce programme sera un moyen sûr et efficace d’étendre la transplantation rénale à partir d’un bassin de donneurs auparavant non utilisés.

Beta oscillations (~13-30 Hz) recorded from the sensorimotor cortex have canonical amplitude changes during movement. Specifically, a movement-related beta decrease (MRBD) occurs before movement, and a post-movement beta rebound (PMBR) follows. We investigated how the MRBD and PMBR vary with movement speed. Individuals performed a task with blocks that generated longer reaction times (RTs) and shorter RTs (Slow and Fast blocks, respectively) while scalp-electroencephalography (EEG) was recorded. The timing of task events before movement was also modulated to generate blocks with certain and uncertain timing (Fixed and Varied blocks, respectively). Beta modulation was reduced in Slow blocks compared to Fast blocks (i.e., a less negative MRBD and less positive PMBR). For the movement certainty manipulation, we saw mixed behavioral and EEG results. Our primary findings align with previous work which has shown reduced movement-related beta modulation in patients with Parkinson’s disease. We propose that a “slowed movement state”, whether it is experimentally induced or a manifestation of Parkinson’s disease bradykinesia, is represented through reduced beta dynamics. Altogether, the MRBD and PMBR may represent motor speed on a continuum with Parkinson’s disease as an extreme example of slowed movement.

Introduction Pneumocystis jirovecii pneumonia (PJP) is a significant cause of morbidity and mortality in transplant patients yet little is known about their adherence to prophylaxis. The goal of this study was to evaluate patient uptake and long-term adherence after implementing universal, lifelong PJP prophylaxis. Materials and methods This retrospective cohort study evaluated an adult kidney transplant program 18-months after initiating trimethoprim-sulfamethoxazole (TMP-SMX) 80/400 mg thrice-weekly following a cluster of PJP cases. The protocol incorporated multi-modal patient education and drug tolerability strategies to improve adherence, including a modified re-challenge strategy for TMP-SMX intolerance. Adherence was independently confirmed by the transplant pharmacist and nurse for each patient, with an a priori target ≥ 75% population on prophylaxis. Results Initial uptake was high with 237/250 (94.8%) patients starting prophylaxis. Long-term maintenance was high with 192/237 (81.0%) patients remaining on prophylaxis at 18-months. Of the remaining 45 patients who initiated prophylaxis, 36/237 (15.2%) were non-adherent and 9/237 (3.8%) discontinued prophylaxis by 18-months. Reasons for non-adherence included gastrointestinal upset, fear of drug reactions and cost; but the majority of reasons were not delineated by the patients (31/36, 86.1%). There was a statistically significant increase in serum creatinine 3.3 µmol/L (0.3-6.3 µmol/L 95% CI) and potassium 0.08 mmol/L (0.03-0.15 mmol/L 95% CI) in those prescribed TMP-SMX with only 3/237 (1.3%) patients discontinuing TMP-SMX for an increase in creatinine. Conclusion High rates of patient uptake (94.8%) and long-term adherence (81.0%) were observed after implementing universal lifelong PJP prophylaxis. This may be due in part to the in-depth patient education and drug tolerability strategies employed.

Value in healthcare must focus on accessibility, quality, and affordability. This article describes how a healthcare team provides value by meeting the needs of a rare disease patient and underscores the importance of a chronic multiorgan rare disease home. A nurse practitioner can ensure that barriers to evaluation are removed and communication is prioritized in order to provide accessible and affordable care to a patient with rare disease without jeopardizing quality of care.

Eosinophilic esophagitis is an adaptive immune response to patient-specific antigens, mostly foods. Eosinophilic esophagitis is not solely IgE-mediated and is likely characterized by Th2 lymphocytes with an impaired esophageal barrier function. The key cytokines and chemokines are thymic stromal lymphopoeitin, interleukin-13, CCL26/eotaxin-3, and transforming growth factor-β, all involved in eosinophil recruitment and remodeling. Chronic food dysphagia and food impactions, the feared late complications, are related in part to dense subepithelial fibrosis, likely induced by interleukin-13 and transforming growth factor-β.

In systemic sclerosis (SSc) the most common gastrointestinal tract (GIT) complaint is gastroesophageal reflux disease (GERD), which may contribute to oesophagitis, stricture, Barrett's oesophagus, and oesophageal adenocarcinoma. We used a genealogical resource the Utah Population Database (UPDB) to analyse SSc pedigrees for hereditability of oesophageal disease.SSc, GERD, oesophagitis, stricture, Barrett's, and oesophageal adenocarcinoma were defined by ICD Ninth and Tenth Revision codes. Familial aggregation, relative risk (RR) of the GIT disease in SSc proband and their relatives was estimated by Cox regression model. The model (adjusted for sex and birth year) was used to evaluate the effects of having or being related to, a case or control for SSc, on GIT diseases.We identified 2,227 unique SSc patients and 11,136 randomly selected controls matched by birth year, gender, and whether born in Utah, in an approximately 1:5 ratio. A SSc proband had a significant high risk of GERD (RR: 3.28), dysphagia (RR 5.58), oesophageal stricture (RR: 5.16), oesophagitis (RR: 4.86), and Barrett's (RR: 4.52) all with significant p-values2e-16. First-degree relatives of a SSc proband were at elevated risk of GERD (RR: 1.14, p=6.85e-05), dysphagia (RR: 1.22 p=0.002), and oesophagitis (RR: 1.37, p=2.10e-06). First cousins (RR: 1.09, p=0.03) and spouses (RR; 1.37, p=0.02) were at increased risk of esophagitis and dysphagia.These data suggest that independent of GERD, oesophagitis in SSc patients and their relatives may have both a hereditable and environmental etiology. There does not seem to be a heritable component to Barrett's oesophagus.

BACKGROUND & AIMS: Pharmacologic treatment of eosinophilic esophagitis (EoE) is limited to off-label use of corticosteroids not optimized for esophageal delivery. We performed a randomized, controlled phase 2 trial to assess the ability of budesonide oral suspension (BOS), a novel muco-adherent topical steroid formulation, to reduce symptoms and esophageal eosinophilia in adolescents and adults with EoE. METHODS: In this multicenter, randomized, double-blind, placebo-controlled, parallel-group trial, 93 EoE patients between the ages of 11 and 40 years with dysphagia and active esophageal eosinophilia were randomized to receive either BOS 2 mg or placebo twice daily for 12 weeks. Co-primary outcomes were change in Dysphagia Symptom Questionnaire (DSQ) score from baseline, and proportion of patients with a histologic response (≤6 eosinophils/high-power field) after treatment. Endoscopic severity scores and safety parameters were assessed. RESULTS: At baseline, mean DSQ scores were 29.3 and 29.0, and mean peak eosinophil counts were 156 and 130 per hpf in the BOS and placebo groups, respectively. After treatment, DSQ scores were 15.0 and 21.5, and mean peak eosinophil counts were 39 and 113 per high-power field, respectively (P < .05 for all). For BOS vs placebo, change in DSQ score was -14.3 vs -7.5 (P = .0096), histologic response rates were 39% vs 3% (P < .0001), and change in endoscopic severity score was -3.8 vs 0.4 (P < .0001). Adverse events were similar between groups. CONCLUSIONS: Treatment with BOS was well tolerated in adolescent and young adult patients with EoE and resulted in improvement in symptomatic, endoscopic, and histologic parameters using validated outcome instruments. ClinicalTrials.gov ID NCT01642212.

Eosinophilic esophagitis (EoE) is an esophageal disease characterized by dysphagia and food impaction triggered by food or drug hypersensitivity with a prevalence of ~1/1,000 people. A conclusive diagnosis of EoE requires endoscopy and multiple biopsies, followed by eosinophil counts in multiple high-power fields. This procedure is painful and expensive, and due to the focal nature of the lesions, misdiagnoses are possible if biopsies do not sample enough diseased tissue. RNA sequencing allows the entire transcriptome within a biological sample to be assayed, but due to the vastness of the data, bioinformatics tools are required for meaningful interpretation. We have trained different machine learning classification algorithms and characterized their performance. We show that accurate classification is generalizable to biopsies that were not controlled for depth and were sequenced using different protocols and machines. Furthermore, we assess whether EoE status can be predicted using buccal epithelial tissue biopsies, which can be collected non-invasively but lack histological change. Together, these results show that machine-learning algorithms based on RNA-seq data could enable more accurate diagnosis of EoE using less invasive and lower-cost biopsy protocols.

To determine the relative risk of having eosinophilic esophagitis (EoE) coexist with chronic rhinosinusitis (CRS) in probands and their families using the Utah Population Database (UPDB).This retrospective observational cohort study with population-based matched controls utilized the UPDB, a genealogical database linked to medical records. It was used to identify CRS and EoE patients diagnosed at any age between 2008 and 2012. The familial risks of an EoE diagnosis (International Classification of Diseases, Ninth Revision, Clinical Modification code 530.13) in CRS probands, and vice versa, and their first- through fifth-degree relatives and spouses were calculated using logistic regression models in comparison to controls randomly selected from the Utah population and individually matched 6:1 on sex and birth year.Probands with CRS demonstrated a 3.4-fold increased risk of having EoE themselves (P10(-15) ). First-degree relatives (parents, siblings, and children) of CRS probands had a 1.5-fold increased risk of having EoE (P10(-4) ), whereas more distant relatives did not show a significant increased risk. Spouses of probands had a 1.4-fold increased risk of having EoE (P = 0.055). Conversely, risk estimates of having CRS in EoE probands were consistent.We observed an increased risk of comorbid EoE in patients with CRS and their families. An association between CRS and EoE as comorbid conditions suggests that a familial component is contributing to the etiology of both diseases. Further analyses regarding the pathophysiology of the development of CRS in these specific patients will lead to a better understanding of both disease processes and may help target therapy.3b. Laryngoscope, 126:1279-1283, 2016.

International usability testing presents unique challenges for planning and conducting labs. Many factors that affect the design and execution of an international study — factors such as travel requirements, participant recruiting, test plan and interface localization, translation, and legal agreements — make the challenges seem insurmountable. However, increasing preparation time, using local resources, and utilizing remote user testing tools will significantly reduce costs and barriers to success.

Objective: To compare endometrial cancer treatment strategies and outcomes across the province of Ontario, Canada. Methods: A retrospective cohort study was conducted of 195 women diagnosed with endometrial cancer in Ontario between 1996 and 1998, as a sample of the population. The women's charts were randomly selected by the medical records departments at 5 tertiary care centres in Ontario. The outcomes measured included 5-year overall survival (OS) and disease-free survival (DFS), use of adjuvant radiotherapy, treatment complications, and prognostic factors for survival. Results: The 2 main treatment strategies were (1) total abdominal hysterectomy and bilateral salpingo-oophorectomy (TAH BSO) and (2) surgical staging (defined as TAH BSO and pelvic lymph node dissection with or without cytology, peritoneal biopsies, and omentectomy). Surgical staging rates across the province ranged from 0% to 88%. Stratified survival analysis revealed a significant difference in OS among centres (log rank P = .039). Crude survival analysis revealed no difference in 5-year OS or DFS between the 2 treatment strategies. The Cox proportional hazards model identified advanced stage of tumour as being the most predictive factor of DFS, and the woman's age at diagnosis and tumour grade as predictive of OS. Discussion: There was a significant difference in 5-year OS among the 5 tertiary care centres. There was no significant difference between surgical staging and TAH BSO with respect to 5-year DFS or OS. Conclusion: As there were significant differences in the treatment of endometrial carcinoma and OS across the province, a population-based study of endometrial cancer treatment strategies and outcomes is required.

Background: Human sexual classical conditioning effects are less robust compared with those obtained in other animals. The artificiality of the laboratory environment and/or the unconditioned stimulus (US) used (e.g. watching erotic film clips as opposed to participating in sexual activity) may contribute to this discrepancy. The present experiment used a field study design to explore the conditioning of human sexual arousal. Method: Seven heterosexual couples were instructed to include a novel, neutrally preferred scent as the conditioned stimulus (CS+) during sexual interaction and another novel scent during non-sexual coupledinteraction (e.g. watching a movie, studying together). Seven control couples used both scents during nonsexual interaction. Conducted over a 2-week period, both experimental and control couples had three sexual interactions (oral sex and/or intercourse). In addition, experimental couples had three, while the controls had six, non-sexual interactions. Genital responding to and affective preference for the odors were assessed in the laboratory before and after the experience in the men. Results: We observed significantly increased genital responding to the CS+in the experimental relative to the control group; however, conditioned responses were not much stronger than those obtained during laboratory conditioning. Experimental males also showed a trend for decreased preference for the CS-odor. They may have learned that this odor predicted that sexual interaction with their partner would not occur. Conclusion: The present study provides another demonstration of conditioned sexual arousal in men, specifically an instance of such learning that happened in a real-world setting. It also suggests that inhibitory learning may occur, at least with the affective measure. Keywords: sexual classical conditioning; humans; evaluative conditioning (Published: 15 March 2012) Citation: Socioaffective Neuroscience & Psychology 2012, 2 : 17336 - DOI: 10.3402/snp.v2i0.17336

Teacher evaluation is a serious responsibility, say these writers, who offer some guidelines to follow when developing an evalu ation system.

Decisiveness is one of several skills considered necessary for effective administration. Some have described it as the key to the administrative process. The authors explore its characteristics here with the hope that readers may understand the concept more as a behavior than a trait.