Identifying a therapeutic window of opportunity for people living with primary sclerosing cholangitis: Embryology and the overlap of inflammatory bowel disease with immune mediated liver injury.

Primary sclerosing cholangitis (PSC) is a variably progressive, fibrosis-causing autoimmune disorder of the intra- and extra-hepatic bile ducts of unclear etiology. PSC is commonly (in 60-90% of cases) associated with an inflammatory bowel disease (IBD) like PSC-IBD, and less commonly with an autoimmune hepatitis (AIH) like PSC-AIH or AIH-overlap disorder. Hepatologists and Gastroenterologists often consider these combined conditions as distinctly different from the classical forms in isolation. Here, we review recent epidemiologic observations and highlight that PSC-IBD and PSC-AIH overlap appear to represent aspects of a common PSC clinico-pathological pathway and manifest in an age-of-presentation dependent manner. Particularly from the pediatric experience, we hypothesize that all cases of PSC likely originate from a complex "Early PSC"-"IBD"-"AIH" overlap in which PSC defines the uniquely and variably associated "AIH" and "IBD" components along an individualized lifetime continuum. We speculate that a distinctly unique, 'diverticular autoimmunity' against the embryonic cecal- and hepatic diverticulum derived tissues may be the origin of this combined syndrome, where "AIH" and "IBD" variably commence then variably fade while PSC progresses with age. Our hypothesis provides an explanation for the age-dependent variation in the presentation and progression of PSC. This is critical for the optimal targeting of studies into PSC etiopathogenesis and emphasizes the concept of a "developmental window of opportunity for therapeutic mitigation" in what is currently recognized as an irreversible disease process. The discovery of such a window would be critically important for the targeting of interventions, both administration of current therapies and therapeutic trial planning.

Immunotherapy withdrawal by step-down to mesalamine in pediatric patients with ulcerative colitis.

Objective: Parents and pediatric patients with ulcerative colitis (UC) who progressed to systemic immunotherapy are concerned about lifelong risks from such treatments. There is limited knowledge about withdrawal of such agents and step-down (SD) to enteral 5-aminosalicylic acid (mesalamine) before transitioning to adult care. Methods: We studied nine pediatric cases with moderate to severe UC who after a median of 2.18 years of clinical remission on systemic immunotherapy stepped down to oral mesalamine treatment. Results: Average follow-up time from SD was 3.49 years. Five patients (55.5%) had sustained remission (without any flare noted) after SD during follow-up. Sustained clinical remission was 88.9% (8/9) at 1 year, 87.5% (7/8) at 2 years, and 66.7% (4/6) at 3 years after SD. Out of those tested (one patient was not tested), 62.5% (5/8) had fecal calprotectin <50 µg/g. Four out of six patients examined (66.6%) had mucosal healing on post-SD colonoscopy. Conclusion: We propose that SD to mesalamine can be a reasonable therapeutic consideration for pediatric patients with UC before transitioning to adult gastroenterology care. Shared decision-making is important before such treatment changes.

Antecedents and components of burnout among Hungarian teachers in a cross-sectional study: Development of the Burnout Antecedents and Components Questionnaire.

BACKGROUND: Studies have focused more on the outcome than on the antecedents of burnout. We aimed to develop a new measurement tool for burnout, including the antecedents and different components drawing from theories of the developmental aspect of burnout. METHODS: In this cross-sectional study we tested the Burnout Antecedents and Components Questionnaire on a convenience sample of teachers (n = 618, 83.9 % women; mean age 44.52 years). We used confirmatory factor analyses to test our measurement model. We examined the concurrent validity with the Maslach Burnout Inventory. We also tested construct validity with depression, overcommitment, demographic characteristics and work-related factors. RESULTS: The confirmatory factor analyses supported our measurement model with seven primary factors (need to prove oneself, overload of tasks, neglecting one's needs, conflict between values, interpersonal conflicts, passivity, and emotional drain) and three second-order factors (excessive effort, conflict, and total depletion). The covariates in the Maslach Burnout Inventory showed that emotional exhaustion had a strong relationship with the first- and second-order factors. Overcommitment showed a stronger relationship with factors at the beginning whereas depression showed a stronger relationship with factors at the end of the process. Demographic characteristics and work-related factors did not show strong associations. CONCLUSIONS: The Burnout Antecedents and Components Questionnaire is a promising measurement tool with good convergent validity. Future research should further validate our questionnaire for burnout research, prevention, and screening. It adds a new dimension to the measurement of burnout. The approach involving the antecedents in measuring burnout among teachers can guide future research and tailored prevention programs.

Utility of Flow Cytometry of Bronchoalveolar Lavage in the Diagnosis of T and NK Cell Malignancies in Critically Ill Patients.

OBJECTIVE: The value of bronchoalveolar lavage (BAL) in the diagnosis of pulmonary diseases of diverse etiologies is widely accepted. Cytospin and cell-block preparations for cytomorphological (CM) evaluation and for immunohistochemical studies are the standard method to evaluate BAL, though it may be time-consuming. Flow cytometric (FC) evaluation, on the other hand, has a short turnaround time, and is a useful methodology to differentiate reactive processes from hematological neoplasms, or detect a small aberrant population in an inflammatory background. BAL specimens provide an excellent source for FC studies. CASE REPORTS: We describe two cases of critically ill patients with no history of hematolymphoid neoplasms, who presented with non-specific symptoms. Abnormal pulmonary imaging studies prompted bronchoscopic evaluation and collection of BAL during the initial evaluation. FC analysis of the BAL fluid aided to the early diagnosis of aggressive NK cell leukemia and adult T cell leukemia/lymphoma, respectively. CONCLUSIONS: Flow cytometric immunophenotyping in addition to the CM assessment increases the diagnostic value and provides timely diagnosis from BAL specimens, which is especially important for critically ill patients.

Natural unblinding of BCG vaccination trials.

There is significant public and clinical interest in the potential for Bacillus Calmette-Guérin (BCG) vaccination to protect against type 2 Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2) induced COVID-19. This question could be best answered by blinded and placebo controlled clinical trials. However, a skin reaction occurs within days at the site of BCG injection, making it rather challenging to blind this vaccination. Here, we examined registered clinical trials in ClinicalTrials.gov on BCG against COVID-19 by October 9th 2020, and found that 94.7% of such trials were listed as placebo controlled (all with normal saline as placebo), and single to quadruple blinded. The mode of overcoming the natural unblinding by the BCG induced skin reaction was not clarified on the website in either of the trials. We conclude that detailed description of the strategy towards overcoming the BCG vaccination induced skin reaction associated unblinding hurdle will be important for the interpretation of the theoretically blinded COVID-19 directed clinical trials.

BCG epidemiology supports its protection against COVID-19? A word of caution.

The COVID-19 pandemic, caused by type 2 Severe Acute Respiratory Syndrome Coronavirus (SARS-CoV-2), puts all of us to the test. Epidemiologic observations could critically aid the development of protective measures to combat this devastating viral outbreak. Recent observations, linked nation based universal Bacillus Calmette-Guerin (BCG) vaccination to potential protection against morbidity and mortality from SARS-CoV-2, and received much attention in public media. We wished to validate the findings by examining the country based association between COVID-19 mortality per million population, or daily rates of COVID-19 case fatality (i.e. Death Per Case/Days of the endemic [dpc/d]) and the presence of universal BCG vaccination before 1980, or the year of the establishment of universal BCG vaccination. These associations were examined in multiple regression modeling based on publicly available databases on both April 3rd and May 15th of 2020. COVID-19 deaths per million negatively associated with universal BCG vaccination in a country before 1980 based on May 15th data, but this was not true for COVID-19 dpc/d on either of days of inquiry. We also demonstrate possible arbitrary selection bias in such analyses. Consequently, caution should be exercised amidst the publication surge on COVID-19, due to political/economical-, arbitrary selection-, and fear/anxiety related biases, which may obscure scientific rigor. We argue that global COVID-19 epidemiologic data is unreliable and therefore should be critically scrutinized before using it as a nidus for subsequent hypothesis driven scientific discovery.

Clinicopathologic Features and Prognostic Impact of Lymph Node Involvement in Patients With Breast Implant-associated Anaplastic Large Cell Lymphoma.

Breast implant-associated anaplastic large cell lymphoma (BI-ALCL) is a rare T-cell lymphoma that arises around breast implants. Most patients manifest with periprosthetic effusion, whereas a subset of patients develops a tumor mass or lymph node involvement (LNI). The aim of this study is to describe the pathologic features of lymph nodes from patients with BI-ALCL and assess the prognostic impact of LNI. Clinical findings and histopathologic features of lymph nodes were assessed in 70 patients with BI-ALCL. LNI was defined by the histologic demonstration of ALCL in lymph nodes. Fourteen (20%) patients with BI-ALCL had LNI, all lymph nodes involved were regional, the most frequent were axillary (93%). The pattern of involvement was sinusoidal in 13 (92.9%) cases, often associated with perifollicular, interfollicular, and diffuse patterns. Two cases had Hodgkin-like patterns. The 5-year overall survival was 75% for patients with LNI and 97.9% for patients without LNI at presentation (P=0.003). Six of 49 (12.2%) of patients with tumor confined by the capsule had LNI, compared with LNI in 8/21 (38%) patients with tumor beyond the capsule. Most patients with LNI achieved complete remission after various therapeutic approaches. Two of 14 (14.3%) patients with LNI died of disease compared with 0/56 (0%) patients without LNI. Twenty percent of patients with BI-ALCL had LNI by lymphoma, most often in a sinusoidal pattern. We conclude that BI-ALCL beyond capsule is associated with a higher risk of LNI. Involvement of lymph nodes was associated with decreased overall survival. Misdiagnosis as Hodgkin lymphoma is a pitfall.

Burnout and depressive symptoms in teachers: Factor structure and construct validity of the Maslach Burnout inventory-educators survey among elementary and secondary school teachers in Hungary.

This study validated the Hungarian version of the Maslach Burnout Inventory-Educators Survey on a sample of n = 211 elementary and secondary teachers. To test factorial validity, we ran a series of confirmatory analysis with eight models. The best fitting model was the bifactor model with general burnout and three specific factors: emotional exhaustion, depersonalization, and personal accomplishment. Analyzing the covariates revealed that gender and age were not associated with burnout, but depressive symptoms and overcommitment had a significant relationship with general burnout, and overcommitment was related to emotional exhaustion as well.

Colonic Mucosal Epigenome and Microbiome Development in Children and Adolescents.

Epigenetic and microbiome changes during pediatric development have been implicated as important elements in the developmental origins of inflammatory bowel diseases (IBDs) including Crohn's disease (CD) and ulcerative colitis (UC), which are linked to early onset colorectal cancer (CRC). Colonic mucosal samples from 22 control children between 3.5 and 17.5 years of age were studied by Infinium HumanMethylation450 BeadChips and, in 10 cases, by 454 pyrosequencing of the bacterial 16S rRNA gene. Intercalating age-specific DNA methylation and microbiome changes were identified, which may have significant translational relevance in the developmental origins of IBD and CRC.

Lambda Immunoglobulin Light Chain Restricted B Cells in the Ascitic Fluid in Association with Terminal Ileal Florid Follicular Hyperplasia.

Distinguishing reactive changes from neoplastic processes during lymphoid tissue evaluation is oftentimes difficult. Ancillary studies, such as flow cytometry, may aid the diagnosis by demonstrating monotypic or polytypic light chain expression on the B cells. The detection of immunoglobulin light chain restricted B cell population is considered a surrogate marker of clonality, which can be confirmed by molecular assays. In general, the presence of a monotypic B cell population in the ascitic fluid is considered lymphomatous involvement rather than a reactive condition. We describe a young, previously healthy male patient who developed ascites with a lambda light chain restricted B cell population. Further investigation revealed florid follicular hyperplasia, histologically mimicking diffuse large B cell lymphoma, in the terminal ileum. Follicular hyperplasia in the gastrointestinal tract with lambda light chain restricted B cells has been recently described in the pediatric population. Importantly, our case demonstrates that such entity can occur in older age groups. This recognition could prevent misdiagnosis and unnecessary treatment in similar cases.

Transdermal Diagnosis of Malaria Using Vapor Nanobubbles.

A fast, precise, noninvasive, high-throughput, and simple approach for detecting malaria in humans and mosquitoes is not possible with current techniques that depend on blood sampling, reagents, facilities, tedious procedures, and trained personnel. We designed a device for rapid (20-second) noninvasive diagnosis of Plasmodium falciparum infection in a malaria patient without drawing blood or using any reagent. This method uses transdermal optical excitation and acoustic detection of vapor nanobubbles around intraparasite hemozoin. The same device also identified individual malaria parasite-infected Anopheles mosquitoes in a few seconds and can be realized as a low-cost universal tool for clinical and field diagnoses.

DNA methylation-associated colonic mucosal immune and defense responses in treatment-naïve pediatric ulcerative colitis.

Inflammatory bowel diseases (IBD) are emerging globally, indicating that environmental factors may be important in their pathogenesis. Colonic mucosal epigenetic changes, such as DNA methylation, can occur in response to the environment and have been implicated in IBD pathology. However, mucosal DNA methylation has not been examined in treatment-naïve patients. We studied DNA methylation in untreated, left sided colonic biopsy specimens using the Infinium HumanMethylation450 BeadChip array. We analyzed 22 control (C) patients, 15 untreated Crohn's disease (CD) patients, and 9 untreated ulcerative colitis (UC) patients from two cohorts. Samples obtained at the time of clinical remission from two of the treatment-naïve UC patients were also included into the analysis. UC-specific gene expression was interrogated in a subset of adjacent samples (5 C and 5 UC) using the Affymetrix GeneChip PrimeView Human Gene Expression Arrays. Only treatment-naïve UC separated from control. One-hundred-and-twenty genes with significant expression change in UC (> 2-fold, P<0.05) were associated with differentially methylated regions (DMRs). Epigenetically associated gene expression changes (including gene expression changes in the IFITM1, ITGB2, S100A9, SLPI, SAA1, and STAT3 genes) were linked to colonic mucosal immune and defense responses. These findings underscore the relationship between epigenetic changes and inflammation in pediatric treatment-naïve UC and may have potential etiologic, diagnostic, and therapeutic relevance for IBD.

Global self-esteem and method effects: competing factor structures, longitudinal invariance, and response styles in adolescents.

The Rosenberg Self-Esteem Scale (RSES) is a widely used measure for assessing self-esteem, but its factor structure is debated. Our goals were to compare 10 alternative models for the RSES and to quantify and predict the method effects. This sample involves two waves (N =2,513 9th-grade and 2,370 10th-grade students) from five waves of a school-based longitudinal study. The RSES was administered in each wave. The global self-esteem factor with two latent method factors yielded the best fit to the data. The global factor explained a large amount of the common variance (61% and 46%); however, a relatively large proportion of the common variance was attributed to the negative method factor (34 % and 41%), and a small proportion of the common variance was explained by the positive method factor (5% and 13%). We conceptualized the method effect as a response style and found that being a girl and having a higher number of depressive symptoms were associated with both low self-esteem and negative response style, as measured by the negative method factor. Our study supported the one global self-esteem construct and quantified the method effects in adolescents.