A validated regulatory network for Th17 cell specification.

Th17 cells have critical roles in mucosal defense and are major contributors to inflammatory disease. Their differentiation requires the nuclear hormone receptor RORγt working with multiple other essential transcription factors (TFs). We have used an iterative systems approach, combining genome-wide TF occupancy, expression profiling of TF mutants, and expression time series to delineate the Th17 global transcriptional regulatory network. We find that cooperatively bound BATF and IRF4 contribute to initial chromatin accessibility and, with STAT3, initiate a transcriptional program that is then globally tuned by the lineage-specifying TF RORγt, which plays a focal deterministic role at key loci. Integration of multiple data sets allowed inference of an accurate predictive model that we computationally and experimentally validated, identifying multiple new Th17 regulators, including Fosl2, a key determinant of cellular plasticity. This interconnected network can be used to investigate new therapeutic approaches to manipulate Th17 functions in the setting of inflammatory disease.

Development and Validation of a Tool for Assessing Adherence to Gluten-Free Diet in Patients With Celiac Disease.

INTRODUCTION: Life-long adherence to gluten-free diet (GFD) and its assessment is essential for patients with celiac disease (CeD). We have developed and validated a tool for assessing adherence to GFD which can be used by both physicians and dietitians. METHODS: Phase 1: Development, content validation, and assessment of reliability of tool. Phase 2: Validation of tool against standard dietary evaluation (SDE) (gold standard), immunoglobulin A - anti-tissue transglutaminase antibodies (IgA anti-tTG Ab), and gluten immunogenic peptides in urine. Overall, 380 biopsy-confirmed patients with CeD (derivation cohort: n = 100 [phase 1], n = 210 [phase 2] and independent validation cohort, n = 70) were recruited. RESULTS: Of an initial 90-point questionnaire, 84 items (Celiac Disease: Compliance Assessment Test [CD-CAT.v1]) were retained after content validation and pilot testing. In phase 1, upon administering CD-CAT.v1 on 100 patients, a comprehensive 35-item tool (CD-CAT.v2; α = 0.86) was obtained after removing items with low test-retest reliability and item-rest correlation values. In phase 2, upon administering CD-CAT.v2 on 210 patients, 22 items were removed having low correlation values (R < 0.4) with SDE. Finally, a 13-item tool (CD-CAT.v3; α = 0.84) was obtained with high criterion validity with SDE ( r = 0.806, P < 0.001), moderate convergent validity with celiac disease adherence test ( r = 0.602, P = 0.007), and moderate to weak correlation with urine gluten immunogenic peptides ( r = 0.46, P = 0.001) and IgA anti-tTG Ab ( r = 0.39, P = 0.008), respectively. The final 13-item tool also strongly correlated with SDE ( r = 0.78, P < 0.001) in an independent validation cohort of 70 patients with CeD. Principal component analysis identified 3 relevant subscales with a cumulative variance of 62%. The sensitivity and specificity of CD-CAT.v3 were 80% and 91%, respectively, with an area under curve of 0.905 with SDE. The obtained cutoff score of <19 from the receiver operating characteristic curve was further categorized as 13 = excellent, 14-18 = very good, 19-28 = average, and >28 = poor adherence to GFD. DISCUSSION: CD-CAT is a new and rapid tool for monitoring dietary adherence to GFD with high sensitivity and specificity, which can be administered by both physicians and dietitians.

Patients with Celiac Disease Have High Prevalence of Fatty Liver and Metabolic Syndrome.

OBJECTIVE: In recent years, patients with celiac disease (CeD) have been reported to have a high prevalence of fatty liver and metabolic syndrome. We conducted a systematic review and meta-analysis to assess the prevalence of fatty liver and metabolic syndrome in patients with CeD and effect of gluten-free diet in them. METHODS: The PubMed, Embase and the Cochrane Library databases were searched for original studies upto November 18, 2022. We included full-text articles published in the English language after 1990 that used well-defined criteria for CeD, fatty liver and metabolic syndrome. A random effects model was used to calculate pooled prevalence. RESULTS: Of 350 studies identified, 11 studies (n = 2578) were included in the analysis. On analysis of both cross-sectional and longitudinal studies, pooled prevalence of fatty liver and metabolic syndrome in treatment-naïve patients with CeD were 18.2% (95% CI 8.3-30.8%, n = 1237) and 4.3% (95% CI 2.4-6.7, n = 1239) and in those on GFD of varying duration was 28.2% (95% CI 20.7-36.4%, n = 1368) and 21.3% (95% CI 11.7-32.9%, n = 2193), respectively. There was no difference in the prevalence of fatty liver and metabolic syndrome between low- or high-income group countries. CONCLUSIONS: Patients with CeD have a high prevalence of fatty liver and metabolic syndrome which increases further with the initiation of GFD. Patients with CeD should thus be screened and monitored for development of fatty liver and metabolic syndrome. They should be counselled appropriately regarding their diet and inclusion of physical activity in their lifestyle.

Pan-Gastrointestinal Tract Mucosal Pathologies in Patients with Celiac Disease with the Demonstration of IgA Anti-Transglutaminase Mucosal Deposits: A Case-Control Study.

BACKGROUND: While celiac disease (CeD) is considered to affect primarily the small intestine, pathological changes in other parts of the gastrointestinal tract (GIT) are also known to occur. IgA anti-tissue transglutaminase-2 antibody (anti-TG2 Ab) deposits at the site of involvement is one of the methods to establish CeD-related tissue pathology. AIMS: To explore the utility of IgA anti-TG2 Ab deposits in pan-gastrointestinal mucosal biopsies as evidence of CeD-related pathologies. METHODS: Forty-two treatment-naive patients with CeD and 45 patients with irritable bowel syndrome were included as cases and controls, respectively. Mucosal biopsies were collected from the esophagus, stomach, duodenum, and rectosigmoid regions at baseline from cases and controls, and additionally after 6-months of gluten-free diet in cases. All biopsies were evaluated for histological changes and subjected to dual-color immunohistochemical staining for identifying IgA anti-TG2 Ab deposits. RESULTS: Significantly higher number of patients with CeD had lymphocytic esophagitis (9.7% vs. 0%, P = 0.05), lymphocytic gastritis (35% vs. 8.8%, P < 0.01) and lymphocytic colitis (17.4% vs. 0%, P < 0.05) than that in controls. IgA anti-TG2 Ab deposits were observed in significantly more numbers in esophagus (30.9% vs. 6%, P < 0.001), stomach (62.2% vs. 9.3%, P < 0.01), duodenum (88.5% vs. 0%, P < 0.001) and rectum (17.4% vs. 0%, P < 0.05) than that in controls. There was a decline, but not statistically significant, in severity of lymphocytosis and intensity of IgA anti-TG2 Ab deposits in follow-up biopsies. CONCLUSION: Significantly higher number of patients with CeD had evidence of lymphocytic infiltration and IgA anti-TG2 deposits along GIT suggesting that CeD affects other parts of GIT.

Mortality audit of COVID-19 infection among children.

Background & objectives: As severe COVID-19 and mortality are not common in children, there is a scarcity of data regarding the cause of mortality in children infected with SARS-CoV-2. This study was aimed to describe the all-cause mortality and COVID-19 death (disease-specific mortality) in children with SARS-CoV-2 infection admitted to a paediatric COVID facility in a tertiary care centre. Methods: Data with respect to clinical, epidemiological profile and causes of death in non-survivors (0-12 yr old) of SARS-CoV-2 infection admitted to a dedicated tertiary care COVID hospital in north India between April 2020 and June 2021 were retrieved and analyzed retrospectively. Results: A total of 475 SARS-CoV-2-positive children were admitted during the study period, of whom 47 died [18 neonates, 14 post-neonatal infants and 15 children (1-12 yr of age)]. The all-cause mortality and COVID-19 death (disease-specific mortality) were 9.9 per cent (47 of 475) and 1.9 per cent (9 of 475), respectively. Underlying comorbidities were present in 35 (74.5%) children, the most common being prematurity and perinatal complications (n=11, 24%) followed by congenital heart disease (n=6, 13%). The common causes of death included septic shock in 10 (21%), COVID pneumonia/severe acute respiratory distress syndrome in nine (19%), neonatal illnesses in eight (17%), primary central nervous system disease in seven (15%) and congenital heart disease with complication in six (13%) children. Interpretation & conclusions: Our results showed a high prevalence of underlying comorbidities and a low COVID-19 death (disease-specific mortality). Our findings highlight that mortality due to COVID-19 can be overestimated if COVID-19 death and all-cause mortality in children infected with SARS-CoV-2 are not separated. Standardized recording of cause of death in children with SARS-CoV-2 infection is important.

Pulmonary embolism and gastric bleed with disseminated mucormycosis - treading dangerous waters.

Mucormycosis is an opportunistic infection seen in immunocompromised patients or in surgical and trauma settings with Mucorales wound contamination. In immunocompetent people, disseminated mucormycosis is uncommon. To ensure survival, patients with mucormycosis require early diagnosis and aggressive treatment using a multi-modality approach. We present a case of disseminated mucormycosis in an immunocompetent patient who also had pulmonary embolism and gastrointestinal bleeding. A recent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, identified retrospectively by a positive IgM against SARS-CoV-2, was the only risk factor present. This report emphasizes the increased risk of mucormycosis and thromboembolic complications following a recent SARS-CoV-2 infection, as well as its successful treatment with medical therapy alone.

Combination chemotherapy versus temozolomide for patients with methylated MGMT (m-MGMT) glioblastoma: results of computational biological modeling to predict the magnitude of treatment benefit.

BACKGROUND: A randomized trial in glioblastoma patients with methylated-MGMT (m-MGMT) found an improvement in median survival of 16.7 months for combination therapy with temozolomide (TMZ) and lomustine, however the approach remains controversial and relatively under-utilized. Therefore, we sought to determine whether comprehensive genomic analysis can predict which patients would derive large, intermediate, or negligible benefits from the combination compared to single agent chemotherapy. METHODS: Comprehensive genomic information from 274 newly diagnosed patients with methylated-MGMT glioblastoma (GBM) was downloaded from TCGA. Mutation and copy number changes were input into a computational biologic model to create an avatar of disease behavior and the malignant phenotypes representing hallmark behavior of cancers. In silico responses to TMZ, lomustine, and combination treatment were biosimulated. Efficacy scores representing the effect of treatment for each treatment strategy were generated and compared to each other to ascertain the differential benefit in drug response. RESULTS: Differential benefits for each drug were identified, including strong, modest-intermediate, negligible, and deleterious (harmful) effects for subgroups of patients. Similarly, the benefits of combination therapy ranged from synergy, little or negligible benefit, and deleterious effects compared to single agent approaches. CONCLUSIONS: The benefit of combination chemotherapy is predicted to vary widely in the population. Biosimulation appears to be a useful tool to address the disease heterogeneity, drug response, and the relevance of particular clinical trials observations to individual patients. Biosimulation has potential to spare some patients the experience of over-treatment while identifying patients uniquely situated to benefit from combination treatment. Validation of this new artificial intelligence tool is needed.

Mobile phone ingestion requiring endoscopic retrieval.

A 24-year-old male was brought to our emergency with complaints of abdominal pain for two days. There was a history of foreign body ingestion five days earlier, details of which he refused to reveal. After investigation with abdominal X ray and ultrasound, the foreign body was detected to be a mobile phone containing a battery. Clinical evaluation revealed no signs of lithium toxicity due to battery leak. The patient underwent endoscopy for removal of the mobile phone. The case shows the importance of thorough investigation and prompt attempt at endoscopic removal in the event of ingestion of foreign bodies containing batteries.

Better Groundwork Can Avoid Troubled Waters: A Developing Country Perspective on Drowning.

OBJECTIVE: Drowning is a leading cause of unintentional injury-related death in low- and middle-income countries (LMICs). This study was undertaken to know the epidemiology, intensive care needs and predictors of outcome of children with drowning. METHODS: Records of children below 12 years admitted with drowning to the emergency room and/or paediatric intensive care unit (PICU) of a tertiary care hospital in North India were retrospectively analysed. 'Favourable outcome' was defined as normal neurological status at discharge (normal cognition and no motor deficits) and 'unfavourable outcome' as death or abnormal neurological status at discharge. Multivariable analysis was done for predictors of unfavourable outcome. RESULTS: Twenty-seven children were analyzed, 14 (51.8%) were boys. Median (IQR) age was 18 months (12-30). The median (IQR) duration of submersion was 4 min (3-9). Six children (22.2%) presented in pulseless arrest, and 7 (43.7%) had both hypoxaemia (saturation <94% on room air) and encephalopathy (GCS <13) at admission. Ten children (37%) were transferred to PICU; principal indications being hypoxic ischaemic encephalopathy (HIE) (n = 6) and ventilation (n = 4). One child died, four survived with sequalae. Predictors of unfavourable outcome on univariable analysis were hypoxaemia, or pulseless arrest at admission, HIE and need for mechanical ventilation; none of these could predict outcome on multivariable analysis. CONCLUSION: Hypoxaemia or pulseless arrest at admission, HIE and need for ventilation predict unfavourable outcome. Appropriate on-site resuscitation and early stabilization may improve outcome in children with drowning in LMIC.

API-ISG Consensus Guidelines for Management of Gastrooesophageal Reflux Disease.

Gastroesophageal reflux disease (GERD) is a common problem in the community. The Indian Society of Gastroenterology and Association of Physicians of India have developed this evidence-based practice guideline for management of GERD in adults. A modified Delphi process was used to develop this consensus containing 43 statements, which were generated by electronic voting iteration as well as face-to-face meeting, and review of the supporting literature primarily from India. These statements include 4 on epidemiology, 9 on clinical presentation, 11 on investigations, 18 on treatment (including medical, endoscopic, and surgical modalities), and one on complications of GERD. The statement was regarded as accepted when the proportion of those who voted either to accept completely or with minor reservation was 80% or higher. The prevalence of GERD in large population-based studies in India is approximately 10% and is probably increasing due to lifestyle changes and increase in obesity. The diagnosis of GERD in the community should be mainly based on presence of classical symptoms like heartburn and sour regurgitation, and empiric treatment with a proton pump inhibitor (PPI) or H2 receptor antagonist should be given. All PPIs in equipotent doses are similar in their efficacy in the management of symptoms. Patients in whom symptoms do not respond adequately to PPI are regarded as having PPIrefractory GERD. Invasive investigations should be limited to patients with alarm symptoms and those with refractory GERD.