Nonalcoholic fatty liver disease risk and histologic severity are associated with genetic polymorphisms in children.

BACKGROUND AND AIMS: NAFLD is the most common chronic liver disease in children. Large pediatric studies identifying single nucleotide polymorphisms (SNPs) associated with risk and histologic severity of NAFLD are limited. Study aims included investigating SNPs associated with risk for NAFLD using family trios and association of candidate alleles with histologic severity. APPROACH AND RESULTS: Children with biopsy-confirmed NAFLD were enrolled from the NASH Clinical Research Network. The Expert Pathology Committee reviewed liver histology. Genotyping was conducted with allele-specific primers for 60 candidate SNPs. Parents were enrolled for trio analysis. To assess risk for NAFLD, the transmission disequilibrium test was conducted in trios. Among cases, regression analysis assessed associations with histologic severity. A total of 822 children with NAFLD had mean age 13.2 years (SD 2.7) and mean ALT 101 U/L (SD 90). PNPLA3 (rs738409) demonstrated the strongest risk ( p = 2.24 × 10 -14 ) for NAFLD. Among children with NAFLD, stratifying by PNPLA3 s738409 genotype, the variant genotype associated with steatosis ( p = 0.005), lobular ( p = 0.03) and portal inflammation ( p = 0.002). Steatosis grade associated with TM6SF2 ( p = 0.0009), GCKR ( p = 0.0032), PNPLA3 rs738409 ( p = 0.0053), and MTTP ( p = 0.0051). Fibrosis stage associated with PARVB rs6006473 ( p = 0.0001), NR1I2 ( p = 0.0021), ADIPOR2 ( p = 0.0038), and OXTR ( p = 0.0065). PNPLA3 rs738409 ( p = 0.0002) associated with borderline zone 1 NASH. CONCLUSIONS: This study demonstrated disease-associated SNPs in children with NAFLD. In particular, rs6006473 was highly associated with severity of fibrosis. These hypothesis-generating results support future mechanistic studies of development of adverse outcomes such as fibrosis and generation of therapeutic targets for NAFLD in children.

Prevalence of Elevated ALT in Adolescents in the US 2011-2018.

OBJECTIVE: The objective of this study is to characterize suspected nonalcoholic fatty liver disease (NAFLD) using elevated alanine aminotransferase (ALT) in a diverse and nationally representative cohort of adolescents and to characterize higher ALT elevation in adolescents with obesity. METHODS: Data from the National Health and Nutrition Examination Survey 2011-2018 were analyzed for adolescents 12-19 years. Participants with causes for elevated ALT other than NAFLD were excluded. Race and ethnicity, sex, body mass index (BMI), and ALT were examined. Elevated ALT was defined as >22 U/L (females) and >26 U/L (males) using the biologic upper normal limit (ULN). Elevated ALT thresholds up to 2X-ULN were examined among adolescents with obesity. Multivariable logistic regression was used to determine the association of race/ethnicity and elevated ALT, adjusting for age, sex, and BMI. RESULTS: Prevalence of elevated ALT in adolescents was 16.5% overall and 39.5% among those with obesity. For White, Hispanic, and Asian adolescents, prevalence was 15.8%, 21.8%, and 16.5% overall, 12.8%, 17.7%, and 27.0% in those with overweight, and 43.0%, 43.5%, and 43.1% in those with obesity, respectively. Prevalence was much lower in Black adolescents (10.7% overall, 8.4% for overweight, 20.7% for obesity). Prevalence of ALT at 2X-ULN was 6.6% in adolescents with obesity. Hispanic ethnicity, age, male sex, and higher BMI were independent predictors of elevated ALT. CONCLUSIONS: Prevalence of elevated ALT in U.S. adolescents is high, affecting 1 in 6 adolescents during 2011-2018. The risk is highest in Hispanic adolescents. Asian adolescents with elevated BMI may comprise an emerging risk group for elevated ALT.

An Open Label, Randomized, Multicenter Study of Elafibranor in Children With Nonalcoholic Steatohepatitis.

OBJECTIVES: Nonalcoholic fatty liver disease is the most common chronic liver disease in children. Elafibranor, a dual peroxisome proliferator-activated receptor α/δ agonist, has been proposed as a treatment for nonalcoholic steatohepatitis (NASH). The aims were to (1) describe pharmacokinetics (PK), safety, and tolerability of oral elafibranor at 2 doses (80 and 120 mg) in children 8-17 years and (2) assess changes in aminotransferases. METHODS: Children with NASH were randomized to open-label elafibranor 80 mg or 120 mg daily for 12 weeks. The intent-to-treat analysis included all participants who received at least 1 dose. Standard descriptive statistics and PK analyses were performed. RESULTS: Ten males [mean 15.1 years, standard deviation (SD) 2.2] with NASH were randomized to 80 mg (n = 5) or 120 mg (n = 5). Baseline mean alanine aminotransferase (ALT) was 82 U/L (SD 13) and 87 U/L (SD 20) for 80 mg and 120 mg groups, respectively. Elafibranor was rapidly absorbed and well tolerated. Elafibranor plasma exposure increased between the 80 mg and 120 mg dose with a 1.9- and 1.3-fold increase in median Cmax and AUC 0-24 , respectively. End of treatment mean ALT was 52 U/L (SD 20) for the 120 mg group, with a relative mean ALT change from baseline of -37.4% (SD 23.8%) at 12 weeks. CONCLUSIONS: Once daily dosing of elafibranor was well tolerated in children with NASH. There was a 37.4% relative reduction from mean baseline ALT in the 120 mg group. Decreasing ALT may be associated with improvement in liver histology, thus could be considered a surrogate for histology in early phase trials. These results may support further exploration of elafibranor in children with NASH.

Incidence of Enteric Fever in a Pediatric Cohort in North India: Comparison with Estimates from 20 Years Earlier.

BACKGROUND: An earlier cohort in 1995-1996 showed a very high burden of typhoid in Delhi. Our aim was to estimate the current overall and age-specific incidence of culture-confirmed enteric fever among children aged 6 months to 15 years in Delhi. METHODS: We enrolled a cohort of 6000 children aged 6 months to <14 years in South Delhi and followed them up weekly for 24 months or until 15 completed years of child age, whichever was earlier. Blood culture to confirm enteric fever was done in children with ≥3 consecutive days of fever. RESULTS: We recorded a total of 14 650 episodes of fever in the 11 510 person-years (PY) of follow-up. A total of 81 fever episodes were positive for enteric fever. The incidence (95% confidence interval) of all enteric fever was 703.7 (560.5-874.7) per 100 000 PY. The incidences of typhoid and paratyphoid fevers were 608.1 (95% confidence interval, 481.1-768.7) and 111.7 (59.5-191.1) per 100 000 PY, respectively, highest among children aged 10-15 years. CONCLUSIONS: Despite a 35% reduction in incidence compared with the 1995-1996 cohort, our study suggested a substantial burden of enteric fever in the population. Continued efforts to improve water, sanitation, and hygiene parameters along with implementation of novel vaccination strategies and disease surveillance can help achieve the goal of disease elimination.

Incidence of Depression and Anxiety in a Cohort of Adolescents With Nonalcoholic Fatty Liver Disease.

OBJECTIVES: To determine the incidence of clinically diagnosed depression and anxiety in adolescents with nonalcoholic fatty liver disease (NAFLD). METHODS: This was a prospective, longitudinal cohort study between January 1, 2012 and July 1, 2018 conducted in a Children's Hospital Pediatric Gastroenterology Clinic. Participants included adolescents 12 to 17 years old at baseline with biopsy-confirmed NAFLD. The primary outcomes were having depression and/or anxiety based upon a clinical diagnosis established by a physician or psychologist. The rates of depression and anxiety were measured at baseline and longitudinally throughout follow-up. RESULTS: A total of 160 adolescents with NAFLD were followed for a mean of 3.8 years. At baseline, 8.1% had a diagnosis of depression. During follow-up, an additional 9.5% (95% confidence interval, 4.7-14.3) developed depression. The incidence density of depression was 27 new cases per 1000 person-years at risk. In adolescents with NAFLD, 6.3% had anxiety at baseline and 6.7% (95% confidence interval, 2.6-10.7) developed anxiety during follow-up. The incidence density of anxiety was 18 new cases per 1000 person-years at risk. The change in alanine aminotransferase was significantly worse for adolescents with NAFLD who developed depression compared to those who did not develop depression (P < 0.01). CONCLUSIONS: Adolescents with NAFLD had a high incidence of clinically diagnosed depression and anxiety. The rates were higher than expected relative to the available data in the general population. Addressing this mental health burden will require efforts at both the patient level and the systems level.

Dairy Fat Intake, Plasma Pentadecanoic Acid, and Plasma Iso-heptadecanoic Acid Are Inversely Associated With Liver Fat in Children.

OBJECTIVES: We sought to evaluate the relevance of pediatric dairy fat recommendations for children at risk for nonalcoholic fatty liver disease (NAFLD) by studying the association between dairy fat intake and the amount of liver fat. The effects of dairy fat may be mediated by odd chain fatty acids (OCFA), such as pentadecanoic acid (C15:0), and monomethyl branched chain fatty acids (BCFA), such as iso-heptadecanoic acid (iso-C17:0). Therefore, we also evaluated the association between plasma levels of OCFA and BCFA with the amount of liver fat. METHODS: Observational, cross-sectional, community-based sample of 237 children ages 8 to 17. Dairy fat intake was assessed by 3 24-hour dietary recalls. Plasma fatty acids were measured by gas chromatography-mass spectrometry. Main outcome was hepatic steatosis measured by whole liver magnetic resonance imaging proton density fat fraction (MRI-PDFF). RESULTS: Median dairy fat intake was 10.6 grams/day (range 0.0--44.5 g/day). Median liver MRI-PDFF was 4.5% (range 0.9%-45.1%). Dairy fat intake was inversely correlated with liver MRI-PDFF (r = -0.162; P = .012). In multivariable log linear regression, plasma C15:0 and iso-C17:0 were inverse predictors of liver MRI-PDFF (B = -0.247, P = 0.048; and B = -0.234, P = 0.009). CONCLUSIONS: Dairy fat intake, plasma C15:0, and plasma iso-C17:0 were inversely correlated with hepatic steatosis in children. These hypothesis-generating findings should be tested through clinical trials to better inform dietary guidelines.

Emerging role of integrated PET-MRI in osteoarthritis.

Osteoarthritis (OA) is a common degenerative disorder of the articular cartilage, which is associated with hypertrophic changes in the bone, synovial inflammation, subchondral sclerosis, and joint space narrowing (JSN). Radiography remains the first line of imaging till now. Due to the lack of soft-tissue depiction in radiography, researchers are exploring various imaging techniques to detect OA at an early stage and understand its pathophysiology to restrict its progression and discover disease-modifying agents in OA. As the OA relates to the degradation of articular cartilage and remodeling of the underlying bone, an optimal imaging tool must be sensitive to the bone and soft tissue health. In that line, many non-invasive imaging and minimally invasive techniques have been explored. Out of these, the non-invasive compositional magnetic resonance imaging (MRI) for evaluation of the integrity of articular cartilage and positron emission tomography (PET) scan with fluorodeoxyglucose (FDG) and more specific bone-seeking tracer like sodium fluoride (18F-NaF) for bone cartilage interface are some of the leading areas of ongoing work. Integrated PET-MRI system, a new hybrid modality that combines the virtues of the above two individual modalities, allows detailed imaging of the entire joint, including soft tissue cartilage and bone, and holds great potential to research complex disease processes of OA. This narrative review attempts to signify individual characteristics of MRI, PET, the fusion of these characteristics in PET-MRI, and the ongoing research on PET-MRI as a potential tool to understand the pathophysiology of OA.

Microbiome Signatures Associated With Steatohepatitis and Moderate to Severe Fibrosis in Children With Nonalcoholic Fatty Liver Disease.

BACKGROUND & AIMS: The intestinal microbiome might affect the development and severity of nonalcoholic fatty liver disease (NAFLD). We analyzed microbiomes of children with and without NAFLD. METHODS: We performed a prospective, observational, cross-sectional study of 87 children (age range, 8-17 years) with biopsy-proven NAFLD and 37 children with obesity without NAFLD (controls). Fecal samples were collected and microbiome composition and functions were assessed using 16S ribosomal RNA amplicon sequencing and metagenomic shotgun sequencing. Microbial taxa were identified using zero-inflated negative binomial modeling. Genes contributing to bacterial pathways were identified using gene set enrichment analysis. RESULTS: Fecal microbiomes of children with NAFLD had lower α-diversity than those of control children (3.32 vs 3.52, P = .016). Fecal microbiomes from children with nonalcoholic steatohepatitis (NASH) had the lowest α-diversity (control, 3.52; NAFLD, 3.36; borderline NASH, 3.37; NASH, 2.97; P = .001). High abundance of Prevotella copri was associated with more severe fibrosis (P = .036). Genes for lipopolysaccharide biosynthesis were enriched in microbiomes from children with NASH (P < .001). Classification and regression tree model with level of alanine aminotransferase and relative abundance of the lipopolysaccharide pathway gene encoding 3-deoxy-d-manno-octulosonate 8-phosphate-phosphatase identified patients with NASH with an area under the receiver operating characteristic curve value of 0.92. Genes involved in flagellar assembly were enriched in the fecal microbiomes of patients with moderate to severe fibrosis (P < .001). Classification and regression tree models based on level of alanine aminotransferase and abundance of genes encoding flagellar biosynthesis protein had good accuracy for identifying case children with moderate to severe fibrosis (area under the receiver operating characteristic curve, 0.87). CONCLUSIONS: In an analysis of fecal microbiomes of children with NAFLD, we associated NAFLD and NASH with intestinal dysbiosis. NAFLD and its severity were associated with greater abundance of genes encoding inflammatory bacterial products. Alterations to the intestinal microbiome might contribute to the pathogenesis of NAFLD and be used as markers of disease or severity.

Normal range for MR elastography measured liver stiffness in children without liver disease.

BACKGROUND: Magnetic resonance elastography (MRE) can determine the presence and stage of liver fibrosis. Data on normative MRE values, while reported in adults, are limited in children. PURPOSE: To determine the distribution of MRE-measured liver stiffness in children without liver disease. STUDY TYPE: Prospective, observational. POPULATION: Eighty-one healthy children (mean 12.6 ± 2.6 years, range 8-17 years). FIELD STRENGTH/SEQUENCE: 3.0T Signa HDxt, General Electric MR Scanner; 2D GRE MRE sequence. ASSESSMENT: History, examination, laboratory evaluation, and (MR) exams (proton density fat fraction, PDFF, and MRE) were performed. MR elastograms were analyzed manually at two reading centers and compared with each other for agreement and with published values in healthy adults and thresholds for fibrosis in adult and pediatric patients. STATISTICAL TESTS: Descriptive statistics, Bland-Altman analysis, t-test to compare hepatic stiffness values with reference standards. RESULTS: Stiffness values obtained at both reading centers were similar, without significant bias (P = 0.362) and with excellent correlation (intraclass correlation coefficient [ICC] = 0.782). Mean hepatic stiffness value for the study population was 2.45 ± 0.35 kPa (95th percentile 3.19 kPa), which was significantly higher than reported values for healthy adult subjects (2.10 ± 0.23 kPa, P < 0.001). In all, 74-85% of subjects had stiffness measurements suggestive of no fibrosis. DATA CONCLUSION: Mean liver stiffness measured with MRE in this cohort was significantly higher than that reported in healthy adults. Despite rigorous screening, some healthy children had stiffness measurements suggestive of liver fibrosis using current published thresholds. Although MRE has the potential to provide noninvasive assessment in patients with suspected hepatic disease, further refinement of this technology will help advance its use as a diagnostic tool for evidence of fibrosis in pediatric populations. LEVEL OF EVIDENCE: 1 Technical Efficacy: 5 J. Magn. Reson. Imaging 2020;51:919-927.

Evaluation of Quantitative Imaging Biomarkers for Early-phase Clinical Trials of Steatohepatitis in Adolescents.

OBJECTIVES: Early-phase pediatric nonalcoholic fatty liver disease (NAFLD) clinical trials are designed with noninvasive parameters to assess potential efficacy. Increasingly, these parameters include magnetic resonance imaging (MRI)-derived proton density fat fraction (PDFF) and MR elastography (MRE)-derived shear stiffness as biomarkers of hepatic steatosis and fibrosis, respectively. Understanding fluctuations in these measures is essential for calculating trial sample sizes, interpreting results, and planning clinical drug trials in children with NAFLD. Lack of such data in children constitutes a critical knowledge gap. Therefore, the primary aim of this study was to assess whole-liver MRI-PDFF change in adolescents with nonalcoholic steatohepatitis (NASH) over 12 weeks. METHODS: Adolescents 12 to 19 years with biopsy-proven NASH undergoing standard-of-care treatment were enrolled. Baseline and week-12 assessments of anthropometrics, transaminases, MRI-PDFF, and MRE stiffness were obtained. RESULTS: Fifteen adolescents were included (mean age 15.7 [SD 2.9] years). Hepatic MRI-PDFF was stable over 12 weeks (mean absolute change -0.8%, P = 0.24). Correlation between baseline and week-12 values of MRI-PDFF was high (ICC = 0.97, 95% CI 0.90-0.99). MRE stiffness was stable (mean percentage change 2.7%, P = 0.44); correlation between baseline and week-12 values was moderate (ICC = 0.47; 95% CI 0-0.79). Changes in weight, BMI, and aminotransferases were not statistically significant. CONCLUSION: In adolescents with NASH, fluctuations in hepatic MRI-PDFF and MRE stiffness over 12 weeks of standard-of-care were small. These data on the natural fluctuations in quantitative imaging biomarkers can serve as a reference for interventional trials in pediatric NASH and inform the interpretation and planning of clinical trials.

Prevalence of Nonalcoholic Fatty Liver Disease in Children with Obesity.

OBJECTIVES: To determine the prevalence of nonalcoholic fatty liver disease (NAFLD) in children with obesity because current estimates range from 1.7% to 85%. A second objective was to evaluate the diagnostic accuracy of alanine aminotransferase (ALT) for NAFLD in children with obesity. STUDY DESIGN: We evaluated children aged 9-17 years with obesity for the presence of NAFLD. Diseases other than NAFLD were excluded by history and laboratories. Hepatic steatosis was measured by liver magnetic resonance imaging proton density fat fraction. The diagnostic accuracy of ALT for detecting NAFLD was evaluated. RESULTS: The study included 408 children with obesity that had a mean age of 13.2 years and mean body mass index percentile of 98.0. The study population had a mean ALT of 32 U/L and median hepatic magnetic resonance imaging proton density fat fraction of 3.7%. The estimated prevalence of NAFLD was 26.0% (95% CI 24.2%-27.7%), 29.4% in male patients (CI 26.1%-32.7%) and 22.6% in female patients (CI 16.0%-29.1%). Optimal ALT cut-point was 42 U/L (47.8% sensitivity, 93.2% specificity) for male and 30 U/L (52.1% sensitivity, 88.8% specificity) for female patients. The classification and regression tree model with sex, ALT, and insulin had 80% diagnostic accuracy for NAFLD. CONCLUSIONS: NAFLD is common in children with obesity, but NAFLD and obesity are not concomitant. In children with obesity, NAFLD is present in nearly one-third of boys and one-fourth of girls.

Clinical Practice Approach to Nonalcoholic Fatty Liver Disease by Pediatric Gastroenterologists in the United States.

OBJECTIVES: Nonalcoholic fatty liver disease (NAFLD) is common; however, no information is available on how pediatric gastroenterologists in the United States manage NAFLD. Therefore, study objectives were to understand how pediatric gastroenterologists in the US approach the management of NAFLD, and to identify barriers to care for children with NAFLD. METHODS: We performed structured one-on-one interviews to ascertain each individual pediatric gastroenterologist's approach to the management of NAFLD in children. Responses were recorded from open-ended questions regarding screening for comorbidities, recommendations regarding nutrition, physical activity, medications, and perceived barriers to care. RESULTS: Response rate was 72.0% (486/675). Mean number of patients examined per week was 3 (standard deviation [SD] 3.5). Dietary intervention was recommended by 98.4% of pediatric gastroenterologists. Notably, 18 different dietary recommendations were reported. A majority of physicians provided targets for exercise frequency (72.6%, mean 5.6 days/wk, SD 1.6) and duration (69.9%, mean 40.2 minutes/session, SD 16.4). Medications were prescribed by 50.6%. Almost one-half of physicians (47.5%) screened for type 2 diabetes, dyslipidemia, and hypertension. Providers who spent more than 25 minutes at the initial visit were more likely to screen for comorbidities (P = 0.003). Barriers to care were reported by 92.8% with 29.0% reporting ≥3 barriers. CONCLUSIONS: The majority of US pediatric gastroenterologists regularly encounter children with NAFLD. Varied recommendations regarding diet and exercise highlight the need for prospective clinical trials. NAFLD requires a multidimensional approach with adequate resources in the home, community, and clinical setting.

A Bibliometric Analysis of Clinical and Translational Research in Pediatric Gastroenterology From 1970 to 2017.

OBJECTIVES: Pediatric gastroenterology is a clinical and research discipline principally developed over the past 50 years. Bibliometric methods provide quantitative analysis and identify research trends. Study aims were to characterize the growth and trends in pediatric gastroenterology clinical and translational research using citation analysis. METHODS: Using citations analysis software, a search strategy specific for pediatric gastroenterology was implemented for the years 1970 to 2017. The 50 most-cited research articles per decade were identified. These 250 articles were coded for topic and study attribute. Analysis included authors, affiliations, journals, countries, and funding sources. RESULTS: Overall average annual growth rate for pediatric gastroenterology publications was significantly higher than that for general pediatrics (51.7% vs 6.2%; P < 0.05). Among the top 250 cited articles, the distribution of study focus was epidemiology (43%), pathophysiology (18%), treatment (16%), diagnosis (8%), prevention (8%), and comorbidities of gastrointestinal diseases (7%).There were 38 different topics represented and there was a notable shift in topic focus over time. Cholestasis, biliary atresia, and total parenteral nutrition were common topics from 1970 to 1989 and obesity, nonalcoholic fatty liver disease, and eosinophilic esophagitis were common topics after 1990. Notably, 2.3% of the authors accounted for 30% of the top 250 articles. CONCLUSIONS: Pediatric gastroenterology research has undergone rapid growth yielding advancements in the management of gastrointestinal conditions in children. The emergence of new diseases in need of better diagnostics and therapeutics led to a temporal shift in research focus. Further advancements will require multidisciplinary collaborations and continued funding for pediatric gastroenterology research.

Degradation of azo dye methyl red by alkaliphilic, halotolerant Nesterenkonia lacusekhoensis EMLA3: application in alkaline and salt-rich dyeing effluent treatment.

Effluents from textile industries are highly colored due to vast use of various azo dyes and color is the first visual indicator of pollution. Biological treatment of textile effluent is often hampered due to the alkaline pH and high salinity; a common characteristic of many textile industrial wastewaters. Considering this, the present study explores the potential of a newly isolated halotolerant and alkaliphilic bacterium Nesterenkonia lacusekhoensis EMLA3 for degradation of methyl red (MR) dye under alkaline condition. Strain EMLA3 showed 97% degradation of 50 mg L-1 MR after 16 h at initial pH of 11.5 in nutrient medium. Dye degradation by the isolate is supported by the formation of low-molecular weight metabolites as divulge through GC-MS & FTIR studies Optimum dye degradation was observed in the pH range of 8.0-11.5 and temperature range of 30-35 °C. Significant MR degrading activity of the strain could be achieved in the presence of very high salt level (100-120 g L-1 NaCl) and in co-presence of different heavy metals. Application of strain to alkaline pH, salt, and heavy metals laden-textile effluent resulted in overall 83% dye removal from the effluent after 120 h of treatment under static condition. Furthermore, the property of microbe to drop-down the pH of wastewater from 11.5 to 8.60 after treatment also lowers the need of additional neutralization treatment. The entire study thus comes out with novel application of N. lacusekhoensis-a less explored extremophilic bacterium-for treatment of alkaline and salt-rich azo dye-containing wastewaters.

Acute fibrinous and organizing pneumonia: A rare form of nonbacterial pneumonia.

Acute fibrinous and organizing pneumonia (AFOP) is a rare disease characterized by bilateral basilar infiltrates and histological findings of organizing pneumonia and intra-alveolar fibrin in the form of "fibrin balls." Here, we report a 43-year-old female with complaints of fever, dry cough, and shortness of breath with hypoxemia. High-resolution computed tomography thorax revealed diffuse confluent consolidation in bilateral lung zones. Bronchoscopy and transbronchial biopsy revealed features of AFOP. With prednisolone treatment, there was an improvement in her condition. AFOP is a rare disease and should be taken into consideration and differential diagnosis of severe acute pneumonias with no significant comorbidities.

Efficacy of a monovalent human-bovine (116E) rotavirus vaccine in Indian infants: a randomised, double-blind, placebo-controlled trial.

BACKGROUND: Rotavirus is the most common cause of severe dehydrating gastroenteritis in developing countries. Safe, effective, and affordable rotavirus vaccines are needed in these countries. We aimed to assess the efficacy and tolerability of a monovalent human-bovine rotavirus vaccine for severe rotavirus gastroenteritis in low-resource urban and rural settings in India. METHODS: We did a randomised double-blind, placebo-controlled, multicentre trial at three sites in Delhi (urban), Pune (rural), and Vellore (urban and rural) between March 11, 2011, and Nov 5, 2012. Infants aged 6-7 weeks were randomly assigned (2:1), via a central interactive voice or web response system with a block size of 12, to receive either three doses of oral human-bovine natural reassortant vaccine (116E) or placebo at ages 6-7 weeks, 10 weeks, and 14 weeks. Infants' families, study investigators, paediatricians in referral hospitals, laboratory staff, and committee members were all masked to treatment allocation. The primary outcome was incidence of severe rotavirus gastroenteritis (≥11 on the Vesikari scale). Efficacy outcomes and adverse events were ascertained through active surveillance. Analysis was by intention to treat and per protocol. The trial is registered with Clinical Trial Registry-India (CTRI/2010/091/000102) and ClinicalTrials.gov (NCT01305109). FINDINGS: 4532 infants were assigned to receive the 116E vaccine and 2267 to receive placebo, of whom 4354 (96%) and 2187 (96%) infants, respectively, were included in the primary per-protocol efficacy analysis. 71 events of severe rotavirus gastroenteritis were reported in 4752 person-years in infants in the vaccine group compared with 76 events in 2360 person-years in those in the placebo group; vaccine efficacy against severe rotavirus gastroenteritis was 53·6% (95% CI 35·0-66·9; p=0·0013) and 56·4% (36·6-70·1; p<0·0001) in the first year of life. The number of infants needed to be immunised to prevent one severe rotavirus gastroenteritis episode was 55 (95% CI 37-97). The incidence of severe rotavirus gastroenteritis per 100 person-years was 1·5 in the vaccine group and 3·2 in the placebo group, with an incidence rate ratio of 0·46 (95% CI 0·33-0·65). Prevalence of immediate, solicited, and serious adverse events was similar in both groups. One case of urticaria in the vaccine group and one each of acute gastroenteritis and suspected sepsis in the placebo group were regarded as related to the study product. We recorded six cases of intussusception in the vaccine group and two in the placebo group, all of which happened after the third dose. 25 (<1%) infants in the vaccine group and 17 (<1%) in the placebo group died; no death was regarded as related to the study product. INTERPRETATION: Monovalent human-bovine (116E) rotavirus vaccine is effective and well tolerated in Indian infants. FUNDING: Department of Biotechnology and the Biotechnology Industry Research Assistance Council, Government of India; Bill & Melinda Gates Foundation to PATH, USA; Research Council of Norway; UK Department for International Development; National Institutes of Health, Bethesda, USA; and Bharat Biotech International, Hyderabad, India.

Potential role of nitric oxide synthase isoforms in pathophysiology of neuropathic pain.

Neuropathic pain triggers a cascade of events in the sensory neurons. It is the main complication of diabetes after cardiovascular disease. Nitric oxide (NO) produced from nitric oxide synthases (NOS) is an important signaling molecule which is crucial for many physiological processes such as synaptic plasticity, neuronal survival, vasodilation, vascular homeostasis, immune regulation. Overproduction of NO due to changes in NOS isoforms level involves pathological processes such as neurotoxicity, septic shock and neuropathic pain. All three isoforms of NOS as well as their end product, NO have modulatory effect on neuropathic pain. Overactivation of the N-Methyl-D-Aspartate receptor and peroxynitrite formation results in high levels of neuronal NOS (nNOS) and endothelial NOS (eNOS) which suggest that nNOS and eNOS are critical for pain hypersensitivity. Inducible NOS induced in glia by inflammation due to activation of Tumor Necrosis Factor α, Calcitonin Gene Regulating Peptide, Mitogen Activated Protein Kinases, Extracellular signal Regulated Kinase, c-Jun N-terminal kinases can induce neuronal death. This review focuses on different nitric oxide synthases and their role in pathophysiology of neuropathic pain considering NOS as an important therapeutic target.

Animal models of inflammatory bowel disease: a review.

Inflammatory bowel disease (IBD) represents a group of idiopathic chronic inflammatory intestinal conditions associated with various areas of the GI tract, including two types of inflammatory conditions, i.e., ulcerative colitis (UC) and Crohn's disease (CD). Both UC and CD are chronic inflammatory disorders of the intestine; in UC, inflammation starts in the rectum and generally extends proximally in a continuous manner through the entire colon. Bloody diarrhea, presence of blood and mucus mixed with stool, accompanied by lower abdominal cramping, are the characteristic symptoms of the disease. While in CD, inflammatory condition may affect any part of the GI tract from mouth to anus. It mainly causes abdominal pain, diarrhea, vomiting and weight loss. Although the basic etiology of IBD is unknown, there are several factors that may contribute to the pathogenesis of this disease, such as dysregulation of immune system or commensal bacteria, oxidative stress and inflammatory mediators. In order to understand these different etiological factors, a number of experimental models are available in the scientific research, including chemical-induced, spontaneous, genetically engineered and transgenic models. These models represent a major source of information about biological systems and are clinically relevant to the human IBD. Since there is less collective data available in one single article discussing about all these models, in this review an effort is made to study the outline of pathophysiology and various types of animal models used in the research study of IBD and other disease-related complications.

Predictive Models for Canadian Healthcare Workers Mental Health During COVID-19.

PURPOSE: COVID-19 impact on the population's mental health has been reported worldwide. Predicting healthcare workers' mental health and life stress is needed to proactively plan for future emergencies. DESIGN: Statistics Canada has surveyed Canadian healthcare workers and those working in healthcare settings to gauge their perceived mental health and perceived life stress. SETTING: A cross-sectional survey of healthcare workers in Canada. SUBJECTS: A sample of 18,139 healthcare workers respondents. ANALYSIS: Eight algorithms, including Logistic Regression, Random Forest (RF), Naive Bayes (NB), K Nearest Neighbours (KNN), Adaptive boost (AdaBoost), Multi-layer perceptron (MLP), XGBoost, and LightBoost. AUC scores, accuracy and precision were measured for all models. RESULTS: XGBoost provided the highest performing model AUC score (AUC = 82.07%) for predicting perceived mental health, and Random Forest performed the best for predicting perceived life stress (AUC = 77.74%). Perceived health, age group of participants, and perceived mental health compared to before the pandemic were found to be the most important 3 features to predict perceived mental health and perceived stress. Perceived mental health compared to before the pandemic was the most important predictor for perceived life stress. CONCLUSION: Our models are highly predictive of healthcare workers' perceived mental health and life stress. Implementing scalable, non-expensive virtual mental health solutions to address mental health challenges in the workplace could mitigate the impact of workplace conditions on healthcare workers' mental health.

Technologies that empower women for better access to healthcare in India - A scoping review.

Women from low- and middle-income countries face challenges in accessing and utilising quality healthcare. Technologies can aid in overcoming these challenges and the present scoping review is aimed at summarising the range of technologies used by women and assessing their role in enabling Indian women to learn about and access healthcare services. We conducted a comprehensive search from the date of inception of database till 2022 in PubMed and Google Scholar. Data was extracted from 43 studies and were thematically analysed. The range of technologies used by Indian women included integrated voice response system, short message services, audio-visual aids, telephone calls and mobile applications operated by health workers. Majority of the studies were community-based (79.1%), from five states (60.5%), done in rural settings (58.1%) and with interventional design (48.8%). Maternal and child health has been the major focus of studies, with lesser representation in domains of non-communicable and communicable diseases. The review also summarised barriers related to using technology - from health system and participant perspective. Technology-based interventions are enabling women to improve awareness about and accessibility to healthcare in India. Imparting digital literacy and scaling up technology use are potential solutions to scale-up healthcare access among women in India.