Epigenome-wide association study of body mass index, and the adverse outcomes of adiposity.

Approximately 1.5 billion people worldwide are overweight or affected by obesity, and are at risk of developing type 2 diabetes, cardiovascular disease and related metabolic and inflammatory disturbances. Although the mechanisms linking adiposity to associated clinical conditions are poorly understood, recent studies suggest that adiposity may influence DNA methylation, a key regulator of gene expression and molecular phenotype. Here we use epigenome-wide association to show that body mass index (BMI; a key measure of adiposity) is associated with widespread changes in DNA methylation (187 genetic loci with P < 1 × 10-7, range P = 9.2 × 10-8 to 6.0 × 10-46; n = 10,261 samples). Genetic association analyses demonstrate that the alterations in DNA methylation are predominantly the consequence of adiposity, rather than the cause. We find that methylation loci are enriched for functional genomic features in multiple tissues (P < 0.05), and show that sentinel methylation markers identify gene expression signatures at 38 loci (P < 9.0 × 10-6, range P = 5.5 × 10-6 to 6.1 × 10-35, n = 1,785 samples). The methylation loci identify genes involved in lipid and lipoprotein metabolism, substrate transport and inflammatory pathways. Finally, we show that the disturbances in DNA methylation predict future development of type 2 diabetes (relative risk per 1 standard deviation increase in methylation risk score: 2.3 (2.07-2.56); P = 1.1 × 10-54). Our results provide new insights into the biologic pathways influenced by adiposity, and may enable development of new strategies for prediction and prevention of type 2 diabetes and other adverse clinical consequences of obesity.

Food environment and diabetes mellitus in South Asia: A geospatial analysis of health outcome data.

BACKGROUND: The global epidemic of type 2 diabetes mellitus (T2DM) renders its prevention a major public health priority. A key risk factor of diabetes is obesity and poor diets. Food environments have been found to influence people's diets and obesity, positing they may play a role in the prevalence of diabetes. Yet, there is scant evidence on the role they may play in the context of low- and middle-income countries (LMICs). We examined the associations of food environments on T2DM among adults and its heterogeneity by income and sex. METHODS AND FINDINGS: We linked individual health outcome data of 12,167 individuals from a network of health surveillance sites (the South Asia Biobank) to the density and proximity of food outlets geolocated around their homes from environment mapping survey data collected between 2018 and 2020 in Bangladesh and Sri Lanka. Density was defined as share of food outlets within 300 m from study participant's home, and proximity was defined as having at least 1 outlet within 100 m from home. The outcome variables include fasting blood glucose level, high blood glucose, and self-reported diagnosed diabetes. Control variables included demographics, socioeconomic status (SES), health status, healthcare utilization, and physical activities. Data were analyzed in ArcMap 10.3 and STATA 15.1. A higher share of fast-food restaurants (FFR) was associated with a 9.21 mg/dl blood glucose increase (95% CI: 0.17, 18.24; p < 0.05). Having at least 1 FFR in the proximity was associated with 2.14 mg/dl blood glucose increase (CI: 0.55, 3.72; p < 0.01). A 1% increase in the share of FFR near an individual's home was associated with 8% increase in the probability of being clinically diagnosed as a diabetic (average marginal effects (AMEs): 0.08; CI: 0.02, 0.14; p < 0.05). Having at least 1 FFR near home was associated with 16% (odds ratio [OR]: 1.16; CI: 1.01, 1.33; p < 0.05) and 19% (OR: 1.19; CI: 1.03, 1.38; p < 0.05) increases in the odds of higher blood glucose levels and diagnosed diabetes, respectively. The positive association between FFR density and blood glucose level was stronger among women than men, but the association between FFR proximity and blood glucose level was stronger among men as well as among those with higher incomes. One of the study's key limitations is that we measured exposure to food environments around residency geolocation; however, participants may source their meals elsewhere. CONCLUSIONS: Our results suggest that the exposure to fast-food outlets may have a detrimental impact on the risk of T2DM, especially among females and higher-income earners. Policies should target changes in the food environments to promote better diets and prevent T2DM.

Reference equations for evaluation of spirometry function tests in South Asia, and among South Asians living in other countries.

BACKGROUND: There are few data to support accurate interpretation of spirometry data in South Asia, a major global region with a high reported burden of chronic respiratory disease. METHOD: We measured lung function in 7453 healthy men and women aged ≥18 years, from Bangladesh, North India, South India, Pakistan and Sri Lanka, as part of the South Asia Biobank study. First, we assessed the accuracy of existing equations for predicting normal forced vital capacity (FVC), forced expiratory volume in 1 s (FEV1) and FEV1/FVC ratio. Then, we used our data to derive (n=5589) and internally validate (n=1864) new prediction equations among South Asians, with further external validation among 339 healthy South Asians living in Singapore. RESULTS: The Global Lung Initiative (GLI) and National Health and Nutrition Examination Survey consistently overestimated expiratory volumes (best fit GLI-African American, mean±sd z-score: FEV1 -0.94±1.05, FVC -0.91±1.10; n=7453). Age, height and weight were strong predictors of lung function in our participants (p<0.001), and sex-specific reference equations using these three variables were highly accurate in both internal validation (z-scores: FEV1 0.03±0.99, FVC 0.04±0.97, FEV1/FVC -0.03±0.99) and external validation (z-scores: FEV1 0.31±0.99, FVC 0.24±0.97, FEV1/FVC 0.16±0.91). Further adjustment for study regions improves the model fit, with highest accuracy for estimation of region-specific lung function in South Asia. CONCLUSION: We present improved equations for predicting lung function in South Asians. These offer the opportunity to enhance diagnosis and management of acute and chronic lung diseases in this major global population.

Prevalence of Flu-like Symptoms and COVID-19 in Healthcare Workers from India.

BACKGROUND: The current COVID-19 pandemic is unprecedented. As the numbers expand exponentially, a paucity of data regarding health care workers (HCWs), who are at the forefront of this disaster, exists. Hence we decided to conduct a study amongst the HCWs to determine the prevalence and risk factor stratification. METHODS: This was an online questionnaire-based survey of healthcare workers conducted at Max Super Speciality Hospital, Saket, New Delhi, India from 23rd March to 30th April 2020. Data on flu-like symptoms, travel history, posting in high-risk or low risk zones, and prophylactic drugs was collected. RESULTS: Out of the 18000 HCWs who were approached 4403 responded and adequate data of 3667 was available for analysis. 14.7% had flu-like symptoms. 1.8% (20/1113) of the participants tested were positive for the virus. HCWs posted in the high-risk zones had more symptoms than those working in low-risk zones (169/539, 31.4% vs 679/3128, 21.7%), p<0.001; but no difference in COVID-19 positivity rates (p=0.849). Symptomatic HCWs had higher positivity (10/193, 5.2%) than the asymptomatic ones (10/920, 1.1%), p=0.001. HCQ was taken by 755/1113 (67.8%) people and 14 (1.9%) of these reported positive for the virus. CONCLUSION: This is the first study on healthcare workers from India to the best of our knowledge. Our findings suggest that posting in a high-risk zone with adequate PPE does not pose higher risk to the HCWs. Moreover, HCQ as a prophylactic has no use. CLINICALTRIALS.GOV IDENTIFIER: NCT04339608.

Adoption of Gla-100 in India and its Impact on Insulin Usage Patterns.

Fueled by perceptions regarding Indian dietary patterns and premixed insulin's claim to fame of providing dual fasting and post-prandial control, there was a greater inclination towards using premixed insulins in clinical practice until the last decade. However, the advent of insulin glargine 100 U/mL (Gla-100) opened up a new dimension in insulin therapy landscape in India. The data from the last 5 years reveal that Gla-100 has gained more traction among Indian clinical practitioners. Basis evidences that have emerged from various clinical studies, this present review elaborates on certain key issues which have helped Gla-100 carve its own niche and effected a progressive shift in insulin prescription pattern in India.

From Individualized to Personalized Medicine in Diabetes: An Expert Overview.

Personalized medicine is an individualized and stratified approach to the management of a disease. Personalized medicine can reform the prevention, prediction, and management of diabetes. Use of genetic information in polygenic and monogenic forms of diabetes can help to identify genetic variants and reclassify patients into pathophysiological subgroups. Targeted diagnostic, preventive, and therapeutic interventions can be defined for these groups for effective management of diabetes. Pharmacogenetics combines genotypic and phenotypic factors to develop personalized care in various pathophysiological subgroups of persons with diabetes. Personalized medicine finds wider utility in monogenic (especially Maturity Onset Diabetes of the Young (MODY) and Neonatal Diabetes Mellitus [NDM]) than in polygenic, diabetes. The most frequently mutated genes in MODY include HNF1A and HNF3A. the common genes responsible for NDM include KCNJ11 and ABCC8 (SUR) genes. These genes influence various aspects of glucose metabolism such as ß-cell K-ATP channel modulation, production of insulin and development of pancreas. The Madras Diabetes Research Foundation has fostered research in personalized medicine for diabetes based upon genetic information and has developed a national registry for neonatal diabetes and other monogenic form of diabetes.

Effectiveness of Pregabalin Compared to Duloxetine in Diabetic Peripheral Neuropathic Pain: An Observational Study.

INTRODUCTION: Neuropathy is a comorbid complication of diabetes and Pregabalin and Duloxetine are the two most common drugs used for the treatment of neuropathic pain. AIM: To determine the effectiveness and side effects of Pregabalin and Duloxetine in patients with diabetic peripheral neuropathic pain. MATERIALS AND METHODS: This prospective observational study was conducted at Max Super Speciality Hospital. Patients attending the endocrinology department, above 18 years of age who were prescribed with Pregabalin or Duloxetine were screened and included in this study. The data was collected for all study participants using a specially designed case record form by conducting personal interviews. SF-MPQ, Mc-Gill, NRS and DN-4 questionnaires were used to assess the extent of pain and the side-effects associated with the drugs. RESULTS: Based on the responses from the Numerical Rating Scale and McGill Pain Questionnaire, Pregabalin was seen to be less effective compared to Duloxetine. The only side effect observed with Pregabalin was drowsiness, which was observed in 4% cases at 50 mg dose whereas those reported with Duloxetine were drowsiness (22.2% at 20 mg and 33.3% at 30 mg), vomiting (11.1% at 20mg and 30mg), headache (11.1% at 20 mg and 30 mg), and dizziness (0% at 20mg and 11.1% at 30 mg). CONCLUSION: Pregabalin has a better safety profile and tolerability compared to Duloxetine but the latter is more effective in treating Diabetic Peripheral Neuropathic Pain. However, further studies with a larger sample size and longer duration are required to be conducted for finding the effectiveness of these drugs, specifically in the Indian population.

Psychological Insulin Resistance in Patients with Type 2 Diabetes.

AIMS/HYPOTHESIS: To identify risk factors associated with psychological insulin resistance (PIR) in Indian type 2 diabetes (T2DM) population. METHODS: Patients with T2DM, aged 18 years, undergoing treatment with oral hypoglycaemic agents and providing written informed consent were considered eligible for the study. Patient's data was collected by face-to-face interaction using 5 validated diabetes questionnaires--Diabetes Attitude Scale, Diabetes Knowledge Test, Diabetes Self-Efficacy Scale, Interpersonal Processes of Care Survey-29, and Barriers to Insulin Treatment scale. Demographic variables, categories of patients based on their annual family income, education, glycosylated haemoglobin (HbA1c), occupation and type of healthcare setup were correlated with overall scores of validated questionnaires. Statistical analyses were performed using Pearson correlation coefficients, analysis of variance, two-group t-test and hierarchical multiple regression. RESULTS: One hundred ninty-eight patients with T2DM were enrolled where 63% were males, 52% had HbA1c <7% (<53 mmol/mol), 32% were in service, 35% had the annual family income between Rs 100,000-500,000, 50% were graduates and 81% were enrolled from private healthcare set ups. Significant high opposition to use insulin was observed in females, patients based at home, patients with insufficient education, and patients visiting government set-ups compared to males, service-class patients, graduates, and patients approaching private set-ups, respectively. CONCLUSIONS: In India, major factors contributing to PIR were fear of injection or fear of pain during injection, fear of hypoglycemia, social stigma and lack of education. Effective interpersonal interactions with healthcare providers could help to counteract PIR, especially in patients who are not sufficiently literate highlighting the need of skilled healthcare staffs in Indian public hospitals.

Prevalence of depression in patients with type 2 diabetes attending an outpatient clinic in India.

BACKGROUND: Clinical studies have suggested that depression is common among patients with type 2 diabetes (T2D). Depression is an important factor which affects the management and complications of diabetes. However, the available data regarding its prevalence in India are limited. OBJECTIVES: To estimate the prevalence of depression in patients in India with T2D and to compare it with a non-diabetic group; and to determine the association of depression with glycaemic control and complications of diabetes in patients with T2D. METHODS: This case-control study was carried out over 5 months from May to September 2012 at a tertiary care hospital in India. Cases were patients with T2D and controls were individuals without diabetes. Depression was assessed using the Patient Health Questionnaire (PHQ)-9. The sociodemographic profile, duration of diabetes, presence of complications and other medical variables were also analysed. RESULTS: 260 subjects of Indian origin (162 men and 98 women; 130 with known T2D and 130 controls without T2D) were evaluated. The prevalence of depression in subjects with T2D was almost twice that in control subjects (46/130 (35.38%) vs 26/130 (20%); p=0.006). A statistically significant difference was found in the fasting blood glucose levels of subjects with depression and those without depression among the patients with T2D (145.70±53.92 vs 130.61±42.39; p=0.022), but depression was not found to be associated with any of the diabetic complications and glycaemic control. CONCLUSIONS: Our findings demonstrate that there is a higher prevalence of depression in Indian patients with T2D, which is almost twice that in those without T2D. Since patients with T2D are at higher risk of developing depression, assessment of depression should be performed as part of the routine practice in India. TRIAL REGISTRATION NUMBER: CTRI/2012/06/002747.

Increased Abundance of Achromobacter xylosoxidans and Bacillus cereus in Upper Airway Transcriptionally Active Microbiome of COVID-19 Mortality Patients Indicates Role of Co-Infections in Disease Severity and Outcome.

The modulators of severe COVID-19 have emerged as the most intriguing features of SARS-CoV-2 pathogenesis. This is especially true as we are encountering variants of concern (VOC) with increased transmissibility and vaccination breakthroughs. Microbial co-infections are being investigated as one of the crucial factors for exacerbation of disease severity and complications of COVID-19. A key question remains whether early transcriptionally active microbial signature/s in COVID-19 patients can provide a window for future disease severity susceptibility and outcome? Using complementary metagenomics sequencing approaches, respiratory virus oligo panel (RVOP) and Holo-seq, our study highlights the possible functional role of nasopharyngeal early resident transcriptionally active microbes in modulating disease severity, within recovered patients with sub-phenotypes (mild, moderate, severe) and mortality. The integrative analysis combines patients' clinical parameters, SARS-CoV-2 phylogenetic analysis, microbial differential composition, and their functional role. The clinical sub-phenotypes analysis led to the identification of transcriptionally active bacterial species associated with disease severity. We found significant transcript abundance of Achromobacter xylosoxidans and Bacillus cereus in the mortality, Leptotrichia buccalis in the severe, Veillonella parvula in the moderate, and Actinomyces meyeri and Halomonas sp. in the mild COVID-19 patients. Additionally, the metabolic pathways, distinguishing the microbial functional signatures between the clinical sub-phenotypes, were also identified. We report a plausible mechanism wherein the increased transcriptionally active bacterial isolates might contribute to enhanced inflammatory response and co-infections that could modulate the disease severity in these groups. Current study provides an opportunity for potentially using these bacterial species for screening and identifying COVID-19 patient sub-groups with severe disease outcome and priority medical care. IMPORTANCE COVID-19 is invariably a disease of diverse clinical manifestation, with multiple facets involved in modulating the progression and outcome. In this regard, we investigated the role of transcriptionally active microbial co-infections as possible modulators of disease pathology in hospital admitted SARS-CoV-2 infected patients. Specifically, can there be early nasopharyngeal microbial signatures indicative of prospective disease severity? Based on disease severity symptoms, the patients were segregated into clinical sub-phenotypes: mild, moderate, severe (recovered), and mortality. We identified significant presence of transcriptionally active isolates, Achromobacter xylosoxidans and Bacillus cereus in the mortality patients. Importantly, the bacterial species might contribute toward enhancing the inflammatory responses as well as reported to be resistant to common antibiotic therapy, which together hold potential to alter the disease severity and outcome.

WFS1 Gene-associated Diabetes Phenotypes and Identification of a Founder Mutation in Southern India.

CONTEXT: Wolfram syndrome (WFS) is a rare autosomal recessive disorder characterized by juvenile-onset diabetes, diabetes insipidus, optic atrophy, deafness, and progressive neurodegeneration. However, due to the progressive nature of the disease and a lack of complete clinical manifestations, a confirmed diagnosis of WFS at the time of onset of diabetes is a challenge. OBJECTIVE: With WFS1 rare heterozygous variants reported in diabetes, there is a need for comprehensive genetic screening strategies for the early diagnosis of WFS and delineating the phenotypic spectrum associated with the WFS1 gene variants in young-onset diabetes. METHODS: This case series of 11 patients who were positive for WFS1 variants were identified with next-generation sequencing (NGS)-based screening of 17 genemonogenic diabetes panel. These results were further confirmed with Sanger sequencing. RESULTS: 9 out of 11 patients were homozygous for pathogenic/likely pathogenic variants in the WFS1 gene. Interestingly, 3 of these probands were positive for the novel WFS1 (NM_006005.3): c.1107_1108insA (p.Ala370Serfs*173) variant, and haplotype analysis suggested a founder effect in 3 families from Southern India. Additionally, we identified 2 patients with young-onset diabetes who were heterozygous for a likely pathogenic variant or a variant of uncertain significance in the WFS1 gene. CONCLUSION: These results project the need for NGS-based parallel multigene testing as a tool for early diagnosis of WFS and identify heterozygous WFS1 variants implicated in young-onset diabetes.

Food environments and obesity: A geospatial analysis of the South Asia Biobank, income and sex inequalities.

INTRODUCTION: In low-middle income countries (LMICs) the role of food environments on obesity has been understudied. We address this gap by 1) examining the effect of food environments on adults' body size (BMI, waist circumference) and obesity; 2) measuring the heterogeneity of such effects by income and sex. METHODS: This cross-sectional study analysed South Asia Biobank surveillance and environment mapping data for 12,167 adults collected between 2018 and 2020 from 33 surveillance sites in Bangladesh and Sri Lanka. Individual-level data (demographic, socio-economic, and health characteristics) were combined with exposure to healthy and unhealthy food environments measured with geolocations of food outlets (obtained through ground-truth surveys) within 300 m buffer zones around participants' homes. Multivariate regression models were used to assess association of exposure to healthy and unhealthy food environments on waist circumference, BMI, and probability of obesity for the total sample and stratified by sex and income. FINDINGS: The presence of a higher share of supermarkets in the neighbourhood was associated with a reduction in body size (BMI, ß = - 3∙23; p < 0∙0001, and waist circumference, ß = -5∙99; p = 0∙0212) and obesity (Average Marginal Effect (AME): -0∙18; p = 0∙0009). High share of fast-food restaurants in the neighbourhood was not significantly associated with body size, but it significantly increased the probability of obesity measured by BMI (AME: 0∙09; p = 0∙0234) and waist circumference (AME: 0∙21; p = 0∙0021). These effects were stronger among females and low-income individuals. INTERPRETATION: The results suggest the availability of fast-food outlets influences obesity, especially among female and lower-income groups. The availability of supermarkets is associated with reduced body size and obesity, but their effects do not outweigh the role of fast-food outlets. Policies should target food environments to promote better diets and reduce obesity.

The iHealth-T2D study: a cluster randomised trial for the prevention of type 2 diabetes amongst South Asians with central obesity and prediabetes-a statistical analysis plan.

BACKGROUND: South Asians are at high risk of type 2 diabetes (T2D). Lifestyle modification is effective at preventing T2D amongst South Asians, but the approaches to screening and intervention are limited by high costs, poor scalability and thus low impact on T2D burden. An intensive family-based lifestyle modification programme for the prevention of T2D was developed. The aim of the iHealth-T2D trial is to compare the effectiveness of this programme with usual care. METHODS: The iHealth-T2D trial is designed as a cluster randomised controlled trial (RCT) conducted at 120 sites across India, Pakistan, Sri Lanka and the UK. A total of 3682 South Asian men and women with age between 40 and 70 years without T2D but at elevated risk for T2D [defined by central obesity (waist circumference ≥ 95 cm in Sri Lanka or ≥ 100 cm in India, Pakistan and the UK) and/or prediabetes (HbA1c ≥ 6.0%)] were included in the trial. Here, we describe in detail the statistical analysis plan (SAP), which was finalised before outcomes were available to the investigators. The primary outcome will be evaluated after 3 years of follow-up after enrolment to the study and is defined as T2D incidence in the intervention arm compared to usual care. Secondary outcomes are evaluated both after 1 and 3 years of follow-up and include biochemical measurements, anthropometric measurements, behavioural components and treatment compliance. DISCUSSION: The iHealth-T2D trial will provide evidence of whether an intensive family-based lifestyle modification programme for South Asians who are at high risk for T2D is effective in the prevention of T2D. The data from the trial will be analysed according to this pre-specified SAP. ETHICS AND DISSEMINATION: The trial was approved by the international review board of each participating study site. Study findings will be disseminated through peer-reviewed publications and in conference presentations. TRIAL REGISTRATION: EudraCT 2016-001,350-18 . Registered on 14 April 2016. CLINICALTRIALS: gov NCT02949739 . Registered on 31 October 2016.

High failure rate of ChAdOx1-nCoV19 immunization against asymptomatic infection in healthcare workers during a Delta variant surge.

Immunization is expected to confer protection against infection and severe disease for vaccines while reducing risks to unimmunized populations by inhibiting transmission. Here, based on serial serological studies of an observational cohort of healthcare workers, we show that during a Severe Acute Respiratory Syndrome -Coronavirus 2 Delta-variant outbreak in Delhi, 25.3% (95% Confidence Interval 16.9-35.2) of previously uninfected, ChAdOx1-nCoV19 double vaccinated, healthcare workers were infected within less than two months, based on serology. Induction of anti-spike response was similar between groups with breakthrough infection (541 U/ml, Inter Quartile Range 374) and without (342 U/ml, Inter Quartile Range 497), as was the induction of neutralization activity to wildtype. This was not vaccine failure since vaccine effectiveness estimate based on infection rates in an unvaccinated cohort were about 70% and most infections were asymptomatic. We find that while ChAdOx1-nCoV19 vaccination remains effective in preventing severe infections, it is unlikely to be completely able to block transmission and provide herd immunity.

COVID-19 Risk Stratification and Mortality Prediction in Hospitalized Indian Patients: Harnessing clinical data for public health benefits.

The variability of clinical course and prognosis of COVID-19 highlights the necessity of patient sub-group risk stratification based on clinical data. In this study, clinical data from a cohort of Indian COVID-19 hospitalized patients is used to develop risk stratification and mortality prediction models. We analyzed a set of 70 clinical parameters including physiological and hematological for developing machine learning models to identify biomarkers. We also compared the Indian and Wuhan cohort, and analyzed the role of steroids. A bootstrap averaged ensemble of Bayesian networks was also learned to construct an explainable model for discovering actionable influences on mortality and days to outcome. We discovered blood parameters, diabetes, co-morbidity and SpO2 levels as important risk stratification features, whereas mortality prediction is dependent only on blood parameters. XGboost and logistic regression model yielded the best performance on risk stratification and mortality prediction, respectively (AUC score 0.83, AUC score 0.92). Blood coagulation parameters (ferritin, D-Dimer and INR), immune and inflammation parameters IL6, LDH and Neutrophil (%) are common features for both risk and mortality prediction. Compared with Wuhan patients, Indian patients with extreme blood parameters indicated higher survival rate. Analyses of medications suggest that a higher proportion of survivors and mild patients who were administered steroids had extreme neutrophil and lymphocyte percentages. The ensemble averaged Bayesian network structure revealed serum ferritin to be the most important predictor for mortality and Vitamin D to influence severity independent of days to outcome. The findings are important for effective triage during strains on healthcare infrastructure.

HCQ prophylaxis in COVID-19 did not show any QTc prolongation in Healthcare workers.

BACKGROUND: HCQ is a commonly recommended drug for the prophylaxis of COVID-19. One of its rare side-effect includes QTc prolongation. METHODS: This was a prospective, cross sectional and observational study conducted on Hydroxychloroquine (HCQ) among Healthcare Workers (HCWs) at Max Super Speciality Hospital, Saket, New Delhi, India. A 3-lead ECG (only limb leads, it does not require chest leads) was performed. The QTc cut offs were pre decided, QTC < 470 ms for males and <480 ms for females was considered within the normal limits and anything above this was regarded as QTc prolongation. RESULTS: There were 274 HCWs enrolled into the study, including 175 males and 99 females. Majority of the HCWs were young and had a mean age of 32.19 ± 9.29 years. Out of these, 218 were taking HCQ as per the Indian Council of Medical Research (ICMR) guidelines. The median cumulative dose being taken was 1600 mg and the median QTc of these participants was 390 ms in males and 391.5 ms in females. Subsequently, 33 participants were followed-up and found to have a median QTc of 389 ms and a cumulative dose of HCQ as 2000 mg. CONCLUSION: In conclusion, ours is a first study in the middle of the pandemic which showed that HCQ prophylaxis in young HCWs without comorbidities did not show any QTc prolongation.

Respiratory Co-Infections: Modulators of SARS-CoV-2 Patients' Clinical Sub-Phenotype.

Co-infection with ancillary pathogens is a significant modulator of morbidity and mortality in infectious diseases. There have been limited reports of co-infections accompanying SARS-CoV-2 infections, albeit lacking India specific study. The present study has made an effort toward elucidating the prevalence, diversity and characterization of co-infecting respiratory pathogens in the nasopharyngeal tract of SARS-CoV-2 positive patients. Two complementary metagenomics based sequencing approaches, Respiratory Virus Oligo Panel (RVOP) and Holo-seq, were utilized for unbiased detection of co-infecting viruses and bacteria. The limited SARS-CoV-2 clade diversity along with differential clinical phenotype seems to be partially explained by the observed spectrum of co-infections. We found a total of 43 bacteria and 29 viruses amongst the patients, with 18 viruses commonly captured by both the approaches. In addition to SARS-CoV-2, Human Mastadenovirus, known to cause respiratory distress, was present in a majority of the samples. We also found significant differences of bacterial reads based on clinical phenotype. Of all the bacterial species identified, ∼60% have been known to be involved in respiratory distress. Among the co-pathogens present in our sample cohort, anaerobic bacteria accounted for a preponderance of bacterial diversity with possible role in respiratory distress. Clostridium botulinum, Bacillus cereus and Halomonas sp. are anaerobes found abundantly across the samples. Our findings highlight the significance of metagenomics based diagnosis and detection of SARS-CoV-2 and other respiratory co-infections in the current pandemic to enable efficient treatment administration and better clinical management. To our knowledge this is the first study from India with a focus on the role of co-infections in SARS-CoV-2 clinical sub-phenotype.

Clinico-Genomic Analysis Reveals Mutations Associated with COVID-19 Disease Severity: Possible Modulation by RNA Structure.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) manifests a broad spectrum of clinical presentations, varying in severity from asymptomatic to mortality. As the viral infection spread, it evolved and developed into many variants of concern. Understanding the impact of mutations in the SARS-CoV-2 genome on the clinical phenotype and associated co-morbidities is important for treatment and preventionas the pandemic progresses. Based on the mild, moderate, and severe clinical phenotypes, we analyzed the possible association between both, the clinical sub-phenotypes and genomic mutations with respect to the severity and outcome of the patients. We found a significant association between the requirement of respiratory support and co-morbidities. We also identified six SARS-CoV-2 genome mutations that were significantly correlated with severity and mortality in our cohort. We examined structural alterations at the RNA and protein levels as a result of three of these mutations: A26194T, T28854T, and C25611A, present in the Orf3a and N protein. The RNA secondary structure change due to the above mutations can be one of the modulators of the disease outcome. Our findings highlight the importance of integrative analysis in which clinical and genetic components of the disease are co-analyzed. In combination with genomic surveillance, the clinical outcome-associated mutations could help identify individuals for priority medical support.

Effects of a lifestyle intervention programme after 1 year of follow-up among South Asians at high risk of type 2 diabetes: a cluster randomised controlled trial.

INTRODUCTION: South Asians are at high risk of type 2 diabetes (T2D). We assessed whether intensive family-based lifestyle intervention leads to significant weight loss, improved glycaemia and blood pressure in adults at elevated risk for T2D. METHODS: This cluster randomised controlled trial (iHealth-T2D) was conducted at 120 locations across India, Pakistan, Sri Lanka and the UK. We included 3684 South Asian men and women, aged 40-70 years, without T2D but with raised haemoglobin A1c (HbA1c) and/or waist circumference. Participants were randomly allocated either to the family-based lifestyle intervention or control group by location clusters. Participants in the intervention received 9 visits and 13 telephone contacts by community health workers over 1-year period, and the control group received usual care. Reductions in weight (aim >7% reduction), waist circumference (aim ≥5 cm reduction), blood pressure and HbA1C at 12 months of follow-up were assessed. Our linear mixed-effects regression analysis was based on intention-to-treat principle and adjusted for age, sex and baseline values. RESULTS: There were 1846 participants in the control and 1838 in the intervention group. Between baseline and 12 months, mean weight of participants in the intervention group reduced by 1.8 kg compared with 0.4 kg in the control group (adjusted mean difference -1.10 kg (95% CI -1.70 to -1.06), p<0.001). The adjusted mean difference for waist circumference was -1.9 cm (95% CI -2.5; to 1.3), p<0.001). No overall difference was observed for blood pressure or HbA1c. People who attended multiple intervention sessions had a dose-dependent effect on waist circumference, blood pressure and HbA1c, but not on weight. CONCLUSION: An intensive family-based lifestyle intervention adopting low-resource strategies led to effective reduction in weight and waist circumference at 12 months, which has potential long-term benefits for preventing T2D. A higher number of attended sessions increased the effect on waist circumference, blood pressure and HbA1c. TRIAL REGISTRATION NUMBER: EudraCT: 2016-001350-18; ClinicalTrials.gov: NCT02949739.