Jawaharlal Institute of Post Graduate Medical Education and Research

Over the past 2 decades, nonalcoholic fatty liver disease (NAFLD) has grown from a relatively unknown disease to the most common cause of chronic liver disease in the world. In fact, 25% of the world's population is currently thought to have NAFLD. Nonalcoholic steatohepatitis (NASH) is the subtype of NAFLD that can progress to cirrhosis, hepatocellular carcinoma (HCC), and death. NAFLD and NASH are not only found in adults-there is also a high prevalence of these diseases in children and adolescents. Because of the close association of NAFLD with type 2 diabetes (T2DM) and obesity, the latest models predict that the prevalence of NAFLD and NASH will increase, causing a tremendous clinical and economic burden and poor patient-reported outcomes. Nonetheless, there is no accurate noninvasive method to detect NASH, and treatment of this disease is limited to lifestyle modifications. To examine the state of NAFLD among different regions and understand the global trajectory of this disease, an international group of experts came together during the 2017 American Association for the Study of Liver Diseases Global NAFLD Forum. We provide a summary of this forum and an assessment of the current state of NAFLD and NASH worldwide.

BACKGROUND: Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0-60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0-60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development. METHODS: In this systematic analysis, we expanded our global RSV disease burden dataset by obtaining new data from an updated search for papers published between Jan 1, 2017, and Dec 31, 2020, from MEDLINE, Embase, Global Health, CINAHL, Web of Science, LILACS, OpenGrey, CNKI, Wanfang, and ChongqingVIP. We also included unpublished data from RSV GEN collaborators. Eligible studies reported data for children aged 0-60 months with RSV as primary infection with acute lower respiratory infection in community settings, or acute lower respiratory infection necessitating hospital admission; reported data for at least 12 consecutive months, except for in-hospital case fatality ratio (CFR) or for where RSV seasonality is well-defined; and reported incidence rate, hospital admission rate, RSV positive proportion in acute lower respiratory infection hospital admission, or in-hospital CFR. Studies were excluded if case definition was not clearly defined or not consistently applied, RSV infection was not laboratory confirmed or based on serology alone, or if the report included fewer than 50 cases of acute lower respiratory infection. We applied a generalised linear mixed-effects model (GLMM) to estimate RSV-associated acute lower respiratory infection incidence, hospital admission, and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. We estimated country-level RSV-associated acute lower respiratory infection incidence through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality. This review was registered in PROSPERO (CRD42021252400). FINDINGS: In addition to 317 studies included in our previous review, we identified and included 113 new eligible studies and unpublished data from 51 studies, for a total of 481 studies. We estimated that globally in 2019, there were 33·0 million RSV-associated acute lower respiratory infection episodes (uncertainty range [UR] 25·4-44·6 million), 3·6 million RSV-associated acute lower respiratory infection hospital admissions (2·9-4·6 million), 26 300 RSV-associated acute lower respiratory infection in-hospital deaths (15 100-49 100), and 101 400 RSV-attributable overall deaths (84 500-125 200) in children aged 0-60 months. In infants aged 0-6 months, we estimated that there were 6·6 million RSV-associated acute lower respiratory infection episodes (4·6-9·7 million), 1·4 million RSV-associated acute lower respiratory infection hospital admissions (1·0-2·0 million), 13 300 RSV-associated acute lower respiratory infection in-hospital deaths (6800-28 100), and 45 700 RSV-attributable overall deaths (38 400-55 900). 2·0% of deaths in children aged 0-60 months (UR 1·6-2·4) and 3·6% of deaths in children aged 28 days to 6 months (3·0-4·4) were attributable to RSV. More than 95% of RSV-associated acute lower respiratory infection episodes and more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries (LMICs). INTERPRETATION: RSV contributes substantially to morbidity and mortality burden globally in children aged 0-60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0-60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented. FUNDING: EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).

BACKGROUND: Misconceptions about ADHD stigmatize affected people, reduce credibility of providers, and prevent/delay treatment. To challenge misconceptions, we curated findings with strong evidence base. METHODS: We reviewed studies with more than 2000 participants or meta-analyses from five or more studies or 2000 or more participants. We excluded meta-analyses that did not assess publication bias, except for meta-analyses of prevalence. For network meta-analyses we required comparison adjusted funnel plots. We excluded treatment studies with waiting-list or treatment as usual controls. From this literature, we extracted evidence-based assertions about the disorder. RESULTS: We generated 208 empirically supported statements about ADHD. The status of the included statements as empirically supported is approved by 80 authors from 27 countries and 6 continents. The contents of the manuscript are endorsed by 366 people who have read this document and agree with its contents. CONCLUSIONS: Many findings in ADHD are supported by meta-analysis. These allow for firm statements about the nature, course, outcome causes, and treatments for disorders that are useful for reducing misconceptions and stigma.

BACKGROUND: Viral epidemics or pandemics of acute respiratory infections like influenza or severe acute respiratory syndrome pose a global threat. Antiviral drugs and vaccinations may be insufficient to prevent their spread. OBJECTIVES: To review the effectiveness of physical interventions to interrupt or reduce the spread of respiratory viruses. SEARCH STRATEGY: We searched The Cochrane Library, the Cochrane Central Register of Controlled Trials (CENTRAL 2010, Issue 3), which includes the Acute Respiratory Infections Group's Specialised Register, MEDLINE (1966 to October 2010), OLDMEDLINE (1950 to 1965), EMBASE (1990 to October 2010), CINAHL (1982 to October 2010), LILACS (2008 to October 2010), Indian MEDLARS (2008 to October 2010) and IMSEAR (2008 to October 2010). SELECTION CRITERIA: In this update, two review authors independently applied the inclusion criteria to all identified and retrieved articles and extracted data. We scanned 3775 titles, excluded 3560 and retrieved full papers of 215 studies, to include 66 papers of 67 studies. We included physical interventions (screening at entry ports, isolation, quarantine, social distancing, barriers, personal protection, hand hygiene) to prevent respiratory virus transmission. We included randomised controlled trials (RCTs), cohorts, case-controls, before-after and time series studies. DATA COLLECTION AND ANALYSIS: We used a standardised form to assess trial eligibility. We assessed RCTs by randomisation method, allocation generation, concealment, blinding and follow up. We assessed non-RCTs for potential confounders and classified them as low, medium and high risk of bias. MAIN RESULTS: We included 67 studies including randomised controlled trials and observational studies with a mixed risk of bias. A total number of participants is not included as the total would be made up of a heterogenous set of observations (participant people, observations on participants and countries (object of some studies)). The risk of bias for five RCTs and most cluster-RCTs was high. Observational studies were of mixed quality. Only case-control data were sufficiently homogeneous to allow meta-analysis. The highest quality cluster-RCTs suggest respiratory virus spread can be prevented by hygienic measures, such as handwashing, especially around younger children. Benefit from reduced transmission from children to household members is broadly supported also in other study designs where the potential for confounding is greater. Nine case-control studies suggested implementing transmission barriers, isolation and hygienic measures are effective at containing respiratory virus epidemics. Surgical masks or N95 respirators were the most consistent and comprehensive supportive measures. N95 respirators were non-inferior to simple surgical masks but more expensive, uncomfortable and irritating to skin. Adding virucidals or antiseptics to normal handwashing to decrease respiratory disease transmission remains uncertain. Global measures, such as screening at entry ports, led to a non-significant marginal delay in spread. There was limited evidence that social distancing was effective, especially if related to the risk of exposure. AUTHORS' CONCLUSIONS: Simple and low-cost interventions would be useful for reducing transmission of epidemic respiratory viruses. Routine long-term implementation of some measures assessed might be difficult without the threat of an epidemic.

BACKGROUND: Well designed and properly executed randomised trials are considered the most reliable evidence on the benefits of healthcare interventions. However, there is overwhelming evidence that the quality of reporting is not optimal. The CONSORT (Consolidated Standards of Reporting Trials) statement was designed to improve the quality of reporting and provides a minimum set of items to be included in a report of a randomised trial. CONSORT was first published in 1996, then updated in 2001 and 2010. Here, we present the updated CONSORT 2025 statement, which aims to account for recent methodological advancements and feedback from end users. METHODS: We conducted a scoping review of the literature and developed a project-specific database of empirical and theoretical evidence related to CONSORT, to generate a list of potential changes to the checklist. The list was enriched with recommendations provided by the lead authors of existing CONSORT extensions (Harms, Outcomes, Non-pharmacological Treatment), other related reporting guidelines (TIDieR) and recommendations from other sources (eg, personal communications). The list of potential changes to the checklist was assessed in a large, international, online, three-round Delphi survey involving 317 participants and discussed at a two-day online expert consensus meeting of 30 invited international experts. RESULTS: We have made substantive changes to the CONSORT checklist. We added seven new checklist items, revised three items, deleted one item, and integrated several items from key CONSORT extensions. We also restructured the CONSORT checklist, with a new section on open science. The CONSORT 2025 statement consists of a 30-item checklist of essential items that should be included when reporting the results of a randomised trial and a diagram for documenting the flow of participants through the trial. To facilitate implementation of CONSORT 2025, we have also developed an expanded version of the CONSORT 2025 checklist, with bullet points eliciting critical elements of each item. CONCLUSION: Authors, editors, reviewers, and other potential users should use CONSORT 2025 when writing and evaluating manuscripts of randomised trials to ensure that trial reports are clear and transparent.

Knowledge, attitude, and practice (KAP) surveys are popular in health care because they provide useful information and appear easy to design and execute. There are subtleties, however, in such surveys that early career researchers need to be aware of. This article does not provide a detailed review of the subject, nor does it address theory; rather, it provides practical guidance on matters such as identifying the need for the survey; defining the target population; preparing the questions that address knowledge, attitudes, and practice; preparing options for the answers to the items in the questionnaire; deciding how to score the instrument and analyze the results; and validating the instrument. Specific examples are presented to help readers understand and apply the guidance in various contexts.

Toxicity testing of new compounds is essential for drug development process. The preclinical toxicity testing on various biological systems reveals the species-, organ- and dose- specific toxic effects of an investigational product. The toxicity of substances can be observed by (a) studying the accidental exposures to a substance (b) in vitro studies using cells/ cell lines (c) in vivo exposure on experimental animals. This review mainly focuses on the various experimental animal models and methods used for toxicity testing of substances. The pre-clinical toxicity testing helps to calculate "No Observed Adverse Effect Level" which is needed to initiate the clinical evaluation of investigational products.

Silymarin, a flavonolignan from 'milk thistle' (Silybum marianum) plant is used almost exclusively for hepatoprotection and amounts to 180 million US dollars business in Germany alone. In this review we discuss about its safety, efficacy and future uses in liver diseases. The use of silymarin may replace the polyherbal formulations and will avoid the major problems of standardization, quality control and contamination with heavy metals or bacterial toxins. Silymarin consists of four flavonolignan isomers namely--silybin, isosilybin, silydianin and silychristin. Among them, silybin being the most active and commonly used. Silymarin is orally absorbed and is excreted mainly through bile as sulphates and conjugates. Silymarin offers good protection in various toxic models of experimental liver diseases in laboratory animals. It acts by antioxidative, anti-lipid peroxidative, antifibrotic, anti-inflammatory, membrane stabilizing, immunomodulatory and liver regenerating mechanisms. Silymarin has clinical applications in alcoholic liver diseases, liver cirrhosis, Amanita mushroom poisoning, viral hepatitis, toxic and drug induced liver diseases and in diabetic patients. Though silymarin does not have antiviral properties against hepatitis virus, it promotes protein synthesis, helps in regenerating liver tissue, controls inflammation, enhances glucuronidation and protects against glutathione depletion. Silymarin may prove to be a useful drug for hepatoprotection in hepatobiliary diseases and in hepatotoxicity due to drugs. The non traditional use of silymarin may make a breakthrough as a new approach to protect other organs in addition to liver. As it is having a good safety profile, better patient tolerability and an effective drug at an affordable price, in near future new derivatives or new combinations of this drug may prove to be useful.

Purpose: COVID-19-associated rhino-orbital-cerebral mucormycosis (ROCM) has reached epidemic proportion during India's second wave of COVID-19 pandemic, with several risk factors being implicated in its pathogenesis. This study aimed to determine the patient demographics, risk factors including comorbidities, and medications used to treat COVID-19, presenting symptoms and signs, and the outcome of management. Methods: This was a retrospective, observational study of patients with COVID-19-associated ROCM managed or co-managed by ophthalmologists in India from January 1, 2020 to May 26, 2021. Results: Of the 2826 patients, the states of Gujarat (22%) and Maharashtra (21%) reported the highest number of ROCM. The mean age of patients was 51.9 years with a male preponderance (71%). While 57% of the patients needed oxygen support for COVID-19 infection, 87% of the patients were treated with corticosteroids, (21% for > 10 days). Diabetes mellitus (DM) was present in 78% of all patients. Most of the cases showed onset of symptoms of ROCM between day 10 and day 15 from the diagnosis of COVID-19, 56% developed within 14 days after COVID-19 diagnosis, while 44% had delayed onset beyond 14 days. Orbit was involved in 72% of patients, with stage 3c forming the bulk (27%). Overall treatment included intravenous amphotericin B in 73%, functional endoscopic sinus surgery (FESS)/paranasal sinus (PNS) debridement in 56%, orbital exenteration in 15%, and both FESS/PNS debridement and orbital exenteration in 17%. Intraorbital injection of amphotericin B was administered in 22%. At final follow-up, mortality was 14%. Disease stage >3b had poorer prognosis. Paranasal sinus debridement and orbital exenteration reduced the mortality rate from 52% to 39% in patients with stage 4 disease with intracranial extension (p < 0.05). Conclusion: : Corticosteroids and DM are the most important predisposing factors in the development of COVID-19-associated ROCM. COVID-19 patients must be followed up beyond recovery. Awareness of red flag symptoms and signs, high index of clinical suspicion, prompt diagnosis, and early initiation of treatment with amphotericin B, aggressive surgical debridement of the PNS, and orbital exenteration, where indicated, are essential for successful outcome.

AIM: To study the pattern and prevalence of dyslipidemia in a large representative sample of four selected regions in India. METHODS: Phase I of the Indian Council of Medical Research-India Diabetes (ICMR-INDIAB) study was conducted in a representative population of three states of India [Tamil Nadu, Maharashtra and Jharkhand] and one Union Territory [Chandigarh], and covered a population of 213 million people using stratified multistage sampling design to recruit individuals ≥20 years of age. All the study subjects (n = 16,607) underwent anthropometric measurements and oral glucose tolerance tests were done using capillary blood (except in self-reported diabetes). In addition, in every 5th subject (n = 2042), a fasting venous sample was collected and assayed for lipids. Dyslipidemia was diagnosed using National Cholesterol Education Programme (NCEP) guidelines. RESULTS: Of the subjects studied, 13.9% had hypercholesterolemia, 29.5% had hypertriglyceridemia, 72.3% had low HDL-C, 11.8% had high LDL-C levels and 79% had abnormalities in one of the lipid parameters. Regional disparity exists with the highest rates of hypercholesterolemia observed in Tamilnadu (18.3%), highest rates of hypertriglyceridemia in Chandigarh (38.6%), highest rates of low HDL-C in Jharkhand (76.8%) and highest rates of high LDL-C in Tamilnadu (15.8%). Except for low HDL-C and in the state of Maharashtra, in all other states, urban residents had the highest prevalence of lipid abnormalities compared to rural residents. Low HDL-C was the most common lipid abnormality (72.3%) in all the four regions studied; in 44.9% of subjects, it was present as an isolated abnormality. Common significant risk factors for dyslipidemia included obesity, diabetes, and dysglycemia. CONCLUSION: The prevalence of dyslipidemia is very high in India, which calls for urgent lifestyle intervention strategies to prevent and manage this important cardiovascular risk factor.

BACKGROUND: The rising prevalence of diabetes and obesity in India can be attributed, at least in part, to increasing levels of physical inactivity. However, there has been no nationwide survey in India on physical activity levels involving both the urban and rural areas in whole states of India. The aim of the present study was to assess physical activity patterns across India - as part of the Indian Council of Medical Research-India Diabetes (ICMR-INDIAB) study. METHODS: Phase 1 of the ICMR-INDIAB study was conducted in four regions of India (Tamilnadu, Maharashtra, Jharkhand and Chandigarh representing the south, west, east and north of India respectively) with a combined population of 213 million people. Physical activity was assessed using the Global Physical Activity Questionnaire (GPAQ) in 14227 individuals aged ≥ 20 years [urban- 4,173; rural- 10,054], selected from the above regions using a stratified multistage design. RESULTS: Of the 14227 individuals studied, 54.4% (n=7737) were inactive (males: 41.7%), while 31.9% (n=4537) (males: 58.3%) were active and 13.7% (n=1953) (males: 61.3%) were highly active. Subjects were more inactive in urban, compared to rural, areas (65.0% vs. 50.0%; p<0.001). Males were significantly more active than females (p<0.001). Subjects in all four regions spent more active minutes at work than in the commuting and recreation domains. Absence of recreational activity was reported by 88.4%, 94.8%, 91.3% and 93.1% of the subjects in Chandigarh, Jharkhand, Maharashtra and Tamilnadu respectively. The percentage of individuals with no recreational activity increased with age (Trend χ(2): 199.1, p<0.001). CONCLUSIONS: The study shows that a large percentage of people in India are inactive with fewer than 10% engaging in recreational physical activity. Therefore, urgent steps need to be initiated to promote physical activity to stem the twin epidemics of diabetes and obesity in India.

BACKGROUND: Obstructive sleep apnea is associated with an increased prevalence of the metabolic syndrome and its components. It is unclear whether treatment of obstructive sleep apnea syndrome with continuous positive airway pressure (CPAP) would modify these outcomes. METHODS: In our double-blind, placebo-controlled trial, we randomly assigned patients with obstructive sleep apnea syndrome to undergo 3 months of therapeutic CPAP followed by 3 months of sham CPAP, or vice versa, with a washout period of 1 month in between. Before and after each intervention, we obtained measurements of anthropometric variables, blood pressure, fasting blood glucose levels, insulin resistance (with the use of homeostasis model assessment), fasting blood lipid profile, glycated hemoglobin levels, carotid intima-media thickness, and visceral fat. The metabolic syndrome was defined according to National Cholesterol Education Program Adult Treatment Panel III criteria, with Asian cutoff values for abdominal obesity. RESULTS: A total of 86 patients completed the study, 75 (87%) of whom had the metabolic syndrome. CPAP treatment (vs. sham CPAP) was associated with significant mean decreases in systolic blood pressure (3.9 mm Hg; 95% confidence interval [CI], 1.4 to 6.4; P=0.001), diastolic blood pressure (2.5 mm Hg; 95% CI, 0.9 to 4.1; P<0.001), serum total cholesterol (13.3 mg per deciliter; 95% CI, 5.3 to 21.3; P=0.005), non-high-density lipoprotein cholesterol (13.3 mg per deciliter; 95% CI, 4.8 to 21.8; P=0.009), low-density lipoprotein cholesterol (9.6 mg per deciliter; 95% CI, 2.5 to 16.7; P=0.008), triglycerides (18.7 mg per deciliter; 95% CI, 4.3 to 41.6; P=0.02), and glycated hemoglobin (0.2%; 95% CI, 0.1 to 0.4; P=0.003). The frequency of the metabolic syndrome was reduced after CPAP therapy (reversal found in 11 of 86 patients [13%] undergoing CPAP therapy vs. 1 of 86 [1%] undergoing sham CPAP). Accelerated hypertension developed 1 patient receiving CPAP therapy first, intolerance to CPAP developed in 2 others, and another patient declined to continue sham CPAP. CONCLUSIONS: In patients with moderate-to-severe obstructive sleep apnea syndrome, 3 months of CPAP therapy lowers blood pressure and partially reverses metabolic abnormalities. (Funded by Pfizer; ClinicalTrials.gov number, NCT00694616.).

INTRODUCTION: To mitigate the spread of the pandemic coronavirus infection (COVID-19), governments across the world have adopted "lockdowns" which have confined many individuals to their homes. This disrupts normal life routines, elements of which are important circadian cues. The pandemic is also associated with new stressors, altered roles, and uncertainties about health and economic security, which are also likely to affect sleep. The current study is an online survey of sleep experience, routines, physical activity, and symptoms of anxiety and depression, to study the alterations associated with the lockdown. MATERIALS AND METHODS: The survey was conducted in early May 2020 using a questionnaire circulated through social media platforms. Questions related to demographic characteristics, current and previous sleep schedules, routine, and working patterns. Insomnia (Insomnia Severity Index - 4), Stress (Perceived Stress Scale - 4), anxiety and depressive symptoms (Patient Health Questionnaire - 4) and physical activity (International Physical Activities Questionnaire) were assessed using standardized instruments. RESULTS: A total of 958 valid responses were received. Compared to the prelockdown period, there was a shift to a later bedtime and waking time, with a reduction in night-time sleep and an increase in day-time napping. These effects were visible across occupational groups, but mostly affected working individuals except health professionals. Sleep quality deteriorated across groups. Reductions in sleep duration were associated with depressive symptoms. CONCLUSIONS: The COVID-19 lockdown is associated with changes in sleep schedule and in the quantity and quality of night-time sleep. Although these changes are associated with elevated rates of emotional symptoms, it is unclear from these cross-sectional results, whether sleep deterioration produces psychological distress, or vice versa.

BACKGROUND: Inconsistent evidence exists regarding the strength, direction, and moderators in the relationship between obesity and psychiatric disorders. AIM: This study aims to summarize the evidence on the association between psychiatric illness and obesity with particular attention to the strength and direction of association and also the possible moderators in each postulated link. MATERIALS AND METHODS: Systematic electronic searches of MEDLINE through PubMed, ScienceDirect, PsycINFO, and Google Scholar were carried out from inception till October 2016. Generated abstracts were screened for eligibility to be included in the review. Study designs that evaluated the strength of relationship between obesity and psychiatric disorders were included in the study. Quality assessment of included studies was done using the Newcastle-Ottawa checklist tool. RESULTS: From a total of 2424 search results, 21 eligible articles were identified and reviewed. These included studies on obesity and depression (n = 15), obesity and anxiety (four) and one each on obesity and personality disorders, eating disorder (ED), attention deficit hyperactivity disorder, and alcohol use. Maximal evidence existed for the association between depression and obesity with longitudinal studies demonstrating a bidirectional link between the two conditions. The odds ratios (ORs) were similar for developing depression in obesity (OR: 1.21-5.8) and vice versa (OR: 1.18-3.76) with a stronger association observed in women. For anxiety disorders, evidence was mostly cross-sectional, and associations were of modest magnitude (OR: 1.27-1.40). Among other disorders, obesity, and EDs appear to have a close link (OR: 4.5). Alcohol use appears to be a risk factor for obesity and not vice versa but only among women (OR: 3.84). CONCLUSION: Obesity and depression have a significant and bidirectional association. Evidence is modest for anxiety disorders and inadequate for other psychiatric conditions. Gender appears to be an important mediator in these relationships.

BACKGROUND: For more than three decades, the Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) has provided a framework to quantify health loss due to diseases, injuries, and associated risk factors. This paper presents GBD 2023 findings on disease and injury burden and risk-attributable health loss, offering a global audit of the state of world health to inform public health priorities. This work captures the evolving landscape of health metrics across age groups, sexes, and locations, while reflecting on the remaining post-COVID-19 challenges to achieving our collective global health ambitions. METHODS: The GBD 2023 combined analysis estimated years lived with disability (YLDs), years of life lost (YLLs), and disability-adjusted life-years (DALYs) for 375 diseases and injuries, and risk-attributable burden associated with 88 modifiable risk factors. Of the more than 310 000 total data sources used for all GBD 2023 (about 30% of which were new to this estimation round), more than 120 000 sources were used for estimation of disease and injury burden and 59 000 for risk factor estimation, and included vital registration systems, surveys, disease registries, and published scientific literature. Data were analysed using previously established modelling approaches, such as disease modelling meta-regression version 2.1 (DisMod-MR 2.1) and comparative risk assessment methods. Diseases and injuries were categorised into four levels on the basis of the established GBD cause hierarchy, as were risk factors using the GBD risk hierarchy. Estimates stratified by age, sex, location, and year from 1990 to 2023 were focused on disease-specific time trends over the 2010-23 period and presented as counts (to three significant figures) and age-standardised rates per 100 000 person-years (to one decimal place). For each measure, 95% uncertainty intervals [UIs] were calculated with the 2·5th and 97·5th percentile ordered values from a 250-draw distribution. FINDINGS: Total numbers of global DALYs grew 6·1% (95% UI 4·0-8·1), from 2·64 billion (2·46-2·86) in 2010 to 2·80 billion (2·57-3·08) in 2023, but age-standardised DALY rates, which account for population growth and ageing, decreased by 12·6% (11·0-14·1), revealing large long-term health improvements. Non-communicable diseases (NCDs) contributed 1·45 billion (1·31-1·61) global DALYs in 2010, increasing to 1·80 billion (1·63-2·03) in 2023, alongside a concurrent 4·1% (1·9-6·3) reduction in age-standardised rates. Based on DALY counts, the leading level 3 NCDs in 2023 were ischaemic heart disease (193 million [176-209] DALYs), stroke (157 million [141-172]), and diabetes (90·2 million [75·2-107]), with the largest increases in age-standardised rates since 2010 occurring for anxiety disorders (62·8% [34·0-107·5]), depressive disorders (26·3% [11·6-42·9]), and diabetes (14·9% [7·5-25·6]). Remarkable health gains were made for communicable, maternal, neonatal, and nutritional (CMNN) diseases, with DALYs falling from 874 million (837-917) in 2010 to 681 million (642-736) in 2023, and a 25·8% (22·6-28·7) reduction in age-standardised DALY rates. During the COVID-19 pandemic, DALYs due to CMNN diseases rose but returned to pre-pandemic levels by 2023. From 2010 to 2023, decreases in age-standardised rates for CMNN diseases were led by rate decreases of 49·1% (32·7-61·0) for diarrhoeal diseases, 42·9% (38·0-48·0) for HIV/AIDS, and 42·2% (23·6-56·6) for tuberculosis. Neonatal disorders and lower respiratory infections remained the leading level 3 CMNN causes globally in 2023, although both showed notable rate decreases from 2010, declining by 16·5% (10·6-22·0) and 24·8% (7·4-36·7), respectively. Injury-related age-standardised DALY rates decreased by 15·6% (10·7-19·8) over the same period. Differences in burden due to NCDs, CMNN diseases, and injuries persisted across age, sex, time, and location. Based on our risk analysis, nearly 50% (1·27 billion [1·18-1·38]) of the roughly 2·80 billion total global DALYs in 2023 were attributable to the 88 risk factors analysed in GBD. Globally, the five level 3 risk factors contributing the highest proportion of risk-attributable DALYs were high systolic blood pressure (SBP), particulate matter pollution, high fasting plasma glucose (FPG), smoking, and low birthweight and short gestation-with high SBP accounting for 8·4% (6·9-10·0) of total DALYs. Of the three overarching level 1 GBD risk factor categories-behavioural, metabolic, and environmental and occupational-risk-attributable DALYs rose between 2010 and 2023 only for metabolic risks, increasing by 30·7% (24·8-37·3); however, age-standardised DALY rates attributable to metabolic risks decreased by 6·7% (2·0-11·0) over the same period. For all but three of the 25 leading level 3 risk factors, age-standardised rates dropped between 2010 and 2023-eg, declining by 54·4% (38·7-65·3) for unsafe sanitation, 50·5% (33·3-63·1) for unsafe water source, and 45·2% (25·6-72·0) for no access to handwashing facility, and by 44·9% (37·3-53·5) for child growth failure. The three leading level 3 risk factors for which age-standardised attributable DALY rates rose were high BMI (10·5% [0·1 to 20·9]), drug use (8·4% [2·6 to 15·3]), and high FPG (6·2% [-2·7 to 15·6]; non-significant). INTERPRETATION: Our findings underscore the complex and dynamic nature of global health challenges. Since 2010, there have been large decreases in burden due to CMNN diseases and many environmental and behavioural risk factors, juxtaposed with sizeable increases in DALYs attributable to metabolic risk factors and NCDs in growing and ageing populations. This long-observed consequence of the global epidemiological transition was only temporarily interrupted by the COVID-19 pandemic. The substantially decreasing CMNN disease burden, despite the 2008 global financial crisis and pandemic-related disruptions, is one of the greatest collective public health successes known. However, these achievements are at risk of being reversed due to major cuts to development assistance for health globally, the effects of which will hit low-income countries with high burden the hardest. Without sustained investment in evidence-based interventions and policies, progress could stall or reverse, leading to widespread human costs and geopolitical instability. Moreover, the rising NCD burden necessitates intensified efforts to mitigate exposure to leading risk factors-eg, air pollution, smoking, and metabolic risks, such as high SBP, BMI, and FPG-including policies that promote food security, healthier diets, physical activity, and equitable and expanded access to potential treatments, such as GLP-1 receptor agonists. Decisive, coordinated action is needed to address long-standing yet growing health challenges, including depressive and anxiety disorders. Yet this can be only part of the solution. Our response to the NCD syndemic-the complex interaction of multiple health risks, social determinants, and systemic challenges-will define the future landscape of global health. To ensure human wellbeing, economic stability, and social equity, global action to sustain and advance health gains must prioritise reducing disparities by addressing socioeconomic and demographic determinants, ensuring equitable health-care access, tackling malnutrition, strengthening health systems, and improving vaccination coverage. We live in times of great opportunity. FUNDING: Gates Foundation and Bloomberg Philanthropies.

The All India Difficult Airway Association (AIDAA) guidelines for management of the unanticipated difficult airway in adults provide a structured, stepwise approach to manage unanticipated difficulty during tracheal intubation in adults. They have been developed based on the available evidence; wherever robust evidence was lacking, or to suit the needs and situation in India, recommendations were arrived at by consensus opinion of airway experts, incorporating the responses to a questionnaire sent to members of the AIDAA and the Indian Society of Anaesthesiologists. We recommend optimum pre-oxygenation and nasal insufflation of 15 L/min oxygen during apnoea in all patients, and calling for help if the initial attempt at intubation is unsuccessful. Transnasal humidified rapid insufflations of oxygen at 70 L/min (transnasal humidified rapid insufflation ventilatory exchange) should be used when available. We recommend no more than three attempts at tracheal intubation and two attempts at supraglottic airway device (SAD) insertion if intubation fails, provided oxygen saturation remains ≥ 95%. Intubation should be confirmed by capnography. Blind tracheal intubation through the SAD is not recommended. If SAD insertion fails, one final attempt at mask ventilation should be tried after ensuring neuromuscular blockade using the optimal technique for mask ventilation. Failure to intubate the trachea as well as an inability to ventilate the lungs by face mask and SAD constitutes 'complete ventilation failure', and emergency cricothyroidotomy should be performed. Patient counselling, documentation and standard reporting of the airway difficulty using a 'difficult airway alert form' must be done. In addition, the AIDAA provides suggestions for the contents of a difficult airway cart.

BACKGROUND & OBJECTIVES: Practice of breathing exercises like pranayama is known to improve autonomic function by changing sympathetic or parasympathetic activity. Therefore, in the present study the effect of breathing exercises on autonomic functions was performed in young volunteers in the age group of 17-19 yr. METHODS: A total of 60 male undergraduate medical students were randomly divided into two groups: slow breathing group (that practiced slow breathing exercise) and the fast breathing group (that practiced fast breathing exercise). The breathing exercises were practiced for a period of three months. Autonomic function tests were performed before and after the practice of breathing exercises. RESULTS: The increased parasympathetic activity and decreased sympathetic activity were observed in slow breathing group, whereas no significant change in autonomic functions was observed in the fast breathing group. INTERPRETATION & CONCLUSION: The findings of the present study show that regular practice of slow breathing exercise for three months improves autonomic functions, while practice of fast breathing exercise for the same duration does not affect the autonomic functions.

We describe an indirect method for assessing variation in 3-hydroxy-3-methylglutaryl-coenzyme A reductase (NADPH) activity in liver tissue. 3-Hydroxy-3-methyglutaryl-CoA and mevalonate concentrations in the tissue homogenate are estimated in terms of absorbances and the ratio between the two is taken as an index of activity of the enzyme, which catalyzes the conversion of 3-hydroxy-3-methylglutaryl-CoZ to mevalonate. The ratio increases under conditions in which activity of this enzyme in liver reportedly decreases (e.g., fasting, cholesterol feeding) and decreases under conditions in which the activity of this enzyme reportedly increases (e.g., Triton injection, phenobarbital treatment). We assessed the magnitude of hepatic cholesterogenesis in intact male albino rats by using [1,2-14C] acetate, in fed controls, fasted, cholesterol-fed, Triton-treated, and phenobarbital-treated. The ratio, 3-hydroxy-3-methylglutaryl-CoA/mevalonate was estimated in liver tissue for all the above groups. The method is simple, reproducible, and does not require any unusual chemicals.

Dear Editor, The 2019 novel coronavirus (2019-nCoV) or severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) first reported in Wuhan, Hubei province in China, quickly spread to other parts of the world forming a global pandemic.[1] The disease pattern of COVID-19 can range from mild to life-threatening pneumonia with associated bacterial and fungal coinfections.[2] Due to the associated comorbidities (e.g., diabetes mellitus, chronic obstructive pulmonary disease) and immunocompromised conditions (e.g. corticosteroid therapy, ventilation, intensive care unit stay), these patients are prone to develop severe opportunistic infections. There are reports of the development of severe opportunistic infections such as oropharyngeal candidiasis, pneumocystis jiroveci pneumonia, pulmonary aspergillosis, bloodstream candida infections, etc., in patients affected with COVID-19 disease.[34] There are also few isolated case reports of rhino-orbital mucormycosis in COVID-19 disease.[25] Sen et al. recently reported a series of six cases of COVID-19 disease with rhino-orbital mucormycosis. One patient in this series had concurrent COVID-19 and mucormycosis at admission, while five other patients developed mucormycosis during treatment with systemic steroids for COVID-19.[6] We, hereby, report a cluster of 10 cases of clinically diagnosed orbital mucormycosis with concurrent COVID-19 illness at our institute over the last 2 months (October and November 2020). They presented to us with clinical features of orbital mucormycosis and COVID-19 was diagnosed on routine screening. Demographic and clinical profiles of the patients are provided in [Table 1]. Microbiological and radiological diagnosis along with treatment received and final outcome are provided in [Table 2]. Potassium hydroxide (KOH) wet mount and fungal culture/sensitivity were done from biopsy obtained during debridement or from nasal swab obtained during diagnostic nasal endoscopy. Microbiological diagnosis of mucormycosis was proven in six patients. Reverse transcriptase-polymerase chain reaction (RT-PCR) tests for COVID-19 were positive in all the patients. All patients in our series were known diabetics. Diabetic ketoacidosis (DKA) was evident in four patients during admission while five more patients developed DKA after the initiation of corticosteroid therapy for COVID-19 disease. All patients in our series had received intravenous dexamethasone for COVID-19 disease as per The National Institute of Health recommendations[7] and Liposomal Amphotericin B for mucormycosis. Besides, four patients received an injection of Remdesivir, and nine patients required ventilatory support during their hospital stay. The use of steroids, monoclonal antibodies, and broad-spectrum antibiotics for the management of COVID-19 illness can increase the chances of new-onset fungal infection or exacerbate a preexisting one.[2] All patients in our series had received intravenous dexamethasone for COVID-19 disease and Liposomal Amphotericin B for mucormycosis. Four patients in our series expired within 1 month of the diagnosis, five patients had satisfactory systemic outcomes, but with irreversible vision loss, while only one patient had both ocular and systemic favorable outcomes.Table 1: Demographic and clinical profiles of the patientsTable 2: Radiological and microbiological diagnosis, treatment, and final outcome of the patientsCOVID-19 disease has a propensity to cause extensive pulmonary disease and subsequent alveolo-interstitial pathology. This by itself may predispose to invasive fungal infections of the airways including the sinuses and the lungs.[28] Furthermore, there is an alteration of the innate immunity due to COVID-19-associated immune dysregulation characterized by decreased T cells, including CD4 and CD8 cells.[26] All physicians including ophthalmologists should, therefore, be mindful of the probability of development of fungal infections such as mucormycosis in patients with COVID-19 illness, especially in those with comorbidities and on immunosuppressive agents in the coming future.[6] Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.

Antimicrobial resistance is an important concern for the public health authorities at global level. However, in developing countries like India, recent hospital and some community based data showed increase in burden of antimicrobial resistance. Research related to antimicrobial use, determinants and development of antimicrobial resistance, regional variation and interventional strategies according to the existing health care situation in each country is a big challenge. This paper discusses the situational analysis of antimicrobial resistance with respect to its problem, determinants and challenges ahead with strategies required in future to reduce the burden in India. Recent data from Google search, Medline and other sources were collected which was reviewed and analyzed by the authors. Hospital based studies showed higher and varied spectrum of resistance in different regions while there are limited number of community based studies at country level. There exists lacunae in the structure and functioning of public health care delivery system with regard to quantification of the problem and various determining factors related to antimicrobial resistance. There is an urgent need to develop and strengthen antimicrobial policy, standard treatment guidelines, national plan for containment of AMR and research related to public health aspects of AMR at community and hospital level in India.