Institute of Post Graduate Medical Education and Research

The first consensus report of the working party of the Asian Pacific Association for the Study of the Liver (APASL) set up in 2004 on acute-on-chronic liver failure (ACLF) was published in 2009. With international groups volunteering to join, the “APASL ACLF Research Consortium (AARC)” was formed in 2012, which continued to collect prospective ACLF patient data. Based on the prospective data analysis of nearly 1400 patients, the AARC consensus was published in 2014. In the past nearly four-and-a-half years, the AARC database has been enriched to about 5200 cases by major hepatology centers across Asia. The data published during the interim period were carefully analyzed and areas of contention and new developments in the field of ACLF were prioritized in a systematic manner. The AARC database was also approached for answering some of the issues where published data were limited, such as liver failure grading, its impact on the ‘Golden Therapeutic Window’, extrahepatic organ dysfunction and failure, development of sepsis, distinctive features of acute decompensation from ACLF and pediatric ACLF and the issues were analyzed. These initiatives concluded in a two-day meeting in October 2018 at New Delhi with finalization of the new AARC consensus. Only those statements, which were based on evidence using the Grade System and were unanimously recommended, were accepted. Finalized statements were again circulated to all the experts and subsequently presented at the AARC investigators meeting at the AASLD in November 2018. The suggestions from the experts were used to revise and finalize the consensus. After detailed deliberations and data analysis, the original definition of ACLF was found to withstand the test of time and be able to identify a homogenous group of patients presenting with liver failure. New management options including the algorithms for the management of coagulation disorders, renal replacement therapy, sepsis, variceal bleed, antivirals and criteria for liver transplantation for ACLF patients were proposed. The final consensus statements along with the relevant background information and areas requiring future studies are presented here.

In microtitrations constant volumes of fluids are picked up and delivered by specially constructed and calibrated metallic microdiluters.According to the Microtiter Instruction Manual of the Cooke Engineering Company (1965), their high titanium, stainless steel, new-pattern microdiluters with a precisely slotted tip are not supposed to rust, but in the hot and humid climate of Calcutta they do rust, though they con- tinue to deliver fluids properly when tested on the special 'go-no-go' delivery tester supplied by the manufacturer.Many of the rust particles become detached from the microdiluters during their agitation in the wells of the dilution plates and produce, both with human group 0 and goose erythrocytes, an atypical settling pattern at the bottom of disposable plastic V plates.There is a small central button of erythrocytes, showing as well as the peripheral deposit, small black particles rimmed by a clear space.The peripheral concentric erythrocyte deposit closely simulated the typical haemagglutination pattern.Microscopically many black rust particles of various sizes and shapes were observed among discrete erythrocytes, and we have called this atypical pattern pseudohaemagglutination.The rusted particles did not alter the typical agglutination pattern or the titre of some of the haemagglutininpositive enteroviruses and arboviruses.They, however, produced pseudo-haemagglutination with the haemagglutinin-negative enteroviruses as well as the uninoculated tissue culture maintenance medium.It appears that the rusted microdiluters, if used for diluting the antisera or the haemagglutinin-positive antigens, are not likely to modify the positive haemagglutination patterns.But one has to be cautious in using the rusted microdiluters for screening antigens as the detached rust may of itself produce a false-positive haemagglutination pattern.

Although medical literature shows that children are minimally susceptible to 2019-Corona virus disease (COVID-19), they are hit the hardest by psychosocial impact of this pandemic. Being quarantined in homes and institutions may impose greater psychological burden than the physical sufferings caused by the virus. School closure, lack of outdoor activity, aberrant dietary and sleeping habits are likely to disrupt children's usual lifestyle and can potentially promote monotony, distress, impatience, annoyance and varied neuropsychiatric manifestations. Incidences of domestic violence, child abuse, adulterated online contents are on the rise. Children of single parent and frontline workers suffer unique problems. The children from marginalized communities are particularly susceptible to the infection and may suffer from extended ill-consequences of this pandemic, such as child labor, child trafficking, child marriage, sexual exploitation and death etc. Parents, pediatricians, psychologists, social workers, hospital authorities, government and non-governmental organizations have important roles to play to mitigate the psychosocial ill-effects of COVID-19 on children and adolescents. To provide the basic amenities, social security, medical care, and to minimize the educational inequities among the children of the different strata of the society are foremost priorities.

BACKGROUND: A cross-sectional survey was conducted between April 1995 and March 1996 to investigate arsenic-associated skin lesions of keratosis and hyperpigmentation in West Bengal, India, and to determine their relationship to arsenic water levels. METHODS: In all, 7683 participants were examined and interviewed, and the arsenic levels in their drinking water measured. RESULTS: Although water concentrations ranged up to 3400 microg/l of arsenic, over 80% of participants were consuming water containing <500 microg/l. The age-adjusted prevalence of keratosis was strongly related to water arsenic levels, rising from zero in the lowest exposure level (<50 microg/l) to 8.3 per 100 for females drinking water containing >800 microg/l, and increasing from 0.2 per 100 in the lowest exposure category to 10.7 per 100 for males in the highest exposure level (> or =800 microg/l). However, 12 cases with keratosis (2 females and 10 males) were drinking water containing <100 microg/l of arsenic. Findings were similar for hyperpigmentation, with strong dose-response relationships. Among those with hyperpigmentation, 29 cases were exposed to drinking water containing <100 microg/l. Calculation by dose per body weight showed that men had roughly two to three times the prevalence of both keratosis and hyperpigmentation compared to women apparently ingesting the same dose of arsenic from drinking water. Subjects who were below 80% of the standard body weight for their age and sex had a 1.6 fold increase in the prevalence of keratoses, suggesting that malnutrition may play a small role in increasing susceptibility. CONCLUSION: The surprising finding of cases who had arsenic-associated skin lesions with apparently low exposure to arsenic in drinking water needs to be confirmed in studies with more detailed exposure assessment. Further research is also needed concerning susceptibility factors which might be present in the exposed population.

Liver diseases are fast emerging as global health priorities. Fatty liver is described in the setting of non-alcoholic fatty liver disease (NAFLD) as well as alcoholic liver disease (ALD), the pathogenesis of excess fat being different in the two conditions while both are important components of the changing face of burden of liver diseases worldwide. They are intimately associated with a globalized economy and an increasingly homogenous socio- cultural order with a westernized lifestyle. The accompanying adoption of a progressively sedentary life, consumption of diet dense in calories facilitate development of NAFLD while a spiraling upward trend in alcohol use along with earlier age of drinking as well as increased amount of per capita alcohol consumption increases the prevalence of ALD globally. Adverse health outcomes in NAFLD as well as ALD are caused not only by progressive liver fibrosis that is the most significant factor for liver related and all-cause mortality in both but also by non-liver (cardiovascular, cancer, accidents, neurological) clinical outcomes that calls for a multidisciplinary and social approach to these conditions. We present here an outline of facets of epidemiology of both NAFLD as well as ALD along with its' public health implications. A broad-based integrated approach that incorporates social, behavioral as well as biological targets need to be undertaken at a health system level in a planned manner for these evolving liver health priorities that disproportionately challenges the low- and middle-income countries of Asia, South America and Africa.

UNLABELLED: There is a paucity of community-based epidemiological data on nonalcoholic fatty liver (NAFL) among nonaffluent populations in developing countries. Available studies are radiological and/or biochemical and lack histological assessment, limiting their strength. We conducted a prospective epidemiological study comprising a 1:3 subsample of all adult (>18 years) inhabitants of a rural administrative unit of West Bengal, India. Subjects positive for hepatitis B virus and/or hepatitis C virus infection and consuming any amount of alcohol were excluded. Diagnosis of NAFL was by dual radiological screening protocol consisting of ultrasonographic and computed tomographic examination of the liver. Transient elastographic examination and liver biopsy were performed in a subset to identify significant liver disease. The risk factors of having NAFL were analyzed. A total of 1,911 individuals were analyzed, 7% of whom were overweight and 11% of whom had abdominal obesity. The prevalence of NAFL, NAFL with elevated alanine aminotransferase, and cryptogenic cirrhosis was 8.7%, 2.3%, and 0.2%, respectively. Seventy-five percent of NAFL subjects had a body mass index (BMI) <25 kg/m(2), and 54% were neither overweight nor had abdominal obesity. The subjects with the highest risk of having NAFL were those with a BMI >25 kg/m(2) (odds ratio 4.3, 95% confidence interval 1.6-11.5). Abdominal obesity, dysglycemia (fasting plasma glucose >100 mg/dL or elevated homeostatic model assessment of insulin resistance), and higher income were the other risk factors. Even having a normal BMI (18.5-24.9 kg/m(2)) was associated with a 2-fold increased risk of NAFL versus those with a BMI <18.5 kg/m(2). CONCLUSION: There is a significant prevalence of NAFL and potentially significant liver disease, including cryptogenic cirrhosis, in this predominantly nonobese, nonaffluent population in a developing country. NAFL will be a major determinant of future liver disease burden in countries of the developing world.

Antimicrobial resistance in neonatal sepsis is rising, yet mechanisms of resistance that often spread between species via mobile genetic elements, ultimately limiting treatments in low- and middle-income countries (LMICs), are poorly characterized. The Burden of Antibiotic Resistance in Neonates from Developing Societies (BARNARDS) network was initiated to characterize the cause and burden of antimicrobial resistance in neonatal sepsis for seven LMICs in Africa and South Asia. A total of 36,285 neonates were enrolled in the BARNARDS study between November 2015 and December 2017, of whom 2,483 were diagnosed with culture-confirmed sepsis. Klebsiella pneumoniae (n = 258) was the main cause of neonatal sepsis, with Serratia marcescens (n = 151), Klebsiella michiganensis (n = 117), Escherichia coli (n = 75) and Enterobacter cloacae complex (n = 57) also detected. We present whole-genome sequencing, antimicrobial susceptibility and clinical data for 916 out of 1,038 neonatal sepsis isolates (97 isolates were not recovered from initial isolation at local sites). Enterobacterales (K. pneumoniae, E. coli and E. cloacae) harboured multiple cephalosporin and carbapenem resistance genes. All isolated pathogens were resistant to multiple antibiotic classes, including those used to treat neonatal sepsis. Intraspecies diversity of K. pneumoniae and E. coli indicated that multiple antibiotic-resistant lineages cause neonatal sepsis. Our results will underpin research towards better treatments for neonatal sepsis in LMICs.

Treatment failure is a major cause of concern for the Helicobacter pylori-related gastroduodenal diseases like gastritis, peptic ulcer, and gastric cancer. Curcumin, diferuloylmethane from turmeric, has recently been shown to arrest H. pylori growth. The antibacterial activity of curcumin against 65 clinical isolates of H. pylori in vitro and during protection against H. pylori infection in vivo was examined. The MIC of curcumin ranges from 5 microg/ml to 50 microg/ml, showing its effectiveness in inhibiting H. pylori growth in vitro irrespective of the genetic makeup of the strains. The nucleotide sequences of the aroE genes, encoding shikimate dehydrogenase, against which curcumin seems to act as a noncompetitive inhibitor, from H. pylori strains presenting differential curcumin MICs showed that curcumin-mediated growth inhibition of Indian H. pylori strains may not be always dependent on the shikimate pathway. The antimicrobial effect of curcumin in H. pylori-infected C57BL/6 mice and its efficacy in reducing the gastric damage due to infection were examined histologically. Curcumin showed immense therapeutic potential against H. pylori infection as it was highly effective in eradication of H. pylori from infected mice as well as in restoration of H. pylori-induced gastric damage. This study provides novel insights into the therapeutic effect of curcumin against H. pylori infection, suggesting its potential as an alternative therapy, and opens the way for further studies on identification of novel antimicrobial targets of curcumin.

Biomedical research is seldom done with entire populations but rather with samples drawn from a population. Although we work with samples, our goal is to describe and draw inferences regarding the underlying population. It is possible to use a sample statistic and estimates of error in the sample to get a fair idea of the population parameter, not as a single value, but as a range of values. This range is the confidence interval (CI) which is estimated on the basis of a desired confidence level. Calculation of the CI of a sample statistic takes the general form: CI = Point estimate ± Margin of error, where the margin of error is given by the product of a critical value (z) derived from the standard normal curve and the standard error of point estimate. Calculation of the standard error varies depending on whether the sample statistic of interest is a mean, proportion, odds ratio (OR), and so on. The factors affecting the width of the CI include the desired confidence level, the sample size and the variability in the sample. Although the 95% CI is most often used in biomedical research, a CI can be calculated for any level of confidence. A 99% CI will be wider than 95% CI for the same sample. Conflict between clinical importance and statistical significance is an important issue in biomedical research. Clinical importance is best inferred by looking at the effect size, that is how much is the actual change or difference. However, statistical significance in terms of P only suggests whether there is any difference in probability terms. Use of the CI supplements the P value by providing an estimate of actual clinical effect. Of late, clinical trials are being designed specifically as superiority, non-inferiority or equivalence studies. The conclusions from these alternative trial designs are based on CI values rather than the P value from intergroup comparison.

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.

Synapses are essential components of neurons and allow information to travel coordinately throughout the nervous system to adjust behavior to environmental stimuli and to control body functions, memories, and emotions. Thus, optimal synaptic communication is required for proper brain physiology, and slight perturbations of synapse function can lead to brain disorders. In fact, increasing evidence has demonstrated the relevance of synapse dysfunction as a major determinant of many neurological diseases. This notion has led to the concept of synaptopathies as brain diseases with synapse defects as shared pathogenic features. In this review, which was initiated at the 13th International Society for Neurochemistry Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental disorders (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer and Parkinson disease). We finally discuss the appropriateness and potential implications of gathering synapse diseases under a single term. Understanding common causes and intrinsic differences in disease-associated synaptic dysfunction could offer novel clues toward synapse-based therapeutic intervention for neurological and neuropsychiatric disorders. In this Review, which was initiated at the 13th International Society for Neurochemistry (ISN) Advanced School, we discuss basic concepts of synapse structure and function, and provide a critical view of how aberrant synapse physiology may contribute to neurodevelopmental (autism, Down syndrome, startle disease, and epilepsy) as well as neurodegenerative disorders (Alzheimer's and Parkinson's diseases), gathered together under the term of synaptopathies. Read the Editorial Highlight for this article on page 783.

Numerical data that are normally distributed can be analyzed with parametric tests, that is, tests which are based on the parameters that define a normal distribution curve. If the distribution is uncertain, the data can be plotted as a normal probability plot and visually inspected, or tested for normality using one of a number of goodness of fit tests, such as the Kolmogorov-Smirnov test. The widely used Student's t-test has three variants. The one-sample t-test is used to assess if a sample mean (as an estimate of the population mean) differs significantly from a given population mean. The means of two independent samples may be compared for a statistically significant difference by the unpaired or independent samples t-test. If the data sets are related in some way, their means may be compared by the paired or dependent samples t-test. The t-test should not be used to compare the means of more than two groups. Although it is possible to compare groups in pairs, when there are more than two groups, this will increase the probability of a Type I error. The one-way analysis of variance (ANOVA) is employed to compare the means of three or more independent data sets that are normally distributed. Multiple measurements from the same set of subjects cannot be treated as separate, unrelated data sets. Comparison of means in such a situation requires repeated measures ANOVA. It is to be noted that while a multiple group comparison test such as ANOVA can point to a significant difference, it does not identify exactly between which two groups the difference lies. To do this, multiple group comparison needs to be followed up by an appropriate post hoc test. An example is the Tukey's honestly significant difference test following ANOVA. If the assumptions for parametric tests are not met, there are nonparametric alternatives for comparing data sets. These include Mann-Whitney U-test as the nonparametric counterpart of the unpaired Student's t-test, Wilcoxon signed-rank test as the counterpart of the paired Student's t-test, Kruskal-Wallis test as the nonparametric equivalent of ANOVA and the Friedman's test as the counterpart of repeated measures ANOVA.

Abstract In its wake, the COVID‐19 pandemic has ushered in a surge in the number of cases of mucormycosis. Most cases are temporally linked to COVID‐19; hence, the entity is described as COVID‐19‐associated mucormycosis (CAM). The present systematic review was undertaken to provide an up‐to‐date summary of the hitherto available literature on CAM. PubMed, Scopus and Google Scholar databases were systematically searched using appropriate keywords till 14 May 2021, to identify case reports/case series pertaining to mucormycosis in patients with COVID‐19. Relevant data extracted included demographic characteristics, comorbidity profile, clinical category of mucormycosis, glucocorticoid use, treatment offered and patient outcome. We identified 30 case reports/case series, pooling data retrieved from 99 patients with CAM. Most cases were reported from India (72%). The majority of the patients was male (78%) and had diabetes mellitus (85%). A prior history of COVID‐19 was present in 37% patients with mucormycosis developing after an initial recovery. The median time interval between COVID‐19 diagnosis and the first evidence of mucormycosis infection or CAM diagnosis was 15 days. Glucocorticoid use was reported in 85% of cases. Rhino‐orbital mucormycosis was most common (42%), followed by rhino‐orbito‐cerebral mucormycosis (24%). Pulmonary mucormycosis was observed in 10 patients (10%). The mortality rate was 34%; the use of adjunct surgery, which was undertaken in 81% of patients, was associated with better clinical outcomes ( p &lt; .001). In conclusion, CAM is an emerging problem necessitating increased vigilance in COVID‐19 patients, even those who have recovered. CAM portends a poor prognosis and warrants early diagnosis and treatment.

Chronic arsenic exposure is known to produce arsenicosis and cancer. To ascertain whether perturbation of methylation plays a role in such carcinogenesis, the degree of methylation of p53 and p16 gene in DNA obtained from blood samples of people chronically exposed to arsenic and skin cancer subjects was studied. Methylation-specific restriction endonuclease digestion followed by polymerase chain reaction (PCR) of gene p53 and bisulfite treatment followed by methylation-sensitive PCR of gene p16 have been carried out to analyze the methylation status of the samples studied. Significant DNA hypermethylation of promoter region of p53 gene was observed in DNA of arsenic-exposed people compared to control subjects. This hypermethylation showed a dose-response relationship. Further, hypermethylation of p53 gene was also observed in arsenic-induced skin cancer patients compared to subjects having skin cancer unrelated to arsenic, though not at significant level. However, a small subgroup of cases showed hypomethylation with high arsenic exposure. Significant hypermethylation of gene p16 was also observed in cases of arsenicosis exposed to high level of arsenic. In man, arsenic has the ability to alter DNA methylation patterns in gene p53 and p16, which are important in carcinogenesis.

Abstract: Alzheimer’s disease and Parkinson’s disease are two common neurodegenerative diseases of the elderly people that have devastating effects in terms of morbidity and mortality. The predominant form of the disease in either case is sporadic with uncertain etiology. The clinical features of Parkinson’s disease are primarily motor deficits, while the patients of Alzheimer’s disease present with dementia and cognitive impairment. Though neuronal death is a common element in both the disorders, the postmortem histopathology of the brain is very characteristic in each case and different from each other. In terms of molecular pathogenesis, however, both the diseases have a significant commonality, and proteinopathy (abnormal accumulation of misfolded proteins), mitochondrial dysfunction and oxidative stress are the cardinal features in either case. These three damage mechanisms work in concert, reinforcing each other to drive the pathology in the aging brain for both the diseases; very interestingly, the nature of interactions among these three damage mechanisms is very similar in both the diseases, and this review attempts to highlight these aspects. In the case of Alzheimer’s disease, the peptide amyloid beta (Aβ) is responsible for the proteinopathy, while α-synuclein plays a similar role in Parkinson’s disease. The expression levels of these two proteins and their aggregation processes are modulated by reactive oxygen radicals and transition metal ions in a similar manner. In turn, these proteins – as oligomers or in aggregated forms – cause mitochondrial impairment by apparently following similar mechanisms. Understanding the common nature of these interactions may, therefore, help us to identify putative neuroprotective strategies that would be beneficial in both the clinical conditions. Keywords: proteinopathy, amyloid beta, oxidative stress, α-synuclein, mitochondrial dysfunction

This study highlights the severity of arsenic contamination in the Ganga River basin (GRB), which encompasses significant geographic portions of India, Bangladesh, Nepal, and Tibet. The entire GRB experiences elevated levels of arsenic in the groundwater (up to 4730 µg/L), irrigation water (~1000 µg/L), and in food materials (up to 3947 µg/kg), all exceeding the World Health Organization's standards for drinking water, the United Nations Food and Agricultural Organization's standard for irrigation water (100 µg/L), and the Chinese Ministry of Health's standard for food in South Asia (0.15 mg/kg), respectively. Several individuals demonstrated dermal, neurological, reproductive, cognitive, and cancerous effects; many children have been diagnosed with a range of arsenicosis symptoms, and numerous arsenic-induced deaths of youthful victims are reported in the GRB. Victims of arsenic exposure face critical social challenges in the form of social isolation and hatred by their respective communities. Reluctance to establish arsenic standards and unsustainable arsenic mitigation programs have aggravated the arsenic calamity in the GRB and put millions of lives in danger. This alarming situation resembles a ticking time bomb. We feel that after 29 years of arsenic research in the GRB, we have seen the tip of the iceberg with respect to the actual magnitude of the catastrophe; thus, a reduced arsenic standard for drinking water, testing all available drinking water sources, and sustainable and cost-effective arsenic mitigation programs that include the participation of the people are urgently needed.

BACKGROUND: Timely and comprehensive analyses of causes of death stratified by age, sex, and location are essential for shaping effective health policies aimed at reducing global mortality. The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2023 provides cause-specific mortality estimates measured in counts, rates, and years of life lost (YLLs). GBD 2023 aimed to enhance our understanding of the relationship between age and cause of death by quantifying the probability of dying before age 70 years (70q0) and the mean age at death by cause and sex. This study enables comparisons of the impact of causes of death over time, offering a deeper understanding of how these causes affect global populations. METHODS: GBD 2023 produced estimates for 292 causes of death disaggregated by age-sex-location-year in 204 countries and territories and 660 subnational locations for each year from 1990 until 2023. We used a modelling tool developed for GBD, the Cause of Death Ensemble model (CODEm), to estimate cause-specific death rates for most causes. We computed YLLs as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. Probability of death was calculated as the chance of dying from a given cause in a specific age period, for a specific population. Mean age at death was calculated by first assigning the midpoint age of each age group for every death, followed by computing the mean of all midpoint ages across all deaths attributed to a given cause. We used GBD death estimates to calculate the observed mean age at death and to model the expected mean age across causes, sexes, years, and locations. The expected mean age reflects the expected mean age at death for individuals within a population, based on global mortality rates and the population's age structure. Comparatively, the observed mean age represents the actual mean age at death, influenced by all factors unique to a location-specific population, including its age structure. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 250-draw distribution for each metric. Findings are reported as counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2023 include a correction for the misclassification of deaths due to COVID-19, updates to the method used to estimate COVID-19, and updates to the CODEm modelling framework. This analysis used 55 761 data sources, including vital registration and verbal autopsy data as well as data from surveys, censuses, surveillance systems, and cancer registries, among others. For GBD 2023, there were 312 new country-years of vital registration cause-of-death data, 3 country-years of surveillance data, 51 country-years of verbal autopsy data, and 144 country-years of other data types that were added to those used in previous GBD rounds. FINDINGS: The initial years of the COVID-19 pandemic caused shifts in long-standing rankings of the leading causes of global deaths: it ranked as the number one age-standardised cause of death at Level 3 of the GBD cause classification hierarchy in 2021. By 2023, COVID-19 dropped to the 20th place among the leading global causes, returning the rankings of the leading two causes to those typical across the time series (ie, ischaemic heart disease and stroke). While ischaemic heart disease and stroke persist as leading causes of death, there has been progress in reducing their age-standardised mortality rates globally. Four other leading causes have also shown large declines in global age-standardised mortality rates across the study period: diarrhoeal diseases, tuberculosis, stomach cancer, and measles. Other causes of death showed disparate patterns between sexes, notably for deaths from conflict and terrorism in some locations. A large reduction in age-standardised rates of YLLs occurred for neonatal disorders. Despite this, neonatal disorders remained the leading cause of global YLLs over the period studied, except in 2021, when COVID-19 was temporarily the leading cause. Compared to 1990, there has been a considerable reduction in total YLLs in many vaccine-preventable diseases, most notably diphtheria, pertussis, tetanus, and measles. In addition, this study quantified the mean age at death for all-cause mortality and cause-specific mortality and found noticeable variation by sex and location. The global all-cause mean age at death increased from 46·8 years (95% UI 46·6-47·0) in 1990 to 63·4 years (63·1-63·7) in 2023. For males, mean age increased from 45·4 years (45·1-45·7) to 61·2 years (60·7-61·6), and for females it increased from 48·5 years (48·1-48·8) to 65·9 years (65·5-66·3), from 1990 to 2023. The highest all-cause mean age at death in 2023 was found in the high-income super-region, where the mean age for females reached 80·9 years (80·9-81·0) and for males 74·8 years (74·8-74·9). By comparison, the lowest all-cause mean age at death occurred in sub-Saharan Africa, where it was 38·0 years (37·5-38·4) for females and 35·6 years (35·2-35·9) for males in 2023. Lastly, our study found that all-cause 70q0 decreased across each GBD super-region and region from 2000 to 2023, although with large variability between them. For females, we found that 70q0 notably increased from drug use disorders and conflict and terrorism. Leading causes that increased 70q0 for males also included drug use disorders, as well as diabetes. In sub-Saharan Africa, there was an increase in 70q0 for many non-communicable diseases (NCDs). Additionally, the mean age at death from NCDs was lower than the expected mean age at death for this super-region. By comparison, there was an increase in 70q0 for drug use disorders in the high-income super-region, which also had an observed mean age at death lower than the expected value. INTERPRETATION: We examined global mortality patterns over the past three decades, highlighting-with enhanced estimation methods-the impacts of major events such as the COVID-19 pandemic, in addition to broader trends such as increasing NCDs in low-income regions that reflect ongoing shifts in the global epidemiological transition. This study also delves into premature mortality patterns, exploring the interplay between age and causes of death and deepening our understanding of where targeted resources could be applied to further reduce preventable sources of mortality. We provide essential insights into global and regional health disparities, identifying locations in need of targeted interventions to address both communicable and non-communicable diseases. There is an ever-present need for strengthened health-care systems that are resilient to future pandemics and the shifting burden of disease, particularly among ageing populations in regions with high mortality rates. Robust estimates of causes of death are increasingly essential to inform health priorities and guide efforts toward achieving global health equity. The need for global collaboration to reduce preventable mortality is more important than ever, as shifting burdens of disease are affecting all nations, albeit at different paces and scales. FUNDING: Gates Foundation.

BACKGROUND AND PURPOSE: Information on essential stroke parameters are lacking in India. This population-based study on stroke disorder was undertaken in the city of Kolkata, India, to determine the subtypes, prevalence, incidence, and case fatality rates of stroke. METHODS: This was a longitudinal descriptive study comprising 2-stage door-to-door survey of a stratified randomly selected sample of the city population, conducted twice per year for 2 successive years from March 2003 to February 2005. RESULTS: Out of the screened population of 52,377 (27 626 men, 24 751 women), the age standardized prevalence rate of stroke to world standard population is 545.10 (95% CI, 479.86 to 617.05) per 100,000 persons. The age standardized average annual incidence rate to world standard population of first-ever-in-a-lifetime stroke is 145.30 (95% CI, 120.39 to 174.74) per 100,000 persons per year. Thirty-day case fatality rate is 41.08% (95% CI, 30.66 to 53.80). Women have higher incidence and case fatality rates. Despite divergence on socioeconomic status between the slum and nonslum dwellers, stroke parameters were not significantly different. CONCLUSIONS: The age standardized prevalence and incidence rates of stroke in this study are similar to or higher than many Western nations. The overall case fatality rate is among the highest category of stroke fatality in the world. The women have higher incidence and case fatality rates compared with men.

Objectives: SSc is characterized by fibrotic changes in the skin and lung, and the mainstay of treatment has been CYC. B cell involvement suggests that rituximab (RTX) may also be of therapeutic benefit. The aim of the study was to compare the efficacy and safety of RTX compared with CYC in retarding the progression of interstitial lung disease and skin manifestations of primary SSc. Methods: We randomly assigned 60 patients of dcSSc, age 18-60 years with skin and lung involvement, to monthly pulses of CYC 500 mg/m2 or RTX 1000 mg × 2 doses at 0, 15 days. Primary outcomes were forced vital capacity (FVC) percent predicted at 6 months. Secondary outcomes were: absolute change in litres (FVC-l) at 6 months; modified Rodnan skin scores at 6 months, 6-min walk test, Medsgers score and new onset or worsening of existing pulmonary hypertension by echocardiographic criteria. Results: The FVC [%mean (s.d.)] in the RTX group improved from 61.30 (11.28) to 67.52 (13.59), while in the CYC group it declined from 59.25 (12.96) to 58.06 (11.23) at 6 months (P = 0.003). The change of FVC was 1.51 (0.45) l to 1.65 (0.47) l in the RTX group, compared with 1.42 (0.49) to 1.42 (0.46) l in the CYC group. The mRSS changed from 21.77 (9.86) to 12.10 (10.14) in the RTX group and 23.83 (9.28) to 18.33 (7.69) in the CYC group after 6 months. Serious adverse events were more common in the CYC group. Conclusion: RTX is a safe and effective alternative to CYC in the primary therapy of skin and lung manifestations of scleroderma. Trial registration: Clinical Trials Registry - India, www.ctri.nic.in, CTRI/2017/07/009152.

Correlation and linear regression are the most commonly used techniques for quantifying the association between two numeric variables. Correlation quantifies the strength of the linear relationship between paired variables, expressing this as a correlation coefficient. If both variables <i>x</i> and <i>y</i> are normally distributed, we calculate Pearson's correlation coefficient (<i>r</i>). If normality assumption is not met for one or both variables in a correlation analysis, a rank correlation coefficient, such as Spearman's rho (ρ) may be calculated. A hypothesis test of correlation tests whether the linear relationship between the two variables holds in the underlying population, in which case it returns a <i>P</i> < 0.05. A 95% confidence interval of the correlation coefficient can also be calculated for an idea of the correlation in the population. The value <i>r</i>² denotes the proportion of the variability of the dependent variable <i>y</i> that can be attributed to its linear relation with the independent variable <i>x</i> and is called the coefficient of determination. Linear regression is a technique that attempts to link two correlated variables <i>x</i> and <i>y</i> in the form of a mathematical equation (<i>y</i> = <i>a</i> + <i>bx</i>), such that given the value of one variable the other may be predicted. In general, the method of least squares is applied to obtain the equation of the regression line. Correlation and linear regression analysis are based on certain assumptions pertaining to the data sets. If these assumptions are not met, misleading conclusions may be drawn. The first assumption is that of linear relationship between the two variables. A scatter plot is essential before embarking on any correlation-regression analysis to show that this is indeed the case. Outliers or clustering within data sets can distort the correlation coefficient value. Finally, it is vital to remember that though strong correlation can be a pointer toward causation, the two are not synonymous.