Association of family history of cardiometabolic diseases (CMDs) and individual health behaviours: Analysis of CARRS study from South Asia

Objectives: Family history is considered as an important predictor of cardiovascular diseases (CVDs) and diabetes. Available research findings suggest that family history of chronic diseases is associated with perceived risk of disease and adoption of healthy behaviours. We examined the association between family history of cardio-metabolic diseases (CMDs) and healthy behaviours among adults without selfreported CMDs. Methods: Cross-sectional data of 12,484 adults, without self-reported CMDs, from the baseline survey of Centre for cArdiometabolic Risk Reduction in South-Asia (CARRS) cohort study were analysed. Results: Family history was positively associated with non-smoking and high fruits & vegetables consumption in the age group of 45e64 years and moderate to high physical activity in the age group _x0001_65 years after adjusting for sex, education, wealth index, city and body mass index. Conclusions: Understanding perceived risks and cultural or psychological factors related to family history through ethnographic studies may deepen understanding of these associations.

Covid-19-associated rhino-orbito-cerebral mucormycosis (CAROM) in Delhi: Demographics and risk factors in a single-centre consecutive cohort of 200 inpatients

BACKGROUND There was a dramatic rise in the incidence of rhino-orbito-cerebral mucormycosis associated with the 2021 Covid-19 wave in India. We aim to document the demographic characteristics and risk factors of a consecutive cohort of inpatients with Covid-19-associated rhino-orbito-cerebral mucormycosis (CAROM) during the surge of April–June 2021. METHODS We included all patients of CAROM treated at our tertiary referral facility from 1 April to 14 June 2021. We prospectively gathered details with regard to Covid-19 illness and treatment, CAROM presentation, comorbid conditions and risk factors. RESULTS Our prospective cohort consisted of 200 consecutive patients, of which 146 (73%) patients tested positive on the Covid-19 RT-PCR test at presentation. CAROM occurred concurrent with the Covid-19 infection in 86%, and delayed CAROM after seeming recovery from Covid-19 was seen in 14%. Covid-19 was classified as mild, moderate and severe in 54%, 33% and 13%. The surge of CAROM followed the population peak of Covid-19 infections by about 3 weeks. Advanced disease at presentation was frequent with ocular involvement in 56.6% (111/196) and central nervous system involvement in 20% (40/199). One or more comorbid conditions were identified in 191/200 (95.5%) patients. The dominant associations were with diabetes (189/200; 94.5%) and uncontrolled hyper-glycaemia (122/133; 91.7%), recent steroid use (114/ 200; 57%), which was often considered as inappropriate in dosage or duration, lymphopenia (142/176; 80.7%), and increased ferritin levels (140/160; 87.5%). No evidence supported the role of previous oxygen therapy or previous nasal swab testing as risk factors for CAROM. CONCLUSION The inpatient volumes of CAROM were noted to parallel the Covid-19 incidence curve by about 3 weeks. Covid-19 infection may directly predispose to CAROM by way of lymphopenia and increased ferritin levels. Uncontrolled hyperglycaemia is identified as a near-invariable association. Recent steroid use is noted as very frequent and was often received in excess of treatment advisories.

Genomewide association study for C-reactive protein in Indians replicates known associations of common variants

Elevated C-reactive protein (CRP) serves as an independent biomarker for acute and chronic inflammation, and is also associated with metabolic diseases. Genomewide loci regulating CRP level in Indian population, a high-risk group for metabolic illness, is unexplored. Therefore, we aimed to discover common polymorphisms associated with plasma CRP level in 4493 Indians of Indo-European origin using genomewide association study. Genomewide strong associations of two known intronic variants in hepatocyte nuclear factor-1 α gene (HNF1A)were identified among Indian subjects. We also detected prior associations of several variants in/near metabolic and inflammatory process genes: APOC1, LEPR, CRP, HNF4A, IL6R and APOE with modest associations. This study confirms that Indians from Indo-European origin display similar core universal genetic factors for CRP levels.

Genomewide association study of C-peptide surfaces key regulatory genes in IndiansC

Insulin is a commonly used measure of pancreatic β-cell function but exhibits a short half-life in the human body. During biosynthesis, insulin release is accompanied by C-peptide at an equimolar concentration which has a much higher plasma half-life and is therefore projected as a precise measure of β-cell activity than insulin. Despite this, genetic studies of metabolic traits haveneglected the regulatory potential of C-peptide for therapeutic intervention of type-2 diabetes. The present study is aimed to search genomewide variants governing C-peptide levels in genetically diverse and high risk population for metabolic diseases—Indians. We performed whole genome genotyping in 877 healthy Indians of Indo-European origin followed by replication of variants with P ≤ 1 × 10−3 in an independent sample-set of 1829 Indians. Lead-associated signals were also tested in-silico in 773 Hispanics. To secure biological rationale for observed association, we further carried out DNA methylation quantitative trait loci analysis in 233 Indians and publicly available regulatory data was mined. We discovered novel lncRNA gene AC073333.8 with the strongest association with C-peptide levels in Indians that however missed genomewide significance. Also, noncoding genes, RP1-209A6.1 and RPS3AP5; protein gene regulators, ZNF831 and ETS2; and solute carrier protein gene SLC15A5 retained robust association with C-peptide after meta-analysis. Integration of methylation data revealed ETS2 and ZNF831 single-nucleotide polymorphisms as significant meth-QTLs in Indians. All genes showed reasonable expression in the human lung, signifying alternate important organs for C-peptide biology. Our findings mirror polygenic nature of C-peptide where multiple small-effect size variants in the regulatory genome principally govern the trait biology.

Prevalence of vitamin B12 deficiency among individuals with type 2 diabetes mellitus in a South Indian rural community

Background: To estimate the prevalence of vitamin B12 deficiency in a rural south Indian community and to evaluate the association between metformin use and prevalent vitamin B12 deficiency in people with T2DM stratified by oral vitamin B12 supplementation.Methods: Using a cross sectional study design, a random sample of people with T2DM (N=438) was recruited from a rural community. Vitamin B12 deficiency was defined as serum B12 ?200pg/ml. Data on metformin dose, duration of use, oral vitamin B12 supplementation, and diet were collected. Laboratory measurements included complete blood count, tests for hepatic, renal, and thyroid function, as well as serum vitamin B12 levels and HbA1c.Results: The prevalence of vitamin B12 deficiency in people with T2DM was 11.2% (95% Confidence Interval (CI) 8.2%-14.1%). The odds of vitamin B12 deficiency in patients receiving a metformin dose of 2 grams/day were 4 times higher compared to those receiving ?1 gram/day, after adjusting for oral B12 supplementation (odds ratio 4.2;95% CI 1.5-11.8). The odds of vitamin B12 deficiency in those taking metformin and receiving oral vitamin B12 supplementation were lower compared to those on metformin and not receiving vitamin B12 supplementation (adjusted odds ratio 0.20; 95% CI 0.06-0.70).Conclusions: Vitamin B12 deficiency affects 1 in 10 people with T2DM, is associated with higher dose metformin use, and oral vitamin B12 supplementation mitigates B12 deficiency in this group.

Prevalence of metabolic syndrome and cardiovascular changes in patients with chronic plaque psoriasis and their correlation with disease severity: A hospital-based cross-sectional study.

Background: Previous epidemiological studies suggest an association between psoriasis and metabolic syndrome and risk of subclinical atherosclerosis. However, there is a paucity of data in the Indian population on these associations. Objectives: To evaluate the prevalence of metabolic syndrome and subclinical atherosclerosis in patients with chronic plaque psoriasis compared to healthy controls and to correlate the prevalence of metabolic syndrome with severity of psoriasis. Methods: A hospital-based cross-sectional study was performed on 140 patients with chronic plaque psoriasis and 140 controls. Psoriasis was categorized as mild, moderate and severe based on psoriasis area and severity index (<10, 10–14 and ≥15, respectively) and as disease of short (<1 year), intermediate (1–3 years) and long duration (>3 years). In all patients and controls, body mass index was calculated, blood pressure and waist circumference were measured and fasting blood sugar and lipid profi le were estimated. Metabolic syndrome was diagnosed by the presence of 3 or more of the modifi ed National Cholesterol Education Program’s Adult Treatment Panel III criteria. A subset of 30 psoriatic patients and 30 healthy controls were selected by the systematic sampling method for cardiac evaluation including electrocardiography, echocardiography and carotid intima-media thickness measurement. Results: The prevalence of metabolic syndrome was signifi cantly more in psoriatic patients than in controls (39.3% vs. 17.1%, odds ratio = 3.13). Psoriatic patients also had a signifi cantly higher prevalence of hypertension, abdominal obesity and diabetes. There was a signifi cant trend to increase in prevalence of metabolic syndrome, hypertension and type 2 diabetes with increased severity and longer duration of the psoriasis. Patients with psoriasis had signifi cantly higher carotid intima-media thickness (mean 0.61 mm ± 0.01 mm vs. 0.37 mm ± 0.01 mm) than controls. Limitation: This was a hospital-based cross-sectional study with a relatively small sample size. A prospective study with a larger sample would have validated the results further. Conclusion: There is a signifi cantly higher prevalence of metabolic syndrome in psoriasis patients as compared to controls; the prevalence of metabolic syndrome and its components increases with severity and duration of psoriasis. There is a higher prevalence of subclinical atherosclerosis in patients with psoriasis thus increasing the risk of cardiovascular disease. We suggest that patients with moderate to severe psoriasis be screened routinely for metabolic syndrome and cardiovascular disease and encouraged to correct modifi able cardiovascular risk factors.

The Opportunities to 'Beat Diabetes.

The theme of the 2016 World Health Day was ‘Beat diabetes’.1 As per the WHO global report on diabetes (2016), the number of adults living with diabetes has almost quadrupled since 1980 to 422 million.2 India is no exception and is one of the epicentres of the diabetes mellitus pandemic. The 2015 update of the International Diabetes Federation (IDF) Atlas (www.diabetesatlas.org/resources/2015–atlas.htm) estimates around 69.2 million people in India to be affected by diabetes. In a study of 24 335 individuals from four Asian countries (China, Japan, India and Singapore), Indians were found to have the highest prevalence of diabetes mellitus. The peak prevalence of the disease was reached approximately 10 years earlier in Indians compared with Chinese and Japanese peers.3 According to the Indian Council of Medical Research–INdia DIABetes (ICMR– INDIAB) study, which was done in urban and rural populations across the country, the ‘take-off point’ for increased prevalence of type 2 diabetes mellitus (T2DM) among Asian Indians is 25–34 years, clearly a decade or two earlier than that in western populations.4 A similar trend has been shown by the latest figures from the CARRS (The Centre for Cardiometabolic Risk Reduction in South Asia) study, with data from metropolitan Chennai and Delhi.5 The change from a traditional cereal-based diet to a refined diet and decreasing physical activity are some of the reasons for the rapid increase in the prevalence of diabetes over the past two decades. Phase 1 of the ICMR–INDIAB study showed that a large percentage of people (54.4%) in India were inactive with fewer than 10% engaging in recreational physical activity.

Childhood obesity and type 2 diabetes in India.

India is witnessing an increase in the burden of childhood obesity, especially among the upper socioeconomic strata and in urban areas. Emerging literature suggests a link between childhood obesity and the diabetes epidemic in India. Asian-Indian children and adolescents are increasingly susceptible to a high percentage of body fat and abdominal adiposity. Further, they are exposed to an obesogenic environment, created by rapid urbanization and nutrition transition in India. Obese children have a higher risk of developing abnormalities that are recognized as precursors to diabetes, such as subclinical inflammation, insulin resistance and metabolic syndrome, which often track to adulthood. A review of the literature suggests the need for more longitudinal studies to improve understanding of the long-term consequences of childhood obesity in India. A life-course approach with a combination of population- and risk-based strategies is warranted, to prevent childhood obesity and curtail its consequences in adulthood.

Association between anthropometry, cardiometabolic risk factors, & early life factors & adult measures of endothelial function: Results from the New Delhi Birth Cohort.

Background & objectives: Abnormal endothelial function represents a preclinical marker of atherosclerosis. This study was conducted to evaluate associations between anthropometry, cardiometabolic risk factors, and early life factors and adult measures of endothelial function in a young urban Indian cohort free of clinical cardiovascular disease. Methods: Absolute changes in brachial artery diameter following cuff inflation and sublingual nitroglycerin (400 μg) were recorded to evaluate endothelium-dependent and -independent measures of endothelial function in 600 participants (362 men; 238 women) from the New Delhi Birth Cohort (2006-2009). Data on anthropometry, cardiometabolic risk factors, medical history, socio-economic position, and lifestyle habits were collected. Height and weight were recorded at birth, two and 11 yr of age. Age- and sex-adjusted linear regression models were developed to evaluate these associations. Results: The mean age of participants was 36±1 yr. Twenty two per cent men and 29 per cent women were obese (BMI > 30 kg/m2). Mean systolic blood pressure (SBP) was 131±14 and 119±13 mmHg, and diabetes prevalence was 12 and 8 per cent for men and women, respectively. Brachial artery diameter was higher for men compared with women both before (3.48±0.37 and 2.95±0.35 cm) and after hyperaemia (3.87±0.37 vs. 3.37±0.35 cm). A similar difference was seen before and after nitroglycerin. Markers of increased adiposity, smoking, SBP, and metabolic syndrome, but not early life anthropometry, were inversely associated with endothelial function after adjustment for age and sex. Interpretation & conclusions: The analysis of the current prospective data from a young urban Indian cohort showed that cardiometabolic risk factors, but not early life anthropometry, were associated with worse endothelial function.

Evaluation of Surrogate Markers for Insulin Resistance for Defining Metabolic Syndrome in Urban Indian Adolescents.

Objective: To compare parameters of insulin resistance, with special reference to McAuley index, in urban Indian adolescents, and to establish their cut-off values for defining metabolic syndrome. Design: Cross-sectional study. Setting: Schools located in four different geographical zones of Delhi, India. Participants: 695 apparently healthy adolescents grouped as normal weight (298), overweight (205) and obese (192). Outcome measures: Cut-off point for indices of insulin resistance was assessed by fasting insulin, insulin glucose ratio, and other methods (HOMA model, QUICKI, McAuley index) to define metabolic syndrome. Results: The McAuley index increased progressively from normal weight to obese adolescents in both sexes. McAuley index was significantly lower in adolescents with metabolic syndrome (5.36 ± 1.28 vs. 7.05 ± 1.88; P<0.001). McAuley index had the highest area under curve of receiver operator characteristics [0.82 (0.02)] as compared to other indices of insulin resistance. McAuley index of 6.23 had the highest specificity (88%) with sensitivity of 63.3% for diagnosing metabolic syndrome, whereas insulin glucose ratio had the highest sensitivity (79.7%) but low (55.5%) specificity. McAuley index was negatively correlated with height (r= -0.257, P=<0.001), weight (r= -0.537, P=<0.001), body mass index (r= -0.579, P<0.001), waist circumference (r= -0.542, p<0.001), and waist hip ratio (r= -0.268, P<0.001). Conclusions: Among various parameters of insulin resistance, McAuley index had the highest specificity, and insulin glucose ratio had the highest sensitivity in diagnosing metabolic syndrome in urban Indian adolescents.

Review of multinational human subjects research: experience from the PHFIEmory Center of Excellence partnership.

Public Health Foundation of India (PHFI), New Delhi, India and Emory University, Atlanta, USA, are lead partners in the National Heart, Lung and Blood Institute/UnitedHealth funded Center of Excellence (COE) in Cardio-metabolic Risk Reduction in South Asia which provides a vehicle for the development of collaborative research projects. With funding from the National Institutes of Health/ Fogarty International Center, a project was commenced to ensure seamless, thorough and efficient review of this collaborative research. The primary activities of the project are: 1) fact-finding activities which included conduct of a case study and review of policies and procedures of the involved ethics review committees (ERCs); 2) training workshops for COE ERC members and staff and 3) piloting of parallel review of continuing reviews and amendments. A process of parallel review of collaborative research has now been initiated and projects are now submitted simultaneously to the Emory institutional review board (IRB) and PHFI institutional ethics committee (IEC).

Effects of sports training & nutrition on bone mineral density in young Indian healthy females.

Background & objectives: Peak bone mass, a major determinant of osteoporosis is influenced by genetic, nutritional, lifestyle and hormonal factors. This study was designed to evaluate the impact of sports training on dietary intake and bone mineral and metabolic parameters in young healthy Indian females. Methods: Healthy female college going students (N=186, sportswomen, 90; controls 96) in the age group of 18-21 yr, residing in New Delhi (India) were evaluated for anthropometry, biochemistry (serum total and ionic calcium, phosphorus, total alkaline phosphatase, 25-hydroxyvitamin D & parathyroid hormone), diet, physical activity and lifestyle. Bone mineral density (BMD) at hip, forearm and lumbar spine were studied using central DXA. Results: Sports related physical activity (3 vs. 0 h/day, P<0.001) and direct sunlight exposure (120 vs. 30 min/day, P<0.001) were significantly higher in sportswomen than in controls with sedentary lifestyle. Significantly higher intake of all macronutrients (energy, protein, carbohydrates and fat) and dietary calcium was noted in the diets of sportswomen. Mean serum 25(OH)D levels were significantly higher (53.0±18.9 vs. 12.9±7.7 nmol/l; P<0.001) while PTH (35.3±17.6 vs. 51.7±44.9 pg/ml; P<0.001) and ALP levels (194.0±51.0 vs. 222.1±51.4 IU/l; P<0.001) were significantly lower in sportswomen when compared to controls. No significant difference was found in ionized calcium and inorganic phosphorus in the two groups. Significantly higher (P<0.001) total BMD and BMD at all sites except femur neck were found in sportswomen than controls (P<0.001). Interpretation & conclusions: Physical activity, optimal nutrition and adequate sun exposure are vital for attaining peak bone mass.

Nationwide reference data for height, weight and body mass index of Indian schoolchildren.

Background. The assessment of growth is crucial for child care and reference data are central to growth monitoring. We aimed to assess the height, weight and body mass index (BMI) of Indian schoolchildren in order to develop genderappropriate growth charts for children 5–18 years of age. Methods. Cross-sectional evaluation of anthropometric parameters (height, weight and BMI) was done in Indian schoolchildren (3–18 years) randomly selected from both fee-paying (upper socioeconomic strata) and non-fee paying (lower socioeconomic strata) schools from 4 regions (north, south, east and west) of India. A total of 106 843 children were evaluated, of which 42 214 children (19 303 boys, 22 911 girls) were from the lower socioeconomic strata and 64 629 children (34 411 boys, 30 218 girls) were from the upper socioeconomic strata. Normative charts, using the lambda–mu–sigma (LMS) method to smoothen the curves, were drawn from children belonging to the upper socioeconomic strata, in view of the gross discrepancy between the two socioeconomic strata. Results. Height, weight and BMI percentile (3rd, 5th, 10th, 25th, 50th, 75th, 90th, 95th and 97th) data were calculated and charts generated. The height of boys and girls was consistently higher at all ages when compared with earlier India data, but the final height was 2–4 cm lower than that reported in the WHO multicentre study of 2007. Weight centiles showed a rising trend both in boys and girls compared not only to earlier Indian data published in 1992, but also to that reported by the WHO multicentre study. The median weight at all ages in both boys and girls was approximately 4 kg more than that reported in affluent Indian children two decades earlier. Conclusion. This large nationwide study indicates secular trends in height, weight and BMI in Indian children from the upper socioeconomic strata. We suggest that the height and weight percentiles reported by us may be used as reference standards for India.

Diabetes & coronary heart disease: Current perspectives.

Coronary heart disease (CHD) is currently the leading cause of death worldwide and together with diabetes, poses a serious health threat, particularly in the Indian Asian population. Risk factor management has evolved considerably with the continued emergence of new and thought-provoking evidence. The stream of laboratory- and population-based research findings as well as unresolved controversies may pose dilemmas and conflicting impulses in most clinicians, and even in our more well-informed patients. As results of the most recent clinical trials on glycaemic control for macrovascular risk reduction are woven into concrete clinical practice guidelines, this paper seeks to sort through unwieldy evidence, keeping these findings in perspective, to deliver a clearer message for the context of South Asia and cardio-metabolic risk management.

Impact of Two Regimens of Vitamin D Supplementation on Calcium - Vitamin D - PTH Axis of Schoolgirls of Delhi.

Objective: To determine the efficacy of supplementation with oral vitamin D3 (cholecalciferol) on bone mineral biochemical parameters of school-going girls. Setting: Government school (government-aided) and Private school (fee paying) in Delhi. Design: Randomized controlled trial. Intervention: Cholecalciferol granules (60,000 IU) orally with water, either once in two months (two-monthly D3 group) or once a month (one-monthly D3 group) for one year. Participants: 290 healthy schoolgirls (6-17 y), 124 from lower socioeconomic strata (LSES) (attending government schools) and 166 from upper socioeconomic strata (USES) (attending private schools). Outcome measures: Serum 25(OH)D, calcium, phosphorus, parathyroid hormone, and alkaline phosphatase levels at 6 and 12 months after start of supplementation. Results: At baseline, 93.7% schoolgirls were vitamin D deficient [25(OH)D<50 nmol/L]. While significant increase in serum calcium and decrease in alkaline phosphatase levels was noted in both groups with both interventions, PTH response was inconsistent. In LSES subjects, twomonthly D3 and one-monthly D3 supplementation resulted in a significant increase in serum 25(OH)D levels by 8.3 nmol/L and 11.0 nmol/L, respectively at 6 months (P<0.05). Similarly, the increase in the two intervention arms in USES subjects was 10.5 nmol/L and 16.0 nmol/L, respectively (P<0.05). In both groups, this increase in serum 25(OH)D levels persisted at 12 months (P<0.05). Despite supplementation with 60,000 IU of Vitamin D3 (monthly or two-monthly), only 47% were vitamin D sufficient at the end of one year. Conclusions: 60,000 IU of cholecalciferol, monthly or two-monthly, resulted in a significant increase in serum 25(OH)D levels in vitamin D deficient schoolgirls.

Primary intestinal lymphangiectasia as a component of autoimmune polyglandular syndrome type I: a report of 2 cases.

Chronic diarrhea and steatorrhea occur frequently in patients with autoimmune polyglandular syndrome (APS) type I. Intestinal lymphangiectasia has been reported earlier as a cause of steatorrhea in a young girl with APS Type I. We describe 2 patients with APS Type I who were found to have intestinal lymphangiectasia, one of whom had symptomatic protein-losing enteropathy.

Biomarkers of susceptibility to type 1 diabetes with special reference to the Indian population.

Type 1 diabetes (T1D) is a polygenic autoimmune disease. Susceptibility to T1D is strongly linked to a major genetic locus that is the major histocompatibility complex (MHC) and several other minor loci including insulin, CTLA4 that contribute to diabetes risk in an epistatic way. MHC harbours genes whose primary function is to govern immune responsiveness. Being the most polymorphic genomic region known in humans, MHC serves as a very exciting minigenome model for studying susceptibility to T1D. We have observed enormous diversity in HLA class I and class II genes in the north Indian population and identified several 'novel alleles' and 'unique haplotypes'. For example, multiple DR3+ve autoimmunity favouring haplotypes have been identified, some of which are unique to the Asian north Indian T1D patients. Our molecular studies have revealed that (i) the classical Caucasian autoimmunity favouring AH8.1 (HLA-A1 B8 DR3) is rare in the Indian population and has been replaced by a variant AH8.1v that differs from the Caucasian AH8.1 at several gene loci, (ii) AH8.2 (HLA-A26 B8 DR3) is the most common DR3 positive haplotype in this population and resembles the Indian AH8.1v rather than Caucasian AH8.1, and (iii) there are additional HLA-DR3 haplotypes HLA-A24 B8 DR3 (AH8.3), A3 B8 DR3 (AH8.4) and A31 B8 DR 3 (AH 8.5) that occur in the Indian population. The studies have led to a hypothesis that AH8.1 and AH8.1v might have co-evolved from a common ancestor but preferential divergence of AH8.2 over AH8.1 leading to survival advantage might have been driven by vigorous pathogenic challenges encountered by the Indian population. These studies have important implications in our understanding of disease pathogenesis, identification of high risk individuals, disease diagnosis, disease management and immunological therapeutic approaches.