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In The Pune Maternal Nutrition Study, vitamin B12 deficiency was seen in 65% of pregnant women, folate deficiency was rare. Maternal total homocysteine concentrations were inversely associated with offspring birthweight, and low vitamin B12 and high folate concentrations predicted higher offspring adiposity and insulin resistance. These findings guided a nested pre-conceptional randomised controlled trial ‘Pune Rural Intervention in Young Adolescents’. The interventions included: (1) vitamin B12+multi-micronutrients as per the United Nations International Multiple Micronutrient Antenatal Preparation, and proteins (B12+MMN), (2) vitamin B12 (B12 alone), and (3) placebo. Intervention improved maternal pre-conceptional and in-pregnancy micronutrient nutrition. Gene expression analysis in cord blood mononuclear cells in 88 pregnancies revealed 75 differentially expressed genes between the B12+MMN and placebo groups. The enriched biological processes included G2/M phase transition, chromosome segregation, and nuclear division. Enriched pathways included, mitotic spindle checkpoint and DNA damage response while enriched human phenotypes were sloping forehead and decreased head circumference. Fructose-bisphosphatase 2 (FBP2) and Cell Division Cycle Associated 2 (CDCA2) genes were under-expressed in the B12 alone group. The latter, involved in chromosome segregation was under-expressed in both intervention groups. Based on the role of B-complex vitamins in the synthesis of nucleotides and S-adenosyl methionine, and the roles of vitamins A and D on gene expression, we propose that the multi-micronutrient intervention epigenetically affected cell cycle dynamics. Neonates in the B12+MMN group had the highest ponderal index. Follow-up studies will reveal if the intervention and the altered biological processes influence offspring diabesity.

BackgroundBased on studies in overweight-obese populations, it is tacitly assumed that maternal hyperglycemia is responsible for obesity-adiposity at birth and in later life.Study designTwo hospital based case control studies: 1) Neonatal outcomes, 2) Later life outcomes.MethodsWe studied associations of neonatal and later life obesity-adiposity [age and sex-adjusted BMI, waist circumference, skinfolds, and body fat percent by Dual energy X-ray Absorptiometry (DXA)] in offspring of mothers with diabetes (ODM) and those of mothers without diabetes (ONDM). Exposures were parental hyperglycemia and overweight-obesity.ResultsNeonatal study included 372 non-diabetic and 816 diabetic pregnancies [74 type 1 diabetes, 102 type 2 diabetes, 640 gestational diabetes (GDM)]. Mothers with type 1 diabetes were the youngest, thinnest, and with highest HbA1c. Maternal glycemia but not BMI was associated with neonatal obesity-adiposity. Thus, neonates of mothers with type 1 diabetes had highest ponderal index, abdominal circumference, and skinfolds.Later life study included 200 ODM (25 type 1 diabetes, 22 type 2 diabetes, 153 GDM) and 177 age, sex and socio-economic matched ONDM (2 to 26 y). Their obesity-adiposity was associated with bi-parental overweight-obesity in an additive manner, but not with parental diabetes. Offspring birth weight was also positively associated. Offspring of mothers with type 1 diabetes had the lowest and offspring of mothers with type 2 diabetes the highest obesity-adiposity.ConclusionNeonatal obesity-adiposity is driven by maternal glycemia while later life obesity-adiposity by bi-parental obesity. Our results provide a clear insight into pathogenesis of obesity-adiposity in the offspring.Article HighlightsIt is tacitly assumed that maternal diabetes is responsible for offspring obesity-adiposity.We examined the determinants of obesity-adiposity in intrauterine and in later life in children born to mothers with type 1, type 2 and GDM. Paternal influence was also investigated.Mothers with type 1 diabetes were the thinnest and most hyperglycemic. Their children were the most obese-adipose at birth but thinnest in later life. Later life obesity-adiposity was driven by bi-parental overweight-obesity, not by diabetes.Our findings suggest that strict maternal metabolic control during pregnancy will reduce macrosomia while targeting obesogenic family environment may reduce later life offspring obesity-adiposity.

Studies from high-income countries report associations of preeclampsia (PE) with reduced cognitive function and adverse behavioural outcomes in children. We examined these associations in Indian children aged 5-7 years. Children of mothers with PE (n=74) and without PE (non-PE; n=234) were recruited at delivery at Bharati Hospital, Pune, India. The cognitive performance was assessed using 3 core tests from the Kaufman Assessment Battery and additional tests including Verbal fluency, Kohs block design, and Coding A (from Wechsler Intelligence Scale for Children). The parent-reported Strengths and Difficulties Questionnaire (SDQ) was used to assess children’s behavioral characteristics. Scores were compared between children from PE and non-PE groups, and associations analyzed further using regression models, adjusted for potential confounders. After adjusting for age, sex, socio-economic status and maternal education, children of PE mothers had lower Kohs block design scores (adjusted odds ratio per score category 0.57, [95% CI 0.34-0.96] p=0.034; 0.62 [95%CI (0.36, 1.07), p=0.09 on further adjustment for birth weight and gestation) compared to children of mothers without PE. In the SDQ, there was a lower prevalence of abnormal ‘conduct problem’ scores in PE group than non-PE group (OR=0.33, 95% CI 0.13-0.83, p=0.018, in the fully adjusted model); there were no differences for other behavioral domains. This preliminary study in Indian children suggests that fetal exposure to maternal PE may have an adverse impact on visuo-spatial performance but does not adversely affect behavior. Further studies with larger sample sizes are essential to understand effects of maternal PE on cognitive/behavioral outcomes in children.

Background: With strong evidence of physical inactivity's link to chronic disease and economic burden - particularly with childhood active living behaviors tracking into adulthood - it is imperative to promote physical activity among children and adolescents in India.Objectives: To evaluate active living patterns among Indian children and adolescents.Methods: The India Report Card (IRC) team, which consists of experts in India and Canada, systematically collected and appraised evidence on 11 indicators of active living, including 5 behavioral (Overall Physical Activity, Organized Sport Participation, Active Play, Active Transportation, Sedentary Behavior), 2 individual-level (Physical Fitness, Yoga) and 4 sources of influence (Family and Peers, School, Community and Built Environment, Government). Peer-reviewed articles were appraised based on national representativeness, sample size, and data quality. Grey literature was appraised based on comprehensiveness, validity of the sources, and representativeness. All indicators were assessed against parameters provided by the Active Healthy Kids Global Alliance.Results: Active Transportation and Government Strategies were ranked highest with a B- and C+ grade, respectively. Overall Physical Activity and Schools were assigned a C grade, while Sedentary Behavior and Community and Built Environment were given D grades. Yoga was the lowest ranking indicator with a D- grade. Organized Sport Participation, Active Play, Family and Peers, and Physical Fitness were all graded incomplete.Conclusions: Active Transportation, Government Strategies, and Overall Physical Activity have improved since the 2018 IRC, a positive trend that needs to be translated to other indicators. However, Sedentary Behavior has consistently worsened, with grades C, C-, and D-, in 2016, 2018, and 2022, respectively. Evidence generated by the 2022 IRC suggests opportunities for improvement not only in India, but also the 56 other countries taking part in Global Matrix 4.0.

There has been an upward trend in developing frameworks that enable neuroimaging researchers to address challenging questions by leveraging data across multiple sites all over the world. One such open-source framework is the Collaborative Informatics and Neuroimaging Suite Toolkit for Anonymous Computation (COINSTAC) that works on Windows, macOS, and Linux operating systems and leverages containerized analysis pipelines to analyze neuroimaging data stored locally across multiple physical locations without the need for pooling the data at any point during the analysis. In this paper, the COINSTAC team partnered with a data collection consortium to implement the first-ever decentralized voxelwise analysis of brain imaging data performed outside the COINSTAC development group. Decentralized voxel-based morphometry analysis of over 2000 structural magnetic resonance imaging data sets collected at 14 different sites across two cohorts and co-located in different countries was performed to study the structural changes in brain gray matter which linked to age, body mass index (BMI), and smoking. Results produced by the decentralized analysis were consistent with and extended previous findings in the literature. In particular, a widespread cortical gray matter reduction (resembling a 'default mode network' pattern) and hippocampal increase with age, bilateral increases in the hypothalamus and basal ganglia with BMI, and cingulate and thalamic decreases with smoking. This work provides a critical real-world test of the COINSTAC framework in a "Large-N" study. It showcases the potential benefits of performing multivoxel and multivariate analyses of large-scale neuroimaging data located at multiple sites.

Objective:To identify peri-conceptional diet patterns among women in Bangalore and examine their associations with risk of gestational diabetes mellitus (GDM).Design:BAngalore Nutrition Gestational diabetes LifEstyle Study, started in June 2016, was a prospective observational study, in which women were recruited at 5–16 weeks’ gestation. Peri-conceptional diet was recalled at recruitment, using a validated 224-item FFQ. GDM was assessed by a 75-g oral glucose tolerance test at 24–28 weeks’ gestation, applying WHO 2013 criteria. Diet patterns were identified using principal component analysis, and diet pattern–GDM associations were examined using multivariate logistic regression, adjusting for ‘a priori’ confounders.Setting:Antenatal clinics of two hospitals, Bangalore, South India.Participants:Seven hundred and eighty-five pregnant women of varied socio-economic status.Results:GDM prevalence was 22 %. Three diet patterns were identified: (a) high-diversity, urban (HDU) characterised by diverse, home-cooked and processed foods was associated with older, more affluent, better-educated and urban women; (b) rice-fried snacks-chicken-sweets (RFCS), characterised by low diet diversity, was associated with younger, less-educated, and lower-income, rural and joint families; and (c) healthy, traditional vegetarian (HTV), characterised by home-cooked vegetarian and non-processed foods, was associated with less-educated, more affluent, and rural and joint families. The HDU pattern was associated with a lower GDM risk (adjusted odds ratio (aOR): 0·80/sd, 95 % CI (0·64, 0·99), P = 0·04) after adjusting for confounders. BMI was strongly related to GDM risk and possibly mediated diet–GDM associations.Conclusions:The findings support global recommendations to encourage women to attain a healthy pre-pregnancy BMI and increase diet diversity. Both healthy and unhealthy foods in the patterns indicate low awareness about healthy foods and a need for public education.

Developmental adversities early in life are associated with later psychopathology. Clustering may be a useful approach to group multiple diverse risks together and study their relation with psychopathology. To generate risk clusters of children, adolescents, and young adults, based on adverse environmental exposure and developmental characteristics, and to examine the association of risk clusters with manifest psychopathology. Participants (n = 8300) between 6 and 23 years were recruited from seven sites in India. We administered questionnaires to elicit history of previous exposure to adverse childhood environments, family history of psychiatric disorders in first-degree relatives, and a range of antenatal and postnatal adversities. We used these variables to generate risk clusters. Mini-International Neuropsychiatric Interview-5 was administered to evaluate manifest psychopathology. Two-step cluster analysis revealed two clusters designated as high-risk cluster (HRC) and low-risk cluster (LRC), comprising 4197 (50.5%) and 4103 (49.5%) participants, respectively. HRC had higher frequencies of family history of mental illness, antenatal and neonatal risk factors, developmental delays, history of migration, and exposure to adverse childhood experiences than LRC. There were significantly higher risks of any psychiatric disorder [Relative Risk (RR) = 2.0, 95% CI 1.8–2.3], externalizing (RR = 4.8, 95% CI 3.6–6.4) and internalizing disorders (RR = 2.6, 95% CI 2.2–2.9), and suicidality (2.3, 95% CI 1.8–2.8) in HRC. Social-environmental and developmental factors could classify Indian children, adolescents and young adults into homogeneous clusters at high or low risk of psychopathology. These biopsychosocial determinants of mental health may have practice, policy and research implications for people in low- and middle-income countries.

Objective:To examine if smaller size at birth, an indicator of growth restriction in utero, is associated with lower cognition in late life, and whether this may be mediated by impaired early life brain development and/or adverse cardiometabolic programming.Design:Longitudinal follow-up of a birth cohort.Setting:CSI Holdsworth Memorial Hospital (HMH), Mysore South India.Participants:721 men and women (55–80 years) whose size at birth was recorded at HMH. Approximately 20 years earlier, a subset (n = 522) of them had assessments for cardiometabolic disorders in mid-life.Measurements:Standardized measurement of cognitive function, depression, sociodemographic, and lifestyle factors; blood tests and assessments for cardiometabolic disordersResults:Participants who were heavier at birth had higher composite cognitive scores (0.12 SD per SD birth weight [95% CI 0.05, 0.19] p = 0.001) in late life. Other lifecourse factors independently positively related to cognition were maternal educational level and participants’ own educational level, adult leg length, body mass index, and socioeconomic position, and negatively were diabetes in mid-life and current depression and stroke. The association of birth weight with cognition was independent cardiometabolic risk factors and was attenuated after adjustment for all lifecourse factors (0.08 SD per SD birth weight [95% CI −0.01, 0.18] p = 0.07).Conclusions:The findings are consistent with positive effects of early life environmental factors (better fetal growth, education, and childhood socioeconomic status) on brain development resulting in greater long-term cognitive function. The results do not support a pathway linking poorer fetal development with reduced late life cognitive function through cardiometabolic programming.

Background: Maternal nutrition in pregnancy has been linked to offspring health in early and later life, with changes to DNA methylation (DNAm) proposed as a mediating mechanism. Objective: We investigated intervention-associated DNAm changes in children whose mothers participated in 2 randomized controlled trials of micronutrient supplementation before and during pregnancy, as part of the EMPHASIS (Epigenetic Mechanisms linking Preconceptional nutrition and Health Assessed in India and sub-Saharan Africa) study (ISRCTN14266771). Design: We conducted epigenome-wide association studies with blood samples from Indian (n = 698) and Gambian (n = 293) children using the Illumina EPIC array and a targeted study of selected loci not on the array. The Indian micronutrient intervention was food based, whereas the Gambian intervention was a micronutrient tablet. Results: We identified 6 differentially methylated CpGs in Gambians [2.5-5.0% reduction in intervention group, all false discovery rate (FDR)

Context Imbalances in maternal 1-carbon nutrients (vitamin B12, folate) have been shown to be associated with higher offspring cardiometabolic risk markers in India. Objective We examined the hypothesis that low plasma vitamin B12 (B12) and high folate and homocysteine concentrations in the mother are associated with higher hypothalamic–pituitary–adrenal axis (cortisol) and cardiovascular responses during the Trier Social Stress Test for Children (TSST-C) in an Indian birth cohort. Methods Adolescents (n = 264; mean age: 13.6 years), whose mothers’ plasma B12, folate and total homocysteine concentrations had been measured during pregnancy, completed 5-minutes each of public speaking and mental arithmetic tasks in front of 2 unfamiliar “judges” (TSST-C). Baseline and poststress salivary cortisol concentrations were measured. Heart rate, blood pressure, stroke volume, cardiac output, and total peripheral resistance were measured continuously at baseline, during the TSST-C, and for 10 minutes after the TSST-C using a finger cuff; beat-to-beat values were averaged for these periods, respectively. Results Maternal low B12 status (plasma B12 < 150 pmol/L) was associated with greater cortisol responses to stress in the offspring (P < .001). Higher homocysteine concentrations were associated with greater offspring heart rate response (P < .001). After adjustment for multiple comparisons, there were nonsignificant associations between higher maternal folate concentrations and offspring total peripheral resistance response (P = .01). Conclusion Our findings suggest that maternal 1-carbon nutritional status may have long-term programming implications for offspring neuroendocrine stress responses.

Size at birth is known to be influenced by various fetal and maternal factors including genetic effects. South Asians have a high burden of low birthweight and cardiometabolic diseases, yet studies of common genetic variations underpinning these phenotypes are lacking. We generated independent, weighted fetal genetic score (fGS) and maternal genetic score (mGS) from 196 birthweight-associated variants identified in Europeans and conducted association analysis with various fetal birth parameters and anthropometric and cardiometabolic traits measured at different follow-up stages (5-6 years’ intervals) from seven Indian and Bangladeshi cohorts of South Asian ancestry. The results from above cohorts were compared with South Asians in UK BioBank and The Exeter Family Study of Childhood Health, a European ancestry cohort. Birthweight increased by 50.7g and 33.6g per standard deviation of fGS (p = 9.1x10-11) and mGS (p = 0.003) respectively in South Asians. A relatively weaker maternal genetic score effect compared to Europeans indicates possible different intrauterine exposures between Europeans and South Asians. Birthweight was strongly associated with body size in both childhood and adolescence (p = 3x10-5 - 1.9x10-51), however, fetal genetic score was associated with body size in childhood only (p < 0.01) and with head circumference, fasting glucose and triglycerides in adults (p < 0.01). The substantially smaller newborn size in South Asians with comparable fetal genetic effect to Europeans on birthweight suggests a significant role of factors related to fetal growth that were not captured by the present genetic scores. These factors may include different environmental exposures, maternal body size, health and nutritional status etc. Persistent influence of genetic loci on size at birth and adult metabolic syndrome in our study supports a common genetic mechanism partly explaining associations between early development and later cardiometabolic health in various populations, despite marked differences in phenotypic and environmental factors in South Asians.

Background: Maternal nutrition influences fetal development and may permanently alter ("program") offspring body composition and metabolism, thereby influencing later risk of diabetes and cardiovascular (cardiometabolic) disease. The prevalence of cardiometabolic disease is rising rapidly in India. Objectives: To test the hypothesis that supplementing low-income Indian women with micronutrient-rich foods preconceptionally and during pregnancy has a beneficial impact on the children's body composition and cardiometabolic risk marker profiles. Methods: Follow-up of 1255 children aged 5-10 y whose mothers took part in the Mumbai Maternal Nutrition Project [Project "SARAS"; International Standard Randomised Controlled Trial Number (ISRCTN)62811278]. Mothers were randomly assigned to receive a daily micronutrient-rich snack or a control snack of lower micronutrient content, both made from local foods, in addition to normal diet, from before pregnancy until delivery. Children's body composition was assessed using anthropometry and DXA. Their blood pressure, plasma glucose, insulin, and lipid concentrations were measured. Outcomes were compared between allocation groups with and without adjustment for confounding factors. Results: Overall, 15% of children were stunted, 34% were wasted, and 3% were overweight. In the intention-To-Treat analysis, there were no differences in body composition or risk markers between children in the intervention and control groups. Among children whose mothers started supplementation ≥3 mo before conception (the "per protocol"sample) the intervention increased adiposity among girls, but not boys. BMI in girls was increased relative to controls by 2% (95% CI: 1, 4; P = 0.01); fat mass index by 10% (95% CI: 3, 18; P = 0.004); and percent fat by 7% (95% CI: 1, 13; P = 0.01) unadjusted, with similar results in adjusted models. Conclusions: Overall, supplementing women with micronutrient-rich foods from before pregnancy until delivery did not alter body composition or cardiometabolic risk markers in the children. Subgroup analyses showed that, if started ≥3 mo before conception, supplementation may increase adiposity among female children.

Introduction: Many of the assessment tools used to study depression amongst older people in low- and middle- income countries (LMICs) are adaptations of instruments developed in other cultural settings. There is a need to validate those instruments in LMICs. Methods: 721 men and women aged 55–80 years from the Mysore Birth Records Cohort underwent standardised assessments for sociodemographic characteristics, cardiometabolic risk factors, cognitive function and mental health. Sensitivity, specificity and level of agreement of EURO-D diagnosis of depression with diagnosis of depression derived by the Geriatric Mental State (GMS) examination were calculated. To validate the EURO-D score against GMS depressive episode, we used maximum Youden's index as the criterion for each cut-off point. Concurrent validity was assessed by measuring correlations with the WHO Disability Assessment Schedule (WHO DAS II). Results: Of the 721 (408 men and 313 women) who participated in this study, 138 (54 men and 84 women) were diagnosed with depression. Women had higher depression scores on the EURO-D scale and disability on the WHO DAS II scale. A maximum Youden's Index of 0.60 was observed at a EURO-D cut-off of 6, which corresponded to 95% sensitivity, 64% specificity, kappa value of 0.6 and area under the curve (AUC) of 80%. There was significant and positive correlation between EURO-D and WHO DAS II scores. Limitations: Future independent validation studies in other settings are required. Discussion: This study supports the use of the EURO-D scale for diagnosing depression amongst older adults in South India.

Background Adverse childhood experiences (ACEs) increases vulnerability to externalising disorders such as substance misuse. The study aims to determine the prevalence of ACEs and its association with substance misuse. Methods Data from the Consortium on Vulnerability to Externalising Disorders and Addictions (cVEDA) in India was used (n = 9010). ACEs were evaluated using the World Health Organisation (WHO) Adverse Childhood Experiences International Questionnaire whilst substance misuse was assessed using the WHO Alcohol, Smoking and Substance Involvement Screening Test. A random-effects, two-stage individual patient data meta-analysis explained the associations between ACEs and substance misuse with adjustments for confounders such as sex and family structure. Results 1 in 2 participants reported child maltreatment ACEs and family level ACEs. Except for sexual abuse, males report more of every individual childhood adversity and are more likely to report misusing substances compared with females (87.3% vs. 12.7%). In adolescents, family level ACEs (adj OR 4.2, 95% CI 1.5–11.7) and collective level ACEs (adj OR 6.6, 95% CI 1.4–31.1) show associations with substance misuse whilst in young adults, child level ACEs such as maltreatment show similar strong associations (adj OR 2.0, 95% CI 1.1–3.5). Conclusion ACEs such as abuse and domestic violence are strongly associated with substance misuse, most commonly tobacco, in adolescent and young adult males in India. The results suggest enhancing current ACE resilience programmes and ‘trauma-informed’ approaches to tackling longer-term impact of ACEs in India. Funding Newton Bhabha Grant jointly funded by the Medical Research Council, UK (MR/N000390/1) and the Indian Council of Medical Research (ICMR/MRC-UK/3/M/2015-NCD-I).

OBJECTIVE India is a double world capital of early-life undernutrition and type 2 diabetes. We aimed to characterize life course growth and metabolic trajectories in those developing glucose intolerance as young adults in the Pune Maternal Nutrition Study (PMNS). RESEARCH DESIGN AND METHODS PMNS is a community-based intergenerational birth cohort established in 1993, with serial information on parents and children through pregnancy, childhood, and adolescence. We compared normal glucose-tolerant and glucose-intolerant participants for serial growth, estimates of insulin sensitivity and secretion (HOMA and dynamic indices), and β-cell compensation accounting for prevailing insulin sensitivity. RESULTS At 18 years (N = 619), 37% of men and 20% of women were glucose intolerant (prediabetes n = 184; diabetes n = 1) despite 48% being underweight (BMI CONCLUSIONS Inadequate compensatory insulin secretory response to decreasing insulin sensitivity in early life is the major pathophysiology underlying glucose intolerance in thin rural Indians. Smaller birth size, maternal pregnancy hyperglycemia, and higher glycemia from childhood herald future glucose intolerance, mandating a strategy for diabetes prevention from early life, preferably intergenerationally.

BackgroundNutritional interventions during the first 1000 days of life improves lifelong health. Better pre-conceptional maternal nutrition improves the nutrition of the early embryo. Vitamins B12 and folate are important for fetal neural development. Vitamin B12 deficiency is common in India.MethodsIn the Pune Rural Intervention in Young Adolescents (PRIYA) adolescents (N=557, 226 females) were provided with vitamin B12 (2µg/day) with or without multiple micronutrients, or a placebo, from preconception until delivery. All groups received mandatory iron and folic acid. We used the Bayley’s Scale of Infant Development (BSID-III) at 24-42 months of age to investigate effects on offspring neurodevelopment. We examined cord blood concentrations of brain-derived neurotropic factor (BDNF).ResultsParticipants in the three groups had similar baseline B12 levels. These improved in the B12 supplemented groups at pre-conceptional and pregnancy (28 weeks gestation) measurements, reflected in higher cord holo-TC levels compared to the placebo. Neurodevelopmental outcomes are available for 74 children. Offspring in the B12 alone group (n=21) performed better than the placebo (n=27) on cognition (p=0.044) and language (p=0.020) domains (adjusted for maternal baseline B12 levels). There were no differences between the B12+MMN (n=26) and placebo group. Cord blood BDNF levels were highest in the B12 alone group (not statistically significant).ConclusionPre-conceptional vitamin B12 supplementation improved maternal B12 status and offspring neurodevelopment at 2 years of age. The usefulness of cord BDNF as a marker of brain development needs further investigation. Our results highlight the importance of intervening in the pre-conceptional period.

Changes in brain morphology have been reported during development, ageing and in relation to different pathologies. Brain morphology described by the shape complexity of gyri and sulci can be captured and quantified using fractal dimension (FD). This measure of brain structural complexity, as well as brain volume, are associated with intelligence, but less is known about the sexual dimorphism of these relationships. In this paper, sex differences in the relationship between brain structural complexity and general intelligence (g) in two diverse geographic and cultural populations (UK and Indian) are investigated. 3D T1-weighted magnetic resonance imaging (MRI) data and a battery of cognitive tests were acquired from participants belonging to three different cohorts: Mysore Parthenon Cohort (MPC); Aberdeen Children of the 1950s (ACONF) and UK Biobank. We computed MRI derived structural brain complexity and g estimated from a battery of cognitive tests for each group. Brain complexity and volume were both positively corelated with intelligence, with the correlations being significant in women but not always in men. This relationship is seen across populations of differing ages and geographical locations and improves understanding of neurobiological sex-differences.

AimsMaternal diabetes in pregnancy increases offspring obesity and diabetes risk. We investigated body size and composition, and glucose tolerance in offspring born to Indian diabetic mothers (ODM) and to non-diabetic mothers (ONDM), and studied maternal and paternal determinants.MethodsWe compared the physical characteristics, body composition (Dual energy X-ray Absorptiometry) and glycemia of ODMs and matched ONDMs. Overweight-obesity was defined using International Obesity Task Force (IOTF) for 2-18 years (cutoff of BMI > 25 kg/m2) and World Health Oraganization (WHO) criteria for >18 years (BMI > 25 kg/m2). Glycemic measures included capillary blood glucose measurement in children =10 years. We calculated separate SD scores for capillary fasting, capillary random and venous fasting plasma glucose. Those above median SD score were classified as glucose intolerant. We evaluated insulin sensitivity (Homeostatic Model Assessment HOMA-S and Matsuda index), beta cell function (HOMA-β and insulinogenic index) and β-cell compensatory response (Disposition Index: [Log (Insulinogenic index) + Log (Matsuda index)]). We studied the association of maternal and paternal body size and glycemia with outcomes in the child.ResultsWe studied 200 ODMs of 176 diabetic mothers (133 GDM, 21 type 2 diabetes, 22 type 1 diabetes), and 177 ONDMs at an average of 9.7 years after delivery. ODMs were heavier, more adipose and more glucose intolerant than ONDMs. Differences for body size parameters were more prominent in males and they also had a wider spectrum of metabolic abnormalities. Three (4%) ODM were receiving treatment for diabetes (diagnosed between 10-25 years of age). On OGTT, the older ODMs (>= 10 years) had higher prevalence of glucose intolerance (1 DM, 14 IFG, 12 IGT and 4 both IFG and IGT) compared to ONDM, (0 DM, 7 IFG, 9 IGT and 1 both IFG and IGT). None of the diabetic and pre-diabetic ODMs, including children of type 1 diabetic mothers, were positive for circulating GAD or ZnT8 antibodies.Younger ODMs (Type 2 diabetic and GDM mothers were heavier compared to type 1 diabetic mothers, and their children were more likely to be overweight-obese. Children of type 1 diabetic mothers were glucose intolerant despite lack of overweight-obesity. In addition, fathers had an independent influence on the child’s phenotype, especially for overweight-obesity. Maternal hyperglycemia during pregnancy had an overriding influence on offspring glucose intolerance.ConclusionsODMs were more overweight-obese and glucose intolerant compared to ONDMs. We propose that these two outcomes in the ODMs are independently programmed by respective parental phenotypes. Preventive strategies will need to be informed by these findings. Studies of genetic and epigenetic mechanisms involved in fetal programming of body size and glycemia will further help our understanding.Research in ContextWhat is already known about this subject?India has experienced a rapid escalation of diabetes in young individuals including diabetes in pregnancy. Short-term effects of maternal hyperglycemia on the offspring are well known.What is the key question?There is little data on long-term effects of maternal hyperglycemia on offspring body size and cardiometabolic risk factors. We compared these in the offspring of diabetic mothers compared to those of non-diabetic mothers. We also sought differences within types of diabetes (type 1, type 2, GDM) and studied paternal determinants of these outcomes.What are the new findings?Type 1 diabetic mothers were thinnest and most hyperglycemic; type 2 diabetic mothers were most overweight-obese, GDM mothers were intermediate. Gestational maternal hyperglycemia was the overriding determinant of offspring hyperglycemia. Maternal hyperglycemia predicted offspring glucose intolerance but not overweight obesity; maternal overweight-obesity predicted offspring overweight-obesity but not hyperglycemia, suggesting an uncoupling of these phenotypes often considered congruent. Fathers had an additive influence on offspring size.How might this impact on clinical practice in the foreseeable future?Knowing the relative independence of influences on body size and metabolic outcomes will inform strategies of their primordial and primary prevention. Establishing genetic and epigenetic mechanisms will help.

Background: In India, stress levels are increasing steadily among youth. We aimed to explore the factors that contribute to psychological stress and coping strategies among adolescents in Mysore, India to inform the development of an intervention. Methods: We recruited 16 volunteers in Mysore, India including 6 younger (12-15 years; 3 girls) and 10 older adolescents/ young adults (17-25 years; 5 girls) using a purposive sampling technique. Older adolescents were recruited from ongoing birth cohort study, and the younger adolescents by word-of-mouth from the community. Individual in-depth interviews were carried out based on a semi-structured interview guide comprising open-ended questions. The interviews were analysed to derive themes and emerging constructs related to stress and coping strategies. Results: Adolescents generally perceived stress in their daily lives. Family conflicts and academic pressures were the main triggers for increased stress. Issues around peer relationships, and social position were also important contributors. Adolescents reported that they had robust coping strategies. These included stress release through rationalising and acceptance of the situation, distraction activities, spirituality, and self-comforting methods. However, they felt the need for further support from their family, and the society in general. In particular they expressed the need for a space to share their concerns and obtain guidance through healthy discussions with adults. Conclusions: Our study indicates that adolescents in India are exposed to a wide range of stressors in their daily lives. The conflict between ‘traditional’ society’s opinions of what adolescents should do and the new age adolescents’ aspirations for autonomy to find ‘informed’ solutions for their issues may hinder the stress management efforts. Moving forward, we propose to develop a culturally acceptable intervention tool that accommodates adolescents’ perspectives and psychosocial context.

We recently reported genetic variants associated with birth weight and their effect on future cardiometabolic risk in Europeans. Despite a higher burden of low birth weight and cardiometabolic disorders, such studies are lacking in South Asians. We generated fetal and maternal genetic scores (fGS and mGS) from 196 birth weight-associated variants identified in Europeans and conducted association analysis with various birth measures and serially measured anthropometric and cardiometabolic traits from seven Indian and Bangladeshi cohorts. Although fGS and mGS were comparable to Europeans, birth weight was substantially smaller suggesting strong environmental constraints on fetal growth in South Asians. Birth weight increased by 50.7g and 33.6g per standard deviation fGS (P=9.1×10−11) and mGS (P=0.003) in South Asians. The fGS was further associated with childhood body size and head circumference, fasting glucose, and triglycerides in adults (P

We recently reported genetic variants associated with birth weight and their effect on future cardiometabolic risk in Europeans. Despite a higher burden of low birth weight and cardiometabolic disorders, such studies are lacking in South Asians. We generated fetal and maternal genetic scores (fGS and mGS) from 196 birth weight-associated variants identified in Europeans and conducted association analysis with various birth measures and serially measured anthropometric and cardiometabolic traits from seven Indian and Bangladeshi cohorts. Although fGS and mGS were comparable to Europeans, birth weight was substantially smaller suggesting strong environmental constraints on fetal growth in South Asians. Birth weight increased by 50.7g and 33.6g per standard deviation fGS (P=9.1x10-11) and mGS (P=0.003) in South Asians. The fGS was further associated with childhood body size and head circumference, fasting glucose, and triglycerides in adults (P

IntroductionThe Healthy Life Trajectories Initiative is an international consortium comprising four harmonised but independently powered trials to evaluate whether an integrated intervention starting preconceptionally will reduce non-communicable disease risk in their children. This paper describes the protocol of the India study.Methods and analysisThe study set in rural Mysore will recruit ~6000 married women over the age of 18 years. The village-based cluster randomised design has three arms (preconception, pregnancy and control; 35 villages per arm). The longitudinal multifaceted intervention package will be delivered by community health workers and comprise: (1) measures to optimise nutrition; (2) a group parenting programme integrated with cognitive–behavioral therapy; (3) a lifestyle behaviour change intervention to support women to achieve a diverse diet, exclusive breast feeding for the first 6 months, timely introduction of diverse and nutritious infant weaning foods, and adopt appropriate hygiene measures; and (4) the reduction of environmental pollution focusing on indoor air pollution and toxin avoidance.The primary outcome is adiposity in children at age 5 years, measured by fat mass index. We will report on a host of intermediate and process outcomes. We will collect a range of biospecimens including blood, urine, stool and saliva from the mothers, as well as umbilical cord blood, placenta and specimens from the offspring.An intention-to-treat analysis will be adopted to assess the effect of interventions on outcomes. We will also undertake process and economic evaluations to determine scalability and public health translation.Ethics and disseminationThe study has been approved by the institutional ethics committee of the lead institute. Findings will be published in peer-reviewed journals. We will interact with policy makers at local, national and international agencies to enable translation. We will also share the findings with the participants and local community through community meetings, newsletters and local radio.Trial registration numberISRCTN20161479, CTRI/2020/12/030134; Pre-results.

Background: Arsenic, a contaminant of groundwater and irrigated crops, is a global public health hazard. Exposure to low levels of arsenic through food extends well beyond the areas with high arsenic water content. While isolated impairments of cognitive function following chronic exposure to high arsenic levels have been described, a comprehensive assessment of the scope of such impairments and their underlying brain mechanisms does not exist, especially not in the case of the much more common low-level arsenic exposure. Methods: We analyse 1014 participants aged 6 to 23 years of the Indian Consortium-on-Vulnerability-to-Externalizing-Disorders-and-Addictions (cVEDA). Participants were characterised using deep phenotyping measures of behaviour, neuropsychology, psychopathology, brain neuroimaging and exposure to developmental adversities and environmental neurotoxins. Arsenic was measured in urine as an index of exposure. Findings: Using sparse-partial least square analysis (sPLS) we describe a correlation of arsenic exposure with impairments in executive function (r=-0.12, p=5.4x10-4), brain structure (r=-0·2, p=1·8x10-8) and functional connectivity (within-network: r=-0·12, p=7·5x10-4, between-network: r=-0·23, p=1·8x10-10). Impairments in executive function were partially mediated by localised changes in grey-matter volume (b=-0·004, CIs=-0·007 to -0·002) and within-network functional connectivity (b=-0·004, CIs=-0·008 to -0·002). Socio Economic Status (SES) and Body Mass Index (BMI) moderated the link between arsenic and changes in grey-matter volume, with the effect of arsenic being strongest in participants from lower SES and with low BMI. Interpretation: We describe a syndrome of impairments in executive function and their brain correlates associated with low-level arsenic exposure. Our results demonstrate detrimental consequences of arsenic exposure well below currently recommended guidelines that affects people beyond endemic risk areas. Precision medicine approaches to study global-mental-health vulnerabilities, highlight widespread but potentially modifiable risk factors and a mechanistic understanding of the impact of low-level arsenic exposure on brain development. Funding Information: Indian Council for Medical Research and Medical Research Council, United Kingdom. Declaration of Interests: All authors report no competing interests. Ethics Approval Statement: The cVEDA Study was approved by the Health Ministry Screening Committee, Ministry of Health and Family Welfare, Government of India. The study protocol was approved by the Institutional Ethics Review Boards of National Institute of Mental Health and Neurosciences (NIMHANS) Bangalore, India (Item No. VII, SI. No. 7·08, Behavioural Sciences) and all other regional collaborating institutions. Informed consent was obtained from participants over the age of 18 and from parents of participants under 18 years of age (along with assent from minor participants).

ObjectiveIndia is a double world capital for early life undernutrition and type 2 diabetes. We aimed to characterise lifecourse growth and metabolic trajectories in those developing glucose intolerance as young adults, in the Pune Maternal Nutrition Study (PMNS).Research design and MethodsPMNS is a community-based intergenerational birth cohort established in 1993, with serial information on parents and children through pregnancy, childhood and adolescence. We compared normal glucose tolerant and glucose intolerant participants for serial growth, estimates of insulin sensitivity and secretion (HOMA and dynamic indices) and beta cell compensation accounting for prevailing insulin sensitivity (disposition index).ResultsAt 18 years (N=619) 37% men and 20% women were glucose intolerant (184 prediabetes, 1 diabetes) despite 48% being underweight (BMI2). Glucose intolerant participants had higher fasting glucose from childhood. Mothers of glucose intolerant participants had higher glycemia in pregnancy. Glucose intolerant participants were shorter at birth. Insulin sensitivity decreased with age in all participants, and the glucose intolerant had consistently lower compensatory insulin secretion from childhood. Participants in the highest quintile of fasting glucose at 6 and 12 years had a 2.5- and 4.0-fold higher risk respectively of 18-year glucose intolerance; this finding was replicated in two other cohorts.ConclusionInadequate compensatory insulin secretory response to increasing insulin insensitivity from early life is the major pathophysiology underlying glucose intolerance in thin rural Indians. Smaller birth size, maternal pregnancy hyperglycemia, and higher glycemia in childhood herald future glucose intolerance, mandating a strategy for diabetes prevention from early life, preferably intergenerationally.

There has been an upward trend in developing frameworks that enable neuroimaging researchers to address challenging questions by leveraging data across multiple sites all over the world. One such open-source framework is the Collaborative Informatics and Neuroimaging Suite Toolkit for Anonymous Computation (COINSTAC) that works on Windows, macOS, and Linux operating systems and leverages containerized analysis pipelines to analyze neuroimaging data stored locally across multiple physical locations without the need for pooling the data at any point during the analysis. In this paper, the COINSTAC team partnered with a data collection consortium to implement the first-ever decentralized voxelwise analysis of brain imaging data performed outside the COINSTAC development group. Decentralized voxel-based morphometry analysis of over 2000 structural magnetic resonance imaging data sets collected at 14 different sites across two cohorts and co-located in different countries was performed to study the structural changes in brain gray matter which linked to age, body mass index (BMI), and smoking. Results produced by the decentralized analysis were consistent with and extended previous findings in the literature. In particular, a widespread cortical gray matter reduction (resembling a 'default mode network' pattern) and hippocampal increase with age, bilateral increases in the hypothalamus and basal ganglia with BMI, and cingulate and thalamic decreases with smoking. This work provides a critical real-world test of the COINSTAC framework in a "Large-N" study. It showcases the potential benefits of performing multivoxel and multivariate analyses of large-scale neuroimaging data located at multiple sites.

Objective:Adolescent diet, physical activity and nutritional status are generally known to be sub-optimal. This is an introduction to a special issue of papers devoted to exploring factors affecting diet and physical activity in adolescents, including food insecure and vulnerable groups.SettingEight settings including urban, peri-urban and rural across sites from five different low- and middle-income countries.Design:Focus groups with adolescents and caregivers carried out by trained researchers.Results:Our results show that adolescents, even in poor settings, know about healthy diet and lifestyles. They want to have energy, feel happy, look good and live longer, but their desire for autonomy, a need to ‘belong’ in their peer group, plus vulnerability to marketing exploiting their aspirations, leads them to make unhealthy choices. They describe significant gender, culture and context-specific barriers. For example, urban adolescents had easy access to energy dense, unhealthy foods bought outside the home, whereas junk foods were only beginning to permeate rural sites. Among adolescents in Indian sites, pressure to excel in exams meant that academic studies were squeezing out physical activity time.Conclusions:Interventions to improve adolescents’ diets and physical activity levels must therefore address structural and environmental issues and influences in their homes and schools, since it is clear that their food and activity choices are the product of an interacting complex of factors. In the next phase of work, the Transforming Adolescent Lives through Nutrition consortium will employ groups of adolescents, caregivers and local stakeholders in each site to develop interventions to improve adolescent nutritional status.

ObjectivesWe investigated whether the relationship between components of height and cardiovascular disease (CVD) risk may be explained by body composition. We also examined relationships between parental heights and offspring CVD risk.DesignA cohort study using cross-sectional data.SettingA secondary care hospital setting in Pune, India.ParticipantsWe studied 357 young adults and their parents in the Pune Children’s Study. Primary and secondary outcomes: we measured weight, total height, leg length, sitting height, plasma glucose, insulin and lipids, and blood pressure (BP). Total and regional lean and fat mass were measured by dual X-ray absorptiometry.ResultsLeg length was inversely related, and sitting height was directly related to BMI. Total height and leg length were directly related to lean mass, while sitting height was directly related to both lean and fat mass. Leg length was inversely related to systolic BP and 120 min glucose, independent of lean and fat mass. Sitting height was directly related to systolic BP and triglycerides; these relationships were attenuated on adjustment for lean and fat mass. When examined simultaneously, greater leg length was protective and greater sitting height was associated with a more detrimental CVD risk profile.ConclusionsShorter adult leg length and greater sitting height are associated with a more adverse CVD risk factor profile. The mechanisms need further study, but our findings suggest a role for lean and fat mass.