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Introduction: We used data from MOBI-Kids, a 14-country international collaborative case-control study of brain tumors (BTs), to study clinical characteristics of the tumors in older children (10 years or older), adolescents and young adults (up to the age of 24). Methods: Information from clinical records was obtained for 899 BT cases, including signs and symptoms, symptom onset, diagnosis date, tumor type and location. Results: Overall, 64% of all tumors were low-grade, 76% were neuroepithelial tumors and 62% gliomas. There were more males than females among neuroepithelial and embryonal tumor cases, but more females with meningeal tumors. The most frequent locations were cerebellum (22%) and frontal (16%) lobe. The most frequent symptom was headaches (60%), overall, as well as for gliomas, embryonal and 'non-neuroepithelial' tumors; it was convulsions/seizures for neuroepithelial tumors other than glioma, and visual signs and symptoms for meningiomas. A cluster analysis showed that headaches and nausea/vomiting was the only combination of symptoms that exceeded a cutoff of 50%, with a joint occurrence of 67%. Overall, the median time from first symptom to diagnosis was 1.42 months (IQR 0.53-4.80); it exceeded 1 year in 12% of cases, though no particular symptom was associated with exceptionally long or short delays.Conclusions: This is the largest clinical epidemiology study of BT in young people conducted so far. Many signs and symptoms were identified, dominated by headaches and nausea/vomiting. Diagnosis was generally rapid but in 12% diagnostic delay exceeded 1 year with none of the symptoms been associated with a distinctly long time until diagnosis. This work was supported by the MOBI-Kids study and the work in this study was obtained from the European Community's Seventh Framework Programme under Grant Agreements Number 226873—the MOBI-Kids Project—and 603794—the GERoNiMO project. Additional funds for the coordination of MOBI-Kids were obtained from the Spanish Ministry of Science and Innovation (MINECO), while complementary funds for the conduct of MOBI-Kids in Spain were obtained from the Spanish Health Research Fund (FIS) of the National Institute for Health Carlos III. Italian participation is partially supported by a Ministry of Health grant (RF-2009-1546284). In Canada, funding was provided by a grant from the Canadian Institutes for Health Research under a peer-reviewed university-industry partnership program that involved the Canadian Wireless Telecommunications Association, who provided technical data on wireless telecommunications practices in Canada. The German study centre received additional support by the Federal Office for Radiation Protection (BfS). Japanese participation in MOBI-Kids was supported by the Ministry of Internal Affairs and Communications. New Zealand participation was supported by Health Research Council and Cure Kids. In France, this study received funds from the French National Agency for Sanitary Safety of Food, Environment and Labour (ANSES, contract FSRF2008-3), French National Cancer Institute (INCa), Pfizer Foundation and League against cancer. India received funding from Board of Research in Nuclear Sciences (BRNS). The funding sources had no role in: the study design; the collection, analysis, and interpretation of data; the writing of the report; and the decision to submit the article for publication.

Purpose Subclinical systemic inflammation may lead to development of type 2 diabetes, but there has been no investigation into its relationship with early progression of glycemic deterioration and insulin resistance, especially in younger population. In this study we assess longitudinal associations of pro- and anti-inflammatory markers with markers that assess glycemia and insulin resistance. Methods This study includes 6537 initially nondiabetic children (mean age at baseline = 6.2 years) with repeated measurements from the IDEFICS/I.Family cohort study (mean follow-up = 5.3 years) from eight European countries. Markers of inflammation were used as independent variables and markers of glycemia/insulin resistance as dependent variables. Associations were examined using two-level growth model. Models were adjusted for sex, age, major lifestyle, metabolic risk factors, early life markers, and other inflammatory markers in final model. Results Children with 6 years of follow-up showed that a one-unit increasea in z-score of leptin level was associated with 0.38 (95% CI = 0.32 to 0.44) unit increase in HOMA-IR z-scores. Leptin continued to be associated with HOMA-IR even when analysis was limited to children with no overall obesity, no abdominal obesity, and low to normal triglyceride levels. An inverse association was observed between IL-15 and HOMA-IR (β = -0.11, 95% CI = -0.15 to -0.07). Main conclusions IL-15 should be evaluated further in the prevention or treatment of prediabetes whereas leptin may prove to be useful in early detection of prediabetes via their association with marker of insulin resistance in European children. This article is protected by copyright. All rights reserved.

COVID-19 poses a major challenge to individuals and societies around the world. Yet, it is difficult to obtain a good overview of studies across different medical fields of research such as clinical trials, epidemiology, and public health. Here, we describe a consensus metadata model to facilitate structured searches of COVID-19 studies and resources along with its implementation in three linked complementary web-based platforms. A relational database serves as central study metadata hub that secures compatibilities with common trials registries (e.g. ICTRP and standards like HL7 FHIR, CDISC ODM, and DataCite). The Central Search Hub was developed as a single-page application, the other two components with additional frontends are based on the SEEK platform and MICA, respectively. These platforms have different features concerning cohort browsing, item browsing, and access to documents and other study resources to meet divergent user needs. By this we want to promote transparent and harmonized COVID-19 research.

Background: The coronavirus disease 2019 (COVID-19) global pandemic required a rapid and effective response. This included ethical and legally appropriate sharing of data. The European Commission (EC) called upon the Research Data Alliance (RDA) to recruit experts worldwide to quickly develop recommendations and guidelines for COVID-related data sharing. Purpose: The purpose of the present work was to explore how the RDA succeeded in engaging the participation of its community of scientists in a rapid response to the EC request. Methods: A survey questionnaire was developed and distributed among RDA COVID-19 work group members. A mixed-methods approach was used for analysis of the survey data. Results: The three constructs of radical collaboration (inclusiveness, distributed digital practices, productive and sustainable collaboration) were found to be well supported in both the quantitative and qualitative analyses of the survey data. Other social factors, such as motivation and group identity were also found to be important to the success of this extreme collaborative effort. Conclusions: Recommendations and suggestions for future work were formulated for consideration by the RDA to strengthen effective expert collaboration and interdisciplinary efforts.

Summary Background Gallbladder cancer is highly lethal, with notable differences in incidence by geography and ethnic background. The aim of this study was to identify common genetic susceptibility alleles for gallbladder cancer. Methods In this case-control genome-wide association study (GWAS), we did a genome-wide scan of gallbladder cancer cases and hospital visitor controls, both of Indian descent, followed by imputation across the genome. Cases were patients aged 20–80 years with microscopically confirmed primary gallbladder cancer diagnosed or treated at Tata Memorial Hospital, Mumbai, India, and enrolled in the study between Sept 12, 2010, and June 8, 2015. We only included patients who had been diagnosed less than 1 year before the date of enrolment and excluded patients with any other malignancies. We recruited visitor controls aged 20–80 years with no history of cancer visiting all departments or units of Tata Memorial Hospital during the same time period and frequency matched them to cases on the basis of age, sex, and current region of residence. We estimated association using logistic regression, adjusting for age, sex, and five eigenvectors. We recruited samples for a replication cohort from patients visiting Tata Memorial Hospital between Aug 4, 2015, and May 17, 2016, and patients visiting the Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India, between July, 2010, and May, 2015. We used the same inclusion and exclusion criteria for the replication set. We examined three of the most significant single-nucleotide polymorphisms (SNPs) in the replication cohort and did a meta-analysis of the GWAS discovery and replication sets to get combined estimates of association. Findings The discovery cohort comprised 1042 gallbladder cancer cases and 1709 controls and the replication cohort contained 428 gallbladder cancer cases and 420 controls. We observed genome-wide significant associations for several markers in the chromosomal region 7q21.12 harbouring both the ABCB1 and ABCB4 genes, with the most notable SNPs after replication and meta-analysis being rs1558375 (GWAS p=3·8 × 10 −9 ; replication p=0·01; combined p=2·3 × 10 −10 ); rs17209837 (GWAS p=2·0 × 10 −8 ; replication p=0·02; combined p=2·3 × 10 −9 ), and rs4148808 (GWAS p=2·4 × 10 −8 ; replication p=0·008; combined p=2·7 × 10 −9 ). Combined estimates of per-allele trend odds ratios were 1·47 (95% CI 1·30–1·66; p=2·31 × 10 −10 ) for rs1558375, 1·61 (1·38–1·89; p=2·26 × 10 −9 ) for rs17209837, and 1·57 (1·35–1·82; p=2·71 × 10 −9 ) for rs4148808. GWAS heritability analysis suggested that common variants are associated with substantial variation in risk of gallbladder cancer (sibling relative risk 3·15 [95% CI 1·80–5·49]). Interpretation To our knowledge, this study is the first report of common genetic variation conferring gallbladder cancer risk at genome-wide significance. This finding, along with in-silico and biological evidence indicating the potential functional significance of ABCB1 and ABCB4 , underlines the likely importance of these hepatobiliary phospholipid transporter genes in the pathology of gallbladder cancer. Funding The Tata Memorial Centre and Department of Biotechnology.

IMPORTANCE Phytoestrogens are becoming popular constituents of human diets and are increasingly used by postmenopausal women. OBJECTIVE Our study aims to determine the effects of phytoestrogen supplementation on intermediate cardiovascular disease (CVD) risk factors in postmenopausal women. EVIDENCE REVIEW Five electronic databases (Medline, EMBASE, Web of Science, Cochrane CENTRAL, Google Scholar) were systematically searched to identify eligible studies, that is, randomized controlled trials (RCTs) that assessed the association of phytoestrogen supplementation with CVD risk factors (serum lipids, homocysteine, fibrinogen, markers of inflammation, oxidative stress and endothelial function, carotid intima-media thickness [CIMT]) in postmenopausal women. Data were extracted by two independent reviewers using a predefined data collection form. FINDINGS In total, 56 RCTs were identified, including 4,039 individual postmenopausal women. There was substantial heterogeneity in quality across studies. Twenty-six (46%) RCTs showed poor quality and there was an indication of publication bias presence for some of the biomarkers. Results are reported in pooled mean difference (95% CI) of changes. Use of phytoestrogens was associated with a decrease in serum total cholesterol (-0.27 mmol/L [-0.41 to -0.13]), low-density lipoprotein (-0.25 mmol/L [-0.37 to -0.13]), triglycerides (-0.20 mmol/L [-0.28 to -0.11]), and apolipoprotein B (-0.13 g/L [-0.23 to -0.03]) and with an increase in serum apolipoprotein A-1 (0.04 g/L [0.02-0.07]. Also, phytoestrogen supplementation was associated with a decrease in serum intercellular adhesion molecule 1 (-18.86 ng/mL [-30.06 to -7.65]) and E-selectin (-2.32 ng/mL [-4.05 to -0.59]). There was no association observed between phytoestrogen supplementation and inflammatory markers, fibrinogen, homocysteine, or other endothelial function markers. In contrast, use of phytoestrogens was associated with an increase in CIMT (9.34 μm [95% CI, 0.39-18.29]). Effect estimates of phytoestrogen supplementation on oxidative stress could not be pooled. CONCLUSIONS AND RELEVANCE Phytoestrogen supplementation seems to modestly improve the CVD risk profile of postmenopausal women by influencing blood lipids and parameters of endothelial function. In women with an increased risk of atherosclerosis, although modest, a harmful effect on CIMT progression may be present. Because of limited quality and the heterogeneous nature of the current evidence, additional rigorous studies are needed to explore the role of phytoestrogens in menopausal cardiovascular health. : Video Summary: http://links.lww.com/MENO/A593.

The systemic challenges of the COVID-19 pandemic require cross-disciplinary collaboration in a global and timely fashion. Such collaboration needs open research practices and the sharing of research outputs, such as data and code, thereby facilitating research and research reproducibility and timely collaboration beyond borders. The Research Data Alliance COVID-19 Working Group recently published a set of recommendations and guidelines on data sharing and related best practices for COVID-19 research. These guidelines include recommendations for clinicians, researchers, policy- and decision-makers, funders, publishers, public health experts, disaster preparedness and response experts, infrastructure providers from the perspective of different domains (Clinical Medicine, Omics, Epidemiology, Social Sciences, Community Participation, Indigenous Peoples, Research Software, Legal and Ethical Considerations), and other potential users. These guidelines include recommendations for researchers, policymakers, funders, publishers and infrastructure providers from the perspective of different domains (Clinical Medicine, Omics, Epidemiology, Social Sciences, Community Participation, Indigenous Peoples, Research Software, Legal and Ethical Considerations). Several overarching themes have emerged from this document such as the need to balance the creation of data adherent to FAIR principles (findable, accessible, interoperable and reusable), with the need for quick data release; the use of trustworthy research data repositories; the use of well-annotated data with meaningful metadata; and practices of documenting methods and software. The resulting document marks an unprecedented cross-disciplinary, cross-sectoral, and cross-jurisdictional effort authored by over 160 experts from around the globe. This letter summarises key points of the Recommendations and Guidelines, highlights the relevant findings, shines a spotlight on the process, and suggests how these developments can be leveraged by the wider scientific community.

Objective To assess the time point during infancy and early childhood at which greater than expected weight gain is associated with overweight in adolescence. Study design Current height, weight, and body mass index (BMI) were assessed in 1520 adolescents (mean age of boys, 15.52 ± 0.84 years; mean age of girls, 15.37 ± 0.77 years). Information on weight and height trajectories during infancy and early childhood (birth and 6 other time points) was extracted from mother-child booklets. Conditional relative weights were computed to estimate greater or lower than expected weight gain (ie, soft tissue gain at a specific age independent of linear growth), and their association with BMI in adolescence was investigated using linear regression analysis. Results The mean BMI in adolescence was 21.77 ± 3.69 in boys and 21.70 ± 3.50 in girls. The proportion of overweight was 14.8% in each group. Overweight adolescents had significantly higher weight z-scores at birth, 1.2 month, 3.3 months, 7.6 months, 1 year, 2 years, and 4 years of age as compared with normal-weight adolescents. There were significant positive associations of weight z-scores and conditional relative weights with adolescent BMI at all ages except birth, which were strongest after the first year of life. In a majority of overweight adolescents, overweight had manifested within the first 4 years of life. Conclusions Greater than expected weigh gain at any time in the first years of life is associated with an increased BMI in adolescence. The effect is strongest after the first year.

Background Osteoprotegerin is a cytokine involved in bone metabolism as well as vascular calcification and atherogenesis. Although circulating osteoprotegerin levels are robustly associated with incident cardiovascular disease ( CVD ) in the general population, its relevance as a biomarker among populations at high CVD risk is less clear. Methods and Results Three independent reviewers systematically searched PubMed, EMBASE , and Web of Science to identify prospective studies that had recruited participants on the basis of having conditions related to high CVD risk. A total of 19 studies were eligible for inclusion, reporting on 27 450 patients with diabetes mellitus (2 studies), kidney disease (7 studies), preexisting heart disease (5 studies), or recent acute coronary syndromes (5 studies) at baseline. Over a mean follow‐up of 4.2 years, 4066 CVD events were recorded. In a random‐effects meta‐analysis, the pooled risk ratio for CVD events comparing people in the top versus the bottom tertile of osteoprotegerin concentration was 1.30 (95% confidence interval, 1.12–1.50; P 2 =68.3%). There was evidence for presence of publication bias ( P value from Egger's test=0.013). Correction for publication bias using the trim‐and‐fill method reduced the risk ratio to 1.21 (95% confidence interval, 1.03–1.42; P Conclusions In populations at high CVD risk, elevated circulating osteoprotegerin levels are associated with a higher risk for future CVD events. The magnitude of association appears weaker than in the general population.

Purpose: Although cancer registry data indicate that there are large differences in breast cancer (BC) rates between rural and urban regions of India, the reasons for these differences are not well understood. Methods: We conducted a hospital based case–control study (1,637 breast cancer cases; 1,515 visitor controls) in Mumbai, India, during the years 2009–2013. Extensive questionnaire data, anthropometry measurement and blood samples were collected on all participants. Using logistic regression models, we estimated risk based on odds ratio (OR) and 95 % confidence intervals (CI) for various reproductive and anthropometric measures, stratified by rural–urban status depending upon residence in first 20 years of life. Results: Waist-to-hip ratio of =0.95 compared to ratio =0.84 was strongly associated with risk of BC in both rural and urban populations (ORurban = 4.10, 95 % CI 3.03–5.56; ORrural = 3.01, 95 % CI 1.85–4.90). First full-term pregnancy after the age of 25 compared to first full-term pregnancy below 20 years of age was associated with risk of BC in both urban and rural women (ORurban = 1.78, 95 % CI 1.32–2.41; ORrural = 2.24, 95 % CI 1.13–4.43). The prevalence of age at first full-term pregnancy was significantly lower in rural (mean age at first full-term pregnancy = 19.39 years) versus urban women (mean age at first full-term pregnancy = 22.62 years), whereas mean waist circumference was much higher in urban women (82.13 cm) compared to rural women (79.26 cm). We did not observe any association between breast feeding and risk of BC. Conclusions: Differences in the prevalence of central adiposity and age at first full-term pregnancy between rural and urban women from India may explain some differences in breast cancer rates between these two populations. © 2015, Springer International Publishing Switzerland.

To date, no studies have investigated the association of the GWAS-identified SNPs with BC risk in Indian population. We investigated the association of 30 previously reported and replicated BC susceptibility SNPs in 1,204 cases and 1,212 controls from a hospital based case-control study conducted at the Tata Memorial Hospital, Mumbai. As a measure of total susceptibility burden, the polygenic risk score (PRS) for each individual was defined by the weighted sum of genotypes from 21 independent SNPs with weights derived from previously published estimates of association odds-ratios. Logistic regression models were used to assess risk associated with individual SNPs and overall PRS, and stratified by menopausal and receptor status. A total of 11 SNPs from eight genomic regions (FGFR2, 9q31.2, MAP3K, CCND1, ZM1Z1, RAD51L11, ESR1 and UST) showed statistically significant (p-value ≤ 0.05) evidence of association, either overall or when stratified by menopausal status or hormone receptor status. BC SNPs previously identified in Caucasian population showed evidence of replication in the Indian population mainly with respect to risk of postmenopausal and hormone receptor positive BC.

Context: Within India, the incidence of gallbladder cancer (GBC) is characterized by marked geographical variation; however, the reasons for these differences are unclear. AIMS: To evaluate the role of place of birth, length of residence, and effect of migration from high- to low-risk region on GBC development. Settings and Design: Population-based cancer registries (PBCRs); case–control study. Subjects and Methods: Data of PBCRs were used to demonstrate geographical variation in GBC incidence rates. A case–control study data examined the role of birth place, residence length, and effect of migration in etiology of GBC. Statistical Analysis: Rate ratios for different PBCRs were estimated using Chennai Cancer Registry as the reference population. Odds ratios (ORs) for developing GBC in a high-risk region compared to a low-risk region and associated 95% confidence interval (CI) were estimated through unconditional logistic regression models using case–control study. Results: GBC shows marked variation in incidence with risk highest in Northeast regions and lowest in South India. OR of 4.82 (95% CI: 3.87–5.99) was observed for developing GBC for individuals born in a high-risk region compared to those born in a low-risk region after adjusting for confounders. A dose–response relationship with increased risk with increased length of residence in a high-risk region was observed (OR lifetime 5.58 [95% CI: 4.42–7.05]; Ptrend ≤ 0.001). The risk persisted even if study participant migrated from high- to low-risk region (OR = 1.36; 95% CI: 1.02–1.82). Conclusions: The present study signifies the importance of place of birth, length of stay, and effect of migration from high- to low-risk region in the development of GBC. The data indicate role of environmental and genetic factors in etiology of disease.

Background Current evidence suggests that the relationship between obesity and breast cancer (BC) risk may vary between ethnic groups. Methods A total of 1633 BC cases and 1504 controls were enrolled in hospital-based case–control study in Mumbai, India, from 2009 to 2013. Along with detailed questionnaire, we collected anthropometric measurements on all participants. We used unconditional logistic regression models to estimate odds ratios (ORs) and 95% confidence interval (CI) for BC risk associated with anthropometry measurements, stratified on tumour subtype and menopausal status. Results Waist-to-hip ratio (WHR) of ≥0.95 was strongly associated with risk of BC compared to WHR ≤0.84 in both premenopausal (OR = 4.3; 95% CI: 2.9–6.3) and postmenopausal women (OR = 3.4; 95% CI: 2.4–4.8) after adjustment for body mass index (BMI). Premenopausal women with a BMI ≥30 were at lower risk compared to women with normal BMI (OR = 0.5; 95% CI: 0.4–0.8). A similar protective effect was observed in women who were postmenopausal for, Highlights • Waist-to-hip ratio increases risk of breast cancer (BC) irrespective of menopausal or hormone receptor status. • High body mass index (BMI) protects the risk of BC in premenopausal women. • The protection in risk of BC continues in women who have high BMI and are postmenopausal for

Background: Little is known about burden of chronic myeloid leukemia (CML) in India. There is a recent interest to observe incidence and mortality because of advent of new diagnostic and treatment policies for CML. Materials and Methods: We extracted data from the oldest population-based cancer registry of Mumbai for 30 years period from 1976−2005 to observe incidence and mortality rates of CML. We classified the data into four age groups 0−14, 15−29, 30−54 and 55−74 to observe incidence rates in the respective age groups. Results: The age specific rates were highest for the age group of 55−74 years. No significant change in trends of CML was observed for 30 years period. However, there was a significant reduction in incidence rate for recent 15-years period (Estimated average annual percentage change=-3.9). No significant reduction in mortality rate was observed till 2005. Conclusion: The study demonstrates that age-specific rates for CML are highest in age group of 55-74 years, although they are lower compared to western populations. Significant reduction in incidence of CML in recent periods might be because of reduced misclassification of leukemias. The data of CML has to be observed for another decade to witness reduction in mortality because of changes in treatment management.

Background : Increasing trends in the incidence of breast cancer have been observed in India, including Mumbai. These have likely stemmed from an increasing adoption of lifestyle factors more akin to those commonly observed in westernized countries. Analyses of breast cancer trends and corresponding estimation of the future burden are necessary to better plan rationale cancer control programmes within the country. Methods : We used data from the population-based Mumbai Cancer Registry to study time trends in breast cancer incidence rates 1976–2005 and stratified them according to younger (25–49) and older age group (50–74). Age-period-cohort models were fitted and the net drift used as a measure of the estimated annual percentage change (EAPC). Age-period-cohort models and population projections were used to predict the age-adjusted rates and number of breast cancer cases circa 2025. Results : Breast cancer incidence increased significantly among older women over three decades (EAPC=1.6%; 95% CI 1.1–2.0), while lesser but significant 1% increase in incidence among younger women was observed (EAPC=1.0; 95% CI 0.2–1.8). Non-linear period and cohort effects were observed; a trends-based model predicted a close-to-doubling of incident cases by 2025 from 1300 mean cases per annum in 2001–2005 to over 2500 cases in 2021–2025. Conclusions : The incidence of breast cancer has increased in Mumbai during last two to three decades, with increases greater among older women. The number of breast cancer cases is predicted to double to over 2500 cases, the vast majority affecting older women.

Context: Breast cancer incidence rates are high in developed countries and much lower in less developed countries including India. Aims: The aim of the following study is to compare breast cancer incidence rates in rural, urban and metro regions of India and to estimate risk of developing breast cancer associated with residence in a rural area. Settings and Design: Descriptive and analytical study design. Materials and Methods: We extracted age adjusted incidence rate from 26 population-based cancer registries and data from hospital-based case-control study to estimate rate and risk ratio for developing breast cancer in an urban region compared with a rural residence. Statistical Analysis: The rate ratios and 95% confidence interval (CI) for developing breast cancer in the urban and metro region compared with rural registry of Barshi were estimated. The odds ratio (OR) and 95% CI for developing breast cancer in women residing in a rural region was estimated by fitting unconditional logistic regression using hospital-based case-control study data. Average annual percentage change in most recent 15 years (1996-2010) for Barshi (rural), Aurangabad (urban), and Mumbai (metro) cancer registry was obtained by fitting a log-linear model using joint point regression. Results: Living first 20 years of life in a rural area reduces the risk of breast cancer (OR = 0.65, 95% CI: 0.56-0.76). Conclusions: The current study demonstrates that lifestyle operative in a rural area is protective against risk of developing breast cancer.