University of the West Indies

The 1000 Genomes Project set out to provide a comprehensive description of common human genetic variation by applying whole-genome sequencing to a diverse set of individuals from multiple populations. Here we report completion of the project, having reconstructed the genomes of 2,504 individuals from 26 populations using a combination of low-coverage whole-genome sequencing, deep exome sequencing, and dense microarray genotyping. We characterized a broad spectrum of genetic variation, in total over 88 million variants (84.7 million single nucleotide polymorphisms (SNPs), 3.6 million short insertions/deletions (indels), and 60,000 structural variants), all phased onto high-quality haplotypes. This resource includes >99% of SNP variants with a frequency of >1% for a variety of ancestries. We describe the distribution of genetic variation across the global sample, and discuss the implications for common disease studies. Results for the final phase of the 1000 Genomes Project are presented including whole-genome sequencing, targeted exome sequencing, and genotyping on high-density SNP arrays for 2,504 individuals across 26 populations, providing a global reference data set to support biomedical genetics. The 1000 Genomes Project has sought to comprehensively catalogue human genetic variation across populations, providing a valuable public genomic resource. The data obtained so far have found applications ranging from association studies and fine mapping studies to the filtering of likely neutral variants in rare-disease cohorts. The authors now report on the final phase of the project, phase 3, which covers previously uncharacterized areas of human genetic diversity in terms of the populations sampled and categories of characterized variation. The sample now includes more than 2,500 individuals from 26 global populations, with low coverage whole-genome and deep exome sequencing, as well as dense microarray genotyping. They find that while most common variants are shared across populations, rarer variants are often restricted to closely related populations. The authors also demonstrate the use of the phase 3 dataset as a reference panel for imputation to improve the resolution in genetic association studies.

Prompted by a recent paper by Maynard and co-workers (Maynard, A. T.; Huang, M.; Rice, W. G.; Covel, D. G. Proc. Natl. Acad. Sci. U.S.A. 1998, 95, 11578), we propose that a specific property of a chemical species, the square of its electronegativity divided by its chemical hardness, be taken as defining its electrophilicity index. We tabulate this quantity for a number of atomic and molecular species, for two different models of the energy−electron number relationships, and we show that it measures the second-order energy change of an electrophile as it is saturated with electrons.

A suite of climate change indices derived from daily temperature and precipitation data, with a primary focus on extreme events, were computed and analyzed. By setting an exact formula for each index and using specially designed software, analyses done in different countries have been combined seamlessly. This has enabled the presentation of the most up‐to‐date and comprehensive global picture of trends in extreme temperature and precipitation indices using results from a number of workshops held in data‐sparse regions and high‐quality station data supplied by numerous scientists world wide. Seasonal and annual indices for the period 1951–2003 were gridded. Trends in the gridded fields were computed and tested for statistical significance. Results showed widespread significant changes in temperature extremes associated with warming, especially for those indices derived from daily minimum temperature. Over 70% of the global land area sampled showed a significant decrease in the annual occurrence of cold nights and a significant increase in the annual occurrence of warm nights. Some regions experienced a more than doubling of these indices. This implies a positive shift in the distribution of daily minimum temperature throughout the globe. Daily maximum temperature indices showed similar changes but with smaller magnitudes. Precipitation changes showed a widespread and significant increase, but the changes are much less spatially coherent compared with temperature change. Probability distributions of indices derived from approximately 200 temperature and 600 precipitation stations, with near‐complete data for 1901–2003 and covering a very large region of the Northern Hemisphere midlatitudes (and parts of Australia for precipitation) were analyzed for the periods 1901–1950, 1951–1978 and 1979–2003. Results indicate a significant warming throughout the 20th century. Differences in temperature indices distributions are particularly pronounced between the most recent two periods and for those indices related to minimum temperature. An analysis of those indices for which seasonal time series are available shows that these changes occur for all seasons although they are generally least pronounced for September to November. Precipitation indices show a tendency toward wetter conditions throughout the 20th century.

BACKGROUND: Rotavirus is a leading cause of childhood gastroenteritis and death worldwide. METHODS: We studied healthy infants approximately 6 to 12 weeks old who were randomly assigned to receive three oral doses of live pentavalent human-bovine (WC3 strain) reassortant rotavirus vaccine containing human serotypes G1, G2, G3, G4, and P[8] or placebo at 4-to-10-week intervals in a blinded fashion. Active surveillance was used to identify subjects with serious adverse and other events. RESULTS: The 34,035 infants in the vaccine group and 34,003 in the placebo group were monitored for serious adverse events. Intussusception occurred in 12 vaccine recipients and 15 placebo recipients within one year after the first dose including six vaccine recipients and five placebo recipients within 42 days after any dose (relative risk, 1.6; 95 percent confidence interval, 0.4 to 6.4). The vaccine reduced hospitalizations and emergency department visits related to G1-G4 rotavirus gastroenteritis occurring 14 or more days after the third dose by 94.5 percent (95 percent confidence interval, 91.2 to 96.6 percent). In a nested substudy, efficacy against any G1-G4 rotavirus gastroenteritis through the first full rotavirus season after vaccination was 74.0 percent (95 percent confidence interval, 66.8 to 79.9 percent); efficacy against severe gastroenteritis was 98.0 percent (95 percent confidence interval, 88.3 to 100 percent). The vaccine reduced clinic visits for G1-G4 rotavirus gastroenteritis by 86.0 percent (95 percent confidence interval, 73.9 to 92.5 percent). CONCLUSIONS: This vaccine was efficacious in preventing rotavirus gastroenteritis, decreasing severe disease and health care contacts. The risk of intussusception was similar in vaccine and placebo recipients. (ClinicalTrials.gov number, NCT00090233.)

Abstract In the last few decades many methods have become available for forecasting. As always, when alternatives exist, choices need to be made so that an appropriate forecasting method can be selected and used for the specific situation being considered. This paper reports the results of a forecasting competition that provides information to facilitate such choice. Seven experts in each of the 24 methods forecasted up to 1001 series for six up to eighteen time horizons. The results of the competition are presented in this paper whose purpose is to provide empirical evidence about differences found to exist among the various extrapolative (time series) methods used in the competition.

Rodríguez, J. P., T. D. Beard, Jr., E. M. Bennett, G. S. Cumming, S. Cork, J. Agard, A. P. Dobson, and G. D. Peterson. 2006. Trade-offs across space, time, and ecosystem services. Ecology and Society 11(1): 28. https://doi.org/10.5751/ES-01667-110128

countries can be reduced by 2035 through inexpensive population-based and clinical interventions. Fiscal policies are an especially promising lever for reducing this burden.

Heavy alcohol consumption is an established risk factor for hypertension; the mechanism by which alcohol consumption impact blood pressure (BP) regulation remains unknown. We hypothesized that a genome-wide association study accounting for gene-alcohol consumption interaction for BP might identify additional BP loci and contribute to the understanding of alcohol-related BP regulation. We conducted a large two-stage investigation incorporating joint testing of main genetic effects and single nucleotide variant (SNV)-alcohol consumption interactions. In Stage 1, genome-wide discovery meta-analyses in ≈131K individuals across several ancestry groups yielded 3,514 SNVs (245 loci) with suggestive evidence of association (P < 1.0 x 10-5). In Stage 2, these SNVs were tested for independent external replication in ≈440K individuals across multiple ancestries. We identified and replicated (at Bonferroni correction threshold) five novel BP loci (380 SNVs in 21 genes) and 49 previously reported BP loci (2,159 SNVs in 109 genes) in European ancestry, and in multi-ancestry meta-analyses (P < 5.0 x 10-8). For African ancestry samples, we detected 18 potentially novel BP loci (P < 5.0 x 10-8) in Stage 1 that warrant further replication. Additionally, correlated meta-analysis identified eight novel BP loci (11 genes). Several genes in these loci (e.g., PINX1, GATA4, BLK, FTO and GABBR2) have been previously reported to be associated with alcohol consumption. These findings provide insights into the role of alcohol consumption in the genetic architecture of hypertension.

Increased concentrations of atmospheric greenhouse gases have led to a global mean surface temperature 1.0°C higher than during the pre-industrial period. We expand on the recent IPCC Special Report on global warming of 1.5°C and review the additional risks associated with higher levels of warming, each having major implications for multiple geographies, climates, and ecosystems. Limiting warming to 1.5°C rather than 2.0°C would be required to maintain substantial proportions of ecosystems and would have clear benefits for human health and economies. These conclusions are relevant for people everywhere, particularly in low- and middle-income countries, where the escalation of climate-related risks may prevent the achievement of the United Nations Sustainable Development Goals.

The adaptive immune system is equipped to eliminate both tumors and pathogenic microorganisms. It requires a series of complex and coordinated signals to drive the activation, proliferation, and differentiation of appropriate T cell subsets. It is now established that changes in cellular activation are coupled to profound changes in cellular metabolism. In addition, emerging evidence now suggest that specific metabolic alterations associated with distinct T cell subsets may be ancillary to their differentiation and influential in their immune functions. The "Warburg effect" originally used to describe a phenomenon in which most cancer cells relied on aerobic glycolysis for their growth is a key process that sustain T cell activation and differentiation. Here, we review how different aspects of metabolism in T cells influence their functions, focusing on the emerging role of key regulators of glucose metabolism such as HIF-1α. A thorough understanding of the role of metabolism in T cell function could provide insights into mechanisms involved in inflammatory-mediated conditions, with the potential for developing novel therapeutic approaches to treat these diseases.

Prompted by the 20th anniversary of the 1993 World Development Report, a Lancet Commission revisited the case for investment in health and developed a new investment framework to achieve dramatic health gains by 2035. The Commission's report has four key messages, each accompanied by opportunities for action by national governments of low-income and middle-income countries and by the international community. First, there is an enormous economic payoff from investing in health. The impressive returns make a strong case for both increased domestic financing of health and for allocating a higher proportion of official development assistance to development of health. Second, modeling by the Commission found that a "grand convergence" in health is achievable by 2035-that is, a reduction in infectious, maternal, and child mortality down to universally low levels. Convergence would require aggressive scale up of existing and new health tools, and it could mostly be financed from the expected economic growth of low- and middle-income countries. The international community can best support convergence by funding the development and delivery of new health technologies and by curbing antibiotic resistance. Third, fiscal policies -such as taxation of tobacco and alcohol- are a powerful and underused lever that governments can use to curb non-communicable diseases and injuries while also raising revenue for health. International action on NCDs and injuries should focus on providing technical assistance on fiscal policies, regional cooperation on tobacco, and funding policy and implementation research on scaling-up of interventions to tackle these conditions. Fourth, progressive universalism, a pathway to universal health coverage (UHC) that includes the poor from the outset, is an efficient way to achieve health and financial risk protection. For national governments, progressive universalism would yield high health gains per dollar spent and poor people would gain the most in terms of health and financial protection. The international community can best support countries to implement progressive UHC by financing policy and implementation research, such as on the mechanics of designing and implementing evolution of the benefits package as the resource envelope for public finance grows.

Chronic kidney disease (CKD) is a non-communicable disease usually caused by diabetes and hypertension. 1 Cardiovascular disease is the major cause of the early morbidity and mortality sustained by patients with CKD. The severity of CKD can be quantified by a low serum creatinine-based estimated glomerular filtration rate (eGFR), which indicates excretory kidney function, and raised urinary albumin measured by the urinary albumin-to-creatinine ratio (ACR), which is a marker of kidney damage. 2 The Kidney Disease: Improving Global Outcomes classification system for staging CKD is based on eGFR and ACR and is widely used in clinical practice.

A substantial literature shows that U.S. early childhood interventions have important long-term economic benefits. However, there is little evidence on this question for developing countries. We report substantial effects on the earnings of participants in a randomized intervention conducted in 1986-1987 that gave psychosocial stimulation to growth-stunted Jamaican toddlers. The intervention consisted of weekly visits from community health workers over a 2-year period that taught parenting skills and encouraged mothers and children to interact in ways that develop cognitive and socioemotional skills. The authors reinterviewed 105 out of 129 study participants 20 years later and found that the intervention increased earnings by 25%, enough for them to catch up to the earnings of a nonstunted comparison group identified at baseline (65 out of 84 participants).

Abstract Body-mass index (BMI) has increased steadily in most countries in parallel with a rise in the proportion of the population who live in cities 1,2 . This has led to a widely reported view that urbanization is one of the most important drivers of the global rise in obesity 3–6 . Here we use 2,009 population-based studies, with measurements of height and weight in more than 112 million adults, to report national, regional and global trends in mean BMI segregated by place of residence (a rural or urban area) from 1985 to 2017. We show that, contrary to the dominant paradigm, more than 55% of the global rise in mean BMI from 1985 to 2017—and more than 80% in some low- and middle-income regions—was due to increases in BMI in rural areas. This large contribution stems from the fact that, with the exception of women in sub-Saharan Africa, BMI is increasing at the same rate or faster in rural areas than in cities in low- and middle-income regions. These trends have in turn resulted in a closing—and in some countries reversal—of the gap in BMI between urban and rural areas in low- and middle-income countries, especially for women. In high-income and industrialized countries, we noted a persistently higher rural BMI, especially for women. There is an urgent need for an integrated approach to rural nutrition that enhances financial and physical access to healthy foods, to avoid replacing the rural undernutrition disadvantage in poor countries with a more general malnutrition disadvantage that entails excessive consumption of low-quality calories.

Coral reefs of north Jamaica, normally sheltered, were severely damaged by Hurricane Allen, the strongest Caribbean hurricane of this century. Immediate studies were made at Discovery Bay, where reef populations were already known in some detail. Data are presented to show how damage varied with the position and orientation of the substraturn and with the shape, size, and mechanical properties of exposed organisms. Data collected over succeeding weeks showed striking differences in the ability of organisms to heal and survive.

Declines in health service use during the Coronavirus Disease 2019 (COVID-19) pandemic could have important effects on population health. In this study, we used an interrupted time series design to assess the immediate effect of the pandemic on 31 health services in two low-income (Ethiopia and Haiti), six middle-income (Ghana, Lao People's Democratic Republic, Mexico, Nepal, South Africa and Thailand) and high-income (Chile and South Korea) countries. Despite efforts to maintain health services, disruptions of varying magnitude and duration were found in every country, with no clear patterns by country income group or pandemic intensity. Disruptions in health services often preceded COVID-19 waves. Cancer screenings, TB screening and detection and HIV testing were most affected (26-96% declines). Total outpatient visits declined by 9-40% at national levels and remained lower than predicted by the end of 2020. Maternal health services were disrupted in approximately half of the countries, with declines ranging from 5% to 33%. Child vaccinations were disrupted for shorter periods, but we estimate that catch-up campaigns might not have reached all children missed. By contrast, provision of antiretrovirals for HIV was not affected. By the end of 2020, substantial disruptions remained in half of the countries. Preliminary data for 2021 indicate that disruptions likely persisted. Although a portion of the declines observed might result from decreased needs during lockdowns (from fewer infectious illnesses or injuries), a larger share likely reflects a shortfall of health system resilience. Countries must plan to compensate for missed healthcare during the current pandemic and invest in strategies for better health system resilience for future emergencies.

Adult T-cell leukemia/lymphoma (ATL), a malignancy of mature CD4-positive lymphocytes, has been etiologically linked to the human retrovirus HTLV-I. Although a long latent period is suggested from migrant studies, little prospective information on the risk of developing ATL among persons with HTLV-I infection is available. We present here a model for ATL risk based upon age- and sex-specific HTLV-I seroprevalence data from a cross-sectional survey of 13,000 Jamaicans and ATL incidence data from a 2 1/2-year case-control study. By examining the age-specific incidence of ATL relative to both adult and childhood-acquired seropositivity versus childhood-acquired seropositivity alone, we provide evidence in support of the hypothesis that childhood infection with HTLV-I is important to the development of ATL. Using this model, the cumulative lifetime risk of ATL for those infected before age 20 is estimated to be 4.0% for males and 4.2% for females. Under this hypothesis, HTLV-I-associated diseases with shorter latent periods, such as tropical spastic paraparesis, should have a higher incidence in adult females than in adult males.

Importance: Early diagnosis of retinoblastoma, the most common intraocular cancer, can save both a child's life and vision. However, anecdotal evidence suggests that many children across the world are diagnosed late. To our knowledge, the clinical presentation of retinoblastoma has never been assessed on a global scale. Objectives: To report the retinoblastoma stage at diagnosis in patients across the world during a single year, to investigate associations between clinical variables and national income level, and to investigate risk factors for advanced disease at diagnosis. Design, Setting, and Participants: A total of 278 retinoblastoma treatment centers were recruited from June 2017 through December 2018 to participate in a cross-sectional analysis of treatment-naive patients with retinoblastoma who were diagnosed in 2017. Main Outcomes and Measures: Age at presentation, proportion of familial history of retinoblastoma, and tumor stage and metastasis. Results: The cohort included 4351 new patients from 153 countries; the median age at diagnosis was 30.5 (interquartile range, 18.3-45.9) months, and 1976 patients (45.4%) were female. Most patients (n = 3685 [84.7%]) were from low- and middle-income countries (LMICs). Globally, the most common indication for referral was leukocoria (n = 2638 [62.8%]), followed by strabismus (n = 429 [10.2%]) and proptosis (n = 309 [7.4%]). Patients from high-income countries (HICs) were diagnosed at a median age of 14.1 months, with 656 of 666 (98.5%) patients having intraocular retinoblastoma and 2 (0.3%) having metastasis. Patients from low-income countries were diagnosed at a median age of 30.5 months, with 256 of 521 (49.1%) having extraocular retinoblastoma and 94 of 498 (18.9%) having metastasis. Lower national income level was associated with older presentation age, higher proportion of locally advanced disease and distant metastasis, and smaller proportion of familial history of retinoblastoma. Advanced disease at diagnosis was more common in LMICs even after adjusting for age (odds ratio for low-income countries vs upper-middle-income countries and HICs, 17.92 [95% CI, 12.94-24.80], and for lower-middle-income countries vs upper-middle-income countries and HICs, 5.74 [95% CI, 4.30-7.68]). Conclusions and Relevance: This study is estimated to have included more than half of all new retinoblastoma cases worldwide in 2017. Children from LMICs, where the main global retinoblastoma burden lies, presented at an older age with more advanced disease and demonstrated a smaller proportion of familial history of retinoblastoma, likely because many do not reach a childbearing age. Given that retinoblastoma is curable, these data are concerning and mandate intervention at national and international levels. Further studies are needed to investigate factors, other than age at presentation, that may be associated with advanced disease in LMICs.

Abstract The causes of impaired skeletal muscle mass and strength during aging are well-studied in healthy populations. Less is known on pathological age-related muscle wasting and weakness termed sarcopenia, which directly impacts physical autonomy and survival. Here, we compare genome-wide transcriptional changes of sarcopenia versus age-matched controls in muscle biopsies from 119 older men from Singapore, Hertfordshire UK and Jamaica. Individuals with sarcopenia reproducibly demonstrate a prominent transcriptional signature of mitochondrial bioenergetic dysfunction in skeletal muscle, with low PGC-1α/ERRα signalling, and downregulation of oxidative phosphorylation and mitochondrial proteostasis genes. These changes translate functionally into fewer mitochondria, reduced mitochondrial respiratory complex expression and activity, and low NAD + levels through perturbed NAD + biosynthesis and salvage in sarcopenic muscle. We provide an integrated molecular profile of human sarcopenia across ethnicities, demonstrating a fundamental role of altered mitochondrial metabolism in the pathological loss of skeletal muscle mass and function in older people.

The most abundant water soluble natural food colors are betacyanins and anthocyanins. Similarly, lycopene, bixin, beta-carotene, and chlorophyll are water insoluble colors. Pure betanin, bixin, lycopene, chlorophyll, beta-carotene, and cyanidin-3-O-glucoside were isolated from Beta vulgaris, Bixa orellana,Lycopersicum esculentum, Spinacia oleracea, Daucus carrota, and Prunus cerasus, respectively. These natural pigments, alone and in combination, were evaluated for their relative potencies against cyclooxygenase enzymes and tumor cell growth inhibition by using MCF-7 (breast), HCT-116 (colon), AGS (stomach), CNS (central nervous system), and NCI-H460 (lung) tumor cell lines. Among the colors tested, betanin, cyanidin-3-O-glucoside, lycopene, and beta-carotene inhibited lipid peroxidation. However, all pigments tested gave COX-1 and COX-2 inhibition and showed a dose-dependent growth inhibition against breast, colon, stomach, central nervous system, and lung tumor cells, respectively. The mixtures of these pigments were also evaluated for their synergistic effects and chemical interactions at various concentrations. The mixture of anthocyanin and betanin negated their efficacy in the cell growth inhibitory assay and did not enhance the COX enzyme inhibitory activity. This is the first report of a comparative evaluation and the impact on biological activities of these pigments alone and in combination.