Elucidating the genetic basis of social interaction and isolation.

The negative impacts of social isolation and loneliness on health are well documented. However, little is known about their possible biological determinants. In up to 452,302 UK Biobank study participants, we perform genome-wide association study analyses for loneliness and regular participation in social activities. We identify 15 genomic loci (P < 5 × 10-8) for loneliness, and demonstrate a likely causal association between adiposity and increased susceptibility to loneliness and depressive symptoms. Further loci were identified for regular attendance at a sports club or gym (N = 6 loci), pub or social club (N = 13) or religious group (N = 18). Across these traits there was strong enrichment for genes expressed in brain regions that control emotional expression and behaviour. We demonstrate aetiological mechanisms specific to each trait, in addition to identifying loci that are pleiotropic across multiple complex traits. Further study of these traits may identify novel modifiable risk factors associated with social withdrawal and isolation

Puberty timing associated with diabetes, cardiovascular disease and also diverse health outcomes in men and women: the UK Biobank study.

Early puberty timing is associated with higher risks for type 2 diabetes (T2D) and cardiovascular disease in women and therefore represents a potential target for early preventive interventions. We characterised the range of diseases and other adverse health outcomes associated with early or late puberty timing in men and women in the very large UK Biobank study. Recalled puberty timing and past/current diseases were self-reported by questionnaire. We limited analyses to individuals of White ethnicity (250,037 women; 197,714 men) and to disease outcomes with at least 500 cases (~ 0.2% prevalence) and we applied stringent correction for multiple testing (corrected threshold P < 7.48 × 10(-5)). In models adjusted for socioeconomic position and adiposity/body composition variables, both in women and men separately, earlier puberty timing was associated with higher risks for angina, hypertension and T2D. Furthermore, compared to the median/average group, earlier or later puberty timing in women or men was associated with higher risks for 48 adverse outcomes, across a range of cancers, cardio-metabolic, gynaecological/obstetric, gastrointestinal, musculoskeletal, and neuro-cognitive categories. Notably, both early and late menarche were associated with higher risks for early natural menopause in women. Puberty timing in both men and women appears to have a profound impact on later health.This research has been conducted using the UK Biobank Resource. This work was supported by the Medical Research Council [Unit Programme number MC_UU_12015/2].This is the final version of the article. It first appeared from NPG via http://dx.doi.org/10.1038/srep1120

Identifying genetic variants that affect viability in large cohorts

A number of open questions in human evolutionary genetics would become tractable if we were able to directly measure evolutionary fitness. As a step towards this goal, we developed a method to examine whether individual genetic variants, or sets of genetic variants, currently influence viability. The approach consists in testing whether the frequency of an allele varies across ages, accounting for variation in ancestry. We applied it to the Genetic Epidemiology Research on Adult Health and Aging (GERA) cohort and to the parents of participants in the UK Biobank. Across the genome, we found only a few common variants with large effects on age-specific mortality: tagging the APOE ε4 allele and near CHRNA3. These results suggest that when large, even late-onset effects are kept at low frequency by purifying selection. Testing viability effects of sets of genetic variants that jointly influence 1 of 42 traits, we detected a number of strong signals. In participants of the UK Biobank of British ancestry, we found that variants that delay puberty timing are associated with a longer parental life span (P~6.2 × 10-6 for fathers and P~2.0 × 10-3 for mothers), consistent with epidemiological studies. Similarly, variants associated with later age at first birth are associated with a longer maternal life span (P~1.4 × 10-3). Signals are also observed for variants influencing cholesterol levels, risk of coronary artery disease (CAD), body mass index, as well as risk of asthma. These signals exhibit consistent effects in the GERA cohort and among participants of the UK Biobank of non-British ancestry. We also found marked differences between males and females, most notably at the CHRNA3 locus, and variants associated with risk of CAD and cholesterol levels. Beyond our findings, the analysis serves as a proof of principle for how upcoming biomedical data sets can be used to learn about selection effects in contemporary humans.Medical Research Council (Unit Programme number MC_UU_12015/2). This grant supported FRD and JRBP. National Institutes of Health (NIH) (grant number R01GM121372). This grant is to MP and JKP. National Institutes of Health (NIH) (grant number R01MH106842). This grant is to JKP. Columbia University. This research was funded in part by a Research Initiative in Science and Engineering grant to MP and JKP. National Institutes of Health (NIH) (grant number R01GM115889). This grant is to Guy Sella, provided partial support for HM

Seroprevalence of Hepatitis B, C and D in Vietnam: A systematic review and meta-analysis.

Background: Vietnam has one of the greatest disease burdens from chronic viral hepatitis. Comprehensive prevalence data are essential to support its elimination as a public health threat. Methods: We searched Medline and Embase from 1990 to 2021 for seroprevalence data relating to Hepatitis B (HBV), C (HCV) and D (HDV) in Vietnam. We estimated pooled prevalence with a DerSimonian-Laird random-effects model and stratified study populations into i) low-risk ii) high-risk exposure and iii) liver disease. We further estimated prevalence by decade and region and rates of HIV-coinfection. Findings: We analysed 72 studies, including 120 HBV, 114 HCV and 23 HDV study populations. Pooled HBV prevalence was low in blood donors (1.86% [1.82-1.90]) but high in antenatal populations (10.8% [10.1-11.6]) and adults in the general population (10.5% [10.0-11.0]). It was similar or modestly increased in groups at highest risk of exposure, suggesting the epidemic is largely driven by chronic infections acquired in childhood. HCV pooled prevalence in the general population was lower than historical estimates: 0.26% (0.09-0.51) have active infection defined by detectable antigen or HCV RNA. In contrast, there is an extremely high prevalence of active HCV infection in people who inject drugs (PWID) (57.8% [56.5-59.1]), which has persisted through the decades despite harm-reduction interventions. HDV appears mainly confined to high-risk groups. Interpretation: Blood safety has improved, but renewed focus on HBV vaccination at birth and targeted HCV screening and treatment of PWID are urgently required to meet elimination targets. Large cross-sectional studies are needed to better characterize HDV prevalence, but mass screening may not be warranted. Funding: This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors

Reproductive Phase Locking of Mosquito Populations in Response to Rainfall Frequency

The frequency of moderate to heavy rainfall events is projected to change in response to global warming. Here we show that these hydrologic changes may have a profound effect on mosquito population dynamics and rates of mosquito-borne disease transmission. We develop a simple model, which treats the mosquito reproductive cycle as a phase oscillator that responds to rainfall frequency forcing. This model reproduces observed mosquito population dynamics and indicates that mosquito-borne disease transmission can be sensitive to rainfall frequency. These findings indicate that changes to the hydrologic cycle, in particular the frequency of moderate to heavy rainfall events, could have a profound effect on the transmission rates of some mosquito-borne diseases

Confronting Standard Models of Proto–Planetary Disks With New Mid–Infrared Sizes from the Keck Interferometer

This is the final version of the article. Available from American Astronomical Society via the DOI in this record.The accepted author manuscript is in ORE at http://hdl.handle.net/10871/21611We present near- and mid-infrared (MIR) interferometric observations made with the Keck Interferometer Nuller and near-contemporaneous spectro-photometry from the infrared telescope facilities (IRTFs) of 11 well-known young stellar objects, several of which were observed for the first time in these spectral and spatial resolution regimes. With au-level spatial resolution, we first establish characteristic sizes of the infrared emission using a simple geometrical model consisting of a hot inner rim and MIR disk emission. We find a high degree of correlation between the stellar luminosity and the MIR disk sizes after using near-infrared data to remove the contribution from the inner rim. We then use a semi-analytical physical model to also find that the very widely used "star + inner dust rim + flared disk" class of models strongly fails to reproduce the spectral energy distribution (SED) and spatially resolved MIR data simultaneously; specifically a more compact source of MIR emission is required than results from the standard flared disk model. We explore the viability of a modification to the model whereby a second dust rim containing smaller dust grains is added, and find that the 2-rim model leads to significantly improved fits in most cases. This complexity is largely missed when carrying out SED modeling alone, although detailed silicate feature fitting by McClure et al. recently came to a similar conclusion. As has been suggested recently by Menu et al., the difficulty in predicting MIR sizes from the SED alone might hint at "transition disk"-like gaps in the inner au; however, the relatively high correlation found in our MIR disk size versus stellar luminosity relation favors layered disk morphologies and points to missing disk model ingredients instead.M.S. was supported by NASA ADAP grant NNX09AC73G. R.W.R. was supported by the IR&D program of The Aerospace Corporation

Comparison of the CDC Backpack aspirator and the Prokopack aspirator for sampling indoor- and outdoor-resting mosquitoes in southern Tanzania.

BACKGROUND\ud \ud Resting mosquitoes can easily be collected using an aspirating device. The most commonly used mechanical aspirator is the CDC Backpack aspirator. Recently, a simple, and low-cost aspirator called the Prokopack has been devised and proved to have comparable performance. The following study evaluates the Prokopack aspirator compared to the CDC backpack aspirator when sampling resting mosquitoes in rural Tanzania.\ud \ud METHODS\ud \ud Mosquitoes were sampled in- and outdoors of 48 typical rural African households using both aspirators. The aspirators were rotated between collectors and households in a randomized, Latin Square design. Outdoor collections were performed using artificial resting places (large barrel and car tyre), underneath the outdoor kitchen (kibanda) roof and from a drop-net. Data were analysed with generalized linear models.\ud \ud RESULTS\ud \ud The number of mosquitoes collected using the CDC Backpack and the Prokopack aspirator were not significantly different both in- and outdoors (indoors p = 0.735; large barrel p = 0.867; car tyre p = 0.418; kibanda p = 0.519). The Prokopack was superior for sampling of drop-nets due to its smaller size. The number mosquitoes collected per technician was more consistent when using the Prokopack aspirator. The Prokopack was more user-friendly: technicians preferred using the it over the CDC backpack aspirator as it weighs considerably less, retains its charge for longer and is easier to manoeuvre.\ud \ud CONCLUSIONS\ud \ud The Prokopack proved in the field to be more advantageous than the CDC Backpack aspirator. It can be self assembled using simple, low-cost and easily attainable materials. This device is a useful tool for researchers or vector-control surveillance programs operating in rural Africa, as it is far simpler and quicker than traditional means of sampling resting mosquitoes. Further longitudinal evaluations of the Prokopack aspirator versus the gold standard pyrethrum spray catch for indoor resting catches are recommended

Elucidating the genetic architecture of reproductive ageing in the Japanese population.

Population studies elucidating the genetic architecture of reproductive ageing have been largely limited to European ancestries, restricting the generalizability of the findings and overlooking possible key genes poorly captured by common European genetic variation. Here, we report 26 loci (all P < 5 × 10-8) for reproductive ageing, i.e. puberty timing or age at menopause, in a non-European population (up to 67,029 women of Japanese ancestry). Highlighted genes for menopause include GNRH1, which supports a primary, rather than passive, role for hypothalamic-pituitary GnRH signalling in the timing of menopause. For puberty timing, we demonstrate an aetiological role for receptor-like protein tyrosine phosphatases by combining evidence across population genetics and pre- and peri-pubertal changes in hypothalamic gene expression in rodent and primate models. Furthermore, our findings demonstrate widespread differences in allele frequencies and effect estimates between Japanese and European associated variants, highlighting the benefits and challenges of large-scale trans-ethnic approaches

Prolonged dopamine signalling in striatum signals proximity and value of distant rewards

Predictions about future rewarding events have a powerful influence on behaviour. The phasic spike activity of dopamine-containing neurons, and corresponding dopamine transients in the striatum, are thought to underlie these predictions, encoding positive and negative reward prediction errors. However, many behaviours are directed towards distant goals, for which transient signals may fail to provide sustained drive. Here we report an extended mode of reward-predictive dopamine signalling in the striatum that emerged as rats moved towards distant goals. These dopamine signals, which were detected with fast-scan cyclic voltammetry (FSCV), gradually increased or—in rare instances—decreased as the animals navigated mazes to reach remote rewards, rather than having phasic or steady tonic profiles. These dopamine increases (ramps) scaled flexibly with both the distance and size of the rewards. During learning, these dopamine signals showed spatial preferences for goals in different locations and readily changed in magnitude to reflect changing values of the distant rewards. Such prolonged dopamine signalling could provide sustained motivational drive, a control mechanism that may be important for normal behaviour and that can be impaired in a range of neurologic and neuropsychiatric disorders.National Institutes of Health (U.S.) (Grant R01 MH060379)National Parkinson Foundation (U.S.)Cure Huntington’s Disease Initiative, Inc. (Grant A-5552)Stanley H. and Sheila G. Sydney Fun

Intrathecal Immunoglobulin for treatment of adult patients with tetanus: A randomized controlled 2x2 factorial trial

Despite long-standing availability of an effective vaccine, tetanus remains a significant problem in many countries. Outcome depends on access to mechanical ventilation and intensive care facilities and in settings where these are limited, mortality remains high. Administration of tetanus antitoxin by the intramuscular route is recommended treatment for tetanus, but as the tetanus toxin acts within the central nervous system, it has been suggested that intrathecal administration of antitoxin may be beneficial. Previous studies have indicated benefit, but with the exception of one small trial no blinded studies have been performed. The objective of this study is to establish whether the addition of intrathecal tetanus antitoxin reduces the need for mechanical ventilation in patients with tetanus. Secondary objectives: to determine whether the addition of intrathecal tetanus antitoxin reduces autonomic nervous system dysfunction and length of hospital/ intensive care unit stay; whether the addition of intrathecal tetanus antitoxin in the treatment of tetanus is safe and cost-effective; to provide data to inform recommendation of human rather than equine antitoxin. This study will enroll adult patients (≥16 years old) with tetanus admitted to the Hospital for Tropical Diseases, Ho Chi Minh City. The study is a 2x2 factorial blinded randomized controlled trial. Eligible patients will be randomized in a 1:1:1:1 manner to the four treatment arms (intrathecal treatment and human intramuscular treatment, intrathecal treatment and equine intramuscular treatment, sham procedure and human intramuscular treatment, sham procedure and equine intramuscular treatment). Primary outcome measure will be requirement for mechanical ventilation. Secondary outcome measures: duration of hospital/ intensive care unit stay, duration of mechanical ventilation, in-hospital and 240-day mortality and disability, new antibiotic prescription, incidence of ventilator associated pneumonia and autonomic nervous system dysfunction, total dose of benzodiazepines and pipecuronium, and incidence of adverse events. Trial registration: ClinicalTrials.gov NCT02999815 Registration date: 21 December 2016