Steroid receptor coactivator-1 modulates the function of Pomc neurons and energy homeostasis

Hypothalamic neurons expressing the anorectic peptide Pro-opiomelanocortin (Pomc) regulate food intake and body weight. Here, we show that Steroid Receptor Coactivator-1 (SRC-1) interacts with a target of leptin receptor activation, phosphorylated STAT3, to potentiate Pomc transcription. Deletion of SRC-1 in Pomc neurons in mice attenuates their depolarization by leptin, decreases Pomc expression and increases food intake leading to high-fat diet-induced obesity. In humans, fifteen rare heterozygous variants in SRC-1 found in severely obese individuals impair leptin-mediated Pomc reporter activity in cells, whilst four variants found in non-obese controls do not. In a knock-in mouse model of a loss of function human variant (SRC-1L1376P), leptin-induced depolarization of Pomc neurons and Pomc expression are significantly reduced, and food intake and body weight are increased. In summary, we demonstrate that SRC-1 modulates the function of hypothalamic Pomc neurons, and suggest that targeting SRC-1 may represent a useful therapeutic strategy for weight loss.Peer reviewe

Low-frequency variation in TP53 has large effects on head circumference and intracranial volume.

Cranial growth and development is a complex process which affects the closely related traits of head circumference (HC) and intracranial volume (ICV). The underlying genetic influences shaping these traits during the transition from childhood to adulthood are little understood, but might include both age-specific genetic factors and low-frequency genetic variation. Here, we model the developmental genetic architecture of HC, showing this is genetically stable and correlated with genetic determinants of ICV. Investigating up to 46,000 children and adults of European descent, we identify association with final HC and/or final ICV + HC at 9 novel common and low-frequency loci, illustrating that genetic variation from a wide allele frequency spectrum contributes to cranial growth. The largest effects are reported for low-frequency variants within TP53, with 0.5 cm wider heads in increaser-allele carriers versus non-carriers during mid-childhood, suggesting a previously unrecognized role of TP53 transcripts in human cranial development

The UK10K project identifies rare variants in health and disease

M. Kivimäki työryhmäjäsen.The contribution of rare and low-frequency variants to human traits is largely unexplored. Here we describe insights from sequencing whole genomes (low read depth, 7x) or exomes (high read depth, 80x) of nearly 10,000 individuals from population-based and disease collections. In extensively phenotyped cohorts we characterize over 24 million novel sequence variants, generate a highly accurate imputation reference panel and identify novel alleles associated with levels of triglycerides (APOB), adiponectin (ADIPOQ) and low-density lipoprotein cholesterol (LDLR and RGAG1) from single-marker and rare variant aggregation tests. We describe population structure and functional annotation of rare and low-frequency variants, use the data to estimate the benefits of sequencing for association studies, and summarize lessons from disease-specific collections. Finally, we make available an extensive resource, including individual-level genetic and phenotypic data and web-based tools to facilitate the exploration of association results.Peer reviewe

Global burden of 288 causes of death and life expectancy decomposition in 204 countries and territories and 811 subnational locations, 1990–2021: a systematic analysis for the Global Burden of Disease Study 2021

BACKGROUND Regular, detailed reporting on population health by underlying cause of death is fundamental for public health decision making. Cause-specific estimates of mortality and the subsequent effects on life expectancy worldwide are valuable metrics to gauge progress in reducing mortality rates. These estimates are particularly important following large-scale mortality spikes, such as the COVID-19 pandemic. When systematically analysed, mortality rates and life expectancy allow comparisons of the consequences of causes of death globally and over time, providing a nuanced understanding of the effect of these causes on global populations. METHODS The Global Burden of Diseases, Injuries, and Risk Factors Study (GBD) 2021 cause-of-death analysis estimated mortality and years of life lost (YLLs) from 288 causes of death by age-sex-location-year in 204 countries and territories and 811 subnational locations for each year from 1990 until 2021. The analysis used 56 604 data sources, including data from vital registration and verbal autopsy as well as surveys, censuses, surveillance systems, and cancer registries, among others. As with previous GBD rounds, cause-specific death rates for most causes were estimated using the Cause of Death Ensemble model-a modelling tool developed for GBD to assess the out-of-sample predictive validity of different statistical models and covariate permutations and combine those results to produce cause-specific mortality estimates-with alternative strategies adapted to model causes with insufficient data, substantial changes in reporting over the study period, or unusual epidemiology. YLLs were computed as the product of the number of deaths for each cause-age-sex-location-year and the standard life expectancy at each age. As part of the modelling process, uncertainty intervals (UIs) were generated using the 2·5th and 97·5th percentiles from a 1000-draw distribution for each metric. We decomposed life expectancy by cause of death, location, and year to show cause-specific effects on life expectancy from 1990 to 2021. We also used the coefficient of variation and the fraction of population affected by 90% of deaths to highlight concentrations of mortality. Findings are reported in counts and age-standardised rates. Methodological improvements for cause-of-death estimates in GBD 2021 include the expansion of under-5-years age group to include four new age groups, enhanced methods to account for stochastic variation of sparse data, and the inclusion of COVID-19 and other pandemic-related mortality-which includes excess mortality associated with the pandemic, excluding COVID-19, lower respiratory infections, measles, malaria, and pertussis. For this analysis, 199 new country-years of vital registration cause-of-death data, 5 country-years of surveillance data, 21 country-years of verbal autopsy data, and 94 country-years of other data types were added to those used in previous GBD rounds. FINDINGS The leading causes of age-standardised deaths globally were the same in 2019 as they were in 1990; in descending order, these were, ischaemic heart disease, stroke, chronic obstructive pulmonary disease, and lower respiratory infections. In 2021, however, COVID-19 replaced stroke as the second-leading age-standardised cause of death, with 94·0 deaths (95% UI 89·2-100·0) per 100 000 population. The COVID-19 pandemic shifted the rankings of the leading five causes, lowering stroke to the third-leading and chronic obstructive pulmonary disease to the fourth-leading position. In 2021, the highest age-standardised death rates from COVID-19 occurred in sub-Saharan Africa (271·0 deaths [250·1-290·7] per 100 000 population) and Latin America and the Caribbean (195·4 deaths [182·1-211·4] per 100 000 population). The lowest age-standardised death rates from COVID-19 were in the high-income super-region (48·1 deaths [47·4-48·8] per 100 000 population) and southeast Asia, east Asia, and Oceania (23·2 deaths [16·3-37·2] per 100 000 population). Globally, life expectancy steadily improved between 1990 and 2019 for 18 of the 22 investigated causes. Decomposition of global and regional life expectancy showed the positive effect that reductions in deaths from enteric infections, lower respiratory infections, stroke, and neonatal deaths, among others have contributed to improved survival over the study period. However, a net reduction of 1·6 years occurred in global life expectancy between 2019 and 2021, primarily due to increased death rates from COVID-19 and other pandemic-related mortality. Life expectancy was highly variable between super-regions over the study period, with southeast Asia, east Asia, and Oceania gaining 8·3 years (6·7-9·9) overall, while having the smallest reduction in life expectancy due to COVID-19 (0·4 years). The largest reduction in life expectancy due to COVID-19 occurred in Latin America and the Caribbean (3·6 years). Additionally, 53 of the 288 causes of death were highly concentrated in locations with less than 50% of the global population as of 2021, and these causes of death became progressively more concentrated since 1990, when only 44 causes showed this pattern. The concentration phenomenon is discussed heuristically with respect to enteric and lower respiratory infections, malaria, HIV/AIDS, neonatal disorders, tuberculosis, and measles. INTERPRETATION Long-standing gains in life expectancy and reductions in many of the leading causes of death have been disrupted by the COVID-19 pandemic, the adverse effects of which were spread unevenly among populations. Despite the pandemic, there has been continued progress in combatting several notable causes of death, leading to improved global life expectancy over the study period. Each of the seven GBD super-regions showed an overall improvement from 1990 and 2021, obscuring the negative effect in the years of the pandemic. Additionally, our findings regarding regional variation in causes of death driving increases in life expectancy hold clear policy utility. Analyses of shifting mortality trends reveal that several causes, once widespread globally, are now increasingly concentrated geographically. These changes in mortality concentration, alongside further investigation of changing risks, interventions, and relevant policy, present an important opportunity to deepen our understanding of mortality-reduction strategies. Examining patterns in mortality concentration might reveal areas where successful public health interventions have been implemented. Translating these successes to locations where certain causes of death remain entrenched can inform policies that work to improve life expectancy for people everywhere. FUNDING Bill & Melinda Gates Foundation

Obstetric management after infertility treatment

No Abstract

Burnout syndrome among multinational nurses working in Saudi Arabia

Background: Nursing Staff is reported to be under extreme state of stress, leading to burnout syndrome (BS). Most of the studies have been conducted among the nurses working in their home countries. This study was conducted to assess the prevalence of BS among a multinational nursing workforce in Saudi Arabia.Materials and Methods: King Fahd University Hospital, AlKhobar, Saudi Arabia, is a tertiary care hospital employing 510 nurses of multinational workforce. Two hundred and fifty Maslach Burnout Inventory (MBI) individual-based questionnaires were distributed after modification to include the age, sex, marital status, nationality, unit working and number of years on the job. The data were entered in the database and analyzed using Statistical Package for the Social Sciences (SPSS), version 14.0. A P value of <0.05 was considered statistically significant .Results: One hundred and ninety-eight nurses (77.2%) completed the questionnaire. Their average age was 34.46 } 5.36 years. Forty-five percent (89) had high emotional exhaustion (EE) and 28.9% (57) had moderate suffering with EE. Staffs who were on the job for longer duration had a lesser frequency of EE (P . 0.001). The frequency of depersonalization (DP) was 83 (42%) and was graded as high and 61 (30.8%) were moderately affected. Personal accomplishment (PA) was moderate to low in the majority of the nurses (71.5%). Married nurses were prone to EE (28.17 } 12.1 versus 22.3 } 9.6) than unmarried nurses (P = 0.003, CI 95% and OR 2.4). The nurses in the patientsfwards and clinics were more emotionally exhausted with higher DP compared to nurses in the high stress and high activity areas (P < 0.001, OR .11.1; and P < 0.001, CI 95% and OR 9.65). Non-Saudi nurses were significantly more prone to EE (27.3 } 12.1 versus 21.6 } 2.9) than Saudi nurses (P = 0.004; 95% CI: <9.64).Conclusion: We found that majority of the nursing staff at our hospital were in a state of burnout with high frequency of EE and DP. Only a quarter of the surveyed staff felt that they had some level of PA. Age and working away from their home countries were the important predictors in the development of BS in nurses. We believe that working conditions have to be improved to develop strategies to cope and alleviate stressful situations

Anxiety and depression during pregnancy in women attending clinics in a University Hospital in Eastern province of Saudi Arabia: prevalence and associated factors

Abdullah H Alqahtani,1 Kholoud Al Khedair,2 Reem Al-Jeheiman,2 Haifa A Al-Turki,2 Nourah H Al Qahtani2 1Department of Psychiatry, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, 2Department of Obstetrics and Gynaecology, College of Medicine, Imam Abdulrahman Bin Faisal University, Dammam, Saudi Arabia Background: Anxiety and depression during the antenatal period is a growing problem with major effects on the mother, the developing fetus, and the neonate.Objectives: To assess the prevalence of anxiety and depression during pregnancy in women attending the hospital for antenatal care and assess the associated factors.Methods: This is a prospective cohort study conducted in the University Hospital of Imam Abdulrahman Bin Faisal University. Anxiety was evaluated using State Trait Anxiety Inventory. Depression was assessed using Edinburgh Postnatal Depression Scale (EPDS).Results: Complete data were available for 575 women. The mean EPDS score was 10.5 (SD 5.5). The prevalence of depression was 26.8%. The mean state-anxiety score was 38.4 (SD 11.4) and mean trait-anxiety score was 38.2 (SD 9.5). The prevalence of anxiety using state-anxiety scale was 23.6%, while using the trait scale it was 23.9%. The risk is higher among unemployed women with history of miscarriage and unplanned pregnancy.Conclusion: Anxiety and depression are common during pregnancy. Keywords: anxiety, depression, pregnanc