Dementia and cognitive decline in women: biological, social, and behavioural aspects

Dementia is a significant global health concern, and its prevalence is expected to increase with the ageing population. However, the evidence on sex differences in the risk of dementia and its precursor, cognitive decline, is mixed, and the underlying causes of these differences are not well understood. This thesis uses data from multiple studies, including the UK Biobank (over 500,000 participants from the United Kingdom), the Cohort Studies of Memory in an International Consortium (COSMIC; 29,850 participants in 18 countries), the Action in Diabetes and Vas cular Disease: Preterax and Diamicron Modified Release Controlled Evaluation (ADVANCE; 11,140 participants with diabetes in 20 countries), and the Perindopril Protection against Recurrent Stroke Study (PROGRESS; 6,105 participants with cerebrovascular diseases in 10 countries), to examine sex differences in cognitive decline/dementia risk. The results demonstrate that the risk of all-cause dementia in the UK Biobank and the risk of cognitive decline/dementia in clinical trials was higher in men than in women. Con versely, in COSMIC, the risk of all-cause dementia was higher in women, particularly in low and lower-middle-income economies. Analyses accounting for sex differences found that several risk factor associations for cognitive decline/dementia varied by sex, with diabetes and former alcohol use more strongly associated in men and higher blood pressure, low estimated glomerular filtration rate, shorter education, anxiety/depression, and higher waist circumference more strongly associated in women. There was no significant difference in the effect of cardiometabolic treatments on cognitive decline/dementia risk. Additionally, reproductive events that resulted in shorter cumulative endogenous oestrogen exposure in women were associated with a higher risk of dementia, while the number of children was similarly associated with dementia risk in both sexes. These findings suggest that sex differences in cognitive decline/dementia risk may vary by geographical region and country-level income levels. While reproductive factors disproportionately contribute to a higher risk of dementia in women, addressing sex differences in risk factors for cognitive decline/dementia and potential disparities through promoting equity in public health and clinical practice can help to reduce these differences. Further research is necessary to validate and investigate the mechanisms underlying these sex differences

Genetic Dissection of Cardiac Remodeling in an Isoproterenol-Induced Heart Failure Mouse Model.

We aimed to understand the genetic control of cardiac remodeling using an isoproterenol-induced heart failure model in mice, which allowed control of confounding factors in an experimental setting. We characterized the changes in cardiac structure and function in response to chronic isoproterenol infusion using echocardiography in a panel of 104 inbred mouse strains. We showed that cardiac structure and function, whether under normal or stress conditions, has a strong genetic component, with heritability estimates of left ventricular mass between 61% and 81%. Association analyses of cardiac remodeling traits, corrected for population structure, body size and heart rate, revealed 17 genome-wide significant loci, including several loci containing previously implicated genes. Cardiac tissue gene expression profiling, expression quantitative trait loci, expression-phenotype correlation, and coding sequence variation analyses were performed to prioritize candidate genes and to generate hypotheses for downstream mechanistic studies. Using this approach, we have validated a novel gene, Myh14, as a negative regulator of ISO-induced left ventricular mass hypertrophy in an in vivo mouse model and demonstrated the up-regulation of immediate early gene Myc, fetal gene Nppb, and fibrosis gene Lgals3 in ISO-treated Myh14 deficient hearts compared to controls

Current and future burdens of heat-related dementia hospital admissions in England.

INTRODUCTION: The impacts of a changing climate on current and future dementia burdens have not been widely explored. METHODS: Time-series negative binomial regression analysis was used to assess acute associations between daily ambient temperature and counts of emergency admissions for dementia in each Government region of England, adjusting for season and day-of-week. Using the latest climate and dementia projections data, we then estimate future heat-related dementia burdens under a high emission scenario (Representative Concentration Pathway (RCP8.5), where global greenhouse gas (GHG) emissions continue to rise, and a low emissions scenario (RCP2.6), where GHG emissions are sizeably reduced under a strong global mitigation policy. RESULTS: A raised risk associated with high temperatures was observed in all regions. Nationally, a 4.5% (95% Confidence interval (CI) 2.9%-6.1%) increase in risk of dementia admission was observed for every 1 °C increase in temperature above 17 °C associated with current climate. Under a high emissions scenario, heat-related admissions are projected to increase by almost 300% by 2040 compared to baseline levels. CONCLUSIONS: People living with dementia should be considered a high-risk group during hot weather. Our results support arguments for more stringent climate change mitigation policies

Loss of murine Paneth cell function alters the immature intestinal microbiome and mimics changes seen in neonatal necrotizing enterocolitis

Necrotizing enterocolitis (NEC) remains the leading cause of gastrointestinal morbidity and mortality in premature infants. Human and animal studies suggest a role for Paneth cells in NEC pathogenesis. Paneth cells play critical roles in host-microbial interactions and epithelial homeostasis. The ramifications of eliminating Paneth cell function on the immature host-microbial axis remains incomplete. Paneth cell function was depleted in the immature murine intestine using chemical and genetic models, which resulted in intestinal injury consistent with NEC. Paneth cell depletion was confirmed using histology, electron microscopy, flow cytometry, and real time RT-PCR. Cecal samples were analyzed at various time points to determine the effects of Paneth cell depletion with and without Klebsiella gavage on the microbiome. Deficient Paneth cell function induced significant compositional changes in the cecal microbiome with a significant increase in Enterobacteriacae species. Further, the bloom of Enterobacteriaceae species that occurs is phenotypically similar to what is seen in human NEC. This further strengthens our understanding of the importance of Paneth cells to intestinal homeostasis in the immature intestine

Missense-depleted regions in population exomes implicate ras superfamily nucleotide-binding protein alteration in patients with brain malformation.

Genomic sequence interpretation can miss clinically relevant missense variants for several reasons. Rare missense variants are numerous in the exome and difficult to prioritise. Affected genes may also not have existing disease association. To improve variant prioritisation, we leverage population exome data to identify intragenic missense-depleted regions (MDRs) genome-wide that may be important in disease. We then use missense depletion analyses to help prioritise undiagnosed disease exome variants. We demonstrate application of this strategy to identify a novel gene association for human brain malformation. We identified de novo missense variants that affect the GDP/GTP-binding site of ARF1 in three unrelated patients. Corresponding functional analysis suggests ARF1 GDP/GTP-activation is affected by the specific missense mutations associated with heterotopia. These findings expand the genetic pathway underpinning neurologic disease that classically includes FLNA. ARF1 along with ARFGEF2 add further evidence implicating ARF/GEFs in the brain. Using functional ontology, top MDR-containing genes were highly enriched for nucleotide-binding function, suggesting these may be candidates for human disease. Routine consideration of MDR in the interpretation of exome data for rare diseases may help identify strong genetic factors for many severe conditions, infertility/reduction in reproductive capability, and embryonic conditions contributing to preterm loss

Exploring the interconnections between gender, health and nature

Objectives Public health has recognized that nature is good for health but there are calls for a review of its gendered aspects. This review attempts to develop and explore a broad analytical theme – the differing interconnections between gender, health and nature. The paper summarizes the interconnections that have been subject to extensive academic enquiry between gender and health, health and space, and gender and space. Methods A combination of key terms including place; gender; health; outdoor space; green space; natural environment; national parks; femininity; masculinity; recreation; physical activity; sustainability; ecofeminism; feminism; environmental degradation; and environmental justice were used to search the electronic databases Sociological Abstracts, Web of Science and Scopus to identify relevant articles. We took two approaches for this review to provide an overview and analysis of the range of research in the field, and to present a framework of research that is an analysis of the intersection of gender, health and nature. Results Four dimensions are distinguished: (1) evaluations of health benefits and ‘toxicities’ of nature; (2) dimensions and qualities of nature/space; (3) environmental justice including accessibility, availability and usability; and (4) identification of boundaries (symbolic/material) that construct differential relationships between nature, gender and health. This paper offers an understanding of how environmental and social conditions may differentially shape the health of women and men. The dimensions direct analytical attention to the diverse linkages that constitute overlapping and inseparable domains of knowledge and practice, to identify complex interconnections between gender, health and nature. Conclusion This review therefore analyses assumptions about the health benefits of nature, and its risks, for gender from an in-depth, analytical perspective that can be used to inform policy

HPC-oriented Canonical Workflows for Machine Learning Applications in Climate and Weather Prediction

Machine learning (ML) applications in weather and climate are gaining momentum as big data and the immense increase in High-performance computing (HPC) power are paving the way. Ensuring FAIR data and reproducible ML practices are significant challenges for Earth system researchers. Even though the FAIR principle is well known to many scientists, research communities are slow to adopt them. Canonical Workflow Framework for Research (CWFR) provides a platform to ensure the FAIRness and reproducibility of these practices without overwhelming researchers. This conceptual paper envisions a holistic CWFR approach towards ML applications in weather and climate, focusing on HPC and big data. Specifically, we discuss Fair Digital Object (FDO) and Research Object (RO) in the DeepRain project to achieve granular reproducibility. DeepRain is a project that aims to improve precipitation forecast in Germany by using ML. Our concept envisages the raster datacube to provide data harmonization and fast and scalable data access. We suggest the Juypter notebook as a single reproducible experiment. In addition, we envision JuypterHub as a scalable and distributed central platform that connects all these elements and the HPC resources to the researchers via an easy-to-use graphical interface

Trends of hypercholesterolemia change in Shenzhen, China during 1997-2018

To demonstrate the trends of hypercholesterolemia change in Shenzhen, China from 1997 to 2018. Participants were residents aged 18 to 69 years in Shenzhen, China, and were recruited using multi-stage cluster sampling. All participants were surveyed about their socio-demographics, lifestyle, occupation, mental health, and social support. Physical measurements and blood samples for subsequent measurements were collected according to a standardized protocol. A total of 26,621 individuals participated in the three surveys with 8,266 in 1997, 8,599 in 2009, and 9,756 in 2018. In both women and men, there was a significant downward linear trend in age-adjusted mean high-density lipoprotein-cholesterol (HDL-C) from 1997 to 2018 (women: 0.17 ± 0.06, p = 0.008 vs. men: 0.21 ± 0.04, p < 0.001). In contrast, the age-adjusted total triglycerides and total cholesterol in both sexes have demonstrated an increasing trend in the past two decades. However, no significant changes in age-adjusted low-density lipoprotein-cholesterol (LDL-C) in both men and women between 2009 and 2018 were found (women: 0.00 ± 0.02, p = 0.85 vs. men 0.02 ± 0.03, p = 0.34). The age-adjusted prevalence of hypercholesterolemia observed a rapid rise from 1997 to 2009 and appeared to be stabilized in 2018, which was similar to the trend of the prevalence of high total triglycerides in women. Changes in trends were varied by different types of lipids traits. Over the observed decades, there was a clear increasing trend of prevalence of low HDL-C (<1.04 mmol/L) in both sexes (women: 8.8% in 1997 and doubled to reach 17.5% in 2018 vs. men was 22.1% in 1997 and increased to 39.1% in 2018), particularly among younger age groups. Hence, a bespoke public health strategy aligned with the characteristics of lipids epidemic considered by sex and age groups needs to be developed and implemented

Contextualising sex and gender research to improve women's health: An early- and mid-career researcher perspective

The field of sex and gender research in health and medicine is growing, and many early- and mid-career researchers (EMCRs) are developing skills in this area. As EMCRs specialising in sex and gender research, we aim to better understand sex- and gender-based determinants of human health, challenge long-standing and pervasive gender biases, and contribute to improving the evidence base upon which clinical guidelines and policy interventions are developed. To effectively achieve these goals, we believe that EMCRs would benefit from understanding the challenges of working in this space and participate in driving change in three key areas. First, in creating greater links between the goals of sex and gender research and addressing systemic bias against women and gender minorities, to effectively translate knowledge about sex and gender differences into improved health outcomes. Second, in expanding the reach of sex and gender research to address women's health in an intersectional way and ensure that it also benefits the health of men, transgender and gender-diverse people and those who are intersex. Third, in working with others in the scientific community to improve methods for sex and gender research, including updating data collection practises, ensuring appropriate statistical analyses and shifting scientific culture to recognise the importance of null findings. By improving focus on these three areas, we see greater potential to translate this research to improve women's health and reduce health inequities for all

Climate change and its implications for developing brains – In utero to youth: A scoping review

The brain health and development implications of climate change are situated within a large and rapidly increasing body of evidence that addresses the physical and mental health impacts and implications of extreme and worsening environments. The costs to individuals and societies of negatively impacted brain development are profound – be it in the form of diagnosable developmental disability, reduced cognitive capacity, or areas of behavioral functioning. We have sought to describe the key risk domains that climate change presents with respect to healthy brain development, from the prenatal through to youth stages. Scoping review methods and an a priori search strategy were used to address the question: What are the major considerations of the peer-reviewed literature that address climate change as it relates to brain development and health from early development through to youth populations? Themes from the identified papers were charted, and findings were summarized through a consensus process. A total of 40 papers were identified in the search, spanning 2008–2022. Based on the thematic analysis, results are organized into the following nine themes: 1) heat extremes, 2) weather extremes and stress, 3) air pollution, 4) vector and waterborne illnesses, 5) malnutrition, 6) equity, 7) economic implications, 8) methods issues, and 9) responses. There is a clear consensus amongst the papers in this review suggesting that changing climate patterns and weather extremes have substantial and wide-ranging effects on developing brains. A range of responses are proposed with an emphasis upon early intervention and better data