Background: Repeated population-based SARS-CoV-2 serosurveillance is key in complementing other surveillance tools. Aim: Assessing trends in infection- and/or vaccine-induced immunity, including breakthrough infections, among (sub)groups and regions in the Dutch population during the Variant of Concern (VOC)-era whilst varying levels of stringency, to evaluate population immunity dynamics and inform future pandemic response planning. Methods: In this prospective population-based cohort, randomly-selected participants (n=9,985) aged 1-92 years (recruited since early-2020) donated home-collected fingerstick blood samples at six timepoints in 2021-2022, covering waves dominated by Alpha, Delta, and Omicron (BA.1, BA.2, BA.5). IgG antibody assessments against Spike-S1 and Nucleoprotein were combined with vaccination- and testing data to estimate infection-induced (inf) and total (infection- and vaccination-induced) seroprevalence. Results: In 2021, nationwide inf-seroprevalence rose modestly from 12% since Alpha to 26% amidst Delta, while total seroprevalence increased rapidly to nearly 90%, particularly fast in vulnerable groups (i.e., elderly and those with comorbidities). Highest infection rates were noticeable in adolescents and young adults, low/middle educated elderly, non-Western, contact professions (other than healthcare), and low-vaccination coverage regions. In 2022, following Omicron emergence, inf-seroprevalence elevated sharply to 62% and further to 86%, with frequent breakthrough infections and reduction of seroprevalence dissimilarities between most groups. Whereas >90% of <60-year-olds had been infected, 30% of vaccinated vulnerable individuals had not acquired hybrid immunity. Conclusion: Although total SARS-CoV-2 seroprevalence had increased rapidly, infection rates were unequally distributed within the Dutch population. Ongoing tailored vaccination efforts and (sero-)monitoring of vulnerable groups remain important given their lowest rate of hybrid immunity and highest susceptibility to severe disease. | Make paid
Background: The WHO AFRO region continues to be severely impacted by HIV and a global public health problem. In Mozambique, as of 2015, HIV prevalence was estimated to be 12.5% among adults. Medical male circumcision (MMC) has been promoted as a national prevention strategy to reduce the risk of HIV in men. We aimed to analyze the association between HIV infection, medical male circumcision and traditional male circumcision among men in Mozambique. Methods: Cross-sectional data from the 2015 Mozambican National and Demographic Health Survey of Immunization, Malaria, and HIV/AIDS (IMASIDA) were used in this analysis. In this study, considered medical male circumcision (MMC) and medical circumcision (MC). Participants were asked about their circumcision status and where the circumcision was performed. In addition, blood samples were collected from participants and tested for HIV antibodies. All analyses were weighted and adjusted for the complex survey design to ensure results and approximate population parameters of interest. Chi-square tests and multiple logistic regression were used in the analyses to assess the associations between male circumcision and HIV infection. Results: A total unweighted sample of 4733 men aged 15-49 consented to the survey and were interviewed. Of those who participated, 4236 consented to an HIV test. Nationally, 62.6% (95% CI 59.6-65.6) of men aged 15-49 years were circumcised. Traditional circumcision was the most common form of circumcision at 32.9% (95% CI 30.1-35.8), followed by MMC at 21.7% (95% CI 19.6-24.1), 8.0% (95% CI 6.5-9.9) did not know whether it was traditional or medical. The prevalence of HIV was highest at 13.4% among uncircumcised men (13.4%, 95% CI 11.3-15.7), and significantly lower among traditionally circumcised men (8.5%, 95% CI 6.8-10.6) and among medically circumcised men (7.5%, 95% CI 5.7-9.6). In multivariable analysis, men circumcised by a medical practitioner had almost 50% reduced odds of infection with HIV compared to uncircumcised men (aOR=0.52; 95% [CI=0.34-0.78], p=0.002), whereas men who were circumcised by traditional methods had a 29% reduced risk, but not significantly different than uncircumcised men (aOR=0.71; 95% [CI=0.47-1.07], p=0.098). Conclusion: We found that HIV prevalence was lower among men aged 15-49 years who were circumcised, and the odds of being HIV positive was about 50% lower among men who were circumcised by a medical practitioner, suggesting a reduced risk of HIV infection. Although Mozambique has not achieved the UNAIDS goal of 80% men circumcised at the time of the IMASIDA 2015 survey, we encourage the continued expansion of voluntary medical male circumcision. | Make paid
Introduction Visceral adiposity is emerging as a key driver of cardio-metabolic risk factors and cardiovascular disease (CVD), but its relationship with cardiac structure and function is not well characterized across sexes. Using the Canadian Alliance for Healthy Heart and Minds (CAHHM), a large population-based cohort study, we sought to determine the association of visceral adipose tissue (VAT) on subclinical left ventricular (LV) remodeling in males and females. Methods As part of the CAHHM study, 6522 participants free of clinical CVD (mean age: 57.4 [8.8 SD] years; 3,671 females, 56%) underwent magnetic resonance imaging (MRI) in which LV parameters and VAT volume were measured. Information about demographic factors, CV risk factors, and anthropometric measurements were obtained. Subclinical cardiac remodelling was defined as altered LV concentricity, represented by increased LV mass-to-volume ratio (LVMV). Results Males had a higher VAT volume (80.8 mL; 95% CI: 74.6 t 86.9) compared to females (64.7 mL; 95% CI: 58.5 to 70.8), adjusted for age and height. Among both males and females, VAT was significantly associated with subclinical cardiac remodeling (increased LVMV), independent of other CV risk factors. In multiple regression models adjusted for cardiovascular risk factors, age, and height, every 1 sex-specific standard deviation increase in VAT corresponded to an increase of 0.037 g/mL in LVMV (95% CI: 0.032 to 0.041; p<0.001), which was consistent across both sexes. Notably, a 1 standard deviation increase in VAT is associated with a LVMV that is 20 times higher than what is observed with natural aging alone (0.0020 g/mL rise in LVMV (95% CI 0.0016 to 0.0025), and 1.5 times higher than the impact of an integrated measure of CV risk factors (0.024 g/mL; 95% CI: 0.020 to 0.028). Conclusion VAT significantly influences subclinical cardiac remodeling in both males and females, independent of other cardiovascular risk factors and age. Further research to understand the pathways by which VAT contributes to accelerated cardiac aging is needed. | Make paid
Adverse hematologic events have been reported after COVID-19 vaccination. The objective of this study was to investigate whether hematologic abnormalities develop after COVID-19 vaccination. Retrospective cohort analyses of data from the Korean National Health Insurance Service (KNHIS) database were conducted from July 2022 to August 2023. We randomly selected data of half of those living in Seoul City as of January 1, 2021 with their diagnostic records up to December 31, 2021. The included participants were vaccinated and nonvaccinated persons aged 20 years or older (n= 4,203,887). Hematologic abnormalities after COVID-19 vaccination were identified as nutritional anemia, hemolytic anemia, aplastic anemia, coagulation defects, and neutropenia using International Classification of Diseases, Tenth Revision codes after index date. Incidence rates of hematologic abnormalities in the vaccination group 3 months after vaccination were significantly higher than those in the nonvaccinated group: 14.79 vs. 9.59 (P<.001) for nutritional anemia, 7.83 vs. 5.00 (P<.001) for aplastic anemia, and 4.85 vs. 1.85 (P<.001) for coagulation defects. COVID-19 mRNA vaccine was associated with higher development of nutritional anemia (odds ratio [OR], 1.230 [95% CI, 1.129-1.339], P<.001) and aplastic anemia (OR, 1.242 [95% CI, 1.110-1.390], P<.001) than the viral vector vaccine. The risk of coagulation defects was increased (OR, 1.986 [95% CI, 1.523-2.589], P<.001) after vaccination, and there was no risk difference between mRNA vaccine and viral vector vaccine (OR, 1.075 [95% CI, 0.936-1.233], P=.306). In conclusions, COVID-19 vaccination increased the risk of hematologic abnormalities. When administering the COVID-19 vaccine, careful observation will be necessary after vaccination. | Make paid
Background: Key population HIV programmes in sub-Saharan Africa (SSA) require epidemiologic information to ensure equitable and equal access to services. We consolidated survey data among female sex workers (FSW), men-who-have-sex-with-men (MSM), people who inject drugs (PWID), and transgender people to estimate national-level key population size, HIV prevalence, and antiretroviral therapy (ART) coverage for mainland SSA. Methods: Key population size estimates (KPSE), HIV prevalence, and ART coverage data from 39 SSA countries between 2010-2022 were collated from existing databases and verified against source documents. We used Bayesian mixed-effects spatial regression to model urban KPSE as a proportion of the gender-matched 15-49 years adult population. We modelled subnational key population HIV prevalence and ART coverage with age/gender/year/province-matched total population estimates as predictors. Findings: We extracted 2062 unique KPSE, 1243 HIV prevalence, and 201 ART coverage data points. Across national urban populations, a median of 1.71% of women were FSW (interquartile range [IQR]=1.21-1.97%); 0.92% of men were MSM (IQR=0.73-1.01%); 0.32% of men injected drugs (IQR=0.28-0.39%), and 0.14% of women were transgender (IQR=0.12-0.17%). Key population HIV prevalence was 4 to 6 times higher than gender-matched total population prevalence. ART coverage was correlated with, but lower than, total population ART coverage. Across SSA, key populations were estimated as 1.3% (95%CI: 0.9-1.7%) of the total population aged 15-49 years but 6.3% (4.6-8.6%) of people living with HIV. Interpretation: Key populations in SSA experience disproportionately higher HIV burden and lower ART coverage, underscoring a need for focused prevention and treatment services. However, data availability and heterogeneity limit precise estimates for programming and monitoring trends. Strengthening key population surveys and routine data within national HIV strategic information systems would support more precise estimates. | Make paid
Aging can be associated with the accumulation of hypobranched glycogen molecules (polyglucosan bodies, PGBs), particularly in astrocytes of the hippocampus. While PGBs have a detrimental effect on cognition in diseases such as adult polyglucosan body disease and Lafora disease, the underlying mechanism and clinical relevance of age-related PGB accumulation remains unknown. Here, we have investigated the genetic basis and functional impact of age-related PGB accumulation in 32 fully sequenced BXD-type strains of mice which exhibit a 400-fold variation in PGB burden in 16-18 month old females. We mapped a major locus controlling PGB density in the hippocampus to chromosome 1 at 72-75 Mb (linkage of 4.9 -logP), which we defined as the Pgb1 locus. To identify potentially causal gene variants within Pgb1, we generated extensive hippocampal transcriptome datasets and identified two strong candidate genes for which mRNA correlates with PGB density, Smarcal1 and Usp37. In addition, both Smarcal1 and Usp37 contain non-synonymous allele variations likely to impact protein function. A phenome-wide association analysis highlighted a trans-regulatory effect of the Pgb1 locus on expression of Hp1bp3, a gene known to play a role in age-related changes in learning and memory. To investigate the potential impact of PGBs on cognition, we performed conditioned fear memory testing on strains displaying varying degrees of PGB burden, and a phenome-wide association scan of ~12,000 behavioral traits. Importantly, we did not find any evidence suggesting a negative impact of PGB burden on cognitive capacity. Taken together, we have identified a major modifier locus controlling PGB burden in the hippocampus and shed light on the genetic architecture and clinical relevance of this strikingly heterogeneous hippocampal phenotype. | Make paid
About two-thirds of those with Alzheimer's disease (AD) are women, most of whom are post-menopausal. Menopause accelerates the risk for dementia by increasing the risk for metabolic, cardiovascular, and cerebrovascular diseases. Mid-life metabolic disease (e.g. obesity, diabetes, or prediabetes) is a well-known risk factor for dementia. A high fat diet can lead to poor metabolic health in both humans and rodents. The goal of this study was to determine the effects of menopause and high fat diet on metabolic outcomes in the AppNL-F knock-in mouse model of Alzheimer's disease. To model menopause, we used an accelerated ovarian failure model (4-vinylcyclohexene diepoxide, VCD). This ovary-intact model is more clinically relevant than an ovariectomy model, as mice go through a perimenopausal period. At 3 months of age, AppNL-F mice were administered VCD or vehicle (oil) and then placed on either a control diet (10% fat) or a high fat diet (HF; 60% fat) and maintained on the diets until 10 months of age. Menopause led to metabolic impairment (weight gain and glucose intolerance) and further exacerbated obesity in response to a high fat diet. Menopause had independent effects on some serum metabolic health biomarkers (insulin) and synergic effects with HF diet on other markers (glucagon). Some metabolic effects of menopause may be centrally mediated, as menopause altered the expression of hypothalamic genes related to energy balance and increased microgliosis in the lateral hypothalamic nucleus. This work highlights the need to model endocrine aging in animal models of dementia and will contribute to further understanding the interaction between menopause and metabolic health in the context of AD. | Make paid
Age is the primary risk factor for most neurodegenerative diseases including amyo-trophic lateral sclerosis (ALS). Despite the clear importance of age on the develop-ment and progression of ALS age is rarely considered a factor in cellular or animal models of ALS. The recent advent of direct reprogramming methodologies, whereby somatic cells such as fibroblasts can be converted into neurons while retaining the age signature of the host, has facilitated the study of age-relevant human cells in vitro for the first time. Despite the promise of this technology, age is a complex, multidimen-sional, and dynamic phenotype that makes the interpretation of the interplay between age and disease a great challenge. To circumvent these challenges, we developed a high-throughput screening platform for directly reprogrammed neurons in an age-relevant human cellular model to better model and identify disease-modifying targets and pathways for ALS. This platform uses deep learning image analysis to screen compounds for efficacy against ALS-associated cellular phenotypes. Our platform effi-ciently classifies ALS-like phenotypic signatures and predicts the age of the original fibroblast donor. Notably, our work identified NCB-0846, a TNIK/MAP4K7 inhibitor, as a novel compound with the ability to revert ALS-like phenotypes. Moreover, we show that chronic dosing of NCB-0846 in the SOD1G93A mouse model of ALS significantly reduced serum neurofilament-L levels. Our findings establish the power of a platform that combines direct reprogramming of human cells and deep learning as a powerful tool for combatting aging and age-related diseases. | Make paid
Importance: COVID-19 continues to cause significant hospitalizations and deaths in the United States. Its continued burden and the impact of annually reformulated vaccines remain unclear. Objective: To project COVID-19 hospitalizations and deaths from April 2023-April 2025 under two plausible assumptions about immune escape (20% per year and 50% per year) and three possible CDC recommendations for the use of annually reformulated vaccines (no vaccine recommendation, vaccination for those aged 65+, vaccination for all eligible groups). Design: The COVID-19 Scenario Modeling Hub solicited projections of COVID-19 hospitalization and deaths between April 15, 2023-April 15, 2025 under six scenarios representing the intersection of considered levels of immune escape and vaccination. State and national projections from eight modeling teams were ensembled to produce projections for each scenario. Setting: The entire United States. Participants: None. Exposure: Annually reformulated vaccines assumed to be 65% effective against strains circulating on June 15 of each year and to become available on September 1. Age and state specific coverage in recommended groups was assumed to match that seen for the first (fall 2021) COVID-19 booster. Main outcomes and measures: Ensemble estimates of weekly and cumulative COVID-19 hospitalizations and deaths. Expected relative and absolute reductions in hospitalizations and deaths due to vaccination over the projection period. Results: From April 15, 2023-April 15, 2025, COVID-19 is projected to cause annual epidemics peaking November-January. In the most pessimistic scenario (high immune escape, no vaccination recommendation), we project 2.1 million (90% PI: 1,438,000-4,270,000) hospitalizations and 209,000 (90% PI: 139,000-461,000) deaths, exceeding pre-pandemic mortality of influenza and pneumonia. In high immune escape scenarios, vaccination of those aged 65+ results in 230,000 (95% CI: 104,000-355,000) fewer hospitalizations and 33,000 (95% CI: 12,000-54,000) fewer deaths, while vaccination of all eligible individuals results in 431,000 (95% CI: 264,000-598,000) fewer hospitalizations and 49,000 (95% CI: 29,000-69,000) fewer deaths. Conclusion and Relevance: COVID-19 is projected to be a significant public health threat over the coming two years. Broad vaccination has the potential to substantially reduce the burden of this disease. | Make paid
Age is a prominent risk factor for cardiometabolic disease, and often leads to heart structural and functional changes. However, precise molecular mechanisms underlying cardiac remodeling and dysfunction resulting from physiological aging per se remain elusive. Understanding these mechanisms requires biological models with optimal translation to humans. Previous research demonstrated that baboons undergo age-related reduction in ejection fraction and increased heart sphericity, mirroring changes observed in humans. The goal of this study was to identify early cardiac molecular alterations that precede functional adaptations, shedding light on the regulation of age-associated changes. We performed unbiased transcriptomics of left ventricle (LV) samples from female baboons aged 7.5-22.1 years (human equivalent ~30-88 years). Weighted-gene correlation network and pathway enrichment analyses were performed to identify potential age-associated mechanisms in LV, with histological validation. Myocardial modules of transcripts negatively associated with age were primarily enriched for cardiac metabolism, including oxidative phosphorylation, tricarboxylic acid cycle, glycolysis, and fatty-acid {beta}-oxidation. Transcripts positively correlated with age suggest upregulation of glucose uptake, pentose phosphate pathway, and hexosamine biosynthetic pathway (HBP), indicating a metabolic shift towards glucose-dependent anabolic pathways. Upregulation of HBP commonly results in increased glycosaminoglycan precursor synthesis. Transcripts involved in glycosaminoglycan synthesis, modification, and intermediate metabolism were also upregulated in older animals, while glycosaminoglycan degradation transcripts were downregulated with age. These alterations would promote glycosaminoglycan accumulation, which was verified histologically. Upregulation of extracellular matrix (ECM)-induced signaling pathways temporally coincided with glycosaminoglycan accumulation. We found a subsequent upregulation of cardiac hypertrophy-related pathways and an increase in cardiomyocyte width. Overall, our findings revealed a transcriptional shift in metabolism from catabolic to anabolic pathways that leads to ECM glycosaminoglycan accumulation through HBP prior to upregulation of transcripts of cardiac hypertrophy-related pathways. This study illuminates cellular mechanisms that precede development of cardiac hypertrophy, providing novel potential targets to remediate age-related cardiac diseases. | Make paid
Tungiasis is a highly neglected tropical skin disease caused by the sand flea, Tunga penetrans. The flea burrows into the skin inducing a strong inflammatory response, leading to chronic pain and discomfort with potential impacts on quality of life. Few countries implement control efforts and there are few data on the impact of the disease to support policy decisions. We conducted a survey to determine the impact of tungiasis among primary school children across nine counties of Kenya. A total of 10,600 pupils aged 8 to 14 years were randomly selected from 97 primary schools and examined for tungiasis. Those with tungiasis (83) were interviewed with respect to their quality of life using a modified dermatological quality of life index. For these cases and 576 randomly selected controls, school attendance and exam scores for maths, English and science were collected from school records. Mixed effect ordered logistic and linear models were used to assess associations between disease status and impact variables. Compared to uninfected pupils, those with tungiasis missed more days of school (adjusted Incidence Rate Ratio (aIRR: 1.50, 95% CI: 1.03-2.21) and were less likely to receive a high score in maths (aOR 0.18, 95% CI: 0.08-0.40) and other subjects. Pupils with severe disease (>10 fleas) were five times more likely to experience severe pain and itching than those with mild disease (OR 5.0, 95% CI: 2.55-10.51) and a higher category of impact on their quality of life than those with mild disease (aOR 3.52, 95% CI: 1.22-10.17) when adjusted for covariates. This study has demonstrated tungiasis has a considerable impact on childrens lives and academic achievement, equivalent to other diseases. This indicates the need for integrated disease management for school-aged children to protect their physical and cognitive development and their future prospects. | Make paid
Introduction: The extent to which genetic variation at the APOE locus explains the burden of late-onset Alzheimer disease (AD) is poorly understood. We aimed to provide new estimates of the proportions of AD and all-cause dementia attributable to combined carriage of {epsilon}3 or {epsilon}4 alleles of APOE. Materials and Methods: We conducted a nested case-control study using data from 171,133 participants of the UK Biobank cohort study, aged 60 years or older at baseline assessments in 2006-2010. Carriage of {epsilon}2/{epsilon}3/{epsilon}4 alleles of APOE were coded from genotyped or imputed microarray data for single nucleotide polymorphisms rs7412 and rs429358. AD and all-cause dementia were ascertained from baseline self-report and follow-up via linked electronic health and death records up to December 2022 (minimum/maximum follow-up: 12.2 / 16.8 years). Risks of these outcomes due to {epsilon}3 and/or {epsilon}4 carriage were modelled with multivariable logistic regression, adjusting for age at baseline, self-reported sex and ethnicity, 10 genetic principal components and genotyping array. Odds ratios and prevalence of {varepsilon}3 and {epsilon}4 carriage were used to calculate population attributable fractions (PAFs) of the outcomes due to these genotypes. Results: 99.4% of the sample had either {epsilon}3 and/or {epsilon}4 carriage. By the end of follow-up, 3026 (1.8%) and 6634 (3.9%) of the sample had AD and all-cause dementia, respectively. The odds ratio for AD risk due to {epsilon}3 and {epsilon}4 carriage with reference to {epsilon}2 homozygotes was 3.80 (95% CI:1.58, 9.17). The equivalent risk for all-cause dementia was 1.74 (95% CI: 1.16, 2.61). PAFs for AD and all-cause dementia burden due to {epsilon}3 and {epsilon}4 exposure were 73.6% (95% CI: 36.6, 89.0) and 42.4% (95% CI: 13.6, 61.6%), respectively. Conclusions: Differences in the molecular physiology of Apolipoprotein E cause most AD and a large fraction of dementia cases. Research into this pathway should be prioritised to facilitate dementia prevention. | Make paid
To understand the neurocognitive mechanisms that underlie heterogeneity in cognitive ageing, recent scientific efforts have led to a growing public availability of imaging cohort data. The Advanced BRain Imaging on ageing and Memory (ABRIM) project aims to add to these existing datasets by taking an adult lifespan approach to provide a cross-sectional, normative database with a particular focus on connectivity, myelinization and iron content of the brain in concurrence with cognitive functioning, mechanisms of reserve, and sleep-wake rhythms. ABRIM freely shares MRI and behavioural data from 295 participants between 18-80 years, stratified by age decade and sex (median age 52, IQR 36-66, 53.20% females). The ABRIM MRI collection consists of both the raw and pre-processed structural and functional MRI data to facilitate data usage among both expert and non-expert users. The ABRIM behavioural collection includes measures of cognitive functioning (i.e., global cognition, processing speed, executive functions, and memory), proxy measures of cognitive reserve (e.g., educational attainment, verbal intelligence, and occupational complexity), and various self-reported questionnaires (e.g., on depressive symptoms, pain, and the use of memory strategies in daily life and during a memory task). In a sub-sample (n = 120), we recorded sleep-wake rhythms with an actigraphy device for a period of 7 consecutive days. Here, we provide an in-depth description of our study protocol, pre-processing pipelines, and data availability. ABRIM provides a cross-sectional database on healthy participants throughout the adult lifespan, including numerous parameters relevant to improve our understanding of cognitive ageing. Therefore, ABRIM enables researchers to model the advanced imaging parameters and cognitive topologies as a function of age, identify the normal range of values of such parameters, and to further investigate the diverse mechanisms of reserve and resilience. | Make paid
Genetic modifier screens provide a useful tool, in diverse organisms from Drosophila to C. elegans and mice, for recovering new genes of interest that may reduce or enhance a phenotype of interest. This study reports a modifier screen, based on N-ethyl-N-nitrosourea (ENU) mutagenesis and outcrossing, designed to increase understanding of the normal function of murine alpha-synuclein (Snca). Human SNCA was the first gene linked to familial Parkinsons disease. Since the discovery of the genetic link of SNCA to Parkinsons nearly three decades ago, numerous studies have investigated the normal function of SNCA protein with divergent roles associated with different cellular compartments. Understanding of the normal function of murine Snca is complicated by the fact that mice with homozygous null mutations live a normal lifespan and have only subtle synaptic deficits. Here, we report that the first genetic modifier (a sensitized mutation) that was identified in our screen was the X-linked gene, ATPase copper transporting alpha (Atp7a). In humans, mutations in Atp7a are linked to to Menkes disease, a disease with pleiotropic phenotypes that include a severe neurological component. Atp7a encodes a trans-Golgi copper transporter that supplies the copper co-factor to enzymes that pass through the ER-Golgi network. Male mice that carry a mutation in Atp7a die within 3 weeks of age regardless of Snca genotype. In contrast, here we show that Snca disruption modifies the phenotype of Atp7a in female mice. Female mice that carry the Atp7a mutation, on an Snca null background, die earlier (prior to 35 days) at a significantly higher rate than those that carry the Atp7a mutation on a wildtype Snca background ATPase copper transporting alpha. Thus, Snca null mutations sensitize female mice to mutations in Atp7a, suggesting that Snca protein may have a protective effect in females, perhaps in neurons, given the co-expression patterns. Although data has suggested diverse functions for human and mouse a-synuclein proteins in multiple cell compartments, this is the first demonstration via use of genetic screening to demonstrate that Snca protein may function in the ER-Golgi system in the mammalian brain in a sex-dependent manner. | Make paid
Microglia are established in embryogenesis forming a self-containing cellular compartment resisting seeding with cells derived from adult definitive hematopoiesis. We report that monocyte-derived macrophages (MoMF) accumulate in the brain of aging mice with distinct topology, including the nigrostriatum and medulla, but not the frontal cortex. Parenchymal MoMF adopt bona fide microglia expression profiles. Unlike microglia, these monocyte-derived microglia (MoMg) are due to their hematopoietic origin targets of clonal hematopoiesis (CH). Using a chimeric transfer model, we show that hematopoietic expression of DNMT3AR822H, a prominent mutation in human CH, renders MoMg pathogenic promoting motor deficits resembling atypical Parkinsonian disorders. Collectively, these data establish in a mouse model that MoMg progressively seed the brains of aging healthy mice, accumulate in selected areas, and, when carrying a somatic mutation associated with CH, can contribute to brain pathology. | Make paid
As the aging population grows, the need to regenerate non-self-repairing tissues becomes increasingly crucial for enhancing our quality of life. Tissue engineering offers a promising solution, particularly in recreating the intricate networks of blood vessels crucial for tissue vitality. These tissues rely on effective nutrient and oxygen circulation, with an optimal oxygen diffusion range of 100-200 m. Yet, crafting vascularized in vitro tissues remains a significant challenge. This study addresses the challenge by using GelMA-based hydrogels as a photocrosslinkable support bath, a biocompatible and versatile choice for biological applications. To enhance the rheological properties for in vitro tissue engineering, Laponite (LPN) is introduced as a rheology modifier. The study optimizes the GelMA-LPN nanocomposite hydrogel composition, ensuring the desired physical, mechanical, and rheological properties, including recovery. The research also explores the biological implications, encapsulating liver cells within the nanocomposite hydrogel, and studying their behavior under perfusion conditions. This research presents a promising avenue for creating vascularized in vitro tissues, potentially advancing tissue engineering and regenerative medicine. | Make paid
Brain aging and cognitive decline are aspects of growing old. Age-related cognitive impairment entails the early stages of cognitive decline, and is extremely common, affecting millions of older people. Investigation into early cognitive decline as a treatable condition is relevant to a wide range of cognitive impairment conditions, since mild age-related neuropathology increases risk for more severe neuropathology and dementia associated with Alzheimer's Disease. Recent studies suggest that the naturally occurring peptide GHK (glycyl-L-histidyl-L-lysine) in its Cu-bound form, has the potential to treat cognitive decline associated with aging. In order to test this concept, male and female C57BL/6 mice, 20 months of age, were given intranasal GHK-Cu, 15 mg/kg daily, for two months. Results showed that mice treated with intranasal GHK-Cu had an enhanced level of cognitive performance in spatial memory and learning navigation tasks, and expressed decreased neuroinflammatory and axonal damage markers compared to mice treated with intranasal saline. These observations suggest that GHK-Cu can enhance resilience to brain aging, and has translational implications for further testing in both preclinical and clinical studies using an atomizer device for intranasal delivery. | Make paid
Thyroid hormones (TH) are known to have various effects on the cardiovascular system. However, the impact of TH levels on preexisting cardiac diseases are still unclear. Pressure overload due to arterial hypertension or aortic stenosis and aging are major risk factors for the development of structural and functional abnormalities and subsequent heart failure. Here, we assessed the sensitivity to altered TH levels in aged mice with maladaptive cardiac hypertrophy and cardiac dysfunction induced by transverse aortic constriction (TAC). Mice at the age of 12 months underwent TAC and after induction of left ventricular pressure overload, received T4 or anti-thyroid medication in the drinking water over the course of 4 weeks. T4 excess or deprivation in older mice had no or only very little impact on cardiac function (fractional shortening), cardiac remodeling (cardiac wall thickness, heart weight, cardiomyocyte size, apoptosis and interstitial fibrosis) and mortality. This is surprising, because T4 excess or deprivation had significantly changed the outcome after TAC in young 8-week-old mice. In summary, our study shows that low and high TH availability have little impact on cardiac function and remodeling in older mice with preexisting pressure induced cardiac damage. This suggests that even though cardiovascular risk is increasing with age, the response to TH stress may be dampened in certain conditions. | Make paid
Aging leads to increased response latencies but the underpinning cognitive and neural mechanisms remain elusive. We modelled older and younger adults response time (RT) data from a 2-choice flanker task with a diffusion drift model (DDM) and employed multi-shell diffusion weighted magnetic resonance imaging and spectroscopy to study neurobiological predictors of DDM components thought to govern RTs: drift rate, boundary separation and non-decision time. Microstructural indices of fractional anisotropy (FA), diffusivities and the restricted signal fraction (FR) from the Composite Hindered and Restricted Model of Diffusion (CHARMED) were derived from white matter pathways of visuo-perceptual and attention networks (optic radiation, inferior and superior longitudinal fasciculi, fornix) and estimates of metabolite concentrations [N-acetyl aspartate (NAA), glutamate (Glx), aminobutyric acid (GABA), creatine (Cr), choline (Cho) and myoinositol (mI)] were measured from occipital (OCC), anterior and posterior cingulate cortices (ACC, PPC). Ageing was associated with increased RT, boundary separation, and non-decision time. Differences in boundary separation but not non-decision time mediated age-related response slowing. Regression analyses revealed a network of brain regions involved in top-down (fornix FA, diffusivities in right SLF) and bottom-up processing (mI in OCC, AD in left optic radiation) and verbal intelligence as significant predictors of RTs and non-decision time (NAA in ACC, AD in the right ILF, creatine in the OCC) while fornix FA was the only predictor for boundary separation. Fornix FA mediated the effects of age on RTs but not vice versa. These results provide novel insights into the cognitive and neural underpinnings of age-related slowing. | Make paid
With the development of the digital phenotyping, repeated measurements of agronomic traits over time are easily accessible, notably for morphological and phenological traits. However high throughput methods for estimating physiological traits such as photosynthesis are lacking. This study demonstrates the links of fluorescence and reflectance imaging with photosynthetic traits. Two wheat cultivars were grown in pots in a controlled environment. Photosynthesis was characterised by gas-exchange and biochemical analysis at five time points, from booting to 21 days post anthesis. On the same days imaging was performed on the same pots, at leaf and plant scale, using indoor and outdoor phenotyping platforms, respectively. Five image variables (Fv/Fm and NDVI at the whole plant level and Fv/Fm, {Phi}(II)532 and {Phi}(NPQ)1077 at the leaf scale) were compared to variables from A-Ci and A-Par curves, biochemical analysis, and fluorescence instruments. The results suggested that the image variables are robust estimators of photosynthetic traits, as long as senescence is driving the variability. Despite contrasting cultivar behaviour, linear regression models which account for the cultivar and the interaction effects, further improved the modelling of photosynthesis indicators. Finally, the results highlight the challenge of discriminating functional to cosmetic stay green genotypes using digital imaging. HighlightA temporal and multi-scale study of fluorescence and NDVI imaging used as a proxy for photosynthetic parameters | Make paid
Aging is associated with robust decline of the brains gray matter. This spatially specific, morphological change in humans has recently been found in chimpanzees. Direct comparison of age-related brain deterioration between these great ape species can provide a unique evolutionary perspective on human brain aging. Here, we present a data-driven, cross-species comparative framework to explore the relationship between gray matter atrophy with age and cross-species cerebral expansion in chimpanzees and humans. In humans, we found a positive relationship between cerebral aging and cortical expansion, whereas, in chimpanzees no such relationship was found. The greater aging and expansion effects in higher-order cognitive regions like the orbito-frontal cortex were observed to be unique to humans. This resembles the last in, first out hypothesis for neurodevelopment and may represent a biological cost for recent evolutionary developments of human faculties. | Make paid
Introduction While individualised falls preventive education has been effective in reducing hospital falls among older patients, there is a dearth of research exploring consumers' perspectives on hospital falls prevention education. Objective This study aimed to explore the knowledge of older consumers regarding preventing falls in hospital and their reflections on the education received during hospitalisation Methods A qualitative, exploratory study incorporating focus groups and semi-structured interviews was undertaken. The participants consisted of a purposively selected sample of community-dwelling consumers aged 65 and above (n=39 older adults and n=9 family carers of older adults) who had been admitted to a hospital within the past five years. Thematic analysis, incorporating deductive and inductive approaches, was applied and a capability-opportunity-motivation-behaviour model was utilised to comprehend the key determinants influencing the implementation of falls education for hospitalised older adults. Results Feedback from the participants (n=46, 25 females) revealed five key themes: distress and disempowerment resulting from hospital falls, anxiety and uncertainty regarding required behaviour while hospitalised, insufficient and inconsistent falls prevention education, inadequate communication, and underlying ageism attitudes. These themes converged to provide the overarching theme: support and education available to engage in safe falls prevention behaviour was not what we expected! Application of the behaviour change model indicated that older consumers often did not acquire falls prevention knowledge, awareness or motivation, and had limited opportunities to engage in falls preventive behaviour during hospitalisation. Discussion In summary, older consumers receive sporadic falls prevention education during hospital admissions, which fails to raise their awareness and knowledge of falls risks or their capability to engage in safe preventive behaviors. Conflicting messages contribute to consumer confusion and anxiety about maintaining safety during hospital stays. Conclusion Further research is required to address these issues to enable older adults to undertake effective falls prevention behaviours in hospital settings. Hospital policies and guidelines need to prioritise falls prevention education. Policies can be designed to emphasise tailored education, effective communication, and the importance of addressing ageism to enhance patient safety and well-being. | Make paid
Background: The 2022 multicountry mpox outbreaks predominantly affected gay, bisexual and other men who have sex with men (GBMSM) in non-endemic countries. Mpox vaccination is most effective if targeting GBMSM most at risk. It is unknown to what extent eligibility criteria for vaccination align with evidence on risk factors for mpox in GBMSM. Methods: We conducted an online self-report survey among GBMSM in the Netherlands between 29 July and 30 August 30, 2022, corresponding to the first month of the Dutch mpox vaccination campaign. GBMSM were recruited via advertisements on social media and gay dating apps. Participants reported on their sexual behaviour, mpox diagnosis, and/or vaccination since the start of the outbreak. Results: Of the 2,460 participants, 73 (3.0%) were diagnosed with mpox and 485 (19.7%) had been vaccinated. Using population sample weights, we estimated that, of the sexually active GBMSM population aged 18-80 years in the Netherlands, 1.1% had been diagnosed with mpox and 7.8% had been vaccinated. In multivariable logistic regression analyses, we found that current HIV-PrEP use, having 20 or more sex partners in the past 12 months and having sex in sex venues or at parties in the past two months were independent risk factors for mpox diagnosis. Conclusion: This study provides novel evidence on risk factors for mpox amongst GBMSM in the Netherlands that has guided a refinement of eligibility criteria for mpox vaccination. The dynamics of any future mpox outbreaks are unknown and continued adjustment of vaccination eligibility may be required to achieve sustained elimination. | Make paid
INTRODUCTION Widespread disruption of neuropeptide (NP) networks in Alzheimer\'s disease (AD) and disproportionate absence of neurons expressing high NP-producing, coined as HNP neurons, have been reported for the entorhinal cortex (EC) of AD brains. Hypothesizing that functional features of HNP neurons are involved in the early pathogenesis of AD, we aim to understand the molecular mechanisms underlying these observations. METHODS Multiscale and spatiotemporal transcriptomic analysis was used to investigate AD-afflicted and healthy brains. Our focus encompassed NP expression dynamics in AD, AD-associated NPs (ADNPs) trajectories with aging, and the neuroanatomical distribution of HNP neuron. RESULTS Findings include that 1) HNP neurons exhibited heightened metabolic needs and an upregulation of gene expressions linked to protein misfolding; 2) dysfunctions of ADNP production occurred in aging and mild cognitive decline; 3) HNP neurons co-expressing ADNPs were preferentially distributed in brain regions susceptible to AD. DISCUSSION We identified potential mechanisms that contribute to the selective vulnerability of HNP neurons to AD. Our results indicate that the functions of HNP neurons predispose them to oxidative stress and protein misfolding, potentially serving as inception sites for misfolded proteins in AD. | Make paid
The interaction between bone mesenchymal stem cells (BMSCs) and macrophages in osteoporosis has gained increasing attention. Aged BMSCs exhibit a senescence-associated secretory phenotype (SASP), which contributes to the inflammatory microenvironment with macrophage inflammaging. USP7, as a key deubiquitinase regulating cellular senescence and inflammation, has been found to promote senolysis when inhibited. We found that USP7 inhibition induced senolysis and osteogenic differentiation in aged BMSCs. For senescent BMDMs, USP7 inhibition suppressed inflammaging and enhanced efferocytosis through EPSIN1/LRP1 pathway, enabling them to efficiently clear apoptotic senescent cells caused by USP7 inhibition. In the femurs and vertebrae of aged mice, it was discovered that USP7 inhibition could rescue bone loss, which may be associated with improved macrophage efferocytosis. This study highlights the potential of USP7 inhibition in promoting senolysis in aged BMSCs and enhancing efferocytosis capacity of senescent BMDMs, which exerts a synergistic therapeutic effect by inducing senescent cell apoptosis and immune clearance. | Make paid
Diverse populations of bacteriophages infect and co-evolve with their bacterial hosts. Although host recognition and infection occurs within microbiomes, the molecular mechanisms underlying host-phage interactions within a community context remain poorly studied. The biofilms (rinds) of aged cheeses contain taxonomically diverse microbial communities that follow reproducible growth patterns and can be manipulated under laboratory conditions. In this study, we use cheese as a model for studying phage-microbe interactions by identifying and characterizing a tractable host-phage pair co-occurring within a model Brie community. We isolated novel bacteriophage TS33 that kills Hafnia sp. JB232 (hereafter Hafnia), a member of the model community. TS33 is easily propagated in the lab and naturally co-occurs in the cheese with the Brie community, rendering it a prime candidate for the study of host-phage interactions. We performed growth assays of the Hafnia, TS33 and the fungal community members, Geotrichum candidum and Penicillium camemberti. Employing Random Barcode Transposon Sequencing (RB-TnSeq) experiments, we identified candidate host factors that contribute to TS33 infectivity, many of which are critical to the integrity of bacterial O-antigen. Notably, disruption of these genes results in decreased susceptibility to infection by phage TS33, while simultaneously exhibiting a significant negative effect on the fitness of Hafnia in the presence of the fungi. Therefore, O-antigen mutations may have pleiotropic effects on the interactions between Hafnia and the rest of the Brie community. Ongoing and future studies aim to unearth the molecular mechanisms by which the O-antigen of Hafnia mediates its interactions with its viral and fungal partners. | Make paid
Background Neurocognitive aging and the associated brain diseases impose a major social and economic burden. Therefore, substantial efforts have been put into revealing the lifestyle, neurobiological and genetic underpinnings of healthy neurocognitive aging. However, these studies take place almost exclusively in a limited number of highly-developed countries. Thus, it is an important open question to what extent their findings may generalize to neurocognitive aging in other, not yet investigated regions. Purpose The purpose of the Hungarian Longitudinal Study of Healthy Brain Aging (HuBA) is to collect multi-modal longitudinal data on healthy neurocognitive aging to address the data gap in this field in Central and Eastern Europe. Methods We adapted the Australian Imaging, Biomarkers and Lifestyle (AIBL) study of aging study protocol to local circumstances and will collect demographic, lifestyle, mental and physical health, medication and medical history related information as well as record a series of magnetic resonance imaging (MRI) data. In addition, participants will also be offered to participate in the collection of blood samples to assess circulating inflammatory biomarkers as well as a sleep study aimed at evaluating the general sleep quality based on multi-day collection of subjective sleep questionnaires and whole-night electroencephalographic (EEG) data. Results & Discussion Data collection will be longitudinal with 18 months between measurements and at least three sessions are intended. The collected data might reveal specific local trends or could also indicate the generalizability of previous findings. Moreover, as the HuBA protocol also offers a sleep study designed for thorough characterization of participants' sleep quality and related factors, our extended multi-modal dataset might provide a base for incorporating these measures into healthy and clinical aging research. Conclusion Besides its straightforward national benefits in terms of health expenditure, we hope that this Hungarian initiative could provide results valid for the whole Central and Eastern European region and could also promote aging and Alzheimer's disease research in these countries. | Make paid
Leisure activities during childhood are vital to quality of life and wellbeing, however parents report poor quality of life and infrequent leisure participation for children with complex disabilities. Sparkle, a charity in South Wales, delivers specialist leisure activities aimed at providing children with disabilities with access to the same opportunities as any other child. We explored the impact of this provision on psychosocial domains of quality of life for children with complex disabilities. Multi-source qualitative case studies including interviews and observations were conducted with: four children/young people - aged 8-15 years with diagnoses including autism, Down syndrome and cerebral palsy - accessing Sparkle leisure activities; their parents/carers and leisure staff supporting them. Data were analysed using coding reliability thematic analysis. Three themes were generated: self-development, friendship and social interaction, and self and family wellbeing. An overarching theme of the need for a specialist provision enabled the other themes linked to positive outcomes for the children. We concluded that a specialist provision contributes to positive psychosocial outcomes linked to leisure participation for children with complex disabilities. Limitations, future research and implications for policy and practice are discussed. | Make paid
Cellular senescence is a phenomenon marked by an irreversible growth arrest with altered physiological properties. Many studies have focused on the characteristics of cells that have already entered a senescent state. However, to elucidate the mechanisms of cellular aging, it is essential to investigate the gradual transition of proliferative cells into senescent cells. We assumed that cellular senescence is a complex and multi-step process, and each stage exhibits unique traits. To test this hypothesis, we utilized publicly available single-cell RNA-Seq (scRNA-Seq) data from human umbilical vein endothelial cells (HUVECs) undergoing replicative senescence. We employed Seurat and Monocle 3 to capture the transition from proliferating to senescent states in HUVECs. Four clusters were identified, and each cluster displayed distinct expression patterns of cellular senescence markers and the senescence-associated secretory phenotypes (SASPs). We also employed SCENIC to identify the expression patterns of core transcription factors (TFs) during replicative senescence. While the majority of TFs exhibited a linear trend, HMGB1, FOSL1, SMC3, RAD21, SOX4, and XBP1 showed fluctuating expression patterns during replicative senescence. Furthermore, the expression patterns of these TFs exhibited slight differences in the ionizing radiation (IR) model of senescence. Overall, our study unveils the distinct characteristics of each phase during replicative senescence and identifies expression trends in TFs that may play pivotal roles in this process. These findings highlight the intricate nature of cellular senescence and provide new insights into the process of cellular aging. | Make paid
Sex and gender are associated with human behavior throughout the lifespan and across health and disease, but whether they are associated with similar or distinct neural phenotypes is unknown. Here, we demonstrate that, in children, sex and gender are uniquely reflected in the intrinsic functional connectivity of the brain. Unimodal networks are more strongly associated with sex while heteromodal networks are more strongly associated with gender. These results suggest sex and gender are irreducible to one another not only in society but also in biology. | Make paid