INTRODUCTION: In South America, heart failure poses a substantial concern due to its widespread occurrence and insufficient data accuracy. Metabolic syndrome, a risk factor for heart disease and diabetes, is the focal point of the study, which seeks to examine its correlation with left ventricular diastolic function (LVDF) and indications of heart failure in adults within a South American hospital. MATERIALS AND METHODS: A cross-sectional study with 2380 adults aged 65-79 in a South American hospital reveals connections between metabolic syndrome (MetS) and heart health. Using ATP-III criteria, MetS was identified, and cardiac function was assessed by echocardiography. Significant associations between MetS and various cardiac indicators were found. RESULTS: Metabolic Syndrome (MetS) affected 33.1% of the sample, showing health differences and cardiac alterations, including ejection fraction changes. Associations with diastolic dysfunction criteria and complex relationships between natriuretic peptides and ventricular filling pressure were observed. CONCLUSIONS:Metabolic syndrome links to significant changes in diastolic function and left ventricular structure, but not with alterations in the left atrium. Nevertheless, individuals with Metabolic Syndrome are more prone to receiving a diagnosis of chronic heart failure. Further extensive studies in diverse populations are advised. | Make paid
Objective: To compare the NHS Health Check Programme with the Polypill Prevention Programme in the primary prevention of heart attacks and strokes. Design: Use of published data and methodology to produce flow charts of the two programmes to determine screening performance and heart attacks and strokes prevented. Setting: The UK population. Intervention: The NHS Health Check Programme using a QRisk score on people aged 40-74 to select those eligible for a statin is compared with the Polypill Prevention programme in people aged 50 or more to select people for a combination of a statin and 3 low dose blood pressure lowering agents. In both programmes people had no history of heart attack or stroke. Main outcome measures: In 1000 people the number of heart attacks and strokes prevented in the two programmes. Results: Assuming 100% uptake and adherence to the screening protocol, in every 1000 persons, the NHS Health Check Programme would prevent 287 cases of a heart attack or stroke in individuals who would gain on average about 4 years of life without a heart attack or stroke, the precise gain depending on the extent of treatment for those with raised blood pressure, and 136 would be prescribed statins with no benefit. The corresponding figures for the Polypill Prevention Programme are 316 individuals who would, on average, gain 8 years of life without a heart attack or stroke with 260 prescribed the polypill with no benefit. Based on published estimates of uptake and adherence to of the NHS Health Check programme, only 24 cases per 1000 are currently benefitting instead of 287. This result could be achieved in the Polypill Prevention Programme with just 8% (24/316) of the eligible population taking part. Conclusions: The Polypill Prevention Programme is by design simpler with the potential of preventing many more heart attacks and strokes; even an uptake of 40% would represent a 5-fold greater preventive effect than the NHS Health Check Programme. | Make paid
Any listening task, from sound recognition to sound-based communication, rests on auditory memory which is known to decline in healthy ageing. However, how this decline maps onto multiple components and stages of auditory memory remains poorly characterised. In an online unsupervised longitudinal study, we tested ageing effects on implicit auditory memory for rapid tone patterns. The test required participants (younger, aged 20-30, and older adults aged 60-70) to quickly respond to rapid regularly repeating patterns emerging from random sequences. Patterns were novel in most trials (REGn), but unbeknownst to the participants, a few distinct patterns reoccurred identically throughout the sessions (REGr). After correcting for processing speed, the response times (RT) to REGn should reflect the information held in echoic and short-term memory before detecting the pattern; long-term memory formation and retention should be reflected by the RT advantage (RTA) to REGr vs REGn which is expected to grow with exposure. Older participants were slower than younger adults in detecting REGn and exhibited a smaller RTA to REGr. Computational simulations using a model of auditory sequence memory indicated that these effects reflect age-related limitations both in early and long-term memory stages. In contrast to ageing-related accelerated forgetting of verbal material, here older adults maintained stable memory traces for REGr patterns up to 6 months after the first exposure. The results demonstrate that ageing is associated with reduced short-term memory and long-term memory formation for tone patterns, but not with forgetting, even over surprisingly long timescales. | Make paid
The brain's biological age has been considered as a promising candidate for a neurologically significant biomarker. However, recent results based on longitudinal magnetic resonance imaging data have raised questions on its interpretation. A central question is whether an increased biological age of the brain is indicative of brain pathology and if changes in brain age correlate with diagnosed pathology (state hypothesis). Alternatively, could the discrepancy in brain age be a stable characteristic unique to each individual (trait hypothesis)? To address this question, we present a comprehensive study on brain aging based on clinical EEG, which is complementary to previous MRI-based investigations. We apply a state-of-the-art Temporal Convolutional Network (TCN) to the task of age regression. We train on recordings of the Temple University Hospital EEG Corpus (TUEG) explicitly labeled as non-pathological and evaluate on recordings of subjects with non-pathological as well as pathological recordings, both with examinations at a single point in time and repeated examinations over time. Therefore, we created four novel subsets of TUEG that include subjects with multiple recordings: I) all labeled non-pathological; II) all labeled pathological; III) at least one recording labeled non-pathological followed by at least one recording labeled pathological; IV) similar to III) but with opposing transition (first pathological then non-pathological). The results show that our TCN reaches state-of-the-art performance in age decoding with a mean absolute error of 6.6 years. Our extensive analyses demonstrate that the model significantly underestimates the age of non-pathological and pathological subjects (-1 and -5 years, paired t-test, p <= 0.18 and p <= 0.0066). Furthermore, the brain age gap biomarker is not indicative of pathological EEG. | Make paid
Introduction: The genetic determinants of fractional exhalation of nitric oxide (FeNO), a marker of lung inflammation, are understudied in Black individuals. Alpha globin (HBA) restricts nitric oxide signaling in arterial endothelial cells via interactions with nitric oxide synthase (NOS); however, its role in regulating the release of NO from respiratory epithelium is less well understood. We hypothesized that an HBA gene deletion, common among Black individuals, would be associated with higher FeNO. Methods: Healthy Black individuals aged 18-40 years were enrolled in a cross-sectional cohort study at four sites in North Carolina from 2005-2008. FeNO was measured in triplicate using a nitric oxide analyzer. The -3.7 kb HBA gene deletion was genotyped using droplet digital PCR on genomic DNA. After accounting for consent for genetic research and data availability, (n=643) individuals were included. The association of HBA genotype with FeNO was evaluated using multivariable linear regression employing a linear effect of HBA copy number, adjusting for age, sex, and total serum IgE levels. A post-hoc analysis was performed with a recessive mode of inheritance and the homozygous deletion genotype (-a/-a) was compared against all other genotypes (-a/aa, aa/aa, and aa/aaa). Results: 895 individuals were in enrolled in the study and 720 consented for future genetic research; 643 had complete data and were included in this analysis. Median (25th, 75th) FeNO was 20 (13, 31) ppb. HBA genotypes were: 30 (4.7%) -a/-a, 197 (30.6%) -a/aa, 405 (63%) aa/aa, and 8 (1.2%) aa/aaa. Subjects were 35% male with median age 20 (19, 22) years. In multivariable linear regression employing a linear effect of HBA copy number on FeNO with adjustment for age, sex, and total serum IgE levels, we found no significant relationship between HBA copy number and FeNO (-0.005 [95% CI: -0.042, 0.033], p=0.81). In a post-hoc sensitivity analysis, we found a significant association when HBA copy number was analyzed using a recessive mode of inheritance (0.107 [95% CI 0.003, 0.212]; p = 0.045) Conclusion: We found no association between HBA copy number and FeNO using a prespecified additive genetic model. However, a post hoc recessive genetic model found FeNO to be higher among subjects homozygous for the HBA deletion. Homozygosity for a common HBA gene deletion appears to be associated with higher fractional exhalation of nitric oxide among healthy Black adults. | Make paid
Wolbachia bacteria of arthropods are at the forefront of basic and translational research on multipartite host-symbiont-pathogen interactions. These microbes are vertically inherited from mother to offspring via the cytoplasm. They are the most widespread endosymbionts on the planet due to their infamous ability to manipulate the reproduction of their hosts to spread themselves in a population, and to provide a variety of fitness benefits to their hosts. Importantly, some strains of Wolbachia can inhibit viral pathogenesis within and between arthropod hosts. Mosquitoes carrying the wMel Wolbachia strain of Drosophila melanogaster have a greatly reduced capacity to spread viruses like dengue and Zika to humans. Therefore, Wolbachia are the basis of several global vector control initiatives. While significant research efforts have focused on viruses, relatively little attention has been given to Wolbachia-fungal interactions despite the ubiquity of fungal entomopathogens in nature. Here, we demonstrate that Wolbachia increase the longevity of their Drosophila melanogaster hosts when challenged with a spectrum of yeast and filamentous fungal pathogens. We find that this pattern can vary based on host genotype, sex, and fungal species. Further, Wolbachia correlates with higher fertility and reduced pathogen titers during initial fungal infection, indicating a significant fitness benefit. This study demonstrates the role of Wolbachia in diverse fungal pathogen interactions and determines that the phenotype is broad, but with several variables that influence both the presence and strength of the phenotype. These results enhance our knowledge of the strategies Wolbachia uses that likely contribute to such a high global symbiont prevalence. | Make paid
MicroRNAs (miRNAs) are a class of regulatory non-coding RNAs that finetune cellular functions by modulating the stability and abundance of their target mRNAs, thereby contributing to regulation of tissue homeostasis. MiRNA genes are transcribed similarly to protein-coding genes and recent studies have enabled their annotation and quantification genome-wide from bulk nascent transcriptomes. Here, we developed an approach to quantify and integrate miRNA gene signatures into single-cell studies. To characterize miRNA gene expression dynamics, we first compared the suitability of droplet and plate-based single-cell RNA-sequencing (scRNA-seq) platforms using the matched datasets provided by the Tabula Muris Senis and Tabula Sapiens consortiums. We found high concordance between the platforms and with cell type-specific bulk expression data. Based on the comprehensive aging profiles, our analysis comparing spleen immune cells between young and old mice revealed a concordant regulation of miRNAs involved in senescence and inflammatory pathways in multiple immune cell types, including up-regulation of mmu-mir-146a, mmu-mir-101a and mmu-mir-30 family genes. To study the aberrant regulation of immune cell homeostasis and tissue inflammation that pre-dispose to aging-related disease development, we collected transcriptome profiles from atherosclerosis development in LDLR-/-ApoB100/100 mice. We found an elevated myeloid cell proportion in the adipose tissue and further characterized the cell subtypes based on reproducible transcriptome clusters. We then compared miRNA gene expression in early versus late disease and upon inflammatory challenge to monitor different stages during disease progression. At atherosclerotic stage, pro-inflammatory mmu-mir-511 expression increased in several macrophage subtypes, while immunosuppressive mmu-mir-23b~mir-24-2~mir-27b up-regulation was specific to Trem2+ lipid-associated macrophages. The infiltrating monocytes up-regulated mmu-mir-1938 and mmu-mir-22 expression and in classical monocytes maturation further increased mmu-mir-221~222, mmu-mir-511 and mmu-mir-155 expression. To validate that these changes detected from single cell profiles represent miRNA gene transcriptional regulation, we used nascent transcriptomics data from ex vivo macrophage cultures with pro-inflammatory stimulation, confirming both rapid and long-lasting transcriptional activation of the miRNA loci studied. Collectively, our work enables integrating miRNA gene analysis to current single cell genomics pipelines and facilitates characterization of miRNA regulatory networks during aging and disease development. | Make paid
Calcium signaling plays a crucial role in various physiological processes, including muscle contraction, cell division, and neurotransmitter release. Dysregulation of calcium levels and signaling has been linked to a range of pathological conditions such as neurodegenerative disorders, cardiovascular disease, and cancer. Here, we suggest that in the endothelium, calcium ion channel activity and calcium signaling can be modulated by applying either a time-varying or static gradient MF. This modulation is achieved by exerting magnetic forces or torques on either biogenic or non-biogenic magnetic nanoparticles that are bound to endothelial cell membranes. Since calcium signaling in endothelial cells induces neuromodulation and impacts blood flow control, the application of a MF shows promise for controlling neurovascular coupling and treating vascular dysfunctions associated with aging and neurodegenerative disorders. Additionally, this approach can enable control over the process of Ca signal decoding, ultimately impacting protein synthesis. The ability to modulate calcium wave frequencies using MFs and the MF-controlled decoding of Ca signaling present promising avenues for treating diseases characterized by calcium dysregulation. Our findings on the magnetic control of calcium signaling may serve as a universal mechanism for influencing living cells, as it is present across all organisms, irrespective of their kingdoms. | Make paid
Neurodegenerative diseases (ND) are characterized by progressive loss of neuronal function. Mechanisms of ND pathogenesis are incompletely understood, hampering the development of effective therapies. Langerhans cell histiocytosis (LCH) is an inflammatory neoplastic disorder caused by hematopoietic progenitors expressing MAPK activating mutations that differentiate into senescent myeloid cells that drive lesion formation. Some patients with LCH subsequently develop progressive and incurable neurodegeneration (LCH-ND). Here, we show that LCH-ND is caused by myeloid cells that are clonal with peripheral LCH cells. We discovered that circulating BRAFV600E+ myeloid cells cause the breakdown of the blood-brain barrier (BBB), enhancing migration into the brain parenchyma where they differentiate into senescent, inflammatory CD11a+ macrophages that accumulate in the brainstem and cerebellum. Blocking MAPK activity and senescence programs reduced parenchymal infiltration, neuroinflammation, neuronal damage and improved neurological outcome in preclinical LCH-ND. MAPK activation and senescence programs in circulating myeloid cells represent novel and targetable mechanisms of ND. | Make paid
Age and disuse-related bone loss both result in decreases in bone mineral density, cortical thickness, and trabecular thickness and connectivity. Disuse induces physiological changes in bone like those seen with aging. Bone microarchitecture and biomechanical properties were compared between 6- and 22-month-old C57BL/6J male control mice and 6-month-old mice that were hindlimb unloaded (HLU) for 3 weeks. Epiphyseal trabecular bone was the compartment most affected by HLU and demonstrated an intermediate bone phenotype between age-matched controls and aged controls. RNA extracted from whole-bone marrow-flushed tibiae was sequenced and analyzed. Differential gene expression analysis additionally included 4-month-old male mice unloaded for 3 weeks compared to age-matched controls. Gene ontology analysis demonstrated that there were age-dependent differences in differentially expressed genes. Genes related to downregulation of cellular processes were most affected in 4-month-old mice after disuse whereas those related to mitochondrial function were most affected in 6-month-old mice. Cell-cycle transition was downregulated with aging. A publicly available dataset (GSE169292) from 3-month female C57BL/6N mice unloaded for 7 days was included in ingenuity pathway analysis with the other datasets. IPA was used to identify the leading canonical pathways and upstream regulators in each HLU age group. IPA identified Senescence Pathway as the second leading canonical pathway enriched in mice exposed to HLU. HLU induced activation of the senescence pathway in 3-month and 4-month-old mice but inhibited it in 6-month-old mice. In conclusion, we demonstrate that hindlimb unloading and aging initiate similar changes in bone microarchitecture and gene expression. However, aging is responsible for more significant transcriptome and tissue-level changes compared to hindlimb unloading. | Make paid
Myeloid cell metabolic reprogramming is a hallmark of inflammatory disease, however, its role in inflammation-induced hypercoagulability is poorly understood. Using novel myeloid cell-based global haemostasis assays and murine models of immunometabolic disease, we evaluated the role of inflammation-associated metabolic reprogramming in regulating blood coagulation. Glycolysis was essential for enhanced activated myeloid cell tissue factor expression and decryption, driving increased cell-dependent thrombin generation in response to inflammatory challenge. Similarly, inhibition of glycolysis enhanced activated macrophage fibrinolytic activity via reduced plasminogen activator inhibitor 1 (PAI-1)-activity. Macrophage polarisation or activation markedly increased endothelial protein C receptor (EPCR) expression on monocytes and macrophages, leading to increased myeloid cell-dependent protein C activation. Importantly, inflammation-dependent EPCR expression on tissue-resident macrophages was also observed in vivo. Adipose tissue macrophages from obese mice fed a high-fat diet exhibited significantly enhanced EPCR expression and APC generation compared to macrophages isolated from the adipose tissue of healthy mice. Similarly, the induction of colitis in mice prompted infiltration of EPCR+ innate myeloid cells within inflamed colonic tissue that were absent from the intestinal tissue of healthy mice. Collectively, this study identifies immunometabolic regulation of myeloid cell hypercoagulability, opening new therapeutic possibilities for targeted mitigation of thrombo-inflammatory disease. | Make paid
Background: Despite its approval for use in acute ischemic stroke(AIS) >25 years ago, intravenous thrombolysis(IVT) remains underutilized, with inequities by age, sex, race/ethnicity, and geography. Little is known about IVT rates by insurance status. We aimed to assess temporal trends in the inequities in IVT use. Methods: We assessed trends from 2002-2015 in IVT for AIS in the Nationwide Inpatient Sample by sex, age, race/ethnicity, hospital location/teaching status, and insurance, using survey-weighted logistic regression, adjusting for sociodemographics, comorbidities, and hospital characteristics. We calculated odds ratios for IVT for each category in 2002-2008 (Period 1) and 2009-2015 (Period 2). Results: Among AIS patients (weighted N=6,694,081), IVT increased from 1.0% in 2002 to 6.8% in 2015 (adjusted annual relative ratio (AARR)=1.15, 95% CI 1.14-1.16). Individuals ?85 years had the most pronounced increase in 2002-2015 (AARR=1.18, 1.17-1.19), but were less likely to receive IVT compared to those aged 18-44 years in both Period 1 (adjusted odds ratio(aOR)=0.23, 0.21-0.26) and Period 2 (aOR=0.36, 0.34-0.38). Women were less likely than men to receive IVT, but the disparity narrowed over time (Period 1 aOR=0.81,0.78-0.84, Period 2 aOR=0.94,0.92-0.97). Inequities in IVT by race/ethnicity resolved for Hispanic individuals in Period 2 but not for Black individuals (Period 2 aOR=0.81, 0.78-0.85). The disparity in IVT for Medicare patients, compared to privately insured patients, lessened over time (Period 1 aOR=0.59,0.56-0.52, Period 2 aOR=0.75,0.72-0.77). Patients treated in rural hospitals were less likely to receive IVT than those treated in urban hospitals; a more dramatic increase in urban areas widened the inequity (Period 2 urban non-teaching vs. rural aOR=2.58, 2.33-2.85, urban teaching vs. rural aOR=3.90, 3.55-4.28). Conclusion: From 2002 through 2015, IVT for AIS increased among adults. Despite encouraging trends, only 1 in 15 AIS patients received IVT and persistent inequities remained for Black individuals, women, government-insured, and those treated in rural areas, highlighting the need for intensified efforts at addressing inequities. | Make paid
Objectives: To assess the potential clinical impact and cost-effectiveness of coronavirus disease 2019 (COVID-19) mRNA vaccines updated for Autumn 2023 in adults aged [≥]60 years and high-risk persons aged 30-59 years in Germany over a 1-year analytic time horizon (September 2023--August 2024). Methods: A compartmental Susceptible-Exposed-Infected-Recovered model was updated and adapted to the German market. Numbers of symptomatic infections, number of COVID-19 related hospitalisations and deaths, costs, and quality-adjusted life-years (QALYs) gained were calculated using a decision tree model. The incremental cost-effectiveness ratio of an Autumn 2023 Moderna updated COVID-19 (mRNA-1273.815) vaccine was compared to no additional vaccination. Potential differences between the mRNA-1273.815 and the Autumn Pfizer-BioNTech updated COVID-19 (XBB.1.5 BNT162b2) vaccines, as well as societal return on investment for the mRNA-1273.815 vaccine relative to no vaccination, were also examined. Results: Compared to no Autumn vaccination, the mRNA-1273.815 campaign is predicted to prevent approximately 1,697,900 symptomatic infections, 85,400 hospitalisations, and 4,100 deaths. Compared to an XBB.1.5 BNT162b2 campaign, the mRNA-1273.815 campaign is also predicted to prevent approximately 90,100 symptomatic infections, 3,500 hospitalisations, and 160 deaths. Across both analyses we found the mRNA-1273.815 campaign to be dominant. Conclusions: The mRNA-1273.815 vaccine can be considered cost-effective relative to the XBB.1.5 BNT162b2 vaccine and highly likely to provide more benefits and save costs compared to no vaccine in Germany, and to offer high societal return on investment. | Make paid
Although lifespan extension remains the gold standard for assessing interventions hypothesized to impact the biology of aging, there are important limitations to this approach. Our reanalysis of lifespan studies from multiple sources suggests that the use of short-lived control cohorts tends to exaggerate the relative efficacy of putative longevity interventions. Moreover, due to the high cost and long timeframes of mouse studies, it is rare that a particular longevity intervention will be independently replicated by multiple groups. To facilitate identification of successful interventions, we propose an alternative approach. The level of confidence we can have in an intervention is proportional to the degree of lifespan extension above the strain- and species-specific upper limit of lifespan, which we can estimate from comparison to historical controls. In the absence of independent replication, a putative mouse longevity intervention should only be considered with high confidence when control lifespans are close to 900 days or if the final lifespan of the treated group is considerably above 900 days. Using this "900-day rule" we identified several candidate interventions from the literature that merit follow-up studies. | Make paid
Single-cell RNA sequencing (scRNA-seq) has provided deeper insights into biological processes by highlighting differences at the cellular level. Within these single-cell omics measurements, researchers are often interested in identifying variations associated with a specific covariate. For instance, in aging research, it becomes vital to differentiate variations related to aging. To address this, we introduce StrastiveVI (Structured Contrastive Variational Inference; https://github.com/suinleelab/StrastiveVI), which effectively separates the variations of interest from other dominant biological signals in scRNA-seq datasets. When deployed on aging and Alzheimer's disease (AD) datasets, StrastiveVI efficiently isolates aging and AD-associated patterns, distinguishing them from dominant variations linked to sex, tissue, and cell type that are unrelated to aging or AD. In doing so, it underscores both well-known genes and potential novel genes related to aging or AD. | Make paid
Calcium signaling plays a crucial role in various physiological processes, including muscle contraction, cell division, and neurotransmitter release. Dysregulation of calcium levels and signaling has been linked to a range of pathological conditions such as neurodegenerative disorders, cardiovascular disease, and cancer. Here, we suggest that in the endothelium, calcium ion channel activity and calcium signaling can be modulated by applying either a time-varying or static gradient MF. This modulation is achieved by exerting magnetic forces or torques on either biogenic or non-biogenic magnetic nanoparticles that are bound to endothelial cell membranes. Since calcium signaling in endothelial cells induces neuromodulation and impacts blood flow control, the application of a MF shows promise for controlling neurovascular coupling and treating vascular dysfunctions associated with aging and neurodegenerative disorders. Additionally, this approach can enable control over the process of Ca signal decoding, ultimately impacting protein synthesis. The ability to modulate calcium wave frequencies using MFs and the MF-controlled decoding of Ca signaling present promising avenues for treating diseases characterized by calcium dysregulation. Our findings on the magnetic control of calcium signaling may serve as a universal mechanism for influencing living cells, as it is present across all organisms, irrespective of their kingdoms. | Make paid
Chronically high blood glucose levels (hyperglycaemia) can compromise healthy ageing and lifespan at the individual level. Elevated oxidative stress can play a central role in hyperglycaemia-induced pathologies. Nevertheless, the lifespan of birds shows no species-level association with blood glucose. This suggests that the potential pathologies of high blood glucose levels can be avoided by adaptations in oxidative physiology at the macroevolutionary scale. However, this hypothesis remains unexplored. Here, we examined this hypothesis using comparative analyses controlled for phylogeny, allometry and fecundity based on data from 51 songbird species (681 individuals with blood glucose and 1021 individuals with oxidative state data). We measured blood glucose at baseline and after stress stimulus and computed glucose stress reactivity as the magnitude of change between the two time points. We also measured three parameters of non-enzymatic antioxidants (uric acid, total antioxidants and glutathione) and a marker of oxidative lipid damage (malondialdehyde). We found no clear evidence for blood glucose concentration being correlated with either antioxidant or lipid damage levels at the macroevolutionary scale, as opposed to the hypothesis postulating that high blood glucose levels entail oxidative costs. The only exception was the moderate evidence for species with a stronger stress-induced increase in blood glucose concentration evolving moderately lower investment into antioxidant defence (uric acid and glutathione). Neither baseline nor stress-induced glucose levels were associated with oxidative physiology. Our findings support the hypothesis that birds evolved adaptations preventing the (glyc)oxidative costs of high blood glucose observed at the within-species level. Such adaptations may explain the decoupled evolution of glycaemia and lifespan in birds and possibly the paradoxical combination of long lifespan and high blood glucose levels relative to mammals. | Make paid
Overweight and obesity are associated with increased chronic disease and death rates globally. In Cambodia, the prevalence of overweight and obesity among women is high and may grow. This study aimed to determine the prevalence and factors associated with overweight and obesity among women of reproductive age (WRA) in Cambodia. We analyzed data from the 2021-2022 Cambodia Demographic and Health Survey (CDHS) that used a two-stage stratified cluster sampling design. Data analysis was restricted to non-pregnant women, resulting in an analytic sample of 9,417 WRA. Multivariable logistic regressions were performed using STATA V17 to examine factors associated with overweight and obesity. Prevalence of overweight and obesity among non-pregnant women of reproductive age was 22.56%, and 5.61% were overweight and obese, respectively. Factors independently associated with increased odds of overweight and obesity included women aged 20-29 years [AOR=1.85; 95% CI: 1.22 - 2.80], 30-39 years [AOR=3.34; 95% CI: 2.21 - 5.04], and 40-49 years [AOR=5.57; 95% CI: 3.76 - 8.25], married women [AOR=2.49; 95% CI: 1.71-3.62], women from middle wealth quintile [AOR=1.21; 95% CI: 1.02-1.44], and rich wealth quintile [AOR=1.44; 95% C: 1.19 - 1.73], having at least three children or more [AOR=1.40; 95% CI: 1.00 - 1.95], ever drink alcohol [AOR=1.24; 95% CI: 1.04 - 1.47], and current drink alcohol [AOR=1.2; 95% CI: 1.01 - 1.45]. On the contrary, the following factors were independently associated with decreased odds of having overweight and obese: women with at least secondary education [AOR=0.73; 95% CI: 0.58-0.91] and working in manual labor jobs [AOR=0.76; 95% CI: (0.64 - 0.90]. Increased age, married women, having at least three children, and alcohol consumption were the main risk factors associated with overweight and obesity. Conversely, higher education and manual labor were negatively associated with overweight and obesity. Cambodia's non-communicable disease (NCD) public health programs should consider these characteristics for targeting interventions further to reduce overweight and obesity in the coming years. | Make paid
Objective: To describe the HPV-Automated Visual Evaluation (PAVE) Study, an international, multi-centric study designed to evaluate a novel cervical screen-triage-treat strategy for resource-limited settings as part of a global strategy to reduce cervical cancer burden. The PAVE strategy involves: 1) screening with self-sampled HPV testing; 2) triage of HPV-positive participants with a combination of extended genotyping and visual evaluation of the cervix assisted by deep-learning-based automated visual evaluation (AVE); and 3) treatment with thermal ablation or excision (Large Loop Excision of the Transformation Zone). The PAVE study has two phases: efficacy (2023-2024) and effectiveness (planned to begin in 2024-2025). The efficacy phase aims to refine and validate the screen-triage portion of the protocol. The effectiveness phase will examine implementation of the PAVE strategy into clinical practice, cost-effectiveness, and health communication. Study design: Phase 1 Efficacy: Nonpregnant women, aged 25-49 years, without prior hysterectomy, are being screened at nine study sites in resource-limited settings. Eligible and consenting participants perform self-collection of vaginal specimens for HPV testing using a FLOQSwab (Copan). Swabs are transported dry and undergo testing for HPV using a newly-redesigned isothermal DNA amplification HPV test (ScreenFire), which has been designed to provide HPV genotyping by hierarchical risk groups: HPV16, else HPV18/45, else HPV31/33/35/52/58, else HPV39/51/56/59/68. HPV-negative individuals are considered negative for precancer/cancer and do not undergo further testing. HPV-positive individuals undergo pelvic examination with collection of cervical images and targeted biopsies of all acetowhite areas or endocervical sampling in the absence of visible lesions. Cervical images are used to refine a deep learning AVE algorithm that classifies images as normal, indeterminate, or precancer+. AVE classifications are validated against the histologic endpoint of high-grade precancer determined by biopsy. The combination of HPV genotype and AVE classification is used to generate a risk score that corresponds to the risk of precancer (lower, medium, high, highest). During the efficacy phase, clinicians and patients will receive HPV testing results but not AVE results or risk scores. Treatment during the efficacy phase will be performed per local standard of care: positive Visual Inspection with Acetic Acid impression, high-grade colposcopic impression or CIN2+ on colposcopic biopsy, HPV positivity, or HPV 16,18/45 positivity. The sensitivity of the PAVE strategy for detection of precancer will be compared to current SOC at a given level of specificity. Phase 2 Effectiveness: The AVE software will be downloaded to the new dedicated image analysis and thermal ablation devices (Liger Iris) into which the HPV genotype information can be entered to provide risk HPV-AVE risk scores for precancer to clinicians in real time. The effectiveness phase will examine clinician use of the PAVE strategy in practice, including feasibility and acceptability for clinicians and patients, cost-effectiveness, and health communication. Conclusion: The goal of the PAVE study is to validate a screen-triage-treat protocol using novel biomarkers to provide an accurate, feasible, cost-effective strategy for cervical cancer prevention in resource-limited settings. | Make paid
Aim This study aimed to develop a refined classification of atrial fibrillation (AF) according to comprehensive risk factors to identify patients at high-risk for poor prognosis and their life expectancy. Method A total of 7,391 participants aged 40-69 with AF at baseline, from UK Biobank, were classified into five clusters, based on seven clustering variables including age and six risk factor categories (metabolic disease, respiratory disease, cardiovascular disease, renal/immune-mediated disease, mental health disease, acute illness). Difference in the risk of death and major complications, as well as reductions in life expectancy, among clusters were estimated. Replication was done in 2,399 participants with newly diagnosed AF within two years after baseline. Results Five distinct AF clusters were identified: acute illness-related, mental health-related, cardiovascular disease-related, immune-and-renal disease-related, and respiratory-and-metabolic disease-related AF. Patients with respiratory-and-metabolic disease-related AF had the highest risk of death, acute myocardial infarction, heart failure, and cerebral ischemic stroke, while those with acute illness-related AF had the lowest corresponding risk. In addition, compared with individuals with acute illness-related AF, those with respiratory-and-metabolic disease-related and mental health-related AF had the top 2 greatest loss of life expectancy. Furthermore, genetic variants for AF had different effect among the five clusters. Replication analysis confirmed the result stability. Conclusion A novel AF classification was developed, which provided insights into varying life expectancy and risks of death and complications among AF subgroups with distinct characteristics. It offers a practical approach for identifying high-risk patients, which might help to tailor precise interventions for AF management. | Make paid
Extracellular matrix (ECM) remodeling of cardiac tissue is a key contributor to age-related cardiovascular disease and dysfunction. Aberrant secretion, structural perturbations, and degradation of specific ECM components lead to significant alterations in ECM properties that disrupt healthy cell and tissue homeostasis. These changes in ECM are multifaceted, as alterations in ligand presentation, including both biochemical and architectural aspects, are often accompanied by stiffness changes, clouding our understanding of how and which ECM properties contribute to a dysfunctional state. To identify the specific roles of these interconnected ECM cues and elucidate their mechanistic regulation in cellular function, we developed a material system that can independently present these two distinct matrix properties, i.e., ligand presentation and stiffness, to cultured cells in vitro. We describe a decellularized ECM-synthetic hydrogel hybrid scaffold that maintains native matrix composition and organization of young or aged murine cardiac tissue with independently tunable scaffold mechanics that mimic young or aged tissue stiffness. Seeding these scaffolds with primary cardiac fibroblasts (CFs) from young or aged mice, we identify distinct age- and ECM-dependent mechanisms of CF activation. Importantly, we show that ligand presentation of young ECM can outweigh profibrotic stiffness cues typically present in aged ECM in maintaining or driving CF quiescence, thereby highlighting the unique roles of ECM in aging. Ultimately, these tunable scaffolds can enable the discovery of specific ECM targets to prevent aging dysfunction and promote rejuvenation. | Make paid
Introduction: While HIV incidence declines in most age groups globally, they rise among adolescents and young adults who also experience a higher rate of HIV-related deaths. These tech-savvy individuals might benefit from an online patient portal aimed at increasing awareness, building skills, and promoting patient activation - the willingness and capacity to independently manage their health. However, the impact of such portals on young HIV patients in Kenya remains uncertain. Methods and analysis: HIV patients aged 15-24 with smartphone access will participate in a 12-month stepped wedge cluster randomized trial. The main focus will be the portal's effect on patient activation, with secondary outcomes being self-reported adherence, viral suppression, and social involvement. The study also aims to understand the portal's development, implementation, functionality, usability, and cost. From 47 antiretroviral therapy (ART) sites with electronic medical recording systems, 16 clusters of 30 participants each will be formed. These clusters, over 12 months, will be randomized into 3 intervention sequences every 3 months. Baseline measurements, covering patient activation, adherence, viral load, and social engagement, will be recorded over two weeks, with subsequent checks at 3, 6, and 12 months. Data will be analyzed using generalised linear mixed models. Ethics and dissemination: The protocol has received approval from the AMREF Health Africa Ethics & Scientific Review Committee (ESRC) and local governments. It is registered under the Pan African Clinical Trial Registry as: PACTR202303729957231. Findings will be shared through stakeholder forums, conferences, publications, and media. | Make paid
Background: The provision of long-term care for persons living with dementia (PLWD) who have functional limitations is a significant global public health challenge. However, there is limited evidence on the patterns of care received by PLWD across countries and regions. This study aimed to examine the global trends in the absence of care for PLWD with functional limitations and identify potential sociodemographic disparities. Methods: We used harmonized longitudinal survey data from four Health and Retirement Global Family of Studies that surveyed community-living persons aged 50 and older in the United States, England, 18 European countries and Israel, and China. The analysis focused on persons who reported functional limitations and developed dementia during the study periods (2012-2018). Functional limitations were assessed using activities of daily living (ADL) and instrumental activities of daily living (IADL). Absence of care was evaluated as the proportion of PLWD receiving no care for their ADL/IADL limitations. Results: At least 20% of PLWD in both developed and developing countries received no care for their functional limitations, and this absence of care remained stable over time. The absence of care was notable for both ADL and IADL limitations, as well as for informal and formal care. Moreover, substantial disparities were observed, with less-educated individuals and those living alone experiencing greater absence of formal and informal care, respectively. These patterns and trends were consistent across all countries and regions studied. Discussion and Implications: The findings underscore the pressing need to ensure basic care provision for persons with dementia and functional limitations, especially for those who are less educated or living alone. Policymakers should prioritize addressing these disparities and improving care provision for this population worldwide. | Make paid
IMPORTANCE People with cognitive impairment often have complex care needs. Both healthcare and long-term care are crucial to the well-being of people with mild cognitive impairment (MCI) or dementia. OBJECTIVE To understand the clustering patterns of healthcare and long-term care use in people with MCI or dementia and the relationships between changes in cognitive functioning and transitions of care. DESIGN This cohort study used longitudinal data from three recent waves of the Health and Retirement Study (HRS) collected between 2014 and 2018. SETTING HRS is a nationally representative biennial survey of older persons aged 50 years and over in the US. PARTICIPANTS The study cohort included 4,469 people with MCI or dementia in 2014. The same participants were followed until 2018. The total sample size across the three waves was 10,155. EXPOSURE Changes in cognitive functioning based on the Langa-Weir Classifications. MAIN OUTCOMES AND MEASURES The outcome measures included five types of healthcare and three types of long-term care services. Latent transition analyses were conducted to identify the clustering patterns of healthcare and long-term care use and map out the transition pathways between different care classes over time. Multilevel regression models were estimated to investigate the relationships between changes in cognitive functioning status and care transitions. Sociodemographic, health, and socioeconomic factors before care transitions were controlled for. RESULTS Three user groups were identified: high healthcare and low long-term care (MM-LC, 56%, n=5,657), medium healthcare and high long-term care (HM-HC, 37%, n=3,743), and low healthcare and low long-term care (LM-LC, 7%, n=736). The progression of cognitive impairment was associated with a higher probability of transitioning from MM-LC to HM-HC class ({beta}= 0.070; p<0.001). An improvement in cognitive functioning was associated with a higher probability of transitioning from HM-HC to MM-LC class ({beta} =0.042, p<0.05). CONCLUSION People with MCI or dementia use specific combinations of services to meet their complex care needs, which underscores the importance of integration between healthcare and long-term care. Changes in cognitive functioning are useful indicators that can assist policymakers and practitioners with early care planning, resource allocation, and care coordination from diverse care providers. | Make paid
The contribution of genotypes to the shared and disparate clinical and pathologic features observed across TDP-43 proteinopathies is unclear. TDP-43 pathology can contribute to very different neurodegenerative conditions, including frontotemporal lobar degeneration with TDP-43 (FTLD-TDP), amyotrophic lateral sclerosis (ALS), and hippocampal sclerosis of aging (HS-Aging). Despite mounting evidence for shared genetic risk across these TDP-43 proteinopathies, the drivers of individual-level presentations of these syndromes are unknown. We identified data-driven modules of correlated single nucleotide polymorphisms using GWAS summary statistics. These genomic features were either phenotype specific or shared across TDP-43 proteinopathy phenotypes and may contribute to phenotypic heterogeneity in these cases. Pathway analysis revealed biologically meaningful associations within the identified modules, including common nervous system processes and distinct, phenotype-specific associations. We derived module-specific polygenic scores and hypothesized that they would contribute to individual-level differences in the clinical presentation and corresponding anatomic distribution of pathology. Within characteristic FTLD-TDP brain regions, higher FTLD-TDP polygenic risk associated with higher TDP-43 burden. Further, module-specific ALS and FTLD-TDP polygenic risk associated with clinical phenotypic heterogeneity, even within the context of autosomal dominant mutation carriers. We suggest that genotypic variation across TDP-43 proteinopathies may contribute to individual-level presentations of these syndromes. | Make paid
Aging is associated with changes in the oscillatory (periodic) brain activity in the alpha band (8-12 Hz), as measured with resting-state EEG (rsEEG), and it is characterized by significantly lower alpha frequency and power. Aging can influence the aperiodic component of the power spectrum: at a higher age, the slope flattens, and it may show a significant relationship with cognitive performance. However, it is unclear whether education, a cognitive reserve proxy known for its modulatory role on cognition, may influences such relationship. N=179 healthy participants from the LEMON dataset (Babayan et al., 2019) were classified into three groups based on age and education: young adults (N=123) 20-35 years old with high education, older adults 60-77 years old with high (N=24) and low (N=32) education. Eyes-closed rsEEG power spectrum was decomposed at the occipital level with specparam method. Individual Alpha Peak Frequency, exponent, and offset were analyzed in their relationship with cognitive abilities. Results show lower IAPF, exponent, and offset in older as compared to younger adults. Furthermore, visual attention and working memory were differently predicted by the aperiodic rsEEG component depending on educational levels: in older adults with higher education, increasing exponent predicted slower processing speed and less working memory capacity, with an opposite trend in those with lower education. Although further investigations are necessary, this study shows a potential modulatory role of education and other cognitive reserve proxies in the relationship between aperiodic rsEEG and cognition in aging. | Make paid
Many studies have demonstrated unique trajectories of deep gray matter (GM) volumes over development and aging, suggesting but not measuring microstructural alterations over the lifespan. Only a few studies have measured diffusion tensor imaging (DTI) parameters in deep GM or reported these values across a wide age range in a large cohort. To enable efficient DTI studies of deep GM in large cohorts without the need of T1-weighted images, an automated segmentation technique is proposed here that works solely on parametric maps calculated from DTI. The algorithm segments the globus pallidus, striatum, thalamus, hippocampus and amygdala per hemisphere by deforming 3D models of these structures to their boundaries visible on the contrast provided by diffusion tensor maps and images alone. This new DTI-only method is compared against standard T1-weighted image segmentation for (i) 1.25 mm isotropic diffusion data from the Human Connectome Project (HCP) test-retest cohort (n=44) and (ii) 1.5 mm isotropic test-retest diffusion data from a local normative study (n=24). Dice coefficients of voxel overlap between methods in the HCP test-retest cohort were high (>0.7) for 7 of 10 structures, but were low for the left globus pallidus (0.54) and left/right amygdala (0.67, 0.69). The proposed DTI-only segmentation qualitatively appeared more accurate and yielded smaller volumes than T1w for 8/10 structures in both cohorts, with the exception of the globus pallidus which showed larger volumes in the HCP test-retest data but lower volumes in the local normative study data. The DTI-only segmentation method was then applied to two local single site development/aging lifespan cohorts (cohort 1: n=365 5-90 years, cohort 2: n= 164 5-74 years) to assess age changes in volume, fractional anisotropy (FA) and mean diffusivity (MD). In both cohorts, MD trajectories were quadratic for all five structures, decreasing slightly and then increasing after ~30-35 years. In cohort #1, FA trajectories remained flat from 5 to ~25 years and then started to decrease for the globus pallidus and hippocampus and over 5 to 90 years, FA decreased linearly for amygdala, increased linearly for striatum, and remained constant for the thalamus. In the second cohort, using an alternate acquisition protocol, the FA trajectories of all 5 structures across all ages were similar, except for the globus pallidus and thalamus which both increased in value from 5 ~ 20 years and likely reflect differences in acquisition details. Notably, the development and aging trajectories for DTI were distinct from those of the deep GM volumes. The proposed automated deep GM segmentation method on DTI-only will facilitate the analysis of deep GM DTI (currently ignored in nearly all studies despite the data there within the field-of-view) and will be advantageous particularly for studies that do not have a T1-weighted scan, as in many clinical populations. | Make paid
The exact mechanisms through which the APOE gene influences Alzheimers disease risk (AD) are under intense investigation. Yet, much remains unknown about how APOE alleles interact with age, sex, and diet to confer vulnerability to select brain networks. To address this question, we used mouse models that carry the three major human APOE alleles, and have a mouse like, or humanized innate immune system. This was realized through the replacement of the mouse with the human inducible nitric oxide synthase (iNOS) gene, leading to a lower immune response. Our study combines advanced, accelerated diffusion imaging methods with novel statistical analyses to reveal global and local brain graph differences, associated with each of the following risk factors for abnormal aging and AD: age, APOE genotype, sex, diet, innate immune response. We used a sparse logistic regression model (GraphClass) with complimentary pairs stability selection to identify small and robust subnetworks predictive of individual risk factors. The comparison of APOE3 versus APOE4 carriage identified 773 edges, with no more than 40 false selections; age resulted in 300 high selection probability edges with <5 false selections, sex resulted in 540 high selection probability edges with <7 false selections; diet in 1626 high selection probability edges with <31 false selections; and humanizing NOS in 411 edges with <9 false selections. Our results revealed widespread network differences due to age and diet, including the temporal association cortex, and also regions involved in response to threatening stimuli, such as the amygdala and periaqueductal gray. Sex associated differences affected regions such as the thalamus, insula and hypothalamus, but also fimbria and septum, involved in memory processes. APOE genotype was associated with differences in the connectivity of memory related areas, and also in sensory and motor areas; while diet and innate immunity (HN) were associated with differences in insula and hypothalamus connectivity. We pooled these models to identify common networks across multiple traits, giving insight into shared vulnerability amongst the risk factors. We identified 63 edges out of the total 54,946 edges (0.11% of the connectome) as common to all risk factors tested. Our results revealed common subnetworks vulnerable to several risk factors for AD, in an approach that can provide new biomarkers, and targets for therapies. | Make paid
Replicative senescence is triggered when telomeres reach critically short length and activate permanent DNA damage checkpoint-dependent cell cycle arrest. Mitochondrial dysfunction and increase in oxidative stress are both features of replicative senescence in mammalian cells. Here, we show that reactive oxygen species (ROS) levels increase in the telomerase-negative cells of Saccharomyces cerevisiae during replicative senescence, and that this coincides with the activation of Hog1, a mammalian p38 mitogen-activated protein kinase (MAPK) ortholog. Hog1 activation is dependent on Pbs2, the MAPK kinase (MAPKK) in its canonical pathway, and counteracts increased ROS levels during replicative senescence. While Hog1 deletion accelerates replicative senescence, we found this could stem from decreased telomere length and reduced cell viability prior to telomerase inactivation. ROS levels also increase upon telomerase inactivation when Mec1, the yeast ortholog of ATR, is mutated, suggesting that oxidative stress is not simply a consequence of DNA damage checkpoint activation in budding yeast. We speculate that oxidative stress is a conserved hallmark of telomerase-negative eukaryote cells, and that its sources and consequences can be dissected in S. cerevisiae. | Make paid
The enormous medical burden of stroke is not only due to the brain injury itself and the acute systemic effects, but is largely determined by chronic comorbidities that develop secondarily after stroke. We hypothesized that the high rate of comorbidity developing after a stroke might have a shared immunological cause, however, the chronic effects of brain injury on systemic immunity have so far been barely investigated. Here, we identified myeloid innate immune memory as a cause of remote organ dysfunction after stroke. Using single-cell sequencing, we identified persistent pro-inflammatory transcriptomic changes in resident monocytes/macrophages in multiple organs one month after experimental ischemic brain injury, which was particularly abundant in the heart and associated with the development of cardiac fibrosis and diastolic dysfunction. A similar phenotype was seen in myocardial autopsy samples from stroke versus control patients. We observed chronic functional changes in myeloid hematopoiesis driven by post-stroke IL-1beta-mediated epigenetic changes. These alterations could be transplanted to naive recipient mice and were sufficient to induce cardiac dysfunction. By effectively blocking the trafficking of pro-inflammatory monocytes from the bone marrow to the heart using a dual CCR2/5 inhibitor, we successfully prevented post-stroke cardiac dysfunction. This approach holds promising potential as a novel immune-targeted secondary prevention therapy. We anticipate that the epigenetic immune reprogramming mechanisms detailed here for the brain-heart axis could be generalized to provide a novel framework for explaining the development of various comorbidities after acute tissue injury in remote organs. | Make paid