Structured AbstractO_ST_ABSContextC_ST_ABSPredictive models have been used to aid early diagnosis of PCOS, though existing models are limited to fertility clinic populations. ObjectiveBuild a predictive model based on an outpatient population at risk for PCOS to facilitate earlier diagnosis and risk prediction. DesignRetrospective cohort study from a SafetyNet hospitals electronic medical records (EMR) from 2003-2016. SettingHospital outpatient clinics Patients or Other Participants30,601 women aged 18-45 years without concurrent endocrinopathy who had any visit to Boston Medical Center for primary care, obstetrics/gynecology, endocrinology, family medicine, or general internal medicine. Intervention(s)None Main Outcome Measure(s)Four prediction outcomes based on Rotterdam criteria using ICD-9 codes for PCOS, irregular menstruation, hyperandrogenism, and PCOM on ultrasound. ResultsWe developed predictive models using four machine learning methods: logistic regression, supported vector machine, gradient boosted trees, and random forests. Hormone values (FSH, LH, estradiol, and SHBG) were combined to create a multilayer perceptron score using a neural network classifier. Prediction of PCOS prior to clinical diagnosis in an out-of-sample test set of patients achieved AUC of 85%, 81%, 80%, 82%, respectively in Models I, II, III and IV. Significant positive predictors of PCOS diagnosis across models included hormone levels and obesity; negative predictors included gravidity and positive bHCG. ConclusionsAmong an at-risk population, machine learning algorithms were used to predict PCOS. This approach may guide early detection of PCOS within EMR-interfaced populations to facilitate counseling and interventions that may reduce long-term health consequences, however, additional studies including an entire health system patient population are necessary for model validation. | Make paid
Alzheimers Disease (AD) and other age-related diseases are increasingly among the most devastating strains on public health systems as the population ages, yet few treatments produce clinically significant protection. Although it is widely agreed that proteotoxicity drives impairments in AD and other neurological diseases, many preclinical and case-report studies indicate that increased microglial production of pro-inflammatory cytokines such as TNF-a also drive AD and other neurological conditions. The critical importance of inflammation, especially TNF-a, in driving age-related diseases is indicated by the fact that Humira, simply a monoclonal antibody to TNF-a, has become the top-selling drug in history, even though it does not cross the blood-brain barrier. Since target-based strategies to discover drugs to treat these diseases have largely failed, we developed parallel high-throughput phenotypic screens to discover small molecules which inhibit age-related proteotoxicity in a C. elegans model of AD, AND microglia inflammation (LPS-induced TNF-a). In the initial screen of 2560 compounds to delay Abeta proteotoxicity in C. elegans, the most protective compounds were, in order, phenylbutyrate (HDAC inhibitor), methicillin (beta lactam antibiotic), and quetiapine (tricyclic antipsychotic). These classes of compounds are already robustly implicated as potentially protective in AD and other neurodegenerative diseases. In addition to quetiapine, several other tricyclic antipsychotic drugs also delayed age-related Abeta proteotoxicity and microglial TNF-a. Based on these results we carried out extensive structure-activity relationship studies, leading to the synthesis of a novel congener of quetiapine, #310, which inhibits a wide range of pro-inflammatory cytokines in mouse and human myeloid cells, and delays impairments in animal models of AD, Huntingtons, and stroke. #310 is highly concentrated in brain after oral delivery with no apparent toxicity, increases lifespan, and produces molecular responses highly similar to those produced by dietary restriction. Among these molecular responses are induction of CBP and inhibition of CtBP and CSPR1, and inhibition of glycolysis, reversing gene expression profiles and elevated glycolysis associated with AD. Several lines of investigation strongly supported that the protective effects of #310 are mediated by activating the Sigma-1 receptor, whose protective mechanisms in turn also entail inhibiting glycolysis. Reduced glycolysis has also been implicated in the generally protective effects of dietary restriction, rapamycin, reduced IFG-1 activity, and ketones during aging, suggesting that aging is driven at least in part by glycolysis. Consistent with these observations, the glycolytic inhibitor 2-DG inhibited microglial TNF-a and other markers of inflammation, delayed Abeta proteotoxicity, and increased lifespan. To our knowledge no other known molecule exhibits all these protective effects which makes #310 an attractive candidate to treat AD and other age-related diseases. Indeed it is plausible that #310 or possibly even more effective congeners could displace Humira as a widely used therapy for age-related diseases. Furthermore, these studies suggest that the efficacy of tricyclic compounds to treat psychosis and depression could be due to their anti-inflammatory effects mediated by the Sigma-1 receptor, rather than the D2 receptor, and that better drugs to treat these conditions with fewer metabolic side effects could be developed by focusing on the Sigma-1 receptor rather than the D2 receptor. These results strongly support the value of phenotypic screens to discover drugs to treat AD and other age-related diseases and to elucidate mechanisms driving those diseases. | Make paid
Background: Osteoarthritis (OA) is a degenerative disease of mostly middle-aged and elderly people that contributes a high burden of disease in China and worldwide. However, many putative risk factors associated with OA in elderly populations remain substantially unclear. Methods: In our cross-sectional study, 2177 residents of the Putuo District of Shanghai aged 40 years and above were recruited to complete a questionnaire that queried basic health information and assessed the prevalence of OA. A non-conditional and an ordinal logistic regression model was used to analyze the associations between putative risk factors and the severity of confirmed OA. Results: Among 2099 eligible participants, the average age was 65.21 years( 41.4% were male), and 551 self-reported OA [prevalence = 26.25% (24.13, 28.51)]. The prevalence of knee OA were the most common (23.11% , 21.12 to 25.23). OA was associated with age [≥] 60 years (aOR = 1.56; 1.18, 2.07), overweight BMI (24~27.9 kg/m2) (1.30; 1.02 to 1.65), female sex (1.66; 1.30 to 2.12), unmarried status (1.41; 1.03 to 1.90), a family history of OA (6.23; 4.17 to 9.38), two or more comorbidities (2.18; 1.52 to 3.11), and prior injury to any joint (12.02; 4.86 to 31.22). Conclusions: Old age, Female sex,family history and multiple comorbidities were significant contributors to promote the severity of OA. Appropriate prevention and treatment strategies must be developed to reduce the burden of the disease. | Make paid
Attentional states continuously reflect the predictability and uncertainty in one's environment having important consequences for learning and memory. Beyond well known cortical contributions, rapid shifts in attention are hypothesized to also originate from deep nuclei, such as the basal forebrain (BF) and locus coeruleus (LC) neuromodulatory systems. These systems are also the first to change with aging. Here we characterized the interplay between these systems and their regulation of afferent targets - the hippocampus (HPC) and posterior cingulate cortex (PCC) - across the lifespan. To examine the role of attentional salience on task-dependent functional connectivity, we used a target-distractor go/no go task presented during functional MRI. In younger adults, BF coupling with the HPC, and LC coupling with the PCC, increased with behavioral relevance (targets vs distractors). Although the strength and presence of significant regional coupling changed in middle age, the most striking change in network connectivity was in old age, such that in older adults BF and LC coupling with their cortical afferents was largely absent and replaced by stronger interconnectivity between LC-BF nuclei. Overall rapid changes in attention related to behavioral relevance revealed distinct roles of subcortical neuromodulatory systems. The pronounced changes in functional network architecture across the lifespan suggest a decrease in these distinct roles, with deafferentation of cholinergic and noradrenergic systems associated with a shift towards mutual support during attention guided to external stimuli. | Make paid
The complex biological mechanisms underlying human brain aging remain incompletely understood, involving multiple body organs and chronic diseases. In this study, we used multimodal magnetic resonance imaging and artificial intelligence to examine the genetic architecture of the brain age gap (BAG) derived from gray matter volume (GM-BAG, N=31,557 European ancestry), white matter microstructure (WM-BAG, N=31,674), and functional connectivity (FC-BAG, N=32,017). We identified sixteen genomic loci that reached genome-wide significance (P-value<5x10-8). A gene-drug-disease network highlighted genes linked to GM-BAG for treating neurodegenerative and neuropsychiatric disorders and WM-BAG genes for cancer therapy. GM-BAG showed the highest heritability enrichment for genetic variants in conserved regions, whereas WM-BAG exhibited the highest heritability enrichment in the 5' untranslated regions; oligodendrocytes and astrocytes, but not neurons, showed significant heritability enrichment in WM and FC-BAG, respectively. Mendelian randomization identified potential causal effects of several exposure variables on brain aging, such as type 2 diabetes on GM-BAG (odds ratio=1.05 [1.01, 1.09], P-value=1.96x10-2) and AD on WM-BAG (odds ratio=1.04 [1.02, 1.05], P-value=7.18x10-5). Overall, our results provide valuable insights into the genetics of human brain aging, with clinical implications for potential lifestyle and therapeutic interventions. All results are publicly available at the MEDICINE knowledge portal: https://labs.loni.usc.edu/medicine. | Make paid
Turquoise killifish (Nothobranchius furzeri) are naturally short-lived vertebrates, recapitulating several aspects of human aging, including protein aggregation, telomere shortening, cellular senescence, and declined antibody diversity. The mechanistic causes of systemic aging in killifish are still poorly understood. Here we ask whether killifish undergo significant age-dependent changes in the main hematopoietic organ, which together could contribute to systemic aging. To characterize immune aging in killifish, we employed single-cell RNA sequencing, proteomics, cytometry and a functional in vitro assay. Our data indicate how old killifish display increased inflammatory markers, and while immune cells from adult killifish display increased markers of proliferation and replication-independent DNA repair in progenitor-like cell clusters, progenitors from old killifish display extensive markers of DNA double-strand breaks. In less than 10 weeks, killifish undergo several dramatic spontaneous aging-related changes in the immune niche, which could be functionally linked with its extensive systemic aging and serve as targets for anti-aging interventions. | Make paid
Background: Burkitt lymphoma (BL) is one of the most common childhood cancers in sub-Saharan Africa and aetiologically linked to malaria. However, evidence for an effect of malaria interventions on BL is limited. The aim of this study was to investigate the potential population-level association between large-scale rollout of insecticide-treated bednets (ITNs) in sub-Saharan Africa in the 2000s and BL incidence. Methods: We conducted a systematic review in Embase, Global Health and MEDLINE to assemble all available data on BL incidence rates in children aged 0-15 years in malaria-endemic sub-Saharan African countries between Jan 1, 1990 and Feb 27, 2023. We calculated pooled estimates of BL incidence in sub-Saharan Africa for the time periods before and after ITN introduction. We used model estimates of sub-national ITN use to assess the association between average population ITN use and childhood BL incidence rates in a negative binomial regression model. Results: We included 23 studies comprising 66 datapoints on BL incidence based on 5,226 cancer cases from locations with large-scale ITN use in 17 countries. BL rates were 44% (95% CI 12-64%) lower in the time period after ITN introduction compared to before. The pooled incidence rate of BL was 1.36 (95% CI 0.88-2.10) and 0.76 (95% CI 0.50-1.16) per 100,000 person-years before and after introduction of ITNs, respectively. After adjusting for potential confounders, a 1% increase in average ITN use in the population in the 10 years before BL data collection was associated with a 2% (95% CI 1-4%) reduction in BL incidence. Conclusion: These findings suggest that large-scale rollout of ITNs in the 2000s was associated with a reduction in childhood BL burden in sub-Saharan Africa. Although published data may not be representative of all incidence rates across sub-Saharan Africa, our study highlights a potential additional benefit of malaria control programmes. | Make paid
Background In England, the Joint Committee for Vaccination and Immunisation recommended a spring 2023 booster programme for all adults aged 75 years and older and the immunosuppressed. The vaccines advised were the Sanofi/GSK AS03-adjuvanted monovalent beta variant (VidPrevtyn Beta) booster vaccine and the Pfizer-BioNTech mRNA (Comirnaty Original/Omicron BA.4-5) bivalent vaccine. This is the first time an adjuvanted COVID-19 vaccine has been administered as part of a UK COVID-19 vaccination programme. In clinical trials, the antibody levels generated by the Sanofi/GSK vaccine were comparable to levels generated by COVID-19 mRNA vaccines but to date there are no real-world data on the effectiveness or duration of protection of this vaccine. Methods We used a test-negative case-control study design to estimate the incremental vaccine effectiveness of the Sanofi/GSK and Pfizer bivalent BA.4-5 boosters against hospitalisation amongst those aged 75 years and older in England. The study period for tests contributing to all analyses was from 3rd April 2022 to 27th August 2023. Vaccine effectiveness was estimated relative to those who had received at least two doses prior to their spring booster, with their last dose being an autumn 2022 booster given at least 3 months prior. Findings Overall, there were 14,174 eligible tests from hospitalised individuals aged 75 years and older, with 3,005 being cases and 11,169 being controls. Effectiveness against hospitalisation was highest in the period 9 to 13 days post vaccination for both manufacturers at about 50%; 43.6% (95% C.I.; 20.1 to 60.2%) and 56.4% (95% C.I; 25.8 to 74.4%) for Sanofi/GSK and Pfizer BA.4-5, respectively. There was some evidence of waning with a reduction to about 30% for both manufacturers 5-9 weeks post vaccination. Interpretation Together, these results provide reassuring evidence that both the adjuvanted Sanofi/GSK and Pfizer BA.4-5 booster vaccines provided a good boost to protection against hospitalisation amongst adults aged 75 years and older. The finding that the adjuvanted vaccine targeting the now distant Beta strain had similar effectiveness to the mRNA vaccine targeting more closely matched Omicron sub-lineages BA.4-5 during a period of Omicron circulation may reflect improved protection due to the adjuvant in the Sanofi/GSK product. Funding No external funding. | Make paid
Multidrug interactions are a major cause of mortality for older patients. With an increase in alert fatigue for clinicians using Electronic Health Record systems (EHRs), Adverse Drug Events (ADEs) are increasing within older populations taking various drugs, because the probabilities of the adverse events associated with exposure to interacting drugs are not provided. The Observational Health Data Sciences and Informatics (OHDSI) ATLAS tool was utilized with Columbia University Irving Medical Center (CUIMC) patient data to determine whether Intracranial Hemorrhage (ICH) risk increases after being exposed to various multidrug interactions involving Warfarin in patients aged 60-90 years old one week before an ICH occurrence in patients prescribed ranges of 1-5, 6-10, and 11-15 drugs to also see the impact of polypharmacy on the prevalence of ICH amongst these patients. The prevalence of ICH in patients exposed to two and three-drug combinations involving Warfarin, Aspirin, Acetaminophen, and Amiodarone was measured. Significant increases in ICH risk and prevalence were identified in patients who had taken various combinations of these drugs with three-drug combinations involving Warfarin having a higher ICH risk than two-drug combinations involving Warfarin. Other findings also include that patients prescribed a larger number of drugs also tended to have a higher ICH risk than those prescribed a smaller number of drugs. Understanding the prevalence of such ADEs have crucial implications in the healthcare system, as the increased probabilities for certain ADEs from multidrug combinations can be applied to future EHR systems to counteract alert fatigue issues. | Make paid
Neurofibromatosis type 1 (NF1) is a common genetic condition in which 30-70% of children experience learning challenges including deficits in attention, executive function, and working memory. White matter pathways have been implicated in these cognitive functions; yet, they have not been well characterized in NF1. In this retrospective cohort study, we used diffusion MRI tractography to examine the microstructural properties of major white matter pathways in 20 children with NF1 aged 1 year to 18 years relative to 20 age- and sex-matched controls. An automated approach was used to identify and extract mean diffusivity (MD) and fractional anisotropy (FA) of eight cerebral white matter pathways bilaterally and the anterior and posterior part of the corpus callosum. Compared to controls, children with NF1 had significantly increased MD and significantly decreased FA in multiple white matter pathways including the anterior thalamic radiation, cingulate, uncinate fasciculus, inferior fronto-occipital fasciculus, arcuate fasciculus, and corticospinal tract. Differences in MD and FA remained significant after controlling for intracranial volume. In addition, MD and FA differences between children with NF1 and controls were greater at younger than older ages. These findings have implications for understanding the etiology of the neurocognitive deficits seen in many children with NF1. | Make paid
Background The home-based vaccination card (HBR) is an important health record for determining vaccination status of children during surveys, particularly in low- and middle-income countries (LMICs). However, there are limited evidence on the factors that influence its retention in Ghana. We assessed the predictors of vaccination card retention in Tamale Metropolis, Ghana Methods We conducted a cross-sectional study from 21st December 2022 to 10th January 2023 among children aged 0-59 months in the Tamale Metropolis. Multi-stage sampling was used to select caregivers of children aged 0-59 months for enrolment in the study. Data were collected using validated questionnaire through face-to-face interviews of caregivers. A vaccination card was retained if it was presented for physical inspection by research assistants. The factors that influence vaccination card retention were determined in a multivariate logistic regression analysis at p<0.05. Results A total of 1,566 eligible children were enrolled in this study. Vaccination card retention was 89.5%. Negative predictors of card retention included: being resident in the Nyohini (AOR=0.26; 95% CI=0.15-0.47) and Tamale Central (AOR= 0.52; 95% CI=0.30-0.92) sub-Metro areas, and children belonging to age group 24-59 months (AOR=0.40; 95% CI=0.23-0.67). On the other hand, paying for the vaccination card (AOR=5.20; 95% CI=2.98-9.04) was a positive predictor of vaccination card retention. Conclusion In this study, vaccination card retention among children aged 0-59 months was higher than national estimates. Vaccination card retention was mainly influenced by place of residence, age of child and mode of acquisition of the card such as out-of-pocket payment. There is need to design and deliver tailored messages including the importance of vaccination card retention to caregivers of children based on geographic context. Additionally, the vaccination cards should be supplied to health facilities and made readily accessible to caregivers to prevent out-of-pocket payment | Make paid
Background: Long COVID, characterized by persistent symptoms post-COVID-19, presents challenges like reduced functional capacity, pulmonary function, and dyspnea. Telerehabilitation, a remote healthcare approach, is gaining attention for its potential to address these issues Objectives: The study aims to determine the effect of telerehabilitation on functional capacity by six-minute walk test (MWT), pulmonary function by pulmonary function test (PFT), dyspnea by modified medical research council (mMRC) and level of physical activity by Global physical activity questionnaire (GPAQ) in individuals with long COVID. Materials and Methods: At Al Ain Hospital, UAE, a 6-week telerehabilitation program for Long COVID patients aged 18-75 was studied using single-group pretest-posttest quasi-experimental design . Pre and post assessments included 6MWT, PFT, mMRC, and GPAQ. The study also monitored technical issues and session adherence. Results: Participants had an average age of 49.30 {+/-} 15.46, height of 163.80 {+/-} 9.76, and weight of 78.70 {+/-} 15.58, with a gender ratio of 12 females to 8 males. After six weeks of telerehabilitation, significant improvements were seen in the 6MWT (21% improvement) and PFT (4% FVC increase, 8% FEV1 increase, 1% FEV1/FVC increase, and 11% PEF increase). mMRC scale scores post-rehabilitation were significantly lower, indicating substantial improvement in dyspnea levels with clinical significance. Conclusion: This approach has shown tangible benefits in enhancing functional capacity, pulmonary function, reducing dyspnea, and improving physical activity levels among individuals with Long COVID. The results of the study demonstrate the feasibility and effectiveness of implementing a telerehabilitation program for individuals with Long | Make paid
Importance: Despite several decades of neuroimaging studies reporting brain structural and functional alterations in depression, discrepancies in findings across various studies and limited convergence across several recent meta-analyses have raised questions about the consistency and robustness of the observed brain phenotypes. Objective: To investigate the effects of six different operational criteria of lifetime exposure to depression on functional and structural neuroimaging measures. Design, Setting, Participants: A cross-sectional study analyzed data from the UK biobank in individuals aged 45 to 80 years enrolled from 2014 to 2018. Six operational depression criteria were defined: Help-seeking for depression, Self-reported Depression, Antidepressant usage, Depression defined by Smith, Hospital International Classification of Disease, 10th Edition (ICD-10), and short-form Composite International Diagnostic Interview. Six increasingly conservative groups of lifetime depression were defined based on the six available depression criteria from meeting only one to more restrictive meeting all six criteria. We tested the effect of these definitions on voxel-wise measures of local functional activity, global connectivity, and gray matter volume. Main Outcomes and Measures: Voxel-wise fractional amplitude of low-frequency fluctuations, local connectivity, global connectivity, and gray matter volume. Results: We included 20,484 individuals with lifetime depression (12,645 women [61.73%]; mean [SD] age, 63.92 [7.6 ] years) and 25,462 healthy individuals (11,384 women [44.7%]; mean [SD] age, 65.05 [7.8] years) from the UK biobank. Across all depression definitions, individuals with lifetime depression displayed regionally consistent decreases in local functional activity in sensorimotor regions but not in global connectivity and gray matter volume. Previous hospital ICD10 diagnosis and antidepressant usage resulted in the most pronounced alterations. Conclusions and Relevance: Lifetime exposure to depression is associated with robust functional changes with more restrictive criteria revealing more pronounced alterations. Different inclusion criteria for depression may strongly contribute to the substantial variation of imaging findings reported in the literature. | Make paid
We recently reported accelerated cognitive decline in Europeans aged >70 years with low circulating adropin levels. Adropin is a small, secreted peptide that is highly expressed in the human nervous system. Expression profiling indicate relationships between adropin expression in the human brain and pathways that affect dementia risk. Moreover, increased adropin expression or treatment using synthetic adropin improves cognition in mouse models of aging. Here we report that low circulating adropin concentrations also associate with poor cognition (worst quintile for a composite score derived from the MMSE and semantic fluency test) in late-middle aged community-dwelling African Americans (OR=0.775, P<0.05; age range 45-65y, n=352). The binomial logistic regression controlled for sex, age, education, cardiometabolic disease risk indicators, and obesity. Previous studies using cultured cells from the brains of human donors suggest high expression in astrocytes. In snRNA-seq data from the middle temporal gyrus (MTG) of human donors, adropin expression is higher in astrocytes relative to other cell types. Advanced age suppresses adropin expression in all cell-types, with no effect of dementia status. In cultured human astrocytes, adropin expression also declines with donor age. Additional analysis indicated positive correlations between adropin amd transcriptomic signatures of energy metabolism and protein synthesis that are adversely affected by donor age. Adropin expression is also suppressed by pro-inflammatory factors. Collectively, these data indicate low circulating adropin levels are a potential early risk indicator of cognitive impairment. Suppression of astrocyte adropin expression in the brain is a plausible link between aging, neuroinflammation, and risk of cognitive decline. | Make paid
Aging is a multifactorial process that disturbs homeostasis, increases disease susceptibility, and ultimately results in death. Although the definitive set of molecular mechanisms responsible for aging remain to be discovered, epigenetic change over time is proving to be a promising piece of the puzzle. Several posttranslational histone modifications (PTMs) have been linked to the maintenance of longevity. Here, we focus on lysine 36 of the replication-independent histone protein, H3.3 (H3.3K36). To interrogate the role of this residue in Drosophila developmental gene regulation, we generated a lysine to arginine mutant that blocks the activity of its cognate modifying enzymes. We found that an H3.3BK36R mutation causes a significant reduction in adult lifespan, accompanied by dysregulation of the genomic and transcriptomic architecture. Transgenic co-expression of wild-type H3.3B completely rescues the longevity defect. Because H3.3 is known to accumulate in non-dividing tissues, we carried out transcriptome profiling of young vs aged adult fly heads. The data show that loss of H3.3K36 results in age-dependent misexpression of NF-{kappa}B and other innate immune target genes, as well as defects in silencing of heterochromatin. We propose H3.3K36 maintains the postmitotic epigenomic landscape, supporting longevity by regulating both pericentric and telomeric retrotransposition and by suppressing aberrant immune signaling. | Make paid
Both aging spots (hyperpigmentation) and hair graying (lack of pigmentation) are associated with aging, two seemingly opposite pigmentation phenotypes. It is not clear how they are mechanistically connected. This study investigated the underlying mechanism in a family with an inherited pigmentation disorder. Clinical examinations identified accelerated hair graying and skin dyspigmentation (intermixed hyper and hypopigmentation) in the family members carrying the SASH1-S519N variant. Cell assays indicated that SASH1 promoted stem-like characteristics in human melanocytes, and SASH1-S519N was defective in this function. Multiple assays showed that SASH1 binds to tankyrase 2 (TNKS2), which is required for the promoting role of SASH1 on the stem-like function. Further, the SASH1-S519N variant is in a bona fide Tankyrase-binding motif, and SASH1S519N alters the binding kinetics and affinity. Results here indicate SASH1 as a novel protein regulating the appropriate balance between melanocyte stem cells (McSC) and mature melanocytes (MCs), with S519N variant causing defects. We propose that dysfunction of McSC maintenance connects multiple aging-associated pigmentation phenotypes in the general population. | Make paid
Lewy Body Dementias (LBD), including Parkinson's disease dementia and Dementia with Lewy Bodies, are characterized by widespread accumulation of intracellular alpha-Synuclein protein deposits in regions beyond the brainstem, including in the cortex. Patients with LBDs develop cognitive changes, including abnormalities in executive function, attention, hallucinations, slowed processing, and cognitive fluctuations. The causes of these non-motor symptoms remain unclear; however, accumulation of alpha-Synuclein aggregates in the cortex and subsequent interference of synaptic and cellular function could contribute to psychiatric and cognitive symptoms. It is unknown how the cortex responds to local pathology in the absence of significant secondary effects of alpha-Synuclein pathology in the brainstem. To investigate this, we employed viral overexpression of human alpha-Synuclein protein targeting the mouse prefrontal cortex (PFC). We then used in vivo 2-photon microscopy to image awake head-fixed mice via an implanted chronic cranial window to assess the early consequences of alpha-Synuclein overexpression in the weeks following overexpression. We imaged apical tufts of Layer V pyramidal neurons in the PFC of Thy1-YFP transgenic mice at 1-week intervals from 1-2 weeks before and 9 weeks following viral overexpression, allowing analysis of dynamic changes in dendritic spines. We found an increase in the relative dendritic spine density following local overexpression of alpha-Synuclein, beginning at 5 weeks post-injection, and persisting for the remainder of the study. We found that alpha-Synuclein overexpression led to an increased percentage and longevity of newly persistent spines, without significant changes in the total density of newly formed or eliminated spines. A follow up study utilizing confocal microscopy revealed that the increased spine density is found in cortical cells within the alpha-Synuclein injection site, but negative for alpha-Synuclein phosphorylation at Serine-129, highlighting the potential for effects of dose and local circuits on spine survival. These findings have important implications for the physiological role and early pathological stages of alpha-Synuclein in the cortex. | Make paid
Olfaction is one of the evolutionarily oldest senses and plays a fundamental role in foraging and social interactions across mammals. In primates, the role of olfaction is now well recognized, but better investigated in strepsirrhine and platyrrhine primates than in catarrhines. We observed the sniffing behavior of semi-free ranging Barbary macaques, Macaca sylvanus, at Affenberg Salem, Germany, to assess how frequently macaques sniff and in which contexts, and how sniffing is affected by sex and age. Focal observations of 24 males and 24 females aged 1 to 25 years showed that Barbary macaques sniffed, on average, 5.3 times per hour, with more than 80% of sniffs directed at food. Irrespective of the context, younger individuals sniffed more often than older ones. Females' sniffs were more often directed at food than male sniffs, while males sniffed more often than females in a social context. Sniffs at conspecifics occurred primarily in a sexual context, with 70% of social sniffs directed at female anogenital swellings performed by males. Of the observed 176 anogenital inspections, 51 involved sniffing of the swelling. Olfactory inspections were followed by copulation significantly less often than merely visual inspections, suggesting that anogenital odors provided additional information guiding male mating decisions. In sum, results show that Barbary macaques routinely use olfaction during feeding, but also in a social context. Our study further suggests that odors may guide mating decisions, but the role of olfaction in sexual interactions warrants further investigations. | Make paid
The slow descent in TB burden, the COVID-19 pandemic, along the rise of multidrug-resistant strains of Mycobacterium tuberculosis, seriously threaten TB control and the goals of the End TB strategy. To fight back, several vaccine candidates are under development, with some of them undergoing phases 2B and 3 of the development pipeline. The impact of these vaccines on the general population needs to be addressed using disease-transmission models, and, in a country like China, which last year ranked third in number of cases worldwide, and where the population is undergoing a fast process of demographic aging, the impact of TB vaccination campaigns may depend heavily upon the age of targeted populations and with the mechanistic descriptions of the TB vaccines. For these reasons, transmission models need to capture the coupling between TB dynamics and demographic evolution, as well as to be able to accommodate different mechanistic descriptions of TB vaccine protection. In this work, we studied the potential impact of a new TB vaccine in China targeting adolescents (15-19 y.o.) or elderly people (60-64 y.o.), according to varying vaccine descriptions that represent reasonable mechanisms of action leading to prevention of disease (PoD), or prevention of recurrence (PoR), each of them targetting specific routes to TB disease. To measure the influence of the description of the coupling between transmission dynamics and aging in TB transmission models, we explored two different approaches to compute the evolution of the contact matrices, which relate to the spreading among different age strata. Our results show that the magnitude of model-based impact estimates substantially depends upon the vaccine profile, and it is also strongly related to the modeling approach chosen to describe the time evolution of contact matrices. In spite of these sources of uncertainty, our results also show, in line with previous modeling works, that elder vaccination is a suitable option in China to reduce the incidence of TB. | Make paid
Objective Vaccination reduces the risk of acute COVID-19 in children, but it is less clear whether it protects against long COVID. We estimated vaccine effectiveness (VE) against long COVID in children aged 5 to 17 years. Methods This retrospective cohort study used data from 17 health systems in the RECOVER PCORnet electronic health record (EHR) Program for visits between vaccine availability, and October 29, 2022. Conditional logistic regression was used to estimate VE against long COVID with matching on age group (5 to 11, 12 to 17) and time period and adjustment for sex, ethnicity, health system, comorbidity burden, and pre-exposure health care utilization. We examined both probable (symptom-based) and diagnosed long COVID in the year following vaccination. Results The vaccination rate was 56% in the cohort of 1,037,936 children. The incidence of probably long COVID was 4.5% among patients with COVID-19, while diagnosed long COVID was 0.7%. Adjusted vaccine effectiveness within 12 months was 35.4% (95 CI 24.5 - 44.5) against probable long COVID and 41.7% (15.0- 60.0) against diagnosed long COVID. VE was higher for adolescents 50.3% [36.3 - 61.0]) than children aged 5-11 (23.8% [4.9 -39.0]). VE was higher at 6 months (61.4% [51.0 - 69.6]), but decreased to 10.6% (-26.8 - 37.0%) at 18 months. Discussion This large retrospective study shows a moderate protective effect of SARS-CoV-2 vaccination against long COVID. The effect is stronger in adolescents, who have higher risk of long COVID, and wanes over time. Understanding VE mechanism against long COVID requires more study, including EHR sources and prospective data. Discussion This large retrospective study shows a moderate protective effect of SARS-CoV-2 vaccination against long COVID. The effect is stronger in adolescents, who have higher risk of long COVID, and wanes over time. Understanding VE mechanism against long COVID requires more study, including EHR sources and prospective data. | Make paid
While the molecular mechanisms of acute myeloid leukemia failure to venetoclax-based therapy have been recently clarified, the mechanisms whereby patients with myelodysplastic syndromes (MDS) acquire secondary resistance to venetoclax after an initial response remain to be elucidated. Here, we show for the first time that MDS hematopoietic stem cells (HSCs) can undergo hierarchical differentiation reprogramming toward a granulo-monocytic-biased transcriptional state through the acquisition or expansion of clones with an isolated trisomy 8 cytogenetic aberration and STAG2 or RUNX1 mutations. This hierarchical rewiring changes HSCs' survival dependence from BCL-2-mediated anti-apoptotic pathways to TNFa-induced pro-survival NF-KB signaling and overcomes venetoclax-mediated cytotoxic effect. These findings underscore the importance of close molecular monitoring of patients with MDS enrolled in clinical trials of venetoclax to prevent HSC transcriptional reprogramming before the disease becomes resistant to this therapy. | Make paid
Genomic stability is critical for cellular function, however, postmitotic cells such as highly metabolically active neurons face the biggest challenge as they must maintain their genome over an organismal lifetime. DNA damage in neurons increases with chronological age and is accelerated in Alzheimers disease, and neurodegenerative disorders, resulting in downstream cellular and systemic dysregulation. Distinct DNA damage response pathways have evolved with a host of distinct polymerases that act via different pathways such as nucleotide excision repair, and base excision repair to mend DNA lesions. The Y-family polymerases are known for their key role in bypassing damaged DNA through the process of translesion synthesis in dividing cells, however, their functions in enduring post-mitotic cell types like neurons are largely unknown. We show that one such member of the Y-family polymerases, DNA polymerase kappa protein (POLK), is subcellularly localized in the nucleus and cytoplasm of neurons. With chronological age, there is a significant reduction of nuclear POLK and a concomitant accumulation in the cytoplasm. The reduction of nuclear POLK in old brains is congruent with an increase in nuclear DNA damage. We further report that nuclear POLK expression is not uniform among cell types in the brain with significantly higher levels of nuclear POLK in GABAergic interneurons compared to excitatory pyramidal neurons and non-neurons, possibly reflective of the inherent biological differences such as axonal projection, neuronal activity, and their firing rates. Due to the non-replicative status of differentiated neurons in mature circuits, it is critical to understand the different repair strategies and mechanisms that postmitotic neurons employ to maintain their genomic integrity, which will help design therapies for human longevity and the prevention of neurodegeneration. | Make paid
Tinnitus is a common health condition, affecting approximately 15% of the UK population. The tinnitus treatment with the strongest evidence base is Cognitive Behavioural Therapy (CBT), with standard tinnitus therapy typically augmented with education, relaxation and other techniques. Availability of CBT and conventional tinnitus therapy more broadly is limited for tinnitus sufferers. The DEFINE trial aims to assess whether smartphone-delivered tinnitus therapy, the Oto app, is as effective as current standard care, one-to-one therapist-delivered tinnitus treatment for the treatment of tinnitus in adults. The trial is registered in the ISRCTN Registry: ISRCTN99577932. DEFINE is an open-label, non-inferiority, prospective, parallel design, randomised-controlled trial. Recruitment, interventions and assessments will be remote, enabling UK-wide participant involvement. 198 participants aged 18 years or more will be recruited via social media advertisement or via primary care physicians. A screening process will identify those with tinnitus that impacts health-related quality of life, and following consent smartphone-based audiometry will be performed. Randomisation 1:1 to the Oto app or one-to-one therapist-led tinnitus therapy will be performed centrally by computer, matching groups for age, sex and hearing level. Following participant allocation, the Oto app will be provided for immediate use, or a one-to-one remote therapy appointment booked to occur within approximately 1 week, with up to 6 sessions delivered. Participant outcomes will be collected at 4,12, 26 and 52 weeks via questionnaire and phone call. The primary outcome is the change in Tinnitus Functional Index (TFI) total score measured at 26 weeks following allocation. Adverse events will be recorded. A health economic evaluation in the form of a cost-utility analysis will be performed using data from participant submitted EuroQol 5D-5L and Health Utilities Index Mark 3 scores and resource use data. Trial results will be made publicly available, including a plain English summary. | Make paid
Myelinating oligodendrocytes die in human disease and early in aging. Despite this, little is known about the mechanisms that govern cell death across the oligodendrocyte lineage. Here we used a combination of intravital imaging, single-cell ablation, and cuprizone intoxication to show that oligodendrocyte maturation dictates the dynamics and mechanisms of death. After single-cell genotoxic damage, oligodendrocyte precursor cells underwent programmed cell death within hours, while mature oligodendrocytes died weeks after the same acute damage. Targeting single cells that were actively undergoing oligodendrocyte generation revealed that a switch in the temporal dynamics and morphological progression of death occurs during differentiation. Consistent with this, cuprizone intoxication initiated a caspase-3-dependent form of rapid cell death in differentiating oligodendrocytes, while mature oligodendrocytes never activated this executioner caspase and exhibited delayed cell death initiation. Thus, oligodendrocyte maturation plays a key role in determining the mechanism of death a cell undergoes in response to the same insult. This means that different strategies are likely necessary to confer protection to the entire oligodendrocyte lineage to enable myelin preservation and facilitate the integration of new oligodendrocytes in aging and disease. | Make paid
Background Antibiotic usage, contact with high transmission healthcare settings as well as changes in immune system function all vary by a patients age and sex. Yet, most analyses of antimicrobial resistance (AMR) ignore demographic indicators and provide only country level resistance prevalence values. In this work we use routine surveillance data on serious infections in Europe to characterise the importance of age and sex on incidence and resistance prevalence patterns for 33 different bacteria and antibiotic combinations. We fit Bayesian multilevel regression models to quantify these effects and provide estimates of country-, bacteria- and drug-family effect variation. Results At the European level, we find distinct patterns in resistance prevalence by age that have previously not been explored in detail. Trends often vary more within an antibiotic family than within a bacterium: clear resistance increases by age for methicillin resistant S. aureus (MRSA) contrast with a peak in resistance to several antibiotics at ~30 years of age for P. aeruginosa. This diverges from the known, clear exponential increase in infection incidence rates by age, which are higher for males except for E. coli at ages 15-40. At the country-level, the patterns are highly context specific with national and subnational differences accounting for a large amount of resistance variation (~38%) and a range of associations between age and resistance prevalence. We explore our results in greater depths for two of the most clinically important bacteria-antibiotic combinations. For MRSA, age trends were mostly positive, with 72% of countries seeing an increased resistance between males aged 1 and 100 and more resistance in males. This compares to age trends for aminopenicillin resistance in E. coli which were mostly negative (males: 93% of countries see decreased resistance between ages 1 and 100) with more resistance in females. A change in resistance prevalence between ages 1 and 100 ranged up to ~0.46 (95% CI 0.37 - 0.51, males) for MRSA but varied between 0.16 (95% CI 0.23-0.3, females) to -0.27 (95%CI -0.4 - -0.15, males) across individual countries for aminopenicillin resistance in E. coli. Conclusion Prevalence of resistance in infection varies substantially by the age and sex of the individual revealing gaps in our understanding of AMR epidemiology. These context-specific patterns should now be exploited to improve intervention targeting as well as our understanding of AMR dynamics. | Make paid
Background: Cognitive impairment is projected to rise substantially by 2050, particularly in low- and middle-income countries with aging populations. Reproductive life history may be associated with later-life cognitive function. We aim to estimate the association between number of children and mid- to later-life cognitive performance. Method: Data were from 5059 older adults (46% men) aged [≥]40 years in the population-representative rural cohort of the "Health and Aging in Africa: A Longitudinal Study of an INDEPTH Community in South Africa" (HAALSI). We fit linear regression and modified Poisson models to estimate the associations between number of children and cognitive function. Analyses were stratified by sex/gender, controlling for age, education, literacy, self-reported childhood health, country of birth, and father's occupation. Results: After adjustment, men with any number of children and women with 5+ children had higher cognitive function compared to those without children (estimate;[95% CI]: Men: 1-2: 0.29[0.13 - 0.45], 3-4: 0.50[0.34 - 0.65], 5+: 0.48[0.33 - 0.63]; Women: 5+: 0.17[0.01 - 0.34]). Results from the adjusted modified Poisson regression models found that for men and women, groups with any number of children showed a lower prevalence of cognitive impairment than the group with 0 children (PR[95% CI] Men: 1-2: 0.48[0.31 - 0.75], 3-4: 0.21[0.12 - 0.37], 5+: 0.28[0.19 - 0.41], Women: 1-2: 0.52[0.31 - 0.88], 3-4: 0.55[0.33 - 0.91], 5+: 0.41[0.25 - 0.69]). Conclusion: Among older rural South African adults, having children was associated with greater cognitive performance and lower prevalence of cognitive impairment. Men tended to have larger protective associations than women, which may be due to sex/gender differences in biological and social roles of childbearing and rearing. Understanding the complex relationship between having children and later-life cognitive function may help identify interventions to reduce the impact of cognitive decline. | Make paid
Microglia, the resident macrophage in brain, has gained significant attention due to their involvement in neurodegenerative diseases. Disease associated microglia (DAM) have been identified at sites of amyloid-beta plaques and neurodegeneration. Understanding microglial states in the aging brain has become crucial, especially with the discovery of numerous Alzheimer's disease (AD) risk and protective variants in genes such as TREM2, CD33, APOE, ABCA7, PLCG2, and INPP5D, which are essential to microglia function1. Here we present a thorough examination of microglia-like cell lines and primary mouse microglia at the proteomic and transcriptomic levels to help illuminate the roles these genes and the proteins they encode play in various cell states. This analysis serves as a guide to the exploration of potential therapeutic targets in the context of neurodegeneration. INPP5D, which encodes the SHIP1 protein, is essential for microglia function. SHIP1 has emerged as a target of interest having been nominated as a therapeutic target by three teams within the Accelerating Medicines Partnership for Alzheimer's Disease (AMP-AD). In this study, we compared the proteomic profiles of wildtype, SHIP1 heterozygous knockout, and homozygous knockout primary microglia. Our findings revealed significant proteomic alterations only in the homozygous knockout of the SHIP1 gene, revealing its impact on the microglial proteome. Additionally, we compared the proteomic and transcriptomic profiles of BV2 and HMC3 cells with primary mouse microglia because these cell lines are often used as microglial cellular models. Our results demonstrated a substantial similarity between the proteome of BV2 cells and mouse primary cells, while notable differences were observed between BV2 and human HMC3 cells, with some shared characteristics. Since SHIP1 functions as a lipid phosphatase that modulates phosphatidylinositol (PI) species, we conducted lipidomic analysis to quantify different phosphatidylinositols (PIs), phosphatidylinositol monophosphate (PIPs), and polyphosphoinositides (PPIs) in the HMC3 and BV2 cells. Under basal conditions, PI(3,4,5)P3 and PI(3,4)P2 species were detected at extremely low levels, making confident quantification challenging; however, PIP species within the overall pool were significantly changed upon SHIP1 overexpression in HMC3. This in-depth proteomic analysis of both mouse and human microglia, complemented by targeted lipidomic studies, enhances our understanding of these cellular models. The similarities between primary mouse microglia and the BV2 cell line is especially encouraging, supporting the use of this model for further investigations into the role that SHIP1 and other potential drug targets may play in the regulation of microglial states. | Make paid
The lifelong maintenance of cognitive abilities in an increasingly aging human society is one of the major challenges of future research and medical services. For this, a better understanding of the cellular aging processes in the mammalian brain is a fundamental requirement. In particular, the functioning of postmitotic neurons, which require special strategies for lifelong functionality, is still elusive in many details. Among many other hallmarks of neuronal aging, the impairment of autophagy as an essential element of cellular homeostasis is of particular importance. However, the mechanisms for regulating these processes have not yet been fully elucidated. Establishing an in vitro model from primary cortical cells of the mouse brain, which shows the characteristic features of cellular senescence that are also observed in the total brain, we found the accumulation of dsDNA in the cytosol of neurons. Since dsDNA is a trigger for the activation of the cGAS-STING signaling and its primordial function is a non-canonical activation of autophagy, we analyzed its impact on aging neurons. We were able to demonstrate that the age-dependent downregulation of cGAS-STING signaling in neurons leads to an inhibition of autophagy at different levels. In contrast, activation of STING led to a complete rescue of autophagy in old neurons. Additionally, we found no evidence for age dependent cGAS-STING mediated IFN-I production. Hence, we propose that the primary function of cGAS-STING signaling in neurons is to maintain autophagy rather than contribute to age-related inflammation, and thus represents a target for therapeutic intervention. | Make paid
Cell fate changes are determined by gene regulatory network (GRN), a sophisticated system regulating gene expression in precise spatial and temporal patterns. However, existing methods for reconstructing GRNs suffer from inherent limitations, leading to compromised accuracy and application generalizability. In this study, we introduce CellPolaris, a computational system that leverages transfer learning algorithms to generate high-quality, cell-type-specific GRNs. Diverging from conventional GRN inference models, which heavily rely on integrating epigenomic data with transcriptomic information or adopt causal strategies through gene co-expression networks, CellPolaris employs high-confidence GRN sources for model training, relying exclusively on transcriptomic data to generate previously unknown cell-type-specific GRNs. Applications of CellPolaris demonstrate remarkable efficacy in predicting master regulatory factors and simulating in-silico perturbations of transcription factors during cell fate transition, attaining state-of-the-art performance in accurately predicting candidate key factors and outcomes in cell reprogramming and spermatogenesis with validated datasets. It is worth noting that, with a transfer learning framework, CellPolaris can perform GRN based predictions in all cell types even across species. Together, CellPolaris represents a significant advancement in deciphering the mechanisms of cell fate regulation, thereby enhancing the precision and efficiency of cell fate manipulation at high resolution. | Make paid
Multiple sclerosis (MS) is the most common inflammatory neurodegenerative disease in young adults, resulting in neurological defects and disability. The endogenous mechanisms to resolve inflammation are intact but become defective in patients, resulting in lack of resolution mediators and unresolved chronic inflammation. Docosahexaenoic acid (DHA) metabolism being impaired in MS, we hypothesize that supplementing its downstream metabolite maresin 1 (MaR1) will alleviate inflammation and demyelination in preclinical mouse model of MS; experimental allergic encephalomyelitis (EAE). Restoration of MaR1 by its exogenous administration in EAE mice propagated inflammatory resolution and had a protective effect on neurological deficits, prevented disease progression, and reduced disease severity by reducing immune cell infiltration (CD4+IL17+ and CD4+IFN-{gamma}+) into the CNS. It significantly reduced the proinflammatory cytokine IL17 and promoted an anti-inflammatory response via IL10 and IL4. Neutralization of IL10 abolished the protective effect of MaR1 in EAE confirming IL10 is mediating MaR1 effect in EAE. Furthermore, it improved the pathophysiology and exerted neuroprotective effects by mitigating disease signs in EAE as evidenced by lower levels of NFL in the plasma of treated group compared to control and higher MBP expression in the brain from the MaR1 treated mice, decreased inflammatory infiltrates, and less demyelination and vacuolization in the spinal cord tissue sections of treated mice. SCENITH data confirmed that MaR1 maintains myelin by regulating oligodendrocyte metabolism. Also, it induces metabolic reprogramming in infiltrating CD4 cells and macrophages, which modulate their phenotype. Metabolic changes induced macrophages by MaR1 restores the impaired efferocytosis in EAE, promoting clearance of damaged myelin and dead cells; thereby lowering the disability with disease course. Overall, MaR1 supplementation has anti-inflammatory and neuroprotective effects in preclinical animal models and induces metabolic reprogramming in disease associated cell-types, promotes efferocytosis, implying that it could be a new therapeutic molecule in MS and other autoimmune diseases. | Make paid