For antigenically variable pathogens such as influenza, strain fitness is partly determined by the relative availability of hosts susceptible to infection with that strain compared to others. Antibodies to the hemagglutinin (HA) and neuraminidase (NA) confer substantial protection against influenza infection. We asked if a cross-sectional antibody-derived estimate of population susceptibility to different clades of influenza A (H3N2) could predict the success of clades in the following season. We collected sera from 483 healthy individuals aged 1 to 90 years in the summer of 2017 and analyzed neutralizing responses to the HA and NA of representative strains. The clade to which neutralizing antibody titers were lowest, indicating greater population susceptibility, dominated the next season. Titers to different HA and NA clades varied dramatically between individuals but showed significant associations with age, suggesting dependence on correlated past exposures. Despite this correlation, inter-individual variability in antibody titers to H3N2 strains increased gradually with age. This study indicates how representative measures of population immunity might improve evolutionary forecasts and inform selective pressures on influenza. | Make paid
Introduction Violence exposure has been associated with cardiovascular disease. Less is known about underlying mechanisms, including early cardiometabolic risk factors, and possible sex differences of such associations. Methods We used data from the Swedish LifeGene study on 23,215 males and females, aged 18-50 years. At baseline (2009-1016) participants answered the Life Stressor Checklist-Revised alongside questions on medical diagnoses of hypertension, diabetes, dyslipidemia and smoking history. At a clinical visit, blood pressure, BMI, glycated hemoglobin (HbA1c), total cholesterol, ApoB/ApoA1 ratio, and high-sensitivity C-Reactive Protein (hs-CRP) were measured. Modified Poisson and linear regression were used to test the association between violence and cardiometabolic risk factors. Results At mean age 33{+/-}8 years, lifetime exposure to violence was reported by 23% of females and 15% of males. Those exposed to violence were more likely to smoke (PR 1.86, CI: 1.66-2.07) and report a diagnosis of hypertension (PR 1.39, CI: 1.18-1.64). While no differences were observed in measured systolic blood pressure (B -0.34, CI: -0.70, 0.02), HbA1c (B 0.06, CI: -0.08, 0.20) or total cholesterol (B -0.01, CI: -0.04, 0.02), both males and females exposed to violence had higher BMI (B 0.51, CI: 0.39-0.63) and hs-CRP (B 0.11, CI: 0.06-0.16), after adjustment. Violence in childhood, as opposed to adulthood, and exposure to both sexual and physical violence, as opposed to either type, was more strongly associated with hs-CRP and BMI. Discussion In a young healthy Swedish sample, lifetime exposure to violence was associated with some but not all early cardiometabolic risk factors among both males and females. | Make paid
Background More than half of the predicted cervical cancer deaths are expected to be prevented with improved screening and management strategies. However, the conventional cervical screening procedure is considered as uncomfortable and embarrassing for most women in developing countries, such as Indonesia, leading to a low participation rate of screening. In response, we assessed the performance of the newly developed hrHPV ReadyMix qPCR Kit to detect high-risk human papillomavirus (HPV) in urine samples and conduct simultaneous genotyping of HPV16, HPV18, and HPV52. Methods We enrolled women aged 20-50 years from three cities in Indonesia, specifically Jakarta, Bandung, and Semarang. Participants were instructed to provide self-collected first-void urine samples, followed by a physician-assisted cervical swab sample collection. Nucleic acids were then extracted and tested for HPV with Roche cobas 6800 HPV and hrHPV ReadyMix qPCR kit. Next generation-sequencing (NGS) was employed in cases of discrepant results. hrHPV ReadyMix diagnostics accuracy were assessed against Roche cobas 6800 HPV as a reference test and the utility of urine samples as an alternative sampling method were compared to the standard cervical swab samples. Results 876 paired samples were analysed for HPV detection. The sensitivity of HPV detection in cervical swabs using hrHPV ReadyMix qPCR Kit reached 96.55% and the specificity reached 99.87%. Despite having a tendency to produce higher Ct value in high-risk HPV detection, urine samples produced a high sensitivity at 80.88% and a specificity of 100.00% when compared to cervical swabs. Our developed method enables population-based high-risk HPV analysis with 6.62% HPV prevalence based on cervical swabs and 6.28% HPV prevalence based on urine samples. Urine samples, tested with the hrHPV ReadyMix qPCR Kit, exhibited comparable HPV positivity rate to cervical swabs and similar genotyping capability of HPV16 and HPV18 as the Roche cobas 6800 HPV system. Conclusions We demonstrated that self-collected urine samples can be an alternative specimen to detect HPV infection with a diagnostic accuracy of 98.48%. This study highlights the potential of the hrHPV ReadyMix qPCR Kit in improving cervical cancer screening and provides valuable insights for future interventions. | Make paid
We predictively model damage transition probabilities for binary health outputs of 19 diseases and 25 activities of daily living states (ADLs) between successive waves of the English Longitudinal Study of Aging (ELSA). Model selection between deep neural networks (DNN), random forests, and logistic regression found that a simple one-hidden layer 128-node DNN was best able to predict future health states (AUC [≥] 0.91) and average damage probabilities (R^2 [≥] 0.92). Feature selection from 134 explanatory variables found that 33 variables are sufficient to predict all disease and ADL states well. Deciles of predicted damage transition probabilities were well calibrated, but correlations between predicted health states were stronger than observed. The hazard ratios (HRs) between high-risk deciles and the average were between 3 and 10; high prevalence damage transitions typically had smaller HRs. Model predictions were good across all individual ages. A simple one-hidden layer DNN predicts multiple binary diseases and ADLs with well calibrated damage and repair transition probabilities. | Make paid
Background: Sodium myo-inositol cotransporter-1 (SMIT1) belongs to the sodium-glucose cotransporter (SGLT) family. SMIT1 is expressed in cardiac cells, including fibroblasts and cardiomyocytes. However, the function of SMIT1 in the heart remains unknown. Methods: We used a model of pressure overload induced by transverse aortic constriction in wild type (WT) mice and mice lacking SMIT1 (Smit1-/-), combined with echocardiography, immunoblot and staining, contrast-enhanced microfocus computed tomography, and RNA-sequencing to evaluate the contribution of SMIT1 in cardiac hypertrophy, fibrosis and function. In addition, we used primary cultures of adult mouse and neonatal rat cardiomyocytes to define the molecular pathways affected by SMIT1. Results: We found that aortic banding fails to induce systolic dysfunction, cardiac hypertrophy and fibrosis in Smit1-/- mice, in contrast to WT controls. Deletion of SMIT1 reduces cardiac O-GlcNAcylation and maintains basal levels of Carabin following hemodynamic stress. In the absence of SMIT1, Carabin inhibits calcineurin/NFAT and Ras/ERK1/2 pathways, putting a brake on transcriptional reprogramming and further development of cardiac hypertrophy. In vitro, we showed that the lack of SMIT1 mitigates phenylephrine-induced hypertrophy and calcium increase in isolated cardiomyocytes. Conclusions: This work establishes SMIT1 as a key driver of hypertrophy, suggesting that pharmacological inhibition of this SGLT member can serve as a potential strategy to prevent or treat pathological hypertrophy and heart failure. | Make paid
Microglia and perivascular macrophages, myeloid-origin resident immune cells in the human brain, play crucial roles in Alzheimer's disease (AD)1-4. However, the field lacks a unified taxonomy describing their heterogeneity and plasticity5. To address this, we applied single-cell profiling to two independent, demographically diverse cohorts. The first comprises 543,012 viable myeloid cells from 137 unique postmortem brain specimens, while the second consists of 289,493 myeloid nuclei from 1,470 donors. Collectively, they cover the human lifespan and varying degrees of AD neuropathology. We identify 13 transcriptionally distinct myeloid subtypes, including the "GPNMB" subtype that proliferates with AD. We distinguish two contrasting homeostatic microglial states in AD and with aging: the first ("FRMD4A") wanes over time, while the second ("PICALM") becomes more prevalent. By prioritizing AD-risk genes, including PTPRG, DPYD, and IL15, and placing them into a regulatory hierarchy, we identify common upstream transcriptional regulators, namely MITF and KLF12, that regulate the expression of AD-risk genes in the opposite directions. Through the construction of cell-to-cell interaction networks, we identify candidate ligand-receptor pairs, including APOE:SORL1 and APOE:TREM2, associated with AD progression. We show polygenic risk for AD predisposes and prioritize the GPNMB subtype as a therapeutic target of early intervention. Our findings delineate the relationship between distinct functional states of myeloid cells and their pathophysiological response to aging and AD, providing a significant step toward the mechanistic understanding of the roles of microglia in AD and the identification of novel therapeutics. | Make paid
Introduction: Recent studies show a growing body of evidence suggesting that users of cannabis have consistently higher prevalence rates of depressive disorders in comparison to non-users. Besides, it can be used as a highly effective treatment for depression and other mood disorders. Methods: A study with a cross-sectional design was conducted with data from respondents aged 25-64 who participated in the 2018 Behavioral Risk Factor Surveillance System (BRFSS) survey. The population was assessed for the baseline characteristics, followed by a bivariate analysis, a multivariate logistic regression to control any confounders, and assess the association between the use of cannabis and depression. Results: The sample included 57,757 individuals. The unadjusted binary logistic regression indicated that those who use cannabis are 93% more likely (OR: 1.93) to have a diagnosis of depression. On the other hand, the adjusted analysis indicated that those who use cannabis are 78% more likely (OR: 1.78) to have a diagnosis of depression. Other variables including participants under the age of 45 years were significantly associated with the diagnosis of depression (OR: 1.35). Moreover, participants with an education without a high school diploma (OR: 0.54), and those having a full-time commitment (OR: 0.37) were significantly less likely to have a diagnosis of depression. Conclusion: Findings suggest that selected U.S. participants who use cannabis have an increased risk to report depression. Furthermore, factors such as age, level of education, and a persons time commitment status were found to have a significant influence on whether a diagnosis of depression is present. | Make paid
Objectives: Symptom characterization is critical to urinary tract infection (UTI) diagnosis, but identification of symptoms from the electronic health record (EHR) is challenging, limiting large-scale research, public health surveillance, and EHR-based clinical decision support. We therefore developed and compared two natural language processing (NLP) models to identify UTI symptoms from unstructured emergency department (ED) notes. Methods: The study population consisted of patients aged [≥]18 who presented to the (ED) in a northeastern United States health system between June 2013 and August 2021 and had a urinalysis performed. We annotated a random subset of 1,250 ED clinician notes from these visits for a list of 17 UTI symptoms. We then developed two task-specific large language models (LLMs) to perform the task of named entity recognition (NER): a convolutional neural network (CNN)-based model (SpaCy) and a transformer-based model designed to process longer documents (Longformer). Models were trained on 1,000 notes and tested on a holdout set of 250 notes. We compared model performance (precision, recall, F1 measure) at identifying the presence or absence of UTI symptoms at the note level. Results: 8,135 entities were identified in 1,250 notes; 83.6% of notes included at least one entity. Overall F1 measure for note-level symptom identification weighted by entity frequency was 0.84 for the SpaCy model and 0.88 for the Longformer model. F1 measure for identifying presence or absence of any UTI symptom in a clinical note was 0.96 (232/250 correctly classified) for the SpaCy model and 0.98 (240/250 correctly classified) for the Longformer model. Conclusions: The study demonstrated the utility of LLMs and transformer-based models in particular for extracting UTI symptoms from unstructured ED clinical notes; models were highly accurate for detecting the presence or absence of any UTI symptom on the note level, with variable performance for individual symptoms. | Make paid
Background Blood-based HIV self-testing represents an alternative for increasing screening among key populations or populations with difficult access. In Cameroon, very few studies, on the usability of HIV self-tests based on blood samples, have been carried out among these groups. Objective The aim of this study was to assess the usability of blood-based HIV self-testing among men who have sex with men (MSM) and female sex workers (FSWs) in the cities of Yaounde and Douala, Cameroon. Materials and Methods An observational study was conducted in 17 Community-Based Organisations (CBOs), including 10 MSM and 07 FSWs in Yaounde and Douala from 11 to 22 June 2022. The study population consisted of HCV and MSM aged 21 years and over who agreed to participate in the study. After they were recruited consecutively in their respective CBOs, they received counselling, unassisted HIV blood self-testing and condoms. Data was collected using an administered questionnaire. Three HIV blood self-testing devices were used in the study: Mylan HIV Self-Test, Sure Check HIV Test(R) (Chembio Diagnostics Inc), Check Now HIV Self-Test(Abbott Point Of Care). Analysis was conducted using SPSS 23 software with a 95% confidence level. Results Of 817 participants who completed the HIV blood self-test, just over half were TS 459(56.2%); the median age was 27 years (IQR: 22 years - 34 years) and the 25-49 age group was most represented 482(59.0%). One participant in ten (10%) had never been tested for HIV. However, 98.6% of participants agreed to use the HIV blood self-test and the vast majority (97.1%) followed the steps for carrying out the HIV blood self-test. An MSM was 4 times more likely to pass an HIV blood self-test than a TS (aOR= 4.01; 95% CI: 1.181-13.625; p=0.026). Similarly, TS and MSM who used the Abbott Check Now HIV Self-Test (aOR= 3.85; 95% CI: 1.246-11.908; p=0.019) and Chembio Sure Check HIV Test (aOR= 2.83; 95% CI: 1.072-7.720; p=0.036) were respectively 3.8 and 2.8 times and more likely to pass their self-test than those who used the Mylan blood self-test. Agreement between a participant's HIV blood self-test result and Abbott-trained investigator-observers was moderate ({kappa}=0.485; CI95% (0.359-0.610); p=0.001) while agreement with Chembio and Mylan was respectively low ({kappa}=0.329; CI95% (0.203-0.454); p=0.001) and very low ({kappa}=0.194; CI95%(0.05-0.329); p=0.001). Conclusion HIV blood self-testing is acceptable and usable by key populations in Cameroon. Although usability was limited by problems in interpreting results and incorrect disposal of waste t by key populations, a blood-based HIV Self-Test, with moderate concordance, proved suitable for unassisted use in key populations, what could help improve HIV prevention interventions. | Make paid
Importance: COVID-19 continues to cause significant hospitalizations and deaths in the United States. Its continued burden and the impact of annually reformulated vaccines remain unclear. Objective: To project COVID-19 hospitalizations and deaths from April 2023-April 2025 under two plausible assumptions about immune escape (20% per year and 50% per year) and three possible CDC recommendations for the use of annually reformulated vaccines (no vaccine recommendation, vaccination for those aged 65+, vaccination for all eligible groups). Design: The COVID-19 Scenario Modeling Hub solicited projections of COVID-19 hospitalization and deaths between April 15, 2023-April 15, 2025 under six scenarios representing the intersection of considered levels of immune escape and vaccination. State and national projections from eight modeling teams were ensembled to produce projections for each scenario. Setting: The entire United States. Participants: None. Exposure: Annually reformulated vaccines assumed to be 65% effective against strains circulating on June 15 of each year and to become available on September 1. Age and state specific coverage in recommended groups was assumed to match that seen for the first (fall 2021) COVID-19 booster. Main outcomes and measures: Ensemble estimates of weekly and cumulative COVID-19 hospitalizations and deaths. Expected relative and absolute reductions in hospitalizations and deaths due to vaccination over the projection period. Results: From April 15, 2023-April 15, 2025, COVID-19 is projected to cause annual epidemics peaking November-January. In the most pessimistic scenario (high immune escape, no vaccination recommendation), we project 2.1 million (90% PI: 1,438,000-4,270,000) hospitalizations and 209,000 (90% PI: 139,000-461,000) deaths, exceeding pre-pandemic mortality of influenza and pneumonia. In high immune escape scenarios, vaccination of those aged 65+ results in 230,000 (95% CI: 104,000-355,000) fewer hospitalizations and 33,000 (95% CI: 12,000-54,000) fewer deaths, while vaccination of all eligible individuals results in 431,000 (95% CI: 264,000-598,000) fewer hospitalizations and 49,000 (95% CI: 29,000-69,000) fewer deaths. Conclusion and Relevance: COVID-19 is projected to be a significant public health threat over the coming two years. Broad vaccination has the potential to substantially reduce the burden of this disease. | Make paid
Background: Play is essential for the cognitive, social, and emotional development of all children. Disparities potentially exist in access to play for children with disabilities, and the extent of this inequity is unknown. Methods: Data from 212,194 children aged 2-4 years in 38 Low and Middle-Income Countries were collected in the UNICEF supported Multiple Indicator Cluster Survey (2017 - 2020). Disability was assessed by the Washington Group-Child Functioning Module. Logistic regression models were applied to investigate the relationship between disability and play opportunities, controlling for age, sex, and wealth status. Meta-analysis was used to pool the estimates (overall, and disaggregated by sex), with heterogeneity assessed by Cochran's Q test. Findings: Children with disabilities have approximately 9% fewer play opportunities than those without disabilities (adjusted RR [aRR] =0.88, 95%CI=0.82 - 0.93), and this varied across countries. Mongolia and Democratic Republic of Sao Tome and Principe had the lowest likelihood of play opportunities for children with disabilities ((aRR=0.26,95%CI=0.09 - 0.75; aRR=0.46, 95%CI=0.23 - 0.93, respectively). Moreover, children with disabilities are 17% less likely to be provided with opportunities to play with their mothers (aRR=0.83, 95%CI: 0.73 - 0.93), which is further reduced for girls with disabilities (aRR=0.74, 95% CI:0.60 - 0.90) compared to their peers without disabilities. The associations varied by impairment type, and children with communication and learning impairments are less likely to have opportunities for play with aRR of 0.69 (95%CI: 0.60 - 0.79) and 0.78 (95%CI:0.71 - 0.86), compared to those without disabilities, respectively. Interpretation: Children with disabilities are being left behind in their access to play and this is likely to have negative impacts on their overall development and well-being. | Make paid
Background: Frailty is a geriatric syndrome characterized by chronic inflammation and metabolic insufficiency that creates vulnerability to poor outcomes with aging. We hypothesize that geroscience interventions, which target mechanisms of aging, could ameliorate frailty. Metabolites such as ketone bodies are candidate geroscience interventions, having pleiotropic effects on inflammo-metabolic aging mechanisms. Ketone esters (KEs) induce ketosis without dietary changes, but KEs have not been studied in an older adult population. Our long-term goal is to examine if KEs modulate geroscience mechanisms and clinical outcomes relevant to frailty in older adults. Objectives: The primary objective of this randomized, placebo-controlled, double-blinded, parallel-group, pilot trial is to determine tolerability of 12-weeks of KE ingestion in a generalizable population of older adults ([≥] 65 years). Secondary outcomes include safety and acute blood ketone kinetics. Exploratory outcomes include physical function, cognitive function, quality of life, aging biomarkers and inflammatory measures. Methods: Community-dwelling adults who are independent in activities of daily living, with no unstable acute medical conditions (n=30) will be recruited. The study intervention is a KE or a taste, appearance, and calorie matched placebo beverage. Initially, acute 4-hour ketone kinetics after 12.5g or 25g of KE consumption will be assessed. After collection of baseline safety, functional, and biological measurements, subjects will randomly be allocated to consume KE 25g or placebo once daily for 12-weeks. Questionnaires will assess tolerability daily for 2-weeks, and then via phone interview at bi-monthly intervals. Safety assessments will be repeated at week 4. All measures will be repeated at week 12. Conclusion: This study will evaluate feasibility, tolerability, and safety of KE consumption in older adults and provide exploratory data across a range of geroscience-related endpoints. This data will inform design of larger trials to rigorously test KE effects on geroscience mechanisms and clinical outcomes relevant to frailty. | Make paid
OBJECTIVES: Disulfiram, a low-cost generic drug used for alcohol dependence, holds the potential to mitigate disease progression in patients with moderate COVID-19 by targeting inflammasomes. This study aimed to evaluate the clinical efficacy and safety of disulfiram when administered alongside standard of care for the treatment of hospitalized individuals with moderate COVID-19. DESIGN: A randomized, double-blind, placebo-controlled trial. SETTING: Conducted at four clinical sites in Brazil between December 2020 and August 2021. PARTICIPANTS: 140 participants aged 35 and older with laboratory-confirmed SARS-CoV-2 infection, hospitalized for [≤]5 days with moderate symptoms of COVID-19 were enrolled, 137 were randomized. INTERVENTION: Participants were randomized in a 1:1 ratio to receive a daily dose of 500 mg of disulfiram (N=68) or placebo (N=69) for 14 days while receiving the current standard of care. Randomization was stratified by age and comorbidities (hypertension, diabetes, and BMI [≥]35). MEASUREMENTS AND MAIN RESULTS The primary outcome, median time to clinical improvement [95% CI] did not significantly differ between groups (disulfiram: 3.5 [3.00, 4.00] days; placebo: 4 [3.00, 5.00] days; P=.73). Key secondary outcomes, such as mean days (SD) on supplemental oxygen [disulfiram: 4.4 (6.61) days; placebo: 3.7 (5.80) days, P=.34], median (95% CI) time to hospital discharge [disulfiram: 6.0 (5.00, 8.00) days, placebo: 5.0 (4.00, 7.00)], proportion of participants discharged by day 8 [disulfiram (68%), placebo (63%), odds ratio: 0.801], and proportion of participants who clinically worsened [disulfiram (21%), placebo (19%), P=.79], did not reveal significant differences. While the incidence of adverse events was higher in the disulfiram group, serious adverse events and 28-day mortality were comparable between the two groups. CONCLUSIONS Although disulfiram was found to be safe in hospitalized patients with moderate COVID-19, it did not shorten the time to clinical improvement. These findings do not support the use of disulfiram alongside standard of care in this patient population. TRIAL REGISTRATION ClinicalTrials.gov Identifier: NCT04594343 | Make paid
The dynamicity of the mitochondrial network is crucial for meeting the ever-changing metabolic and energy needs of the cell. Mitochondrial fission promotes the degradation and distribution of mitochondria, while mitochondrial fusion maintains mitochondrial function through the complementation of mitochondrial components. Previously, we have reported that mitochondrial networks are tubular, interconnected and well-organized in young, healthy C. elegans, but become fragmented and disorganized with advancing age and in models of age-associated neurodegenerative disease. In this work, we examine the effects of increasing mitochondrial fission or mitochondrial fusion capacity by ubiquitously overexpressing the mitochondrial fission gene drp-1 or the mitochondrial fusion genes fzo-1 and eat-3, individually or in combination. We then measured mitochondrial function, mitochondrial network morphology, physiologic rates, stress resistance and lifespan. Surprisingly, we found that overexpression of either mitochondrial fission or fusion machinery both resulted in an increase in mitochondrial fragmentation. Similarly, both mitochondrial fission and mitochondrial fusion overexpression strains have extended lifespans and increased stress resistance, which appears to be at least partially due to the upregulation of multiple stress response pathways in these strains. Overall, our work demonstrates that increasing the expression of mitochondrial fission or fusion genes extends lifespan and improves biological resilience without promoting the maintenance of a youthful mitochondrial network morphology. This work highlights the importance of the mitochondria for both resilience and longevity. | Make paid
Aged individuals and astronauts experience bone loss despite rigorous physical activity. Bone mechanoresponse is in-part regulated by mesenchymal stem cells (MSCs) that respond to mechanical stimuli. Direct delivery of low intensity vibration (LIV) recovers MSC proliferation in senescence and simulated microgravity models, indicating that age-related reductions in mechanical signal delivery within bone marrow may contribute to declining bone mechanoresponse. To answer this question, we developed a 3D bone marrow analog that controls trabecular geometry, marrow mechanics and external stimuli. Validated finite element (FE) models were developed to quantify strain environment within hydrogels during LIV. Bone marrow analogs with gyroid-based trabeculae of bone volume fractions (BV/TV) corresponding to adult (25%) and aged (13%) mice were printed using polylactic acid (PLA). MSCs encapsulated in migration-permissive hydrogels within printed trabeculae showed robust cell populations on both PLA surface and hydrogel within a week. Following 14 days of LIV treatment (1g, 100 Hz, 1 hour/day), type-I collagen and F-actin were quantified for the cells in the hydrogel fraction. While LIV increased all measured outcomes, FE models predicted higher von Mises strains for the 13% BV/TV groups (0.2%) when compared to the 25% BV/TV group (0.1%). Despite increased strains, collagen-I and F-actin measures remained lower in the 13% BV/TV groups when compared to 25% BV/TV counterparts, indicating that cell response to LIV does not depend on hydrogel strains and that bone volume fraction (i.e. available bone surface) directly affects cell behavior in the hydrogel phase independent of the external stimuli. Overall, bone marrow analogs offer a robust and repeatable platform to study bone mechanobiology. | Make paid
Aging is an inevitable process with senescence being one of its hallmarks. Recent advances have indicated that the elimination of senescent cells can reduce the signs of aging and increase healthy life span. Here, we identify a negative modulator of aging, Sprr1a, and in turn a negative modulator of Sprr1a, miR-130b. We show that reductions in Sprr1a levels, including via miR-130b expression, promotes cell senescence-like phenotype. We find that mediators of senescence, such as inflammatory cytokines and cell cycle regulators, are modulated by the miR-130b and Sprr1a-related pathway. For example, the levels of p16, p53 and p21 become decreased or increased upon the respective expression of Sprr1a versus miR-130b. Further, as shown in relation to p16 levels and {beta}-galactosidase levels, cells expressing Sprr1a exhibit significant protection from senescence-inducing factors such as radiation or Doxorubicin, suggesting that Sprr1a might contribute to protection against age-related pathologies. Taken together, we introduce two modulators of properties associated with senescence-like phenotype. | Make paid
Background: Depressive disorders, with a prevalence of 15 - 21%, are among the most common disorders in children and adolescents, and increases the risk of suicide, the second leading cause of death in children aged 10 to 19. Aim: To determine the prevalence and correlates of depressive disorders among senior students attending secondary schools in Abeokuta. Method: The study was conducted in five schools randomly selected from a representative sample and was carried out in 2 phases. In the first phase, students were selected via systematic random sampling and given consent forms and GHQ-12 to administer to the parents. In the second phase, students who returned a signed informed consent form and filled out GHQ-12 were interviewed using MINI-KID, Rosenberg's Self-Esteem Scale, Family-APGAR, and sociodemographic questionnaire. Multivariate regression analyses were conducted with p-value <0.05 as level of significance. Results: The mean age was 15.3 years (SD=1.27); 48.8% were male. The twelve-month prevalence of major depression was 11.3% and dysthymia was 1.4%. In the final regression analysis, female gender [OR=4.3, p=0.046], the experience of bullying [OR=7.96, p=0.004], difficulty getting along with friends, [OR=7.5, p=0.004], history of sexual abuse [OR=8.1, p=0.01], and perceived family dysfunction [OR=4.9, p=0,023] were found to be independent predictors of depressive disorders Conclusion: Depressive syndromes are a significant health burden in adolescents. Being female, being bullied, having a history of sexual abuse, and family dysfunctionality are risk factors associated with depression among these population. | Make paid
Background: The study objective was to estimate the incidence of COVID-19 infection, hospitalization, and deaths in Japan from September 2023 to August 2024 and potential impact of a Fall 2023 COVID-19 vaccine for adults 18 years and older on these outcomes. Methods: A previously developed Susceptible Exposed Infected Recovered model for the United States (US) was adapted to Japan. The numbers of symptomatic infections, COVID-19 related hospitalizations, and deaths were calculated. Given differences in vaccination coverage, masking practices and social mixing patterns between the US and Japan, all inputs were updated to reflect the Japanese context. Vaccine effectiveness (VE) values are hypothetical, but predicted based on existing VE values of bivalent BA.4/BA.5 boosters against BA.4/BA.5 in Japan, from the VERSUS test-negative case-control study. Sensitivity analyses were performed. Results: The base case model predicts overall that there will be approximately 35.2 million symptomatic COVID-19 infections, 690,000 hospitalizations, and 62,000 deaths in Japan between September 2023 and August 2024. If an updated COVID-19 vaccine is offered to all adults aged 18 years and older in Fall 2023, the model predicts that 7.3 million infections, 275,000 hospitalizations and 26,000 deaths will be prevented. If vaccines are only given to those aged 65 years and older, only 2.9 million infections, 180,000 hospitalizations and 19,000 deaths will be prevented. Sensitivity analysis results suggest that hospitalizations and deaths prevented are most sensitive to initial vaccine effectiveness (VE) against infection and hospitalizations, and the waning rate associated with VE against infection. Symptomatic infections prevented was most sensitive to initial VE against infection and VE waning. Conclusions: Results suggest that a Fall 2023 COVID-19 vaccine would reduce total numbers of COVID-19 related infections, hospitalizations, and deaths. | Make paid
Background: Cognitive impairment in older adults poses considerable challenges, and the role of family support becomes increasingly crucial. This study aims to examine the impact of children's residential proximity and spousal presence on the key modifiable risk factors for dementia among older adults with cognitive impairment. Methods: Utilizing the Health and Retirement Study (HRS) data from 1995 to 2018, we analyzed 14,731 participants (35,840 person-waves) aged 50 and older with cognitive impairment. Family support was characterized based on the presence of a spouse and residential proximity to children. Smoking, depressive symptoms and social isolation were included as the key modifiable risk factors for dementia identified in later life. Using mixed-effects logistic regressions, associations between access to family support and the modifiable risk factors were determined, adjusting for various socio-demographic and health-related factors. Results: Significant associations were found between access to family support and modifiable risk factors for dementia. Cognitively impaired older adults with less available family support, characterized by distant-residing children and the absence of a spouse, had significantly higher risks of smoking, depressive symptoms, and social isolation. Moreover, we revealed a consistent gradient in the prevalence of the risk factors based on the degree of family support. Relative to older adults with a spouse and co-resident children, those without a spouse and with all children residing further than 10 miles displayed the highest risks of smoking, depressive symptoms, and social isolation. Conclusion: Access to family support, particularly from spouses and proximate children, plays a protective role against key modifiable risk factors for dementia in older adults with cognitive impairment. The findings highlight the need for bolstering family and social support systems to enhance the well-being of this vulnerable population. | Make paid
Dementia has large impact on individuals' decision making, independent living, and wellbeing. Identifying early signals of dementia risk may offer people more time to prepare for the future, helping to delay the onset or slow the progression of dementia. Using the 1995-2018 waves of Health and Retirement Study, we offer novel evidence on the impacts of dementia on a rich set of preventive care utilization and health behaviors. Leveraging both within- and between-individual variations in an event study design, we characterize long-term dynamic changes in preventive care and health behaviors relative to the incidence of dementia and find early behavioral indicators of the disorder. We show that relative to the group of people who never develop dementia during the study periods, people with dementia have consistent and escalating declines in the use of cholesterol test, dental visit, prostate test and mammogram around the incidence of dementia. Significant declines are also found in physical activities and social engagement. Importantly, we demonstrate that the behavioral changes can occur up to 6 years before the incidence of dementia; and these patterns are absent in other chronic or acute conditions. The results are robust to sample selection, model specification, and the further control of aging and cohort effects. Overall, our findings highlight the salient impact of dementia risk on preventive care utilization and health behaviors, which may increase individuals' vulnerability to health shocks. Detecting early signals of dementia and facilitating targeted interventions are thus called for to prevent individuals from adverse behavioral and health consequences. | Make paid
Background Muscle mass loss may be associated with liver fat accumulation, yet scientific consensus is lacking and evidence in older adults is scant. It is unclear which muscle characteristics might contribute to this association in older adults. Methods We associated comprehensive muscle-related phenotypes including muscle mass normalized to body weight (D3-creatine dilution), muscle fat infiltration (MRI), carbohydrate-supported muscle mitochondrial maximal oxidative phosphorylation (respirometry), and cardiorespiratory fitness (VO2 peak) with liver fat among older adults. Linear regression models adjusted for age, gender, technician (respirometry only), daily minutes of moderate to vigorous physical activity, and prediabetes/diabetes status tested main effects and interactions of each independent variable with waist circumference (high: >/=88 cm for women, >/=102 cm for men) and gender. Results Among older adults aged 75 (IQR 73, 79 years; 59.8% women), muscle mass and liver fat were not associated overall but were positively associated among participants with a high waist circumference (Beta: 25.2; 95%CI 11.7, 40.4; p=.0002; N=362). Muscle fat infiltration and liver fat were positively associated (Beta: 15.2; 95%CI 6.8, 24.3; p=.0003; N=378). Carbohydrate-supported maximum oxidative phosphorylation and VO2 peak (adjusted Beta: -12.9; 95%CI -20.3, -4.8; p=0.003; N=361) were inversely associated with liver fat; adjustment attenuated the estimate for maximum oxidative phosphorylation although the point estimate remained negative (Beta: -4.0; 95%CI -11.6, 4.2; p=0.32; N=321). Conclusions Skeletal muscle-related characteristics are metabolically relevant factors linked to liver fat in older adults. Future research should confirm our results to determine whether trials targeting mechanisms common to liver and muscle fat accumulation are warranted. | Make paid
Cornelia de Lange Syndrome (CdLS) largely caused by mutation of the cohesin loader NIPBL is a rare developmental disorder affecting the formation of many organs. Besides a short body size and neurological defects, more than half of CdLS children feature various cardiac malformations. To mimic the disease and test a therapeutic strategy, we generated a C57/Bl6 Nipbl+/- mouse model of the disease. These mice featured a severe delay in both embryonic and postnatal growth. The Nipbl-deficient embryonic and neonatal hearts developed ventricular hypertrophy, aortic and valve defects associated with a persistent truncus arteriosus and a ventricular septal defect. Muscles derived from the second heart field were deficient in the Nipbl haplo-insufficient mouse embryos. The adult hearts then featured a severe aortic senescence phenotype and a stenosis resulting in an increase in aortic flux velocity and persistent left ventricular hypertrophy. Using proteomics and RNA-sequencing in embryos, we identified a dysregulated TGFb pathway in the outflow tract of embryonic hearts as well as the presence of senescent cells as early as in E13.5 Nipbl+/- embryonic hearts, limb primordium cartilage as well as in different post-natal tissues including muscle and brain cortex. Treatment of pregnant Nipbl+/- mice with a TGFbR (ALK5) inhibitor from E9.5 to E13.5 prevented cell -senescence and rescued the cardiac phenotype as well as the body size of mice at birth. Altogether our data revealed that an exacerbated TGFFb pathway associated with cell senescence is at the origin of many defects in a CdL mouse model. This druggable pathway opens the path toward a potential preventive and/or therapeutic strategy for post-natal CdLS patients. | Make paid
The complement system can be viewed as a "moderator" of innate immunity, "instructor" of humoral immunity, and "regulator" of adaptive immunity. While sex and aging are known to affect humoral and cellular immune systems, their impact on the complement pathway in humans and rhesus macaques, a commonly used non-human primate model system, have not been well-studied. To address this knowledge gap, we analyzed serum samples from 90 humans and 75 rhesus macaques for the abundance and activity of the complement system components. While sequences of cascade proteins were highly conserved, dramatically different levels were observed between species. Whereas the low levels detected in rhesus samples raised questions about the suitability of the test, differences in levels of complement proteins were observed in male and female humans. Levels of total and antibody-dependent deposition of C1q and C3b on a glycosylated antigen differed between human and rhesus, suggesting differential recognition of glycans. Functional differences in complement-mediated lysis of antibody-sensitized cells were observed in multiple assays and showed that human females frequently exhibited higher lytic activity than human males or rhesus macaques, which typically did not exhibit such sexual dimorphism. Other differences between species and sexes were observed in more narrow contexts, such as for only certain antibodies, antigens, or assays. Collectively, these results expand our knowledge of sexual dimorphism in the complement system in humans, identifying differences that appear to be absent from rhesus macaques. | Make paid
Vaccination strategies in mice inducing high numbers of memory CD8 T cells specific to a single epitope are able to provide sterilizing protection against infection with Plasmodium sporozoites. We have recently found that Plasmodium-specific CD8 T cells cluster around sporozoite-infected hepatocytes but whether such clusters are important in elimination of the parasite remains incompletely understood. Here we used our previously generated data in which we employed intravital microscopy to longitudinally image 32 GFP-expressing Plasmodium yoelii parasites in livers of mice that had received activated Plasmodium-specific CD8 T cells after sporozoite infection. We found great heterogeneity in the dynamics of the normalized GFP signal from the parasites (termed '' index''or VI) that was weakly correlated with the number of T cells near the parasite. We also found that a simple model assuming mass-action, additive killing by T cells well describes the VI dynamics for most parasites predicting highly variable killing efficacy of individual T cells. Given the estimated median per capita kill rate of k = 0.031/h we predict that a single T cell is typically incapable to kill the the parasite within 48 hour lifespan of the liver stage. Stochastic simulations of T cell clustering and killing of the liver stage also suggested that 1) three or more T cells per liver stage are required to ensure sterilizing protection; 2) both variability in killing efficacy of individual T cells and resistance to killing by individual parasites may contribute to the observed variability in VI decline, and 3) stable VI of some clustered parasites cannot be explained by measurement noise. Taken together, our analysis for the first time provides estimates of efficiency at which individual CD8 T cells eliminate intracellular infection in vivo. | Make paid
Background: A child's socioeconomic environment can shape central aspects of their life, including vulnerability to mental disorders. Negative environmental influences in youth may interfere with the extensive and dynamic brain development occurring at this time. Indeed, there are numerous yet diverging reports of associations between parental socioeconomic status (SES) and child cortical brain morphometry. Most of these studies have used single metric- or unimodal analyses of standard cortical morphometry that downplay the probable scenario where numerous biological pathways in sum account for SES-related cortical differences in youth. Methods: To comprehensively capture such variability, using data from 9758 children aged 8.9-11.1 years from the ABCD Study, we employed linked independent component analysis (LICA) and fused vertex-wise cortical thickness, surface area, curvature and grey-/white-matter contrast (GWC). LICA revealed 70 uni- and multimodal components. We then assessed the linear relationships between parental education, parental income and each of the cortical components, controlling for age, sex, genetic ancestry, and family relatedness. We also assessed whether cortical structure moderated the negative relationships between parental SES and child general psychopathology. Results: Parental education and income were both associated with larger surface area and higher GWC globally, in addition to local increases in surface area and to a lesser extent bidirectional GWC and cortical thickness patterns. The negative relation between parental income and child psychopathology were attenuated in children with a multimodal pattern of larger frontal- and smaller occipital surface area, and lower medial occipital thickness and GWC. Conclusion: Structural brain MRI is sensitive to SES diversity in childhood, with GWC emerging as a particularly relevant marker together with surface area. In low-income families, having a more developed cortex across MRI metrics, appears beneficial for mental health. | Make paid
Background Frailty, a syndrome of physiologic vulnerability, increases cardiovascular disease (CVD) risk. Whether in person or automated frailty tools are ideal for identifying CVD risk remains unclear. We calculated three distinct frailty scores and examined their associations with mortality and CVD events in the Million Veteran Program (MVP). Methods MVP is a prospective cohort of U.S. Veterans that has enrolled nearly one million Veterans. We included participants aged [≥]50 years who enrolled from 2011-2018. Frailty was calculated using three tools: two frailty indices (FI) based on the accumulation of deficits theory, the 36-item MVP-FI using self-reported answers to questionaries, and the 31-item VA-FI developed using claims data. Finally, we calculated the 3-item Study of Osteoporotic Fractures Fried physical frailty score from self-report. The primary outcomes were CVD and all-cause mortality. Multivariable-adjusted Cox proportional hazards models (adjusted for age, sex, smoking, statin use, antihypertensive use, hyperlipidemia, and survey year). Secondary outcomes were myocardial infarction (MI), stroke, and heart failure (HF). Results Among 190,688 MVP participants (mean age 69 {+/-}9 years, 94% male, 85% white), there were 33,233 (17%) all-cause and 10,115 (5%) CVD deaths. Using MVP-FI, 29% were robust, 42% pre-frail, and 29% frail. Frailty prevalence increased by age group, from 27% in 50-59-year-olds to 42% in age?90 years. Follow-up duration was 6{+/-}2 years. Using the MVP-FI, pre-frail and frail Veterans had a higher incidence of both all-cause mortality (pre-frail: HR=1.66, 95%CI: 1.61-1.72; frail: 3.05, 2.95-3.16) and CVD death (pre-frail: 1.76, 1.65-1.88; frail: 3.65, 3.43-3.90), as compared to robust individuals. These findings remained significant among Veterans [≥] 50 years. Findings were similar for CVD events. When frailty was measured using the VA-FI and SOF results were concordant. Conclusion Irrespective of frailty measure used, frailty is associated with a higher risk of all-cause mortality and CVD events. Further study of frailty in individuals <60 years old is warranted. | Make paid
Aims: To assess parental awareness of respiratory syncytial virus (RSV) and the level of acceptance of future RSV prevention strategies. Methods: A cross-sectional online survey was implemented targeting 'future' and 'current' parents of children aged [≤]5 years in Australia. Results: From 1,992 eligible participants, two non-mutually exclusive subgroups were formed; 'current' parents (N=1931) and 'pregnant/planning' parents (N=464; 403 also 'current' parents; 61 'future' parents). Participants were predominantly (86.6%) aged 25-39 years and 68.5% with university education. The majority (89.6% current; 78.7% future) had heard of RSV. Of those, 64.2% (current) and 50.0% (future) were aware that pneumonia is associated with RSV; 71.8% (current) and 52.1% (future) were aware that bronchiolitis is associated. In multivariable logistic regression analyses, Australian-born parents (aOR=2.47 [95%CI:1.48-4.12]), living in the Eastern States (e.g., New South Wales: aOR=6.15 [95%CI:2.10-18.04]), with a university level education (aOR=2.61 [95%CI:1.38-4.94]) and being a current parent (aOR=12.26 [95%CI:2.82-53.28]) were associated with higher RSV awareness. There was a high level of acceptance for maternal vaccines (future: 79.3%) and infant immunisation (all: 81.7%). Conclusion: While RSV awareness and immunisation acceptance was high, there was limited knowledge of severity of RSV, especially in future parents. Education campaigns need to be developed to increase RSV knowledge. | Make paid
Background: Chronic inflammation initiated by inflammatory monocytes underlies the pathogenesis of atherosclerosis. However, approaches that can effectively resolve chronic low-grade inflammation targeting monocytes are not readily available. The small chemical compound 4-phenylbutyric acid (4-PBA) exhibits broad anti-inflammatory effects in reducing atherosclerosis. Selective delivery of 4-PBA reprogrammed monocytes may hold novel potential in providing targeted and precision therapeutics for the treatment of atherosclerosis. Methods: Systems analyses integrating single-cell RNA-sequencing and complementary immunological approaches characterized key resolving characteristics as well as defining markers of reprogrammed monocytes trained by 4-PBA. Molecular mechanisms responsible for monocyte reprogramming was assessed by integrated biochemical and genetic approaches. The inter-cellular propagation of homeostasis resolution was evaluated by co-culture assays with donor monocytes trained by 4-PBA and recipient naive monocytes. The in vivo effects of monocyte resolution and atherosclerosis prevention by 4-PBA were assessed with the high fat diet-fed ApoE-/- mouse model with i.p. 4-PBA administration. Furthermore, the selective efficacy of 4-PBA trained monocytes were examined by i.v. transfusion of ex vivo trained monocytes by 4-PBA into recipient high fat diet-fed ApoE-/- mice. Results: In this study, we found that monocytes can be potently reprogrammed by 4-PBA into an immune-resolving state characterized by reduced adhesion and enhanced expression of anti-inflammatory mediator CD24. Mechanistically, 4-PBA reduced the expression of ICAM-1 via reducing peroxisome stress and attenuating SYK-mTOR signaling. Concurrently, 4-PBA enhanced the expression of resolving mediator CD24 through promoting PPAR{gamma} neddylation mediated by TOLLIP. 4-PBA trained monocytes can effectively propagate anti-inflammation activity to neighboring monocytes through CD24. Our data further demonstrated that 4-PBA trained monocytes effectively reduce atherosclerosis pathogenesis when administered in vivo. Conclusion: Our study describes a robust and effective approach to generate resolving monocytes, characterizes novel mechanisms for targeted monocyte reprogramming, and offers a precision-therapeutics for atherosclerosis based on delivering reprogrammed resolving monocytes. | Make paid
Gestation length, or the duration of pregnancy, is a critical component of mammalian reproductive biology. Eutherian mammals exhibit striking variation in their gestation lengths, which has traditionally been linked to and allometrically scales with variation in other life history traits, including body mass and lifespan. How the phenotypic landscape of gestation length variation, including its associations with body mass and lifespan variation, changed over mammalian evolution remains unknown. Phylogeny-informed analyses of 845 representative extant eutherian mammals showed that gestation length variation substantially differed in both whether and how strongly it was associated with body mass and lifespan across mammalian clades. For example, gestation length variation in Chiroptera and Cetacea was not associated with lifespan or body mass but was strongly associated only with body mass in Carnivora. We also identified 52 adaptive shifts in gestation length variation across the mammal phylogeny and 14 adaptive shifts when considering all three life history traits; the placements of six adaptive shifts are common in the two analyses. Notably, two of these shifts occurred at the roots of Cetacea and Pinnipedia, respectively, coinciding with the transition of these clades to the marine environment. The varying dynamics of the phenotypic landscape of gestation length, coupled with the varying patterns of associations between gestation length and two other major life history traits, raise the hypothesis that evolutionary constraints on gestation length have varied substantially across mammalian phylogeny. This variation in constraints implies that the genetic architecture of gestation length differs between mammal clades. | Make paid
Patients diagnosed with non-small cell lung cancer have a limited lifespan and exhibit poor immunotherapy outcomes. M1 macrophages have been found to be essential for anti-tumor immunity. This study aimed to develop an immunotherapy response evaluation model for NSCLC patients based on transcriptional expression. RNA sequencing profiles of 254 advanced-stage NSCLC patients treated with immunotherapy were downloaded from POPLAR and OAK projects. Immune cell infiltration in NSCLC patients has been examined, and thereafter different co-expressed genes were identified. Following that, the impact of M1 macrophage related genes on the prognosis of NSCLC patients was investigated. Six M1 macrophage co-expression genes, namely NKX2-1, CD8A, SFTA3, IL2RB, IDO1, and CXCL9, exhibited a strong association with the prognosis of NSCLC and served as effective predictors for immunotherapy response. A response model was constructed using Cox regression model and Lasso Cox regression analysis. The M1 genes were validated on our previous TD-FOREKNOW NSCLC clinical trial by RT-qPCR. The response model showed excellent immunotherapy response predicting and prognosis evaluating value in advanced stage of NSCLC. The model can effectively predict advanced NSCLC prognosis and aid in identifying patients who could benefit from customized immunotherapy as well as sensitive drugs. | Make paid