Introduction: The prevalence of frailty is on the rise with the aging population and increasing life expectancy, which often is accompanied by comorbidities. Frailty can be effectively detected using Frailty index such as KCL index. Early detection of frailty allows applying measures that reduce the conversion rate to frail, and improve the quality of life in the frail people. Therefore, to facilitate the screening of frailty status at the primary care level, we suggest to produce a shorter version of the KCL questionnaire. Aim: To understand the importance of KCL components in the decision making process for frailty and use machine learning approach to shorten the Questionnaire while maintaining reasonable accuracy, making it easier to screen for frailty in primary care. Methods: We developed an automated framework of three steps: Feature importance determination using Shap values, testing models with Cross-validation with increased addition of selected features. Moreover, we validated the reliability of KCL to detect frailty by comparing the results of KCL criteria with the unsupervised clustering of the data. Results: Our approach allowed us to identify the most important questions in the KCL questionnaire and demonstrate its performance using a short version with only four questions (4) Do you visit homes of friends?, (6) Are you able to go upstairs without using handrails or the wall for support? (10) Do you feel anxious about falling when you walk?, and (25) (In the past two weeks) Have you felt exhausted for no apparent reason?). We also showed that the data clustering corresponds well with the results of KCL criteria. Discussion and Conclusion: While it is difficult to predict pre-frail status using shorter KCL questionnaire, it was shown to be fairly accurate in predicting frail status using only four questions. | Make paid
Chronological age is a major risk factor for numerous diseases. However, chronological age does not capture the complex biological aging process. Biological aging can occur at a different pace in individuals of the same chronological age. Therefore, the difference between the chronological age and biologically driven aging could be more informative in reflecting health status. Metabolite levels are thought to reflect the integrated effects of both genetic and environmental factors on the rate of aging, and may thus provide a stronger signature for biological age than those previously developed using methylation and proteomics. Here, we set out to develop a metabolomic age prediction model by applying ridge regression and bootstrapping with 826 metabolites (of which 678 endogenous and 148 xenobiotics) measured by an untargeted high-performance liquid chromatography mass spectrometry platform (Metabolon) in 11,977 individuals (50.2% men) from the INTERVAL study (Cambridge, UK). Participants of the INTERVAL study are relatively healthy blood donors aged 18-75 years. After internal validation using bootstrapping, the models demonstrated high performance with an adjusted R2 of 0.82 using the endogenous metabolites only and an adjusted R2 of 0.83 when using the full set of 826 metabolites with age as outcome. The latter model performance could be indicative of xenobiotics predicting frailty. In summary, we developed robust models for predicting metabolomic age in a large relatively healthy population with a wide age range. | Make paid
Background Social media may influence children and young peoples health behaviour, including smoking and e-cigarette use. Methods We analysed data from participants aged 10-25 in the UK Household Longitudinal Study 2015-2022. The amount of social media use reported on a normal weekday, was related to current tobacco smoking and e-cigarette use. Generalised Estimating Equation (GEE) logistic regression models investigated associations of social media use with tobacco and e-cigarette use. Models controlled for possible confounders including age, sex, country of UK, ethnicity, household income and use of tobacco/e-cigarettes by others within the home. Results Among 10,808 participants with 27,962 observations, current tobacco smoking was reported by 2,237 (20.7%) at least one time point, and current e-cigarette use by 1,013 participants (9.4%). In adjusted GEE models, increasing use of social media was associated with greater odds of current smoking and this was particularly apparent at higher levels of use (AOR 3.11, CI 2.41 - 4.03 for more than 7hours/day vs no use). Associations were similar for e-cigarettes, e.g. OR = 3.04, CI 2.11-4.40 for more than 7hours social media use versus none). Conclusions Social media use is associated with an increased risk of e-cigarette and tobacco use, reinforcing the need for policies to address this as an avenue for marketing to children and young people. | Make paid
Background Current primary care cognitive assessment tools are either crude or time-consuming instruments that can only detect cognitive impairment when it is well established. This leads to unnecessary or late referrals to memory services, by which time the disease may have already progressed into more severe stages. Due to the COVID-19 pandemic, some memory services have adapted to the new environment by shifting to remote assessments of patients to meet service user demand. However, the use of remote cognitive assessments has been inconsistent, and there has been little evaluation of the outcome of such a change in clinical practice. Emerging research has highlighted computerised cognitive tests, such as the Integrated Cognitive Assessment (ICA), as the leading candidates for adoption in clinical practice. This is true both during the pandemic and in the post-COVID-19 era as part of healthcare innovation. Objectives The Accelerating Dementias Pathways Technologies (ADePT) Study was initiated in order to address this challenge and develop a real-world evidence basis to support the adoption of ICA as an inexpensive screening tool for the detection of cognitive impairment and improving the efficiency of the dementia care pathway. Methods Ninety-nine patients aged 55-90 who have been referred to a memory clinic by a general practitioner (GP) were recruited. Participants completed the ICA either at home or in the clinic along with medical history and usability questionnaires. The GP referral and ICA outcome were compared with the specialist diagnosis obtained at the memory clinic. Participants were given the option to carry out a retest visit where they were again given the chance to take the ICA test either remotely or face-to-face. Results The primary outcome of the study compared GP referral with specialist diagnosis of MCI/dementia. Of those the GP referred to memory clinics, 78% were necessary referrals, with ~22% unnecessary referrals, or patients who should have been referred to other services as they had disorders other than MCI/dementia. In the same population the ICA was able to correctly identify cognitive impairment in ~90% of patients, with approximately 9% of patients being false negatives. From the subset of unnecessary GP referrals, the ICA classified ~72% of those as not having cognitive impairment, suggesting that these unnecessary referrals may not have been made if the ICA was in use. Conclusions The results from this study demonstrate the potential of the ICA as a screening tool, which can be used to support accurate referrals from primary care settings, along with the work conducted in memory clinics and in secondary care. | Make paid
Background Malaria transmission modelling has demonstrated the potential impact of semi-quantitative glucose-6-phosphate dehydrogenase (G6PD) testing and treatment with single-dose tafenoquine for Plasmodium vivax radical cure. This modelling has focused on predicting the number of vivax cases averted, rather than its cost-effectiveness. Methods We explored the cost-effectiveness of using tafenoquine after G6PD screening as compared to usual practice (7-day low-dose primaquine (0.5 mg/kg/day) without G6PD screening) in Brazil using a 10-year time horizon with 5% discounting considering four scenarios: 1) tafenoquine for adults only assuming 66.7% primaquine treatment adherence, 2) tafenoquine for adults and children aged >2 years assuming 66.7% primaquine adherence, 3) tafenoquine for adults only assuming 90% primaquine adherence, 4) tafenoquine for adults only assuming 30% primaquine adherence. The incremental cost-effectiveness ratios (ICERs) were estimated by dividing the incremental costs by the disability-adjusted life-years (DALYs) averted. These were compared to a willingness to pay threshold of US$7,800 for Brazil, and one-way and probabilistic sensitivity analyses were performed. Results All four scenarios were cost-effective using this willingness to pay threshold with ICERs ranging from US$154-1836. One-way sensitivity analyses showed that the results were most sensitive to severity and mortality due to vivax malaria, the lifetime and number of semi-quantitative G6PD analysers needed, cost per malaria episode and per G6PD test strips, and life expectancy. All scenarios had a 100% likelihood of being cost-effective at the willingness to pay threshold. Conclusions Tafenoquine prescribed after a semi-quantitative G6PD testing is highly likely to be cost-effective in Brazil. | Make paid
To assess the association between sleep and seroconversion after receipt of two doses of inactivated severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) vaccines in pregnant women. The serum level of immunoglobulin (Ig)G antibodies against the nucleic acids of SARS-CoV-2 was measured. Logistic regression was used to analyze the association between sleep and seroconversion. After two doses of SARS-CoV-2 vaccine, 41.2% of the study cohort reached seroconversion. Analysis revealed that pregnant women with poor quality of sleep had a lower serum level of IgG antibodies (P = 0.008, 95%CI = 0.285-0.826) and that sleeping late at night (SLaN) may be a risk factor for a low serum level of IgG antibodies (P = 0.025, 95%CI = 0.436-0.946). Besides sleep, age and the time since vaccination were important influences on seroconversion. A stratified analysis revealed that the effects of sleep quality and SLaN on seroconversion occurred mainly in pregnant women aged <35 years. Thus, sleep quality and SLaN can affect the serum level of IgG antibodies in pregnant women after vaccination with inactivated SARS-CoV-2. | Make paid
In the current decade missions to the Earths moon are of scientific and societal interest, however pose the problem of risks of late effects for returning crew persons, most importantly cancer and circulatory diseases. In this paper, we discuss NSCR-2022 model risk estimates for lunar missions for US racial and ethnic groups comparing never-smokers to US averages for each group and sex. We show that differences within groups between men and women are largely reduced for NS compared to the average population. Race and ethnic group dependent cancer and circulatory disease risks are reduced by 10% to 40% for NS with the largest decrease for Whites. Circulatory disease risks are changed by less than 10% for NS and in several cases modestly increased due to increased lifespan for NS. Asian-Pacific Islander (API) and Hispanics NS are at lower risk compared to Whites and Blacks. Differences between groups is narrowed for NS compared to predictions for average populations, however disparities remain especially for Blacks and to a lesser extent Whites compared to API or Hispanic NS groups. | Make paid
Background Hypertension is a major cause of morbidity and mortality worldwide. Previous efforts to characterize gaps in the hypertension care continuum in India - including diagnosis, treatment, and control - did not assess district level variation. Local data are critical for planning, implementation, and monitoring efforts to curb hypertension burdens. Our objective is to characterize the hypertension care continuum in India among individuals aged 18-98 years old at national, state, and district levels and by socio-demographic group. Methods Data were from 1,895,297 individuals in the nationally representative Fifth National Family Health Survey (NFHS-5), 2019-21. Hypertension was defined as self-reported diagnosis or newly measured blood pressure [≥]140/90 mmHg. Among those with hypertension, we calculated the proportion diagnosed (self-reported). Among those with diagnosed hypertension, we computed the proportion treated (self-reported medication use). Among those treated, we calculated the proportion controlled (BP <140/90 mmHg [20-80 years] or <150/90 mmHg [>80 years]) based on national guidelines. Estimates were also provided among the total with hypertension. To assess differences in the care continuum between or within states (i.e. between districts), we partitioned the variance at both levels using linear mixed models. Results Among 1,691,109 adult respondents nationally (52.6% female; mean age: 41.6 years), 28.2% [95%CI: 28.0-28.4] had hypertension, of whom, 36.7% [36.3- 37.2] were diagnosed. Among those diagnosed, 44.7% [44.1-45.3] reported taking medication (17.7% [17.5-17.9] of total with hypertension). Among those treated, 52.3% [51.4-53.1] had blood pressure control (9.1% [8.9-9.2] of total with hypertension). There were substantial variations across districts in diagnosis [range: 6.3-77.5%], treatment [8.7-97.1%] and control [2.7-76.6%]. Notably, large proportions of the variation in hypertension diagnosis (53.7%), treatment (32.8%), and control (57.7%) were within states, not just between states. Conclusions In India, more than 1 in 4 people have hypertension, and of these, only 1 in 3 are diagnosed, less than 1 in 5 are treated, and only 1 in 11 controlled. National averages hide considerable state- and district-level variation in the care continuum, implying the need for targeted, decentralized solutions to improve the hypertension care continuum in India. | Make paid
The COVID-19 pandemic began impacting Europe in early 2020, posing significant challenges for individuals requiring care. This group is particularly susceptible to severe COVID-19 infections and depends on regular health care services. In this article, we examine the situation of European care recipients aged 50 years and older 18 months after the pandemic outbreak and compare it to the initial phase of the pandemic. In the descriptive section, we illustrate the development of (unmet) care needs and access to health care throughout the pandemic. Additionally, we explore regional variations in health care receipt across Europe. In the analytical section, we shed light on the mid- and long-term health consequences of COVID-19-related restrictions on accessing health care services by making comparisons between care recipients and individuals without care needs. We conducted an analysis using data from the representative Corona Surveys of the Survey of Health, Ageing and Retirement in Europe (SHARE). Our study examines changes in approximately 3,400 care-dependent older Europeans (aged 50+) interviewed in 2020 and 2021, comparing them with more than 45,000 respondents not receiving care. The dataset provides a cross-national perspective on care recipients across 27 European countries and Israel. Our findings reveal that in 2021, compared to the previous year, difficulties in obtaining personal care from someone outside the household were significantly reduced in Western and Southern European countries. Access to health care services improved over the course of the pandemic, particularly with respect to medical treatments and appointments that had been canceled by health care institutions. However, even 18 months after the COVID-19 outbreak, a considerable number of treatments had been postponed either by respondents themselves or by health care institutions. These delayed medical treatments had adverse effects on the physical and mental health of both care receivers and individuals who did not rely on care. | Make paid
Introduction Oral health-promoting school programs play a crucial role in achieving universal coverage of oral health care by addressing oral diseases and promoting the well-being and quality of life of children and adolescents. However, a lack of studies has evaluated the costs associated with implementing these programs, which hinders decision-makers in adopting them on a large scale. This review aims to assess the cost components involved in school-based oral health-promoting programs. Methods This review will include studies that have conducted either partial or full economic evaluations, focusing on describing the cost components of oral health-promoting programs implemented in primary schools involving students aged 6 to 14. A systematic search was conducted across multiple databases: MEDLINE, The Cochrane Library, the Virtual Health Library, the NHS Economic Evaluation Database, Web of Science, Scopus, and EMBASE. Additionally, gray literature was searched using the Health Technology Assessment Database. Two independent reviewers will screen the titles and abstracts, followed by a full-text review based on predefined inclusion criteria. Data extraction and critical appraisal evaluation will also be carried out independently by two reviewers. In case of disagreements, the reviewer team will resolve them through discussion. Discussion The systematic review resulting from this protocol aims to provide evidence regarding the cost components and necessary resources for implementing and maintaining oral health-promoting school programs. This information can assist decision-makers in adopting these programs on a larger scale and effectively addressing oral diseases among children and adolescents. | Make paid
Background. Debates on the allocation of medical resources during the COVID-19 pandemic revealed the need for a better understanding of immunologic risk. Studies highlighted variable clinical outcomes of SARS-CoV-2 infections in individuals with defects in both adaptive and innate immunity, suggesting additional contributions from other factors. Notably, none of these studies controlled for variables linked with social determinants of health. Objective. To determine the contributions of determinants of health to risk of hospitalization for SARS-CoV-2 infection among individuals with inborn errors of immunodeficiencies. Methods. This is a retrospective, single-center cohort study of 166 individuals with inborn errors of immunity, aged two months through 69 years, who developed SARS-CoV-2 infections from March 1, 2020 through March 31, 2022. Risks of hospitalization was assessed using a multivariable logistic regression analysis. Results. The risk of SARS-CoV-2-related hospitalization was associated with underrepresented racial and ethnic populations (odds ratio [OR] 5.29; confidence interval [CI], 1.76-17.0), a diagnosis of any genetically-defined immunodeficiency (OR 4.62; CI, 1.60-14.8), use of B cell depleting therapy within one year of infection (OR 6.1; CI, 1.05-38.5), obesity (OR 3.74; CI, 1.17-12.5), and neurologic disease (OR 5.38; CI, 1.61-17.8). COVID-19 vaccination was associated with reduced hospitalization risk (OR 0.52; CI, 0.31-0.81). Defective T cell function, immune-mediated organ dysfunction, and social vulnerability were not associated with increased risk of hospitalization after controlling for covariates. Conclusions. The associations between race, ethnicity, and obesity with increased risk of hospitalization for SARS-CoV-2 infection indicate the importance of variables linked with social determinants of health as immunologic risk factors for individuals with inborn errors of immunity. | Make paid
Background: Paternal aging has been consistently linked to an increased risk of neurodevelopmental disorders, including autism spectrum disorder (ASD), in offspring. While de novo mutations arising from paternal aging have been extensively studied, recent evidence has highlighted the role of epigenetic factors. We have previously revealed age-related DNA hypomethylation in mouse sperm and alterations in histone modifications during spermatogenesis. Objectives: This study aimed to investigate age-related alterations in the microRNA (miRNA) profile of mouse sperm and analyze the target genes regulated by differentially expressed miRNAs. Materials and Methods: Microarray analyses were conducted to identify differentially expressed miRNAs in sperm samples from mice at different ages: 3 months (3M), over 12M, and beyond 20M. The expression levels of genes potentially regulated by these miRNAs were also accessed. Comprehensive bioinformatic analyses were performed to unravel the intricate relationship between differentially expressed miRNAs and their target genes. Results: We identified 26 miRNAs exhibiting differential expression between the 3M and 20M, 34 miRNAs between the 12M and 20M, and 2 miRNAs between the 3M and 12M mice. Notably, the target genes regulated by these differentially expressed miRNAs were significantly associated with apoptosis and ferroptosis pathways. Some of these target genes were relevant to the nervous system and potentially involvement in ASD. Discussion: The findings suggest that aging induces alterations in the sperm miRNA profiles . Importantly, the target genes regulated by these differentially expressed miRNAs are associated with cell death and ASD, implying a potential link between paternal aging and an increased risk of neurodevelopmental disorders. Conclusion: The observed age-related changes in sperm miRNA profiles have the potential to impact sperm quality and subsequently affect offspring development. Further validation and through investigations are necessary to gain a comprehensive understanding of the precise effects of paternal aging on subsequent generations. | Make paid
Progressive Tau deposition in neurofibrillary tangles and neuropil threads is the hallmark of tauopathies, a disorder group that includes Alzheimer's disease. Since Tau is a microtubule-associated protein, a prevalent concept to explain the pathogenesis of tauopathies is that abnormal Tau modification contributes to dissociation from microtubules, assembly into multimeric {beta}-sheets, proteotoxicity, neuronal dysfunction and cell loss. Tau also localizes in the cell nucleus and evidence supports an emerging function of Tau in DNA stability and epigenetic modulation. To better characterize the possible role of Tau in regulation of chromatin compaction and subsequent gene expression, we performed a bioinformatics analysis of transcriptome data obtained from Tau-depleted human neuroblastoma cells. Among the transcripts deregulated in a Tau-dependent manner, we found an enrichment of target genes for the polycomb repressive complex 2. We further describe decreased cellular amounts of the core components of the polycomb repressive complex 2 complex and a lower histone 3 trimethylation activity in Tau deficient cells. Among the de-repressed polycomb repressive complex 2 target gene products, IGFBP3 protein was found to be linked to increased senescence induction in Tau-deficient cells. Our findings propose a mechanism for Tau-dependent epigenetic modulation of cell senescence, a key event in pathologic aging. | Make paid
Genome-wide association studies have advanced our understanding of complex traits, but studying how a GWAS variant can affect a specific trait in the human population remains challenging due to environmental variability. Drosophila melanogaster is in this regard an excellent model organism for studying the relationship between genetic and phenotypic variation due to its simple handling, standardized growth conditions, low cost, and short lifespan. The Drosophila Genetic Reference Panel (DGRP) in particular has been a valuable tool for studying complex traits, but proper harmonization and indexing of DGRP phenotyping data is necessary to fully capitalize on this resource. To address this, we created a web tool called DGRPool (dgrpool.epfl.ch), which aggregates phenotyping data of 935 phenotypes across 125 DGRP studies in a common environment. DGRPool enables users to download data and run various tools such as genome-wide association analyses (GWAS) and Phenome-WAS analyses. As a proof-of-concept, DGRPool was used to study the longevity phenotype and uncovered both established and unexpected correlations with other phenotypes such as locomotor activity, sleep duration, and oxidative stress resistance. DGRPool has the potential to facilitate new genetic and molecular insights of complex traits in Drosophila and serve as a valuable, interactive tool for the scientific community. | Make paid
Population-averaged brain atlases, that are represented in a standard space with anatomical labels, are instrumental tools in neurosurgical planning and the study of neurodegenerative conditions. Traditional brain atlases are primarily derived from anatomical scans and contain limited information regarding the axonal organization of the white matter. With the advance of diffusion MRI that allows the modelling of fiber orientation distribution (FOD) in the brain tissue, there is an increasing interest for a population-averaged FOD template, especially based on a large healthy aging cohort, to offer structural connectivity information for connectomic surgery and analysis of neurodegeneration. The dataset described in this article contains a set of multi-contrast structural connectomic MRI atlases, including T1w, T2w, and FOD templates, along with the associated whole brain tractograms. The templates were made using multi-contrast group-wise registration based on 3T MRIs of 422 Human Connectome Project in Aging (HCP-A) subjects. To enhance the usability, probabilistic tissue maps and segmentation of 22 subcortical structures are provided. Finally, the subthalamic nucleus shown in the atlas is parcellated into sensorimotor, limbic, and associative sub-regions based on their structural connectivity to facilitate the analysis and planning of deep brain stimulation procedures. The dataset is available on the OSF Repository: https://osf.io/p7syt. | Make paid
Aim To investigate sex differences in the aortic aging by analyzing aortic diameter and tortuosity in different segments of aorta across the age spectrum, using enhanced CT imaging. Method Between July 2021 and April 2022, a retrospective study screened patients with chest and abdomen contrast CT images. The outer edge-to-outer edge method was utilized to measure aortic diameters at five aortic levels, while arterial tortuosity of various segments was measured and calculated using imaging software. Mean values were compared at different age groups, including by sex, and correlation with age was determined. To validate the coherence of arterial elasticity and anticipated age-related arterial alterations, a subset of data from a previously published article in BMJ Open was extracted for the purpose of examining the correlation between age and arterial stiffness, stratified by sexes. Results 208 participants (56.6% men, mean age 60.13{+/-}16.33 years old, mean BMI 23.07{+/-}4.03 kg/m2, mean BSA 1.70{+/-}0.19 m2) were enrolled in this study. The BSA-adjusted aortic diameters showed a positive correlation with age in both sexes, but females demonstrated a more rapid increase in progressive aortic diameters throughout their lifespan than males. In the age groups of 60-69 and above 80 years old, males exhibited significantly larger L1 measurements than females. Conversely, in individuals over 80 years old, females displayed greater L3 values compared to their male counterparts. However, no sexual disparities were observed for L2, L4 and L5 across all ages. Females exhibited greater aortic tortuosity in the descending thoracic region compared to males across all age groups, whereas this sex-based distribution of aortic and abdominal tortuosity was only evident among individuals over 40 years old. The tortuosity of the aorta and descending thoracic aorta exhibits a marked increase with advancing age, particularly in females, while a non-significant linear correlation is observed between abdominal aortic tortuosity and age in both genders. BaPWV consistently increased with age in both males and females, but the increase was more significant in females. Although males initially had higher arterial stiffness, females surpassed them as they aged. Conclusion Patterns of vascular aging in aortic morphology differ between the sexes across the life course, with women experiencing more significant changes, especially in advanced age groups. | Make paid
Abstract Objectives: The aim of this study was to identify differences in hearing aid use among infants aged 0-2 years with respect to clinical and sociodemographic factors in an attempt to better predict which patients and families may benefit from extra support in the early stages of hearing aid fitting to encourage optimum usage. The secondary aim was to investigate how hearing aid use changed over the first two years post-fitting. Methods: A retrospective review of records was performed on 252 patients, aged 0-2 years with permanent childhood hearing loss from a single-site hospital who were fitted with hearing aids between 2005-2022. Ninety-six patients met the inclusion criteria. Datalogging values were collected for six different time points post fitting that coincided with their routine clinical follow-up appointments: 2 weeks, 6 weeks, 6 months, 12 months, 18 months and 24 months. Clinical and sociodemographic information was also collected for each participant. This included sex, average pure tone threshold, unilateral vs bilateral use, speech intelligibility score, additional disabilities, Index of Multiple Deprivation, Income Decile, Education and Skills Decile, Income Deprivation Affecting Children Index (IDACI), ethnicity and home language. Results: The datalogging results indicated a median average of 4.67 hours (3.0-7.3) hours per day use across patients and across the first two years post-fitting. Differences in datalogging according to IDACI Decile was significant (p=0.01), suggesting that infants from the more deprived groups (1-5) used their devices less. All other predictors did not reach statistical significance. There was insufficient data to investigate change in hearing aid use over the first two years post-fitting. Discussion: There were significant amounts of missing datalogging information. Some of the missing data was attributed by the clinical teams to lost hearing aids or unattended appointments. It is also believed that time restraints in clinic are the primary barrier. The datalogging values are lower than expected. It is considered that up to 12 hours per day use is necessary for good speech and language development. The findings highlighted that many families struggle to achieve optimal hearing aid usage in their infants. There was an association between daily device use and one socioeconomic status predictor. Conclusions: Average datalogging values for daily hearing device use were lower than considered optimal for 0-2 year olds with permanent childhood deafness. The only factor related to these findings was IDACI Decile indicating that infants from more deprived backgrounds may achieve lower hearing aid usage than those from the lesser deprived regions. This finding needs to be verified on a larger scale and better understood to explore potential approaches to overcome the problems. The role of multiple factors also needs to be explored with a larger sample size. This would require a multi-centre study to be conducted. | Make paid
Objective: Population-based studies investigating the relationship between physical activity and the gut microbiota composition have mainly relied on self-reported activity, potentially influenced by reporting bias. Here, we investigated associations of accelerometer-based sedentary behaviour and physical activity with the gut microbiota composition and functional profile in the large Swedish CArdioPulmonary bioImage Study. Methods: In 8507 participants aged 50-65, the proportion of time in sedentary (SED), moderate-intensity (MPA), and vigorous-intensity (VPA) physical activity were estimated with hip-worn accelerometer. The gut microbiota was profiled using shotgun metagenomics of fecal samples. We fitted multivariable regression models, and adjusted for sociodemographic, lifestyle, and technical covariates while also accounting for multiple testing. Results: Overall, SED and MPA were associated with microbiota species in opposite directions. For example, the strongest positive regression coefficient for MPA and the strongest negative for SED were with Prevotella copri, a plant-polysaccharide-degrading bacteria. Species associated with VPA aligned with the MPA associations, although with clear discrepancies. For instance, Phocaeicola vulgatus was negatively associated with MPA, while the association with VPA was non-significant and in the positive direction. Additional adjustment for dietary variables or adiposity attenuated some of the associations. For the functional profile, MPA and VPA were generally associated with lower capacity for amino acid degradation. Conclusion: Our findings suggest that sedentary behaviour and physical activity are associated with a similar set of gut microbiota species and functions, but in opposite directions. Furthermore, the intensity of physical activity may have specific effects on certain species of the gut microbiota. | Make paid
Background: HIV pre-exposure prophylaxis (PrEP) has been recommended and partly subsidized in Quebec since 2013. We aimed to evaluate the population-level impact of PrEP on HIV transmission among men who have sex with men (MSM) in Montreal over 2013-2021. Methods: We used an agent-based mathematical model of sexual HIV transmission to estimate the fraction of HIV acquisitions averted by PrEP compared to a counterfactual scenario without PrEP. The model was calibrated to local MSM survey and cohort data and accounted for COVID-19 pandemic impacts on sexual activity, prevention, and care. To assess potential optimization strategies, we modelled hypothetical scenarios prioritizing PrEP to MSM with high sexual activity or aged [≤]45 years, increasing coverage to levels achieved in Vancouver (where PrEP is free-of-charge), and improving retention. Results: Over 2013-2021, the estimated annual HIV incidence decreased from 0.4 (90% credible interval [CrI]: 0.3-0.6) to 0.2 (90%CrI: 0.1-0.2) per 100 person-years. PrEP coverage in HIV-negative MSM remained low until 2015 (<1%). Afterward, coverage increased to a maximum of 10% (15% of those eligible for PrEP) and the cumulative fraction of HIV acquisitions averted over 2015-2021 was 20% (90%CrI: 11%-30%). The hypothetical scenarios modelled showed that PrEP could have averted up to 63% (90%CrI: 54%-70%) of acquisitions if coverage reached 10% in 2015 and 30% in 2019, like in Vancouver. Interpretation: PrEP reduced population-level HIV transmission among Montreal MSM. However, our study suggests missed prevention opportunities and provides support for public policies that provide PrEP free-of-cost to MSM at high risk of HIV acquisition. | Make paid
The body mass index (BMI) provides essential medical information related to body weight for the treatment and prognosis prediction of different diseases. The main goal of the present study was to evaluate the performance of artificial neural network (ANN) and multiple linear regression (MLR) model in the prediction of BMI in children. The data from a total of 5,964 children aged 5 to 12 years were included in study. Age, gender, neck circumference (NC), waist circumference (WC), hip circumference (HpC), and mid upper arm circumference (MUAC) measurements were used to estimate the BMI of children. The ANN and MLR were utilized to predict the BMI. The predictive performance of these methods was also evaluated. Gender-wise average comparison showed that median values of all the anthropometric measurements (except BMI) were significantly higher in boys as compared to girls. For the overall sample, the BMI prediction model was, BMI = - 0.242 - 54 0.147 X Age - 0.367 X Gender + 0.176 X NC + 0.041 X WC + 0.060 X HpC + 0.404 X MUAC. A high R2 value and lower RMSE, MAPE, and MAD indicated that the ANN is the best method for predicting BMI in children. Our results confirm that the BMI of children can be predicted by using ANN and MLR regression methods. However, the ANN method has a higher predictive performance than MLR. | Make paid
Introduction In 2021, an estimated 10.6 million people fell ill with tuberculosis (TB) globally, 1.2 million of these were children. About 40% of them aged between 5 and 14 years with TB are missed annually. In Uganda, 44% of adolescents with chronic cough of >=2 weeks do not seek care from health facilities. Therefore, strategies to promote health care-seeking behaviour among adolescents are urgently needed. We piloted a project (TEEN TB project) aimed at improving uptake of tuberculosis (TB) care services among adolescents at Ugandan health facilities. Methodology We developed an adolescent TB awareness and screening package using the human centred design. This technique puts real people at the centre of the development process. The package consisted of 3 interventions (TB screening cards, adolescent-TB awareness poster messages and a local TB awareness song) deployed in the project health facilities and their surrounding communities. Data on socio-demographic and clinical characteristics of adolescents were collected for the period between October 2021 and March 2022 at 4 project health facilities (Kawolo, Iganga, Gombe and Kiwoko). We collected before and after intervention data from facility level records to determine the effect of the package. Results A total of 394 adolescents were included and the majority (76%) were still in school. Overall, the intervention improved adolescent TB care in the four project health facilities. The average number of adolescents screened increased by 94% from 159 to 309, with an incidence rate ratio (IRR) of 1.9 ( 95% CI: 1.9- 2.0, p <0.001), there was a 2-fold increase among those presumed to have TB; from 13 to 29, IRR of 2.2 (95% CI: 1.9-2.5, p <0.001) and those tested with GeneX-pert and microscopy increased more than 3 times from 8 to 28, IRR of 3.3 ( 95% CI: 2.8-3.8, p <0.001). There was a minimal increase in the average monthly number of adolescents with a positive result from 1.6 to 2.4 and linkage to TB care services from 2 to 3.1. These were not statistically significant at p=0.170 and p=0.154 respectively. Conclusion The project improved uptake of TB services among adolescents along the TB care cascade (screening, TB testing and linkage to care). We recommend a robust and fully powered randomized controlled trial to evaluate the effectiveness of the package. | Make paid
Mitochondria play a central role in muscle metabolism and function. In skeletal muscles, a unique family of iron-sulfur proteins, termed CISD proteins, support mitochondrial function. The abundance of these proteins declines with aging leading to muscle degeneration. Although the function of the outer mitochondrial proteins CISD1 and CISD2 has been defined, the role of the inner mitochondrial protein CISD3, is currently unknown. Here we show that CISD3 deficiency in mice results in muscle atrophy that shares proteomic features with Duchenne Muscular Dystrophy. We further reveal that CISD3 deficiency impairs the function and structure of skeletal muscle mitochondria, and that CISD3 interacts with, and donates its clusters to, Complex I respiratory chain subunit NDUFV2. These findings reveal that CISD3 is important for supporting the biogenesis and function of Complex I, essential for muscle maintenance and function. Interventions that target CISD3 could therefore impact muscle degeneration syndromes, aging, and related conditions. | Make paid
Somatic cell reprogramming is a stochastic process typically resulting in only a small fraction of cells successfully converting into induced pluripotent stem cells (iPSCs). The molecular and cellular basis underlying this stochasticity remains elusive. Here we demonstrate that this stochasticity can be largely eliminated when extracellular signal-regulated kinase(ERK) activity is tuned within a narrow range by using the MEK inhibitor at one tenth the concentration in the 2i media. Without pharmacologic inhibition, cells tune ERK activity by TFII-I[Delta], a multifunctional transcription factor that binds to and mediates ERK's nuclear activation. We find TFII-I[Delta] to be an actin-binding protein. ERK activity is partially inhibited as TFII-I[Delta] binds to actin which accumulates inside the nucleus of cells undergoing morphological remodeling. Manipulating actin's ability to accumulate inside the nucleus alters reprogramming amenability as well cell height. Actin-TFII-I[Delta] drive cell height to go above the minimal height required for pluripotency (10 [mu]m). This work uncovers a mechanistic couple between cell morphology and identity, providing convenient practices to massively increase reprogramming efficiency. | Make paid
Sirtuins act as cellular sensors in the gut that control a substantial change in gut properties in response to environmental changes. Here we show that the only mitochondrial sirtuin of Drosophila, dsirt4, is strongly up-regulated by a protein-reduced diet. Flies with a dSirt4 defect show strong changes in the protein pattern and physiological properties of their intestine. One of the most notable effects was the strong induction of lysozyme gene expression in the intestine, which also translates into enhanced lysozyme activity. This effect was cell autonomous, as it was also observed in flies with dsirt4 was exclusively silenced in enterocytes of the intestine. Although this strongly increased lysozyme expression, it did not reduce total bacterial load in the intestine, but rather changed the composition of the microbiota by reducing the number of gram-positive bacteria. This effect on microbiota composition can be attributed to the dSirt4-dependent lysozyme expression, as it was absent in a lysozyme-deficient background. dsirt4 deficiency in enterocytes reduced lifespan of flies, which was also observed in those flies experiencing ectopic lysozyme overexpression in enterocytes. This implies that strong lysozyme expression leads to a dysbiotic state associated with reduced lifespan. | Make paid
IntroductionDramatic increases in U.S. drug overdose deaths involving synthetic opioids, most prominently fentanyl, beginning around 2014 have driven a marked progression in national rates of overall drug overdose deaths, which sharply rose to unprecedented levels amid the COVID-19 pandemic. Disparities in U.S. drug overdose mortality burden by educational attainment have not been widely scrutinized during the fentanyl era of the drug overdose epidemic and its intersection with the COVID-19 pandemic. MethodsUtilizing restricted-use mortality data from the National Vital Statistics System and population estimates from the American Community Survey, we estimated annual national age-adjusted drug overdose mortality rates jointly stratified by educational attainment and sex for adults aged 25-64 from 2015 to 2021. State-level age-adjusted mortality rates were estimated in 2015 and 2021 to examine geographic trends in the cumulative evolution of disparities in drug overdose deaths by educational attainment over the course of the analysis period. ResultsOver 452,700 drug overdose deaths among U.S. adults aged 25-64 occurred from 2015 to 2021. For both men and women in this age range, age-adjusted mortality rates rose fastest among persons with at most a high school-level education, whereas little to no change in age-adjusted mortality rates was observed for Bachelors degree holders, widening pre-existing disparities in drug overdose mortality burden by educational attainment. During the analysis period, the difference in age-adjusted mortality rates between persons with at most a high school-level education and Bachelors degree holders, for both men and women, increased from less than 8-fold to approximately 13-fold. These disparities widened in nearly every state, and the widening accelerated after the onset of the COVID-19 pandemic. Among non-Bachelors degree holders, age-adjusted mortality rates increased markedly faster among men. ConclusionsThe widening disparities in drug overdose deaths by educational attainment are a likely indicator of a rapidly-increasing socioeconomic divide in drug overdose mortality more broadly. Policy strategies should address the upstream socioeconomic drivers of drug use and overdose, especially among men, and tailor interventions accordingly. | Make paid
Resolution of cohesion between sister telomeres in human cells depends on TRF1-mediated recruitment of the polyADP-ribosyltransferase, tankyrase to telomeres. In cells where tankyrase is deleted or the tankyrase binding site in TRF1 is mutated, sister telomeres remain cohered in mitosis. Human aged cells and ALT cancer cells naturally exhibit persistent telomere cohesion due to shortened telomeres that do not recruit sufficient TRF1/tankyrase for resolution. Persistent cohesion plays a protective role, but the mechanism by which sister telomeres remain cohered is not well understood. Here we show that telomere repeat containing RNA (TERRA) holds sister telomeres together through RNA-DNA hybrid (R-loop) structures. We show that a tankyrase-interacting partner, the RNA-binding protein C19orf43 is required for resolution of telomere cohesion and for repression of TERRA R-loops. Depletion of C19orf43 led to persistent telomere cohesion and an increase in TERRA R-loops. Overexpression of RNaseH1 counteracted persistent cohesion in C19orf43-depleted cells, as well as in aged and ALT cells. In fact, treatment of cohered telomeres in mitotic cells with RNaseH1 in situ, was sufficient to resolve sister telomere cohesion, confirming that RNA-DNA hybrids hold sister telomeres together. Consistent with a protective role for persistent telomere cohesion, depletion of C19orf43 in aged cells reduced DNA damage and significantly delayed replicative senescence. We propose that the inherent inability of shortened telomeres to recruit R-loop repressing machinery permits a controlled onset of senescence. | Make paid
Major Histocompatibility Complex I (MHC-I) CNS cellular localization and function is still being determined after previously being thought to be absent from the brain. MHC-I expression has been reported to increase with brain aging in mouse, rat, and human whole tissue analyses but the cellular localization was undetermined. Neuronal MHC-I is proposed to regulate developmental synapse elimination and tau pathology in Alzheimer's disease (AD). Here we report that across newly generated and publicly available ribosomal profiling, cell sorting, and single-cell data, microglia are the primary source of classical and non-classical MHC-I in mice and humans. Translating Ribosome Affinity Purification-qPCR analysis of 3-6 and 18-22 month old (m.o.) mice revealed significant age-related microglial induction of MHC-I pathway genes B2m, H2-D1, H2-K1, H2-M3, H2-Q6, and Tap1 but not in astrocytes and neurons. Across a timecourse (12-23 m.o.), microglial MHC-I gradually increased until 21 m.o. and then accelerated. MHC-I protein was enriched in microglia and increased with aging. Microglial expression, and absence in astrocytes and neurons, of MHC-I binding Leukocyte Immunoglobulin-like (Lilrs) and Paired immunoglobin-like type 2 (Pilrs) receptor families could enable cell-autonomous MHC-I signaling and increased with aging in mice and humans. Increased microglial MHC-I, Lilrs, and Pilrs were observed in multiple AD mouse models and human AD data across methods and studies. MHC-I expression correlated with p16INK4A, suggesting an association with cellular senescence. Conserved induction of MHC-I, Lilrs, and Pilrs with aging and AD opens the possibility of cell-autonomous MHC-I signaling to regulate microglial reactivation with aging and neurodegeneration. | Make paid
Background Outcomes of community antiretroviral therapy (ART) distribution (CAD), in which provider-led ART teams deliver integrated HIV services at health posts in communities, have been mixed in sub-Saharan African countries. CAD outcomes and costs relative to facility-based care have not been reported from Malawi. Methods We performed a retrospective cohort study in two Malawian districts (Lilongwe and Chikwawa districts), comparing CAD with facility-based ART care. We selected an equal number of clients in CAD and facility-based care who were aged >13 years, had an undetectable viral load (VL) result in the last year and were stable on first-line ART for [≥]1 year. We compared retention in care (alive and no period of [≥]60 days without ART) using Kaplan-Meier survival analysis and Cox regression and maintenance of VL suppression (<1,000 copies/mL) during follow-up using logistic regression. We also compared costs (in US$) from the health system and client perspectives for the two models of care. Data were collected in October and November 2020. Results 700 ART clients (350 CAD, 350 facility-based) were included. The median age was 43 years (IQR 36-51), median duration on ART was 7 years (IQR 4-9), and 75% were female. Retention in care did not differ significantly between clients in CAD (89.4% retained) and facility-based care (89.3%), p=0.95. No significant difference in maintenance of VL suppression were observed between CAD and facility-based care (aOR: 1.24, 95% CI: 0.47-3.20, p=0.70). CAD resulted in slightly higher health system costs than facility-based care: $118/year vs. $108/year per person accessing care; and $133/year vs. $122/year per person retained in care. CAD decreased individual client costs compared to facility-based care: $3.20/year vs. $11.40/year per person accessing care; and $3.60/year vs. $12.90/year per person retained in care. Conclusion Clients in provider-led CAD care in Malawi had very good retention in care and VL suppression outcomes, similar to clients receiving facility-based care. While health system costs were somewhat higher with CAD, costs for clients were reduced substantially. More research is needed to understand the impact of other differentiated service delivery models on costs for the health system and clients. | Make paid
Background: Vascular cognitive impairment (VCI) is one of the most common diseases among the elderly. However, few effective drugs have been approved for VCI. Traditional Chinese medicine (TCM) has been used in dementia for thousands of years. Currently, there is limited high-quality evidence for the efficacy of TCM, and the specific characteristics of its effects and the appropriate patient populations for TCM therapies remain unclear. Herein, we aim to explore the effectiveness and safety of TCM by conducting a longitudinal, patient-centered study. Methods: REgistry for Vascular cognitive Impairment trEatment With Traditional Chinese Medicine (REVIEW-TCM) is a prospective, observational disease registry study. 1000 VCI patients at the Hunan Hospital of Integrated Traditional Chinese and Western Medicine will be recruited based on the following criteria: aged 18 years or older, Montreal Cognitive Assessment (MoCA) score <26, and Hachinski Ischemic Score (HIS)[≥]7. There is no strict limit on the intervention, and different TCM formulas will be focused. Cognition, activity of daily living, quality of life, mental, psychology, ZHENG of TCM, and burden of caregiver will be evaluated at admission, and 6, 12, 18, and 24 months. Meanwhile, biological tests and neuroimaging examination will be applied to further explore the mechanism of TCM. Especially, a mixed-methods embedded design will be applied by adopting quantitative and qualitative studies to explore patients-reported outcomes of TCM. Finally, propensity score matching will be adopted to analyze the effectiveness of TCM. Discussion: To the best of our knowledge, the REVIEW-TCM study is the first comprehensive, prospective, mixed-methods, registry-based study to evaluate TCM treatment in VCI, which will analyze the effectiveness and safety of TCM in the real world and explore population characteristics and subtypes of VCI suitable for TCM. Study registration: This study was registered on www.chictr.org.cn (ChiCTR2200064756). | Make paid
Introduction: To provide evidence to improve cervical screening for women living with HIV (WLHIV), we assessed the accuracy of screening tests that can be used in low-resource settings and give results at the same visit. Methods: We conducted a paired, prospective study among consecutive eligible WLHIV, aged 18 to 65 years, receiving cervical cancer screening at one hospital in Lusaka, Zambia. The histopathological reference standard was multiple biopsies taken at two time points. The target condition was high-grade cervical intraepithelial neoplasia (CIN2+). The index tests were high-risk human papillomavirus detection (hrHPV, Xpert HPV, Cepheid), portable colposcopy (Gynocular, Gynius), and visual inspection with acetic acid (VIA). Accuracy of stand-alone and test combinations were calculated as the point estimate with 95% confidence intervals. A sensitivity analysis considered disease when only visible lesions were biopsied. Results: Among 371 participants with histopathological results, 27% (101/371) women had CIN2+ and 23% (23/101) was not detected by any index test. Sensitivity and specificity for stand-alone tests were: hrHPV, 67.3% (95% CI: 57.7 to 75.7) and 65.3% (59.4 to 70.7); Gynocular 51.5% (41.9 to 61.0) and 80.0% (74.8 to 84.3); and VIA 22.8% (15.7 to 31.9) and 92.6% (88.8 to 95.2), respectively. The combination of hrHPV testing followed by Gynocular had the best balance of sensitivity (42.6% [33.4 to 52.3]) and specificity (89.6% [85.3 to 92.7]). All test accuracies improved in sensitivity analysis. Conclusion: The low accuracy of screening tests assessed might be explained by our reference standard, which reduced verification and misclassification biases. Better screening strategies for WLHIV in low-resource settings are urgently needed. | Make paid