Monitoring influenza-like illness through syndromic surveillance could be an important strategy in the COVID-19 emergence scenario. The study aims to implement syndromic surveillance for children aged 6-11 years in COVID-19 sentinel schools in Catalonia. Data collection was made by self-applied survey to collect daily health status and symptoms. We proceed logistic mixed models and a Latent Class Analysis to investigate associations with syndromes and school absence. Were enrolled 135 students (2163 person-days) that filled 1536 surveys and 60 participants reported illness (29.52 by 100 person/day) and registered 189 absence events, 62 of them (32.8%) related to health reasons. Subgroups of influenza-like illness were founded such as a significantly and positively association with school absences. The findings of this study can be applied to the detection of health events, and association with school absences, offering an opportunity for quick action, or simply for monitoring and understanding the students' health situation. | Make paid
Background: Due to the aging of the population, the prevalence of aortic valve stenosis will increase dramatically in upcoming years. Consequently Transcatheter Aortic Valve Implantation (TAVI) procedures will also expand worldwide. Optimal selection of patients who benefit with improved symptoms and prognosis is key since TAVI is not without risk. Currently we are not able to adequately predict functional outcome after TAVI. Quality of life measurement tools and traditional functional assessment tests do not always agree and can depend on factors unrelated to heart disease. Activity tracking using wearable devices might provide a more comprehensive assessment. Objectives: Identify objective parameters from a wearable device (the Philips Health Watch) associated with improvement after TAVI for severe aortic stenosis. Methods and results: 100 patients undergoing routine TAVI wore a Philips Health Watch for one week before and after the procedure. Watch data were analyzed offline: 97 before and 75 after TAVI. Parameters like the total number of steps and activity time did not change, in contrast to improvements in the six-minute walking test (6MWT) and physical limitation domain of a questionnaire (transformed WHOQOL-BREF). Conclusions: These findings in an elderly TAVI population show that watch-based parameters like the number of steps do not change after TAVI, unlike traditional 6MWT and QoL assessments that do improve. Basic wearable device parameters might be less appropriate for measurement of treatment effects from TAVI. | Make paid
Background: Convenient administration of coronavirus disease 2019 (COVID-19) treatment in community settings is desirable. Sotrovimab is a pan-sarbecovirus dual-action monoclonal antibody formulated for intravenous (IV) or intramuscular (IM) administration for early treatment of mild/moderate COVID-19. Methods: This phase 3, randomized, multicenter, open-label study tested non-inferiority of IM to IV administration using a 3.5% absolute non-inferiority margin. From June to August 2021, patients aged [≥]12 years with COVID-19, not hospitalized or receiving supplemental oxygen, and at high risk for progression were randomized 1:1:1 to a single 500-mg IV sotrovimab infusion or 500-mg or 250-mg IM sotrovimab injection. The primary composite endpoint was progression to all-cause hospitalization for >24 hours for acute management of illness or all-cause death through day 29. Results: Sotrovimab 500 mg IM was non-inferior to 500 mg IV: 10/376 (2.7%) participants in the sotrovimab 500-mg IM group versus 5/378 (1.3%) in the sotrovimab 500-mg IV group met the primary endpoint (absolute adjusted risk difference: 1.06% [95% confidence interval [CI]: -1.15%, 3.26%]). The CI upper limit was lower than the prespecified non-inferiority margin of 3.5%. 250-mg IM group enrollment was discontinued early because a greater proportion of hospitalizations was seen in that group versus the 500-mg groups. Serious adverse events occurred in <1% to 2% of participants across groups. Four participants experienced serious disease related events and died (500 mg IM: 2/393 [<1%]; 250 mg IM: 2/195 [1%]). Conclusions: Sotrovimab 500-mg IM injection was well tolerated and non-inferior to IV administration. IM administration could expand outpatient treatment access for COVID-19. | Make paid
Objectives. Numerous studies of child growth conducted in industrialised countries showed presence of the phenomenon of the adolescent growth spurt to the extent that its presence became a dogma applied to humans as a species. However, earliest observations of growth at adolescence and also observations of adolescent growth conducted in small traditional societies do not show pubertal spurts consistently. Longitudinal observations of growth of individuals in present day societies show strong polymorphism of the age at which puberty starts and ends and the magnitude of growth acceleration during puberty. Some normally developing individuals may not experience the pubertal growth spurt. Design, Seeting, Participants, Longitudinal height growth data of 110 girls aged 6-18 years from homogenous socio-economic situation, ie one medical high school (=nursing college) in one large Polish city of Lodz. Results, 18 (16%) girls did not show statistically significant acceleration of body height growth while they reached the same adult height as their spurting peers. Girls who experienced growth spurt had the age at peak height velocity of 11.2 years and peak height velocity of 69.3 mm, comparable to those found in many other studies. There was a negative correlation of adult height with variation of individual accelerations (r=-0.24, p=0.01) girls whose accelerations differed less from year to year achieved greater adult heights. Conclusions, Findings of no pubertal spurts in some individuals have been made in other samples studied by other authors, though rarely reported. It can be argued that slow growth at adolescence was more favourable in conditions of limited access to nutrition and medical care while polymorphisms determining fast, uneven growth became more prevalent after industrialisation that, together with progress in health sciences, relaxed natural selection on patterns of growth. Individuals who do not experience pubertal growth spurts, but are otherwise healthy, should not be subject to clinical interventions. | Make paid
Background: In the last decade, universally available antiretroviral therapy (ART) has led to greatly improved health and survival of people living with HIV in sub-Saharan Africa, and appears to have contributed to reduced rates of new infections. Individuals acting as sources of infection need to be characterised to design effective prevention strategies. Methods: We used viral genomes to investigate the demographic characteristics of sources of HIV-1 infection. Between 2014 and 2018, the HPTN 071 PopART study was conducted to quantify the public health benefits of ART. Viral samples from 7,124 study participants in Zambia were deep-sequenced as part of HPTN 071-02 PopART Phylogenetics, an ancillary study. We identified 300 likely HIV-1 transmission pairs and investigated the source individuals in those pairs to better understand transmission in the general population. Findings: After demographic weighting, 59.4% of transmissions were male to female, with 43.2% (95% CI: 36.8%-49.7%) of transmissions being from males aged 25-40. Overall, men transmitted 2.09-fold (2.06-2.29) more infections per capita than women, a ratio peaking, when stratified by source age, at 5.88 (2.78-15.8) in the 35-39 age group. 17.4% of sources (12.5%-22.4%) carried viruses resistant to first-line ART. 12.9% (8.5%-17.3%) of transmissions linked individuals from different communities in the trial. Interpretation: HIV-1 transmission in the HPTN 071 study communities comes from a wide range of age and sex groups, and that there is no outsized contribution of importation or drug resistance mutations to new infections. Men aged 25-40, under-served by current treatment and prevention service, should be prioritised for HIV testing and ART. Funding: National Institute of Allergy and Infectious Diseases, US President's Emergency Plan for AIDS Relief, International Initiative for Impact Evaluation, Bill & Melinda Gates Foundation, National Institute on Drug Abuse, and National Institute of Mental Health | Make paid
As the average age of fatherhood increases worldwide, so too does the need for understanding effects of aging in male germline cells. Molecular change, including epigenomic alterations, may impact offspring. Age-associated change to DNA cytosine methylation in the cytosine-guanine (CpG) context is a hallmark of aging tissues, including sperm. Prior studies have led to accurate models that predict a man's age based on specific methylation features in the DNA of sperm, but the relationship between aging and global DNA methylation in sperm remains opaque. Further clarification requires a more complete survey of the methylome with assessment of variability within and between individuals. We collected sperm methylome data in a longitudinal study of ten healthy fertile men. We used whole-genome bisulfite sequencing of samples collected 10 to 18 years apart from each donor. We found that, overall, variability between donors far exceeds age-associated variation. After controlling for donor identity, we see significant age-dependent genome-wide change to the methylome. Notably, trends of change with age depend on genomic location or annotation, with contrasting signatures that correlate with gene density and proximity to centromeres and promoter regions. These molecular signatures reflect a stable process that begins in early adulthood, progressing steadily through most of the lifespan, and warrants consideration in any future study of the aging sperm epigenome. | Make paid
Autophagy, a lysosome-based eukaryotic cellular degradation system, has previously been implicated in lifespan regulation in different animal models. In this report, we show that expression of the RNAi transgenes targeting the transcripts of the key autophagy genes such as Atg1 or Atg18 in adult fly muscle or glia does not affect the overall levels of autophagosomes in those tissues and does not change the lifespan of the tested flies, but lifespan reduction phenotype has become apparent when Atg1 RNAi or Atg18 RNAi is expressed in a non-tissue-specific manner through a Tub-Gal4 in adult flies or after lipophagy is eradicated through the knockdown of Atg1 or Atg18 in adult fly adipocytes. Lifespan reduction was also observed when Atg1 or Atg18 was knocked down in adult fly enteroblasts and middle gut stem cells. Over-expression of wildtype Atg1 in adult fly muscle or adipocytes reduces lifespan. High levels of ubiquitinated protein aggregates could be the culprit of the reduced lifespan of Atg1 over-expression flies. Our research data presented here have highlighted the important functions of the key autophagy genes in adult fly adipocytes, enteroblasts, and midgut stem cells for lifespan regulation and their undetermined functions in adult fly muscle and glia. | Make paid
Declining germline quality is a major cause of reproductive senescence. Potential remedies could be found by studying regulatory pathways that promote germline quality. Several lines of evidence, including a C. elegans male pheromone ascr#10 that counteracts the effects of germline aging in hermaphrodites, suggest that the nervous system plays an important role in regulating germline quality. Inspired by the fact that serotonin mediates ascr#10 signaling, here we show that serotonin reuptake inhibitors recapitulate the effects of ascr#10 on the germline and promote healthy oocyte aging in C. elegans. Surprisingly, we found that pharmacological increase of serotonin signaling stimulates several developmental processes in D. melanogaster, including improved oocyte quality, although underlying mechanisms appear to be different between worms and flies. Our results reveal a plausibly conserved role for serotonin in maintaining germline quality and identify a class of therapeutic interventions using available compounds that could efficiently forestall reproductive aging. | Make paid
Cell-to-cell signalling between niche and stem cells regulates tissue regeneration. While the identity of many mediating factors is known, it is largely unknown whether stem cells optimize their receptiveness to niche signals according to the niche organization. Here, we show that Lgr5+ small intestinal stem cells (ISCs) regulate the morphology and orientation of their secretory apparatus to match the niche architecture, and to increase transport efficiency of niche signal receptors. Unlike the progenitor cells lacking lateral niche contacts, ISCs orient Golgi apparatus laterally towards Paneth cells of the epithelial niche, and divide Golgi into multiple stacks reflecting the number of Paneth cell contacts. Stem cells with a higher number of lateral Golgi transported Epidermal growth factor receptor (Egfr) with a higher efficiency than cells with one Golgi. The lateral Golgi orientation and enhanced Egfr transport required A-kinase anchor protein 9 (Akap9), and was necessary for normal regenerative capacity in vitro. Moreover, reduced Akap9 in aged ISCs renders ISCs insensitive to niche-dependent modulation of Golgi stack number and transport efficiency. Our results reveal stem cell-specific Golgi complex configuration that facilitates efficient niche signal reception and tissue regeneration, which is compromised in the aged epithelium. | Make paid
Damage to light-sensing photoreceptors (PRs) occurs in highly prevalent retinal diseases. As humans cannot regenerate new PRs, these diseases often lead to irreversible blindness. Intriguingly, animals, such as the zebrafish, have the ability to regenerate PRs efficiently and restore functional vision. Upon injury, mature Muller glia (MG) undergo reprogramming to adopt a stem cell-like state. This process is similar to cellular dedifferentiation, and results in the generation of progenitor cells, which, in turn, proliferate and differentiate to replace lost retinal neurons. In this study, we tested whether factors involved in dedifferentiation of Drosophila CNS are implicated in the regenerative response in the zebrafish retina. We found that hairy-related 6 (her6) negatively regulates of PR production by regulating the rate of cell divisions in the MG-derived progenitors. prospero homeobox 1 (prox1) is expressed in differentiated PRs, and likely promotes PR differentiation through phase separation. Interestingly, upon Her6 downregulation, Prox1 is precociously upregulated in the PRs, to promote PR differentiation; conversely, loss of Prox1 also induces a downregulation of Her6. Together, we identified two novel candidates of PR regeneration that cross regulate each other, and may be exploited to promote human retinal regeneration and vision recovery. | Make paid
SET-26, HCF-1, and HDA-1 are highly conserved chromatin factors with key roles in development and aging. Here we present mechanistic insights into how these factors regulate gene expression and modulate longevity in C. elegans. We show that SET-26 and HCF-1 cooperate to regulate a common set of genes, and both antagonize the histone deacetylase HDA-1 to limit longevity. We propose a model in which SET-26 recruits HCF-1 to chromatin in somatic cells, where they stabilize each other at the promoters of a subset of genes, particularly mitochondrial function genes, and regulate their expression. HDA-1 opposes SET-26 and HCF-1 on the regulation of a subset of their common target genes and in longevity. Our findings suggest that SET-26, HCF-1, and HDA-1 comprise a mechanism to fine-tune gene expression and longevity and likely have important implications for the mechanistic understanding of how these factors function in diverse organisms, particularly in aging biology. | Make paid
Maximum lifespan is a species-specific trait that can vary over a broad range, even between closely related species. We selected the few long-lived vertebrates for which reference genome data is available, specifically the blue whale Balaenoptera musculus and the Pinta Island tortoise Chelonoidis abingdonii. For these species, we used established methods of CpG dinucleotide analysis and allometric estimation to compare predicted maximum longevity with the maximum longevities reported in the AnAge database and in the literature. Additionally, we compared protein sequences between these species and closely related short-lived vertebrates. Orthologous protein sequences with higher pairwise alignment scores between either long-lived species, or between short-lived species, than between long-lived and short-lived relatives were identified. High-scoring orthologs were investigated for evidence of positive selection and convergent evolution, and for evidence of deleterious effect on phenotype. Analysis revealed no evidence for either convergent evolution or predicted deleterious protein sequences changes within these orthologs, however evidence of positive selection was identified in two genes: NRG-1 and GALNT17. Further comparison to protein sequences from the long-lived bowhead whale (Balaena mysticetus) additionally supported NRG-1 as exhibiting evidence of positive selection among the selected long-lived species. | Make paid
Mounting evidence suggests considerable diversity in brain aging trajectories, primarily arising from the complex interplay between age, genetic and environmental risk factors, leading to distinct patterns of micro- and macro-cerebral aging. The underlying mechanisms of such effects still remain unclear. We conducted a comprehensive association analysis between cerebral structural measures and prevalent risk factors, using data from 35,035 UK Biobank subjects aged 44-82. Participants were assessed for brain volume, white matter diffusivity, Apolipoprotein E (APOE) genotypes, polygenic risk scores, lifestyles and socioeconomic status. We examined genetic and environmental effects and their interactions with age and sex, and identified 726 signals, with education, alcohol, and smoking affecting most brain regions. Our analysis revealed negative age-APOE-{varepsilon}4 and positive age-APOE-{varepsilon}2 interaction effects, respectively, especially in females on the volume of amygdala, positive age-sex-APOE-{varepsilon}4 interaction on the cerebellar volume, positive age-excessive-alcohol interaction effect on the mean diffusivity of the splenium of the corpus callosum, positive age-healthy-diet interaction effect on the paracentral volume, and negative APOE-{varepsilon}4-moderate-alcohol interaction effects on the axial diffusivity of the superior fronto-occipital fasciculus. These findings highlight the need of considering age, sex, genetic and environmental joint effects in elucidating normal or abnormal brain aging. | Make paid
Background: Evidence on the long-term employment consequences of SARS-CoV-2 infection is lacking. We used data from a large, community-based sample in the UK to estimate associations between Long Covid and subsequent employment outcomes. Methods: This was an observational, longitudinal study using a pre-post design. We included UK COVID-19 Infection Survey participants who completed questionnaires on Long Covid from 3 February 2021 to 30 September 2022 when they were aged 16 to 64 years and not in full-time education. We used conditional logit modelling to explore the time-varying relationship between Long Covid status [≥]12 weeks after a first test-confirmed SARS-CoV-2 infection (reference: pre-infection) and labour market inactivity (neither working nor looking for work) or workplace absence lasting [≥]4 weeks. Results: Of 206,299 included participants (mean age 45 years, 54% female, 92% white), 15% were ever inactive in the labour market and 10% were ever long-term absent during follow-up. Compared with pre-infection, inactivity was higher in participants reporting Long Covid 30 to <40 weeks (adjusted odds ratio (aOR): 1.45; 95% CI: 1.17 to 1.81) or 40 to <52 weeks (1.34; 1.05 to 1.72) post-infection. Compared with pre-infection, reporting Long Covid was also associated with increased odds of long-term absence 18 to <24 weeks (1.40; 1.04 to 1.90) and 24 to <30 weeks (1.45; 1.03 to 2.04) post-infection, but not beyond 30 weeks. Combining with official statistics on Long Covid prevalence, our estimates translate to 27,000 (95% CI: 6,000 to 47,000) working-age adults in the UK being inactive because of their Long Covid symptoms in July 2022. Conclusions: Long Covid is likely to have contributed to reduced levels of participation in the UK labour market, though it is unlikely to be the sole driver. Further research is required to quantify the contribution of other factors, such as indirect health effects of the pandemic. | Make paid
Objective: To create case definitions for confirmed COVID diagnoses, COVID vaccination status, and three separate definitions of high risk of severe COVID, as well as to assess whether the implementation of these definitions in a cohort reflected the sociodemographic and clinical characteristics of COVID epidemiology in England. Design: Retrospective cohort study Setting: Electronic healthcare records from primary care (Clinical Practice Research Datalink, or CPRD) linked to secondary care data (Hospital Episode Statistics, or HES) data covering 24% of the population in England Participants: 2,271,072 persons aged 1 year and older diagnosed with COVID in CPRD Aurum between August 1, 2020 through January 31, 2022. Main Outcome Measures: Age, sex, and regional distribution of COVID cases and COVID vaccine doses received prior to diagnosis were assessed separately for the cohorts of cases identified in primary care and those hospitalized for COVID (primary diagnosis code of ICD-10 U07.1 COVID-19). Smoking status, body mass index and Charlson Comorbidity Index were compared for the two cohorts, as well as for three separate definitions of high risk of severe disease used in the United Kingdom (NHS Highest Risk, PANORAMIC trial eligibility, UK Health Security Agency Clinical Risk prioritization for vaccination). Results: Compared to national estimates, CPRD case estimates underrepresented older adults in both the primary care (age 65-84: 6% in CPRD vs 9% nationally) and hospitalized (31% vs 40%) cohorts, and overrepresented people living in regions with the highest median wealth areas of England (20% primary care and 20% hospital admitted cases in South East, vs 15% nationally). The majority of non-hospitalized cases and all hospitalized cases had not completed primary series vaccination. In primary care, persons meeting high risk definitions were older, more often smokers, overweight or obese, and had higher Charlson Comorbidity Index score. Conclusions: CPRD primary care data is a robust real-world data source and can be used for some COVID research questions, however limitations of the data availability should be carefully considered. Included in this publication are supplemental files for a total of over 28,000 codes to define each of three definitions of high risk of severe disease. | Make paid
Alzheimer's disease (AD) is the leading cause of dementia worldwide, but there are limited therapeutic options and no current cure. While the involvement of microglia in AD has been highly appreciated, the role of other innate and adaptive immune cells remains largely unknown, partly due to their scarcity and heterogeneity. This study aimed to study non-microglial immune cells in wild type and AD-transgenic mouse brains across different ages. Our results uncovered the presence of a unique CD8+ T cell population that were selectively increased in aging AD mouse brains, here referred to as ''disease-associated T cells (DATs)''. These DATs were found to express an elevated tissue-resident memory and Type I interferon-responsive gene signature. Further analysis of aged AD mouse brains showed that these CD8+ T cells were not present in peripheral or meningeal tissues. Preventing CD8+ T cell development in AD-transgenic mice via genetic deletion of beta-2 microglobulin (B2m) led to a reduction of amyloid-{beta} ; plaque formation in aged mice, and improved memory in AD-transgenic mice as early as four months of age. The integration of transcriptomic and epigenomic profiles at the single-cell level revealed potential transcription factors that reshape the regulomes of CD8+ T cells. These findings highlight a critical role for DATs in the progression of AD and provide a new avenue for treatment. | Make paid
Background: There are at least one billion people with disabilities globally. On average they have poorer health, yet worse healthcare access. We aimed to systematically review the association between disability and mortality in low- and middle-income countries (LMICs). Methods: We searched MEDLINE, Global Health, PsycINFO and EMBASE from 1st January 1990 to 14th November 2022. We included any longitudinal epidemiological study in any language with a comparator group that measured the association between disability and all-cause mortality in people of any age. Two reviewers independently assessed study eligibility, extracted data, and assessed risk of bias. We used a random-effects meta-analysis to calculate the pooled hazard ratio (HR) for all-cause mortality by disability status. We then conducted meta-analyses separately for different impairment and age groups. Findings: We identified 6146 unique articles, of which 70 studies (81 cohorts) were included in the systematic review, from 22 countries. There was variability in the methods used to assess and report disability, as well as mortality. The meta-analysis included 53 studies, representing 62 cohorts (comprising 267,415people with disabilities). Pooled HRs for all-cause mortality were 2.06 (95%CI 1.80-2.34) for people with disabilities versus those without disabilities, with high heterogeneity between studies. This association varied by impairment type; from 1.32 (95%CI 1.13-1.55) for visual impairment to 3.39 (95%CI 0.90-12.76) for multiple impairments. The association was highest for children under 18 (4.46, 95%CI 3.01-6.59); and lower in people aged 15-49 (3.53, 95%CI 1.29-9.66); and older people over 60 years (1.97, 95%CI 1.63-2.38). Conclusion: Disability increases the risk of all-cause mortality in LMICs, particularly in childhood. Interventions are needed to improve health of people with disabilities and reduce their risk of death | Make paid
Innate immune signaling through the NLRP3 inflammasome has been implicated in the pathogenesis of Alzheimer's disease (AD), the most prevalent form of dementia. We previously demonstrated that nucleoside reverse transcriptase inhibitors (NRTIs), drugs approved to treat HIV and hepatitis B infections, also inhibit inflammasome activation. Here we report that in humans, NRTI exposure was associated with a significantly lower incidence of AD in two of the largest health insurance databases in the United States. Treatment of aged 5xFAD mice (a mouse model of amyloid-{beta} deposition that expresses five mutations found in familial AD) with Kamuvudine-9 (K-9), an NRTI-derivative with enhanced safety profile, reduced A{beta} deposition and reversed their cognitive deficit by improving their spatial memory and learning performance to that of young wild-type mice. These findings support the concept that inflammasome inhibition could benefit AD and provide a rationale for prospective clinical testing of NRTIs or K-9 in AD. | Make paid
Senescent cells are characterized by an arrest in proliferation. In addition to replicative senescence resulting from telomere exhaustion, sub-lethal genotoxic stress resulting from DNA damage, oncogene activation, mitochondrial dysfunction or reactive metabolites also elicits a senescence phenotype. Senescence is a controlled programme affecting a wide variety of biological processes with some core hallmarks of senescence as well as tissue specific changes. This study presents an integrative multi-omic analysis of proteomic and RNA-seq from proliferating and senescent osteosarcoma cells. This study demonstrates senescence induction in a widely used cell line which can be used as a model system for characterising cancer cell responses to sub-lethal doses of chemotherapeutic agents, and makes available both RNA-seq and proteomic data from proliferating and senescent cells in open access repositories to aid reuse by the community. | Make paid
Senescence, a state of permanent cell-cycle withdrawal, is difficult to distinguish from quiescence, a transient state of cell-cycle withdrawal. This difficulty arises because quiescent and senescent cells are defined by overlapping biomarkers, raising the question of whether quiescence and senescence are truly distinct states. To address this, we used single-cell time-lapse imaging to distinguish slow-cycling quiescent cells from bona fide senescent cells after chemotherapy treatment, followed immediately by staining for various senescence biomarkers. We found that the staining intensity of multiple senescence biomarkers is graded rather than binary and primarily reflects the duration of cell-cycle withdrawal, rather than senescence per se. Together, our data suggest that quiescence and senescence are not distinct cellular states but rather fall on a continuum of cell-cycle withdrawal, where the intensities of canonical senescence biomarkers reflect the likelihood of cell-cycle re-entry. | Make paid
Dementia in general, and Alzheimer's disease (AD) in particular, are age-related diseases (1,2). AD is associated with multiple causative factors (3,4), among which local brain inflammation plays a significant role (5). Microglia, the brain-resident immune cells, are activated along the disease course (6,7). Yet, their contribution to the disease progression is still controversial. Here, using high-throughput mass cytometry for microglial immuno-phenotyping, we identified accumulation of senescent microglia in several pathologies associated with cognitive decline. These senescent microglia have a unique profile conserved across the multiple conditions investigated, including aging, mouse models of amyloidosis, and tauopathy. Moreover, we found that the expression of markers of senescence correlates with levels of TREM2, whose polymorphism was identified by GWAS as an AD risk factor (8,9). A TREM2-null AD mouse model showed lower levels of senescent microglia, relative to TREM2-intact AD mice. Senolysis using the drug ABT-73710,11 in an AD mouse model reduced the abundance of TREM2-senescent microglia without affecting levels of TREM2-dependent activated microglia, ameliorated cognitive deficits, and reduced brain inflammation. These results reveal the unexpected contribution of TREM2 to accumulation of senescent microglia in AD pathology, an effect that must be considered when targeting TREM2 as a therapeutic approach. | Make paid
Purpose: Dynamic assessments (DAs) of word reading skills (e.g., phonological awareness, decoding) demonstrate predictive validity with word reading outcomes but are characterized by substantial heterogeneity in terms of format, administration method, word, and symbol type used, factors which may affect their validity. This systematic review and meta-analysis examined whether the validity of DAs of word reading skills is affected by these characteristics. Method: Five electronic databases (Medline, Embase, PsycINFO, ERIC and CINAHL), 3 preprint repositories (MedRxiv, PsyArxiv and EdArxiv) and the gray literature were searched between March 2022 and March 2023, to identify studies with participants aged 4-10 that reported a Pearson's correlation coefficient between a DA of word reading and a word reading measure. A random effects meta-analysis and 4 subgroup analyses based on DA format, administration method, word and symbol type were conducted. Results: Thirty-two studies from 30 articles were identified. The overall effect size between DAs of word reading skills and word reading is large. There are no significant differences in mean effect sizes based on format (graduated prompt vs. train-test) or administration method (computer vs. in-person). However, DAs that use nonwords and those that use familiar letters or characters demonstrate significantly stronger correlations with word reading measures, than those that use real words and those that use novel symbols. Conclusions: Outcomes provide preliminary evidence to suggest that DAs of word reading skills that use nonwords and familiar letters in their test items are more strongly associated with later word reading ability than those that use real words or novel symbols. There were no significant differences between DAs administered in-person versus via computer. Results inform development of novel DAs of word reading, and clinical practice when it comes to selecting assessment tools. | Make paid
HIV incidence in eastern and southern Africa has historically been concentrated among girls and women aged 15-24 years, but as new cases decline with HIV interventions, population-level infection dynamics may shift by age and gender. Here, we integrated population-based surveillance and longitudinal deepsequence viral phylogenetics to assess how HIV incidence and the population groups driving transmission have evolved over a 15 year period from 2003 to 2018 in Uganda. HIV viral suppression increased more rapidly in women than men, resulting in 1.5-2 fold higher suppression rates in women with HIV by 2018 across age groups. Incidence declined more slowly in women than men, increasing pre-existing gender imbalance in HIV burden. Age-specific transmission flows shifted; the share of transmission to girls and women aged 15-24 years from older men declined by approximately one third, whereas the contribution of transmission to women aged 25-34 years from men aged 0-6 years older doubled from 2003 to 2018. We estimated closing the gender gap in viral suppression could have reduced HIV incidence in women by half in 2018 and ended gender disparities in incidence. This study suggests that male-targeted HIV programs to increase HIV suppression are critical to reduce incidence in women, close gender gaps in infection burden and improve men's health in Africa. | Make paid
HIV testing is a crucial strategy for HIV prevention, treatment, care, and support. However, its uptake is suboptimal among young people, particularly in settings where the HIV burden is highest. In Papua New Guinea (PNG), HIV testing and its predictors among young men are understudied. This study aimed to assess the prevalence and predictors of not testing for HIV among young men aged 15-24 years in PNG. Data were drawn from the 2016-2018 PNG Demographic and Health Survey (DHS). A total of 1,362 young men were included in the study. Multivariable logistic regression using the complex sampling technique was used to determine predictors of not testing for HIV. Results were reported as adjusted Odds Ratios (AOR) with 95% Confidence Intervals (CI). The prevalence of not testing for HIV among young men was 82.7%. Young men who were never married (AOR 1.88; 95% CI: 1.19-2.96), did not own a mobile phone (AOR 1.79; 95% CI: 1.17-2.77), had not paid anyone for sex (AOR 2.82; 95% CI: 1.29-6.14), and had no STIs (AOR 1.97; 95% CI: 1.00-3.85) had higher odds of not testing for HIV. The odds of not testing for HIV remained lower among young men who did not always use a condom during sex (AOR 0.62; 95% CI: 0.39-0.96). HIV testing among young men in this study was much lower, suggesting an urgent need to adopt novel prevention approaches to address this shortfall. Furthermore, youth-oriented health services should be prioritized with a focus on improving HIV knowledge, risk reduction, and behaviour change among young men in this setting. | Make paid
International concern regarding the association between repetitive neurotrauma in sport and long term concerns with ageing continues. While previous studies have reported older (i.e. over 50 years) our study describes corticomotor changes across the lifespan between retired contact sport athletes, between the ages of 30 and 70 years. Retired athletes, minimum five years retired, (n=152; 48.6+/-9.0 years) and age-matched controls (n=72; 47.8+/-9.5 years) were assessed using single and paired-pulse transcranial magnetic stimulation (TMS) for active motor threshold (aMT), motor evoked potential and cortical silent period duration (expressed as MEP:cSP ratio), and short- and long-interval intracortical inhibition (SICI and LICI). Age-matched controls showed significant moderate correlations for MEP:cSP ratios at 130% (rho=0.48), 150% (rho=0.49)and 170% aMT (rho=0.42; all p<0.001) and significant but small negative correlation for SICI (rho=-0.27; p=0.030), and moderate negative correlation for LICI (rho=-0.43; p<0.001). Further, group-wise correlation analysis shows significant stronger corelations (all p<0.05) in the control for each variable than in the retired players. This study is the first to characterise corticomotor differences between retired athletes and age matched controls across the lifespan. in those with a history of repetitive head trauma and provides a foundation for further work to utilise TMS as a prodromal marker useful in supplementing neuropsychological assessment for traumatic encephalopathy syndrome which currently lacks physiological biomarkers. | Make paid
Background: To combat the SARS-CoV-2 pandemic, multiple vaccines using different manufacturing platforms have been developed, including NVX-CoV2373 (an adjuvanted recombinant protein vaccine). As SARS-CoV-2 variants have emerged, some of which evade vaccine-induced immunity, introduction of vaccine booster doses has become critical. Employing different vaccine types for primary series vaccination and boosting could expand vaccine coverage and access. This study assessed whether NVX-CoV2373 would induce similar responses when used as a heterologous or homologous booster. Methods: The 2019nCoV-307 study was a phase 3, randomized, observer-blinded trial evaluating immunogenicity and safety of NVX-CoV2373 in previously vaccinated adults aged 18-49 years in the United States (NCT05463068). Participants were randomized 1:1:1 to receive one intramuscular injection of NVX-CoV2373 from one of three different manufacturing lots. Immunogenicity was assessed by immunoglobulin G (IgG) and neutralizing antibodies (NAb). These responses were compared for the three lots, and for participants with primary series with or without a prior booster dose of the mRNA-1273, BNT162b2, Ad26.COV2.S, or NVX-CoV2373 COVID-19 vaccines. Results: A total of 911 participants were randomized between July 11 and 13, 2022, with 905 being assessed for safety and 848 for immunogenicity. Immunogenicity of NVX-CoV2373 met prespecified equivalence criteria between lots, and the booster dose was well-tolerated. NVX-CoV2373 induced robust IgG and NAb responses when used as a first or later booster dose, regardless of primary series vaccine type. Seroconversion rates were also similar across previous vaccine types. Induced antibodies were strongly reactive, even to the immune-evasive Omicron BA.1 and BA.5 variants. Conclusions: NVX-CoV2373 showed consistent immunogenicity between lots, with no new safety signals identified. Use of NVX-CoV2373 as a homologous or heterologous booster dose (first or later) is supported. | Make paid
Cellular senescence is a cell surveillance mechanism that arrests the cell cycle in damaged cells. The senescent phenotype can spread from cell to cell through paracrine and juxtacrine signalling, but the dynamics of this process are not well understood. Although senescent cells are important in ageing, wound healing, and cancer, it is unclear how the spread of senescence is contained in senescent lesions. In the absence of the immune system, senescence could theoretically spread infinitely from one cell to another, but this contradicts experimental evidence. To investigate this issue, we developed both a minimal mathematical model and a stochastic simulation of senescence spread. Our results suggest that differences in the number of signalling molecules secreted between subtypes of senescent cells can limit the spread of senescence. We found that dynamic, time-dependent paracrine signalling prevents the uncontrolled spread of senescence and we demonstrate how model parameters can be determined using Bayesian inference in a proposed experiment. | Make paid
Tauopathy, including Alzheimer Disease (AD), is characterized by Tau protein accumulation and autophagy dysregulation. Emerging evidence connects polyamine metabolism with the autophagy pathway, however the role of polyamines in Tauopathy remains unclear. In the present study we investigated the role of spermine synthase (SMS) in autophagy regulation and tau protein processing in Drosophila and human cellular models of Tauopathy. Our previous study showed that Drosophila spermine synthase (dSms) deficiency impairs lysosomal function and blocks autophagy flux. Interestingly, partial loss-of-function of SMS in heterozygous dSms flies extends lifespan and improves the climbing performance of flies with human Tau (hTau) overexpression. Mechanistic analysis showed that heterozygous loss-of-function mutation of dSms reduces hTau protein accumulation through enhancing autophagic flux. Measurement of polyamine levels detected a mild elevation of spermidine in flies with heterozygous loss of dSms. SMS knock-down in human neuronal or glial cells also upregulates autophagic flux and reduces Tau protein accumulation. Proteomics analysis of postmortem brain tissue from AD patients showed a significant albeit modest elevation of SMS protein level in AD-relevant brain regions compared to that of control brains consistently across several datasets. Taken together, our study uncovers a correlation between SMS protein level and AD pathogenesis and reveals that SMS reduction upregulates autophagy, promotes Tau clearance, and reduces Tau protein accumulation. These findings provide a new potential therapeutic target of Tauopathy. | Make paid
Organism aging occurs at the multicellular level; however, how pro-longevity mechanisms slow down aging in different cell types remains unclear. We generated single-cell transcriptomic atlases across the lifespan of Caenorhabditis elegans under different pro-longevity conditions (http://mengwanglab.org/atlas). We found cell-specific, age-related changes across somatic and germ cell types and developed transcriptomic aging clocks for different tissues. These clocks enabled us to determine tissue-specific aging-slowing effects of different pro-longevity mechanisms, and identify major cell types sensitive to these regulations. Additionally, we provided a systemic view of alternative polyadenylation events in different cell types, as well as their cell-type-specific changes during aging and under different pro-longevity conditions. Together, this study provides molecular insights into how aging occurs in different cell types and how they respond to pro-longevity strategies. | Make paid
Across diverse taxa, offspring from older mothers have decreased lifespan and fitness. Little is known about whether such maternal age effects vary among genotypes for a given species, however. We compared maternal age effects among four strains of rotifers in the Brachionus plicatilis species complex. For each strain, we measured lifespan, reproductive schedule, and lifetime reproductive output of offspring produced by young, middle-aged, and old mothers. We found unexpected variability among strains in the magnitude and direction of maternal age effects on offspring life history traits. In one strain, offspring of young mothers lived 20% longer than offspring of old mothers, whereas there were no significant effects of maternal age on lifespan for the other strains. Across strains, advanced maternal age had positive effects, negative effects, or no effect on lifetime reproductive output. For all but one strain, older mothers produced offspring that had higher maximum daily reproduction early in life. Maternal age effects appear to be genetically determined traits, not features of life history strategy or due to accumulation of age-related damage in the germline. Investigating intraspecific variability is critical for understanding the ubiquity of maternal age effects and their role in the evolution of life history and aging. | Make paid