Introduction: This study assessed whether the COVID 19 pandemic has altered parent's attitudes toward vaccinating their children against the flu, and the contributing sociodemographic, health related, and behavioral factors, as well as barriers to school based vaccination programs. Methods: We conducted a cross sectional online survey of parents of children aged 6 months to 11 years in Israel (n=975) between December 21 to 31, 2022. A multivariate regression was performed to determine predictors of these parent's willingness to vaccinate their children aged 6 months to 11 years against the flu in the winter of 2023 (December 2022 to February 2023). Results: Overall, 45% of parents stated that they did not intend to vaccinate their children against the flu in the winter of 2023, citing fears of side effects and concerns about vaccine effectiveness. Among those who did not trust the Ministry of Health and pharmaceutical companies prior to the pandemic, this trend increased in 78% of them following the COVID 19 events. In contrast, 39% of parents stated that they had already vaccinated their children against the flu, with an additional 16% intending to do so. Forty one percent reported an increased intention following the pandemic. Only 37% of parents vaccinated their children at school in grades 2 to 4, mainly due to a preference for HMO clinics and lack of available nurses at school. The Health Belief Model variables, namely, perceived susceptibility, severity and benefits, displayed the largest effect sizes. Conclusions: Understanding the impact of the COVID 19 pandemic on parents' willingness to vaccinate their children against the flu is crucial. Notably, the pandemic has increased vaccine receptivity among some parents. Healthcare providers and public health officials need to address parents' concerns about the safety and efficacy of the influenza vaccine to improve vaccination rates among children. Implementing school based vaccination programs is an important strategy for promoting public health, but may be challenging. To increase uptake, nursing staff in student health facilities should be more accessible, and clear explanations about the efficacy of nasal spray vaccinations should be provided. | Make paid
Background During the COVID-19 pandemic social distancing measures were imposed to protect the population from exposure, especially elderly and frail persons who have the highest risk for severe outcomes. These restrictions greatly reduced contacts in the general population, but little is known about behaviour changes among elderly and frail persons themselves. Our aim was to quantify how COVID-19 measures affected contact behaviour of elderly and how this differed between frail and non-frail elderly. Methods In 2021 a contact survey was carried out among persons aged 70 years and older in the Netherlands. A random sample of persons per age group (70-74, 75-79, 80-84, 85-89, 90+) and gender was invited to participate, either during a period with stringent (April 2021) or moderate (October 2021) measures. Participants provided general information on themselves including their frailty, and reported characteristics of all persons with whom they had face-to-face contact on a given day, over the course of a full week. Results In total 720 community-dwelling elderly persons were included (overall response rate of 15%), who reported 16,505 contacts. During the survey period with moderate measures, non-frail participants had significantly more contacts outside their household than frail participants. Especially for women, frailty was a more informative predictor for number of contacts than age. During the survey period with stringent measures, frail and non-frail participants had significantly lower numbers of contacts compared to the survey period with moderate measures. The reduction of number of contacts was largest for the eldest non-frail participants. As they likely interact closely with highly aged and highly frail persons, this reduction of number of contacts indirectly protects frail elderly from SARS-CoV-2 exposure. Conclusions The results of this study reveal that social distancing measures during the COVID-19 pandemic differentially affected the contact patterns of frail and non-frail elderly. The reduction of contacts may have led to direct protection of elderly persons in general but also to indirect protection of frail elderly. | Make paid
Objective: Pediatric hydrocephalus requires evaluation while accounting for growth of intracranial structures, but information on choroid plexus growth in children is lacking. This study aimed to create normal growth curves for intracranial volume, choroid plexus volume, and lateral ventricles volume and assess objectively the degree of hydrocephalus due to choroid plexus hyperplasia (CPH) and the effect of surgeries. Methods: This retrospective study analyzed head computed tomography (CT) scans of pediatric patients with head trauma from Osaka Women's and Children's Hospital between April 2006 and April 2023. The study segmented the intracranial volume, choroid plexus, and lateral ventricles and calculated their volumes. The study also calculated correlation coefficients among the three parameters. Patients aged 0 to 10 years were divided into 15 age-related clusters and mean and standard deviation (SD) values were measured in each cluster. Growth curves were created by plotting mean values sequentially. Volume obtained from patients with CPH were z-normalized using mean and SD values and compared. Results: A total of 222 CT scans (91 from females) were analyzed, and positive correlations were observed among intracranial volume, choroid plexus volume, and lateral ventricles volume, with the strongest correlation between choroid plexus and lateral ventricles volumes. The growth rate of intracranial volume was rapid until approximately 20 months of ages, while those of choroid plexus and lateral ventricles volume increased rapidly by approximately one year of age. After that, the volume reached plateau at 1.5 mL and 10mL in choroid plexus and lateral ventricles volume, respectively. Three patients with CPH were enrolled and quantitatively evaluated by the z-normalized volume (z.v.). Notable abnormal volume of choroid plexus (ranged z.v. 26.00-45.85) and lateral ventricles (ranged z.v.40.93-123.56) were observed. In two patients, z.v. lateral ventricles volumes improved after surgical interventions. Choroid plexus volume reduced by approximately 20% (from z.v. 45.85 to z.v. 36.95) after bilateral endoscopic plexus coagulation in one patient. Conclusions: This study provides normal growth curves for intracranial volume, choroid plexus volume, and lateral ventricles volume. Knowledge of normal values enables objective assessment of abnormal values related to hydrocephalus and choroid plexus disease such as CPH. | Make paid
Objective The aim of this study was to investigate the determinants of not testing for HIV among young adult women aged 15-29 years in Papua New Guinea (PNG). Design and setting The study used secondary data from the 2016-2018 PNG Demographic and Health Survey (PNGDHS), a nationally representative cross-sectional survey that utilised two-stage cluster sampling. Multivariate logistic regression with complex sample analysis was performed to assess the determinants of not testing for HIV. Participants A total of 8,155 young adult women aged 15-29 years were included in the study. Outcome measure Not testing for HIV. Results The prevalence of not testing for HIV was 71.8% (95% CI: 0.71-0.73). Young adult women who were never married (AOR: 4.9, 95% CI: 3.6-6.6), from rural areas (AOR: 2.0, 95% CI: 1.5-2.6), from poor wealth indices (AOR: 1.8, 95% CI: 1.3-2.5), who did not frequently read newspapers or magazines (AOR: 1.7, 95% CI: 1.3-2.1), who did not frequently listen to the radio (AOR: 1.5, 95% CI: 1.1-2.0), who had initiated sex before the age of 20 (AOR: 1.5, 95% CI: 1.1-1.9), and who had one sexual partner (AOR: 1.5, 95% CI: 1.2-2.0) had higher odds of not testing for HIV compared with their counterparts. Conclusions Our study found that more than two-thirds of young women in PNG have never been tested for HIV. Socio-demographics, lack of exposure to media, having one sex partner, and not having had an STI in the past 12 months are associated with not testing for HIV. Multi-sectorial policy and programmatic approaches to strengthen community- and home-based testing to complement facility-based HIV services and overcome barriers associated with HIV testing among this population are necessary. | Make paid
DNA double strand breaks (DSBs), neuroinflammation, and vascular alterations in the brain are all associated with neurodegenerative disorders. However, the interconnections between these neuropathological changes and how they act synergistically to promote irreversible neurodegeneration remain unclear. Here we show that abrogating the BRCA1-associated protein Brap in cerebral cortical neurons, as opposed to vascular endothelium cells, causes cerebrovascular defects. This non-cell autonomous effect is mediated by cellular senescence resulting from persistent neuronal DSBs. We show that in the state of senescence, there is a massive upregulation of genes involved in cell secretion, inflammatory responses, and vascular changes, which coincides with cerebral microclots and microbleeds. The vascular lesions intertwine with neuroinflammation and exacerbate neuronal DSBs, culminating in oxidative stress, metabolic alteration, and downregulation of genes essential for neuronal function. By demonstrating the cerebrovascular impact of cortical neuronal DSBs, our data suggest that senescence-associated secretory phenotype can initiate brain-wide neurodegeneration. | Make paid
Aging is associated with impaired signaling between brain regions when measured using resting-state fMRI. This age-related destabilization and desynchronization of brain networks reverses itself when the brain switches from metabolizing glucose to ketones. Here, we probe the mechanistic basis for these effects. First, we established their neuronal basis using two datasets acquired from resting-state EEG (Lifespan: standard diet, 20-80 years, N = 201; Metabolic: individually weight-dosed and calorically-matched glucose and ketone ester challenge, mean age = 26.9 +/- 11.2 years, N = 36). Then, using the multi-scale Larter-Breakspear neural mass model, we identified the unique set of mechanistic parameters consistent with our clinical data. Together, our results implicate potassium (K+) gradient dysregulation as a mechanism for age-related neural desynchronization and its reversal with ketosis, the latter finding of which is consistent with direct measurement of ion channels. | Make paid
Background Equine-Assisted Therapy (EAT) can boost well-being and recovery of patients with neurological or psychiatric disorders. Objective The goal of this systematic review is to gain a better understanding of the effects of EAT on recovery after stroke. Methods A systematic literature search was performed in the following databases: PubMed, Web of Science and Scopus. Furthermore, reference lists from the articles included were screened. English-written articles published between 2000-2023 that reported on health-related effects of EAT (applied with both horses and riding simulators) on stroke recovery in patients aged between 18 and 85 were included. Methodological quality was assessed by the Mixed Methods Appraisal Tool. Results Following the screening of 2030 and retrieval of 33 articles respectively, 17 reports were included in this systematic review (437 patients, mean age range: 40-70 years). Since several of these studies lacked important methodological information, the overall methodological quality varied. Fourteen of the articles reported physical (balance, gait, postural coordination, activities of daily living (ADL), lower extremity motor impairment, motor function and hand strength), while six studies reported psychological (cognition, quality of life (QoL), depression and perception of the intervention) findings. Only two studies reported physiological findings (muscle thickness and trunk muscle activity). In general, the findings suggest positive effects of EAT on stroke recovery in each domain, whereas the most consistent beneficial effects were reported for balance and gait. Conclusion EAT appears to be a promising multimodal intervention for the recovery of different functions after stroke. However, evidence is sparse and methodological quality limited. Future research should investigate the effects of EAT on stroke recovery more systematically. | Make paid
Objectives: To assess the longitudinal development of humoral immunity in children and adolescents during the COVID-19 pandemic, with a particular focus on how anti-spike IgG antibodies and neutralising response changed during the first Omicron peak (December 2021 to May 2022). Design: Prospective school-based study during the COVID-19 pandemic (June 2020 to July 2022) including five testing rounds with corresponding cross-sectional cohorts and a longitudinal cohort who participated in at least four rounds. Setting: 55 randomly selected schools in the Canton of Zurich, Switzerland. Participants: Between 1875 to 2500 children and adolescents per testing round and 751 in the longitudinal cohort. Main outcome measures: Development of SARS-CoV-2 seroprevalence, anti-spike IgG antibodies and neutralising antibody response over time, persistence of antibodies and variation of antibody levels in individuals only infected, vaccinated or with hybrid immunity during the early Omicron period. Results: By July 2022 96.9% (95% credible interval [CrI] 95.2 to 98.1%) of children and adolescents had anti-spike IgG antibodies against SARS-CoV-2. The substantial increase in seroprevalence during the first peak of the Omicron wave was largely driven by primary infections in mostly unvaccinated children under the age of 12 (28.4% [95% CrI 24.2 to 33.2%] in December 2021, to 95.7% [95% CrI 93.4 to 97.4%] in July 2022). This stands in contrast to adolescents aged 12 years and older (69.4% [95% CrI 64.0 to 75.4%] in December 2021 to 98.4% [95% CrI 97.3 to 99.2%] in July 2022), who were eligible for vaccination since June 2021. Children and adolescents with hybrid immunity or immunity from vaccination had high anti-spike IgG titres (median Mean Fluorescence Intensity (MFI) ratio of 136.2 [Inter Quartile Range [IQR]: 121.9 to 154.3] and 127.6 [IQR: 114.1 to 151.0]) and strong neutralising responses (e.g., anti-Omicron 98.9% [95% Confidence Interval [CI] 96.0 to 99.7%] and 81.6% [95% CI 74.9 to 86.9%]). Meanwhile, infected but unvaccinated children and adolescents had substantially lower anti-spike IgG titres (median MFI ratio of 54.8 [IQR: 22.8 to 89.8]) and neutralising responses (e.g., anti-Omicron 64.9% [95% CI 59.8 to 69.7%]). Conclusion: These findings show that the Omicron wave and the rollout of vaccines led to almost 100% seropositivity and boosted anti-spike IgG titres and neutralising capacity in children and adolescents. This was particularly driven by unvaccinated children (<12 years), who became seropositive due to the highly infectious Omicron variant. Nevertheless, during the entire study parents of only one adolescent reported hospital stay of less than 24 hours related to a possible acute infection. | Make paid
Health effects of vegan diets among children are a controversial public health topic. Thus, we evaluated a broad range of health outcomes among vegan children and adolescents aged 0 to 18 years by a systematic review and meta-analyses. 17 studies met the inclusion criteria (16 cross-sectional studies, one randomized trial). Meta-analyzes showed lower intakes of protein (%E MD[95%CI]: -3.54 [-5.08, -2.00]) and higher intakes of fiber (g/1000kcal MD[95%CI]: 8.01 [6.96, 9.06]) in vegans compared to omnivores. Non-meta-analyzable studies showed lower calorie, vitamin B12 (when not using supplements) and selenium intakes, as well as lower blood levels of ferritin and vitamin B12. By contrast, vegans had significantly higher intakes of folate, vitamin C and iron. Levels of several cardiometabolic biomarkers (cholesterol, LDL) and indicators of bone health (vitamin D and calcium intake, vitamin D blood levels, bone mineral density) were lower in vegans. Risk of Bias was rated as high or very high in seven out of 17 primary studies. The Certainty of the Evidence was low or very low in all meta-analyses. Vegan children and adolescents following a vegan diet may have a beneficial cardiovascular risk profile but may be at risk for impaired bone health. | Make paid
Objectives To quantify healthcare resource utilisation (HCRU) and costs to the National Health Service (NHS) associated with acute COVID-19 in adults in England. Design Population-based retrospective cohort study, using Clinical Practice Research Datalink (CPRD) Aurum primary care electronic medical records linked when available to Hospital Episode Statistics (HES) secondary care administrative data. Setting Patients registered to primary care practices in England. Population 1,706,368 adults with a positive SARS-CoV-2 PCR or antigen test from August 2020 to January 2022 were included; 13,105 within the hospitalised cohort indexed between August 2020 and March 2021, and 1,693,263 within the primary care cohort indexed between August 2020 and January 2022. Main outcome measures Primary and secondary care HCRU and associated costs during the acute phase of COVID-19 ([≤]4 weeks following positive test), stratified by age group, risk of severe COVID-19 and immunocompromised status. Results Among the hospitalised cohort, average total length of stay, as well as in critical care wards, was longer in older adults. Median healthcare cost per hospitalisation was higher in those aged 75 - 84 ({pound}8,942) and [≥]85 years ({pound}8,835) than in those aged <50 years ({pound}7,703). Whilst few (6.0%) patients in critical care required mechanical ventilation, its use was higher in older adults (50 - 74 years: 8.3%; <50 years: 4.3%). HCRU and associated costs were often greater in those at higher risk of severe COVID-19 when compared to the overall cohort, although minimal differences in HCRU were found across the three different high-risk definitions implemented. Among the primary care cohort, GP or nurse consultations were more frequent among older adults and the immunocompromised. Conclusions COVID-19 related hospitalisations in older adults, particularly critical care admissions, were the primary drivers of high resource use of COVID-19 in England. These findings may inform health policy decisions and resource allocation in the prevention and management of COVID-19. | Make paid
Chronically high blood glucose levels (hyperglycaemia) can compromise healthy ageing and lifespan at individual level. Elevated oxidative stress can play a central role in hyperglycaemia-induced pathologies. Nevertheless, the lifespan of birds shows no species-level association with blood glucose. This suggests that the potential pathologies of high blood glucose levels can be avoided at the macroevolutionary scale by adaptations in oxidative physiology. However, this hypothesis remains unexplored. Here we examined this hypothesis using comparative analyses controlled for phylogeny, allometry and fecundity based on data from 51 songbird species. We measured blood glucose at baseline and after stress stimulus and computed glucose stress reactivity as the magnitude of change between the two time points. We also measured three parameters of non-enzymatic antioxidants (uric acid, total antioxidants and glutathione) and a marker of oxidative lipid damage (malondialdehyde). We found no or weak evidence for blood glucose concentration coevolving with either antioxidant or lipid damage levels. The only exceptions were the moderate evidence for species with a stronger stress-induced increase in blood glucose concentration evolving moderately lower investment into antioxidant defence (uric acid and glutathione). Neither baseline nor stress-induced glucose levels were associated with oxidative physiology. Our findings essentially support the hypothesis that birds evolved adaptations preventing the putative (glyc)oxidative costs of high blood glucose. Such adaptations may explain the decoupled evolution of glycaemia and lifespan in birds, and possibly the paradoxical combination of long lifespan and high blood glucose levels in birds relative to mammals. | Make paid
Patients with pre-existing heart failure are at a particularly high risk of morbidity and mortality resulting from SARS-CoV-2 infection. Direct acute cardiac injury or cytokine storms have been proposed to contribute to depressed cardiac function. However, the pathogenic mechanisms underlying the increased vulnerability to heart failure in SARS-CoV-2 infected patients are still largely unknown. Here, we found that the senescent outcome of SARS-CoV-2 spike protein (SARS-2-S)-induced syncytia exacerbated heart failure progression. We first demonstrated that syncytium formation in cells expressing SARS-2-S delivered by DNA plasmid or LNP-mRNA exhibits a senescence-like phenotype. Extracellular vesicles containing SARS-2-S (S-EVs) also confer a potent ability to form senescent syncytia without de novo synthesis of SARS-2-S. Mechanistically, SARS-2-S syncytia provoke the formation of functional MAVS aggregates, which regulate the senescence fate of SARS-2-S syncytia by TNF. We further demonstrate that senescent SARS-2-S syncytia exhibit shrinked morphology, leading to the activation of WNK1 and impaired cardiac metabolism. In pre-existing heart failure mice, the WNK1 inhibitor WNK463, anti-syncytial drug niclosamide, and senolytic dasatinib protect the heart from exacerbated heart failure triggered by pseudovirus expressing SARS-2-S (SARS-2-Spp). Signs of senescent multinucleated cells are identified in ascending aorta from SARS-CoV-2 omicron variant-infected patient. Our findings thus suggest a potential mechanism for COVID-19-mediated cardiac pathology and recommend the application of WNK1 inhibitor for therapy. | Make paid
Alzheimer's Disease (AD) is a leading cause of dementia characterized by amyloid plaques and neurofibrillary tangles, and its pathogenesis remains unclear. Current cellular models for AD often require several months to exhibit phenotypic features due to the lack of an aging environment in vitro. Lamin A is a key component of the nuclear lamina. And progerin, a truncated protein resulting from specific lamin A mutations, causes Hutchinson-Gilford Progeria Syndrome (HGPS), a disease that prematurely ages individuals. Studies have reported that lamin A expression is induced in the brains of AD patients, and overlapping cellular phenotypes have been observed between HGPS and AD cells. In this study, we investigated the effects of exogenous progerin expression on neural progenitor cells carrying familial AD mutations (FAD). Within three to four weeks of differentiation, these cells exhibited robust AD phenotypes, including increased tau phosphorylation, amyloid plaque accumulation, and an elevated A{beta}42 to A{beta}40 ratio. Additionally, progerin expression significantly increased AD cellular phenotypes such as cell death and cell cycle re-entry. Our results suggest that progerin expression could be used to create an accelerated model for AD development and drug screening. | Make paid
Melanocytes serve as a protector of the skin against external stressors such as ultraviolet radiations. While melanocytes remain functional for nearly the entire lifespan of an individual, how they respond efficiently and survive such insults remain elusive. Here, we show the co-existence of multiple distinct states of normal human epidermal melanocytes (NHEMs). Using a progressive pigmentation model, we show that stochasticity in gene expression can lead to the co-existence of multiple melanocyte states. Using active enhancers and gene expression footprint, we identified state-specific transcription factors and constructed a gene regulatory network (GRN). The GRN couples pigmentation and cell cycle regulators and explains the co-existence and transitions of the melanocyte states. Finally, we show that NHEMs respond to external cues by altering the cell state dynamics. These results demonstrate that stochasticity in gene expression followed by epigenetic modification leads to the co-existence of multiple melanocyte states enabling an efficient response to environmental cues. | Make paid
Premature birth disrupts normal lung development and places infants at risk for bronchopulmonary dysplasia (BPD), a disease increasing in incidence which disrupts lung health throughout the lifespan. The TGF{beta} superfamily has been implicated in BPD pathogenesis, however, what cell lineage it impacts remains unclear. We show that Tgfbr2 is critical for AT1 cell fate maintenance and function. Loss of Tgfbr2 in AT1 cells during late lung development leads to AT1-AT2 cell reprogramming and altered pulmonary architecture, which persists into adulthood. Restriction of fetal lung stretch and associated AT1 cell spreading through a model of oligohydramnios enhances AT1-AT2 reprogramming. Transcriptomic and proteomic analysis reveal the necessity of Tgfbr2 expression in AT1 cells for extracellular matrix production. Moreover, TGF{beta} signaling regulates integrin transcription to alter AT1 cell morphology, which further impacts ECM expression through changes in mechanotransduction. These data reveal the cell intrinsic necessity of TGF{beta} signaling in maintaining AT1 cell fate and reveal this cell lineage as a major orchestrator of the alveolar matrisome. | Make paid
More than half of all brain tumour survivors experience debilitating and often progressive cognitive decline after treatment with radiotherapy. Microglia, the resident macrophages in the brain, have been implicated in this decline. In response to various insults microglia can develop innate immune memory (IIM), which can either enhance (priming) or repress (tolerance) the response to subsequent inflammatory challenges. Here, we investigated whether radiation affects the IIM of microglia by irradiating the brains of rats and later exposing them to a secondary inflammatory stimulus. Comparative transcriptomic profiling and protein validation of microglia isolated from irradiated rats showed a stronger immune response to a secondary inflammatory insult demonstrating that radiation can lead to long-lasting molecular reprogramming of microglia. Transcriptomic analysis of post-mortem normal-appearing non-tumour brain tissue of glioblastoma patients indicates that radiation-induced microglial priming is conserved in humans. Targeting microglial priming after radiotherapy or avoiding further inflammatory insults could decrease radiotherapy-induced neurotoxicity. | Make paid
Accumulation of dysfunctional chondrocytes has detrimental consequences on the cartilage homeostasis and is thus thought to play a crucial role during the pathogenesis of osteoarthritis (OA). However, the underlying mechanisms of phenotypical alteration in chondrocytes are incompletely understood. Here, we provide evidence that disruption of the intracellular vimentin network and consequent phenotypical alteration in human chondrocytes results in an externalization of the intermediate filament. The presence of so-called cell surface vimentin (CSV) on chondrocytes was associated with the severity of tissue degeneration in clinical OA samples and was enhanced after mechanical injury of cartilage tissue. By means of a doxorubicine-based in vitro model of stress-induced premature senescence (SIPS), we could confirm the connection between cellular senescence and amount of CSV. Although siRNA-mediated silencing of CDKN2A clearly reduced the senescent phenotype as well as CSV levels of human chondrocytes, cellular senescence could not be completely reversed. Interestingly, knockdown of vimentin resulted in a SIPS-like phenotype and consequently increased CSV. Therefore, we concluded that the integrity of the intracellular vimentin network is crucial to maintain cellular function in chondrocytes. This assumption could be confirmed by chemically-induced collapse of the vimentin network, which resulted in cellular stress and enhanced CSV expression. Regarding its biological function, CSV was found to be associated with enhanced chondrocyte adhesion and plasticity. While osteogenic capacities seemed to be enhanced in chondrocytes expressing high levels of CSV, the chondrogenic potential was clearly compromised. Overall, our study reinforces the importance of the vimentin network in maintenance of the chondrogenic phenotype and introduces CSV as a novel membrane-bound marker of dysfunctional chondrocytes. | Make paid
Cancer incidence escalates exponentially with advancing age; however, the underlying mechanism remains unclear. In this study, we built a chronological molecular clock at the single-cell transcription level with a mammary stem cell-enriched population to depict physiological aging dynamics in mice. We found that the mammary aging process was asynchronous and progressive, initiated by an early senescence program with elevated NF-kB and P53 signaling, succeeded by an entropic late senescence program with reduced NF-kB and P53 signaling and enhanced PI3K-Akt-mTOR, Wnt, Notch and pluripotent activity, vulnerable to cancer predisposition. The transition towards senescence program was governed by the master stem cell factor Bcl11b, loss of which accelerated mammary ageing with enhanced DMBA-induced tumor formation. We identified a drug TPCA-1 that can elevate Bcl11b, rejuvenate mammary cells and significantly reduce aging-related cancer incidence. Our findings established a molecular portrait of progressive mammary cell aging and elucidated the transcriptional regulatory network bridging mammary aging and cancer predisposition, which can be modulated to control cancer initiation; therefore, this study has potential implications for the management of cancer prevalence in the aged. | Make paid
Hyaluronic acid (HA) is a major component of extracellular matrix (ECM) which plays an important role in development, cellular response to injury and inflammation, cell migration, and cancer. The naked mole-rat (NMR, Heterocephalus glaber) contains abundant high-molecular-mass HA (HMM-HA) in its tissues, which contributes to this species' cancer resistance and possibly longevity. Here we report that abundant HMM-HA is found in a wide range of subterranean mammalian species, but not in phylogenetically related aboveground species. These species accumulate abundant HMM-HA by regulating the expression of genes involved in HA degradation and synthesis and contain unique mutations in these genes. The abundant high molecular weight HA may benefit the adaptation to subterranean environment by increasing skin elasticity and protecting from oxidative stress due to hypoxic subterranean environment. HMM-HA may also be coopted to confer cancer resistance and longevity to subterranean mammals. Our work suggests that HMM-HA has evolved with subterranean lifestyle. | Make paid
Bivalent COVID-19 vaccines were introduced in 2022 but knowledge of their effectiveness against severe COVID-19 outcomes is currently limited. In Finnish register-based cohort analyses, we compared the risk of severe COVID-19 outcomes among those who received bivalent vaccination (exposed) between September 2022 and March 2023 to those who did not (unexposed). Among elderly aged 65-110 years, bivalent vaccination reduced the risk of hospitalisation and death due to COVID-19 in September-December 2022; the hazard ratios comparing exposed and unexposed ranged from 0.37 to 0.45 during the first 31-60 days since bivalent vaccination. However, in January-March 2023 the effect disappeared possibly indicating immune evasion of new SARS-CoV-2 variants, waning of vaccine effectiveness and increased presence of hybrid immunity. Among the chronically ill aged 18-64 years bivalent vaccination did not reduce the risk of severe COVID-19 outcomes. These results are important for developing COVID-19 vaccines and programmes worldwide. | Make paid
We explore the impact of multiple branching junctions in axons on the mean age of mitochondria and their age density distributions in demand sites. The study looked at mitochondrial concentration, mean age, and age density distribution in relation to the distance from the soma. We developed models for a symmetric axon containing 14 demand sites and an asymmetric axon containing 10 demand sites. We examined how the concentration of mitochondria changes when an axon splits into two branches at the branching junction. We also studied whether mitochondria concentrations in the branches are affected by what proportion of mitochondrial flux enters the upper branch and what proportion of flux enters the lower branch. Additionally, we explored whether the distributions of mitochondria mean age and age density in branching axons are affected by how the mitochondrial flux splits at the branching junction. When the mitochondrial flux is split unevenly at the branching junction of an asymmetric axon, with a greater proportion of the flux entering the longer branch, the average age of mitochondria (system age) in the axon increases. Our findings elucidate the effects of axonal branching on mitochondria age. Mitochondria aging is the focus of this study as recent research suggests it may be involved in neurodegenerative disorders, such as Parkinson's disease. | Make paid
At over 200 years, the maximum lifespan of the bowhead whale exceeds that of all other mammals. The bowhead is also the second-largest animal on Earth, reaching over 80,000 kg. In spite of its very large number of cells, the bowhead is not highly cancer-prone, an incongruity termed Peto's Paradox. This has been explained by the evolution of additional tumor suppressor genes in larger animals, which is supported by research on elephants demonstrating expansion of the p53 gene. However, we show here that bowhead whale fibroblasts undergo oncogenic transformation after disruption of fewer tumor suppressors than required for human fibroblasts. Instead, analysis of DNA repair revealed that bowhead cells repair double-strand breaks with uniquely high efficiency and accuracy compared to other mammals. Further, we identified two proteins, CIRBP and RPA2, that are present at high levels in bowhead fibroblasts and increase the efficiency and fidelity of DNA repair in human cells. These results suggest that rather than possessing additional tumor suppressor genes as barriers to oncogenesis, the bowhead whale relies on more accurate and efficient DNA repair to preserve genome integrity. This strategy that does not eliminate cells but repairs them may be critical for the long and cancer-free lifespan of the bowhead whale. Our work demonstrates the value of studying long-lived organisms in identifying novel longevity mechanisms and their potential for translation to humans. | Make paid
While weight loss is highly recommended for those with obesity, >60% will regain their lost weight. This weight cycling is associated with elevated risk of cardiovascular disease, relative to never having lost weight. How weight loss/regain directly influence atherosclerotic inflammation is unknown. Thus, we studied short-term caloric restriction (stCR) in obese hypercholesterolemic mice, without confounding effects from changes in diet composition. Weight loss was found to promote atherosclerosis resolution independent of plasma cholesterol. From single-cell RNA-sequencing and subsequent mechanistic studies, this can be partly attributed to a unique subset of macrophages accumulating with stCR in epididymal adipose tissue (eWAT) and atherosclerotic plaques. These macrophages, distinguished by high expression of Fcgr4, help to clear necrotic cores in atherosclerotic plaques. Conversely, weight regain (WR) following stCR accelerated atherosclerosis progression with disappearance of Fcgr4+ macrophages from eWAT and plaques. Furthermore, WR caused reprogramming of immune progenitors, sustaining hyper-inflammatory responsiveness. In summary, we have developed a model to investigate the inflammatory effects of weight cycling on atherosclerosis and the interplay between adipose tissue, bone marrow, and plaques. The findings suggest potential approaches to promote atherosclerotic plaque resolution in obesity and weight cycling through induction of Fcgr4+ macrophages and inhibition of immune progenitor reprogramming. | Make paid
Background: As the elderly population gradually increases, musculoskeletal disorders such as sarcopenia are increasing. Diagnostic techniques such as X-ray, CT, and MRI imaging are used to predict and diagnose sarcopenia, and methods using machine learning are gradually increasing. Purpose: The purpose of this study was to create a model that can predict sarcopenia using physical characteristics and activity-related variables without medical diagnostic equipment such as imaging equipment for the elderly aged 60 years or older. Method: A sarcopenia prediction model was constructed using public data obtained from the Korea National Health and Nutrition Examination Survey. Models were built using the multi-layer perceptron, XGBoost, LightGBM, and RandomForest algorithms, and the feature importance of the model with the highest accuracy was analyzed through evaluation metrics. Result: The sarcopenia prediction model built with the LightGBM algorithm showed the highest test accuracy at 0.852. In constructing the LightGBM model, physical characteristics variables such as BMI showed high importance, and activity-related variables were also used in constructing the model. Conclusion: The sarcopenia prediction model composed only of physical characteristics and activity-related factors showed excellent performance, and the use of this model will help predict sarcopenia in the elderly living in communities with insufficient medical resources or difficult access to medical facilities. | Make paid
BACKGROUND Eye diseases worldwide, including within the United States, are underdiagnosed and undertreated1. A multitude of factors contribute to this deficiency in eye care including, but not limited to, availability of specialists, transportation and mobility barriers, financial burden, lack of education, and poor patient-physician communication and understanding2,3,4. Teleophthalmology, a paradigm of care delivery in which ocular images are interpreted remotely by an eye specialist, has increased in interest since the COVID-19 pandemic, may offer improved access to necessary eye care5. The need for improved access through teleophthalmology is particularly critical for diabetic retinopathy (DR), the leading cause of new cases of blindness among adults aged 20 to 60 affecting more than 100 million patients worldwide6,7. DR arises when elevated levels of blood sugar resulting from either type 1 or 2 diabetes mellitus damage the blood vessels that supply oxygen and nutrients to the retina, the light-sensing part of the eye. The risk of developing DR is directly related to the length of time that a patient has diabetes and usually does not appear for approximately five years after a type 1 diabetes diagnosis, although it may already be present when type 2 diabetes is diagnosed8. In the absence of glycemic control and/or ophthalmic treatment, the disease may progress through three stages of non-proliferative retinopathy (mild, moderate, severe) before proliferative retinopathy develops. Diabetic macular edema can occur with any stage of retinopathy. If DR is diagnosed early, vision loss may be mitigated or prevented9. An annual fundus examination to screen for DR is critical, however, only about half of all patients with diabetes receive proper screening and less than 40% of patients with a high risk of vision loss ever undergo treatment10,11. In 2010, primary care providers (PCPs) delivered clinical care to approximately 90% of individuals with type 2 diabetes, and the proportion has increased over time12. The importance of primary care practitioners ensuring that their diabetic patients receive recommended eye care is reflected in the Healthcare Effectiveness Data and Information Set (HEDIS). This comprehensive set of quality performance measures across six domains of care guide the primary care of chronic medical conditions like diabetes mellitus and includes assessment of whether a diabetic patient receives diabetic eye screening at least every two years13. Attainment of these quality measures is increasingly important for health-system quality ratings and value-based reimbursement models. Practices are increasingly turning to teleophthalmology programs to aid in this goal of care5,14. Traditionally, DR is diagnosed by an eye specialist via an annual in-person fundoscopic examination. However, with appropriate training, non-ophthalmic clinicians and clinical personnel are able to use a fundus camera to take retinal photos that can then be evaluated by an ophthalmologist typically via a store-and-forward model. DR can be determined with high sensitivity and specificity from fundus photography, and a referral for further ophthalmic evaluation or treatment is made for those patients with retinopathy15. Primary care-based teleophthalmology programs have improved the accessibility and cost-effectiveness of DR screening in both rural and urban settings worldwide and are currently being applied to DR screening more commonly than any other ocular pathology16, 17,18. The ongoing COVID-19 pandemic has exacerbated existing barriers and increased the likelihood of ophthalmic appointment postponement or cancellation rendering teleophthalmology services even more critical to DR screening programs19, 20. The prevalence of diabetes in California is more than 40% above the United States national average21. As a means to improve the ophthalmic health of our patients, the Stanford Teleophthalmology Automated Testing and Universal Screening (STATUS) program was developed as a multi-site teleophthalmology DR screening collaboration between the Byers Eye Institute of Stanford (BEIS) and five affiliated primary care clinics throughout the San Francisco Bay Area. The program was initiated two to six months (depending on the site) prior to the onset of the COVID-19 pandemic in the United States and continued to provide remote eye examinations to patients throughout 2020 and 2021. The goal of the program was to evaluate whether the use of teleophthalmology could increase the percentage of patients screened for DR in collaboration with regional primary care clinics. Here, we examine the ability of the 18-month teleophthalmology program to improve and maintain access to DR eye care prior to and during the COVID-19 pandemic. METHODS Clinic Sites Non-mydriatic fundus cameras were deployed at an academic-affiliated primary care site in Santa Clara, CA in September 2019, and in four additional affiliated primary care sites in Los Gatos, Oakland, Hayward, and Pleasanton, CA beginning in February 2020. The primary care sites ranged from 20 miles (25-minute drive) to 42 miles (45-minute drive) away from the BEIS. Store-and-forward teleophthalmology screening for diabetic retinopathy continued at all five locations throughout the study period which ended April 2021. In order to determine whether the teleophthalmology program impacted the adherence rate to annual diabetic eye exams, HEDIS measures at two primary care sites (Pinole, CA and San Pablo, CA) in the same healthcare system that did not deploy the teleophthalmology system were also assessed. The study was approved by the Institutional Review Board at Stanford University. Patient Image Collection and Assessment Patients 18 years or older with type 1 or type 2 diabetes mellitus without a prior DR diagnosis or a DR exam in the past 12 months were offered the opportunity to have fundus photographs taken at the end of their primary care visit. Fundus imaging was performed by a trained medical assistant using the CenterVue DRS fundus camera (Hillrom Inc., Chicago, IL) at the Santa Clara primary clinic site and the TopCon NW400 fundus camera (Welch Allyn Inc., Skaneateles Falls, NY) at the Los Gatos, Oakland, Hayward, and Pleasanton primary care clinics. If medical assistants deemed the image quality to be poor, they repeated image acquisition and did so up to 4 times. The fundus images were forwarded to vitreoretinal specialists at BEIS who evaluated the images within one week. These fundus images were classified as ungradable (such as when opacity, blurring, or decentration impaired visualization of the fundus), or gradable if quality was sufficient for grading of DR. Images of adequate quality had a DR grade assigned in accordance with the International Clinical Diabetic Retinopathy Disease Severity Scale with moderate and severe categories combined on teleophthalmology evaluation (no diabetic retinopathy/mild non-proliferative diabetic retinopathy/moderate to severe non-proliferative diabetic retinopathy/proliferative diabetic retinopathy)22. Patient images were also assessed for the presence of macular edema or other fundus abnormalities. Patients with images of insufficient quality from one or both eyes were recommended to have the images retaken or present for an in-person eye examination. Diagnosis and stage of DR was determined by the eye with more advanced retinopathy. Those with referral-warranted disease were referred for an in-person exam at BEIS or their local ophthalmologist. A subset of patients (N=26) voluntarily presented for a second teleophthalmology screening one year after their first examination. Patient Data Patient files containing information on labs, orders, clinical notes, and patient information were retrieved from The STAnford Research Repository (STARR), an institutional resource for working with clinical data for research purposes. Data was managed and analyzed using Python (version 3.9.0) with Pandas (version 1.3.0). Patients who underwent fundus imaging without a documented assessment by BEIS specialists were excluded (N = 23). For all patients who were seen at BEIS after a referral for in-person examination, data was manually collected from the electronic health record. For analyses comparing patients prior to and during the COVID-19 pandemic, March 16th, 2020, was used as the start of the pandemic since on that date legal stay-at-home orders were announced in Alameda, Contra Costa, Marin, San Francisco, San Mateo, and Santa Clara counties. Longitudinal HEDIS data were only available for three of the teleophthalmology primary care sites and the two non-teleophthalmology comparison sites; two teleophthalmology primary care sites did not have structured HEDIS data available for analysis. | Make paid
Male circumcision has both health benefits and significance to some cultures. We sought to understand perceptions about male circumcision as part of the HIV prevention toolkit among participants enrolled in a preventive HIV vaccine efficacy trial in South Africa. We conducted a qualitative study with 28 people aged 18-35 years old who self-reported that they were not living with HIV, provided informed consent, and who were participating in the HVTN 702 vaccine efficacy trial in Soweto. Using a semi-structured guide, we facilitated four focus group discussions (FGDs) stratified by age, gender, and sexual orientation. FGDs were audio-recorded, transcribed verbatim, translated into English, and thematically analysed. Four main themes emerged. (1) Everyone had accurate knowledge about what male circumcision is, and some participants stated that it partially reduces acquisition of HIV and sexually transmitted infections. (2) There was an emerging distrust of cultural circumcision because of perceived lack of transparency and adverse events. (3) There was a perception that circumcision boosted masculinity. (4) The choice to circumcise was influenced by parents, family, and female partners. In conclusion, the study found that young South African HIV vaccine trial participants accurately understand the HIV prevention benefits of male circumcision, but uptake decisions are embedded within a context that is informed by culture, sexuality and masculinity norms and values. | Make paid
Background The prevalence of cardiometabolic risk factors (CMRFs) is increasing in sub-Saharan Africa and represents a serious health issue. Specific and accurate data are required to implement prevention programs and healthcare strategies. Thus, the aim of this study was to estimate the prevalence rates of CMRFs according to the level of urbanization, age and gender in Gabon. Methods A cross-sectional study was conducted using the World Health Organizations (WHO) stepwise approach for the surveillance of chronic disease risk factors. Participants over 18 years of age, without known underlying disease, from rural and urban areas of Gabon were included. Biological and behavioral data were collected using an adapted version of the standardized WHO survey questionnaire. Results The median age was 38[28-50] years. Tobacco consumption was more frequent in rural areas than in urban areas (26.1% vs 6.2%; p < 0.01). Men were more likely to be smokers than women, in both settings (aOR: 8.0[4.9-13.5], p < 0.01). Excessive alcohol consumption (19.4% vs 9.6%; p < 0.01) predominated in rural than in urban areas. Urban dwellers were less physically active than rural people (29.5% vs 16.3%; p < 0.01). In total, 79.9% of participants aged under 54 years had a high blood pressure (HBP) while 10.6% of the younger participants had pre-hypertension. Metabolic syndrome was higher in women (21.7% vs 10.0%; p < 0.01) than in men. Furthermore, 6.4% of men and 2.5% of women had a high risk of developing coronary heart diseases in the next 10 years (p = 0.03). Finally, 54.0% of the study population had three or four risk factors. Conclusion The prevalence rates of CMRFs were high in the study population. Disparities were observed according to urban and rural areas, gender and age groups. National prevention and healthcare strategies for cardiometabolic diseases in Gabon should take into account these observed differences. | Make paid
Most regression models estimate an exposure's association with the mean value of the outcome, but quantifying how an exposure affects the entire outcome distribution is often important (e.g., when the outcome has non-linear relationships with risk of other adverse outcomes). Quantile regressions offer a powerful way of estimating an exposure's relationship with the outcome distribution but remain underused in epidemiology. We introduce quantile regressions and then present an empirical example in which we fit mean and quantile regressions to investigate the association of educational attainment with later-life systolic blood pressure (SBP). We use data on 8,875 US-born respondents aged 50+ years from the Health and Retirement Study. More education was negatively associated with mean SBP. Conditional and unconditional quantile regressions both suggested a negative association between education and SBP at all levels of SBP, but the absolute magnitudes of these associations were higher at higher SBP quantiles relative to lower quantiles. While all estimators showed more education was associated with a leftward shift of the SBP distribution, quantile regression results additionally revealed that education may have reshaped the SBP distribution through larger protective associations in the right tail, thus benefiting those at highest risk of cardiovascular diseases. | Make paid
Clonal hematopoiesis of indeterminate potential(CHIP) is a recognized consequence of aging and a precursor to myelodysplastic syndrome and acute myeloid leukemia which independently increases all-cause mortality in adults. Childhood cancer survivors experience a phenomenon of accelerated aging with increased all-cause mortality; however, the mechanism of this is not known and the prevalence of CHIP not well defined. We prospectively studied 305 pediatric and young adult childhood cancer survivors to determine the prevalence of clonal hematopoiesis(CH). Targeted next-generation sequencing analysis of peripheral blood mononuclear cells elucidated the prevalence of CH (VAF >1%) at a rate of ~6%, approaching that of adults >50-70 years and much higher than previously reported. This is the first prospective study of CH in pediatric and young adult survivors of childhood cancer and highlights the importance of further investigation to better understand how CH may contribute to treatment-related myeloid neoplasms and other late effects. | Make paid
Bivalent COVID-19 vaccines were introduced in 2022 but knowledge of how their effectiveness against severe COVID-19 outcomes is sustained over time is currently limited. In Finnish register-based cohort analyses, we compared the risk of severe COVID-19 outcomes among those who received bivalent vaccination (exposed) between 1 September 2022 and 31 January 2023 to those who did not (unexposed). Among elderly aged 65-120 years, bivalent vaccination reduced the risk of hospitalisation and death due to COVID-19. Among the elderly the hazard ratios comparing exposed and unexposed ranged from 0.36 to 0.43 during the first 14-30 days since bivalent vaccination but signs of waning were observed as soon as two months after vaccination. Among the chronically ill aged 18-64 years bivalent vaccination did not reduce the risk of severe COVID-19 outcomes. These results are crucial for further developing COVID-19 vaccination programme worldwide. | Make paid