Background: Bangladesh significantly reduced under 5 mortality (U5M) between 2000 and 2015, despite its low economic development and projected high mortality rates in children aged under 5 years. A portion of this success was due to implementation of health systems-delivered evidence based interventions (EBIs) known to reduce U5M. This study aims to understand how Bangladesh was able to achieve this success between 2000 and 2015. Implementation science studies such as this one provides insights on the implementation process that are not sufficiently documented in existing literature. Methods: Between 2017 and 2020, we conducted mixed methods implementation research case studies to examine how six countries including Bangladesh outperformed their regional and economic peers in reducing U5M. Using existing data and reports supplemented by key informant interviews, we studied key implementation strategies and associated implementation outcomes for selected EBIs and contextual factors which facilitated or hindered this work. We used two EBIs, facility-based integrated management of childhood illnesses and insecticide treated nets, as examples of two EBIs that were implemented successfully and with wide reach across the country to understand the strategies put in place as well as the facilitating and challenging contextual factors. Results: We identified strategies which contributed to the successful implementation and wide coverage of the selected EBIs. These included community engagement, data use, and small-scale testing, important to achieving implementation outcomes such as effectiveness, reach and fidelity, although gaps persisted including in quality of care. Key contextual factors including a strong community-based health system, accountable leadership, and female empowerment facilitated implementation of these EBIs. Challenges included human resources for health, dependence on donor funding and poor service quality in the private sector. Conclusion: As countries work to reduce U5M, they should build strong community health systems, follow global guidance, adapt their implementation using local evidence as well as build sustainability into their programs. Strategies need to leverage facilitating contextual factors while addressing challenging ones. Keywords: under 5 mortality; child health; implementation research; Bangladesh; FB-IMCI; ITN | Make paid
Brain-wide association studies (BWAS) are a fundamental tool in discovering brain-behavior associations. Several recent studies showed that thousands of study participants are required to improve the replicability of BWAS because actual effect sizes are much smaller than those reported in smaller studies. Here, we perform a meta-analysis of a robust effect size index (RESI) using 63 longitudinal and cross-sectional magnetic resonance imaging studies (75,255 total scans) to demonstrate that optimizing study design is an important way to improve standardized effect sizes in BWAS. Our results of brain volume associations with demographic and cognitive variables indicate that BWAS with larger standard deviation of the independent variable have larger effect size estimates and that longitudinal studies have systematically larger standardized effect sizes than cross-sectional studies by 290%. We propose a crosssectional RESI to adjust for the systematic difference in effect sizes between cross-sectional and longitudinal studies that allows investigators to quantify the benefit of conducting their study longitudinally. Using bootstrapping in the Lifespan Brain Chart Consortium we show that modifying study design to increase between-subject standard deviation by 45% increases standardized effect sizes by 42% and adding a second measurement per subject can increase effect sizes by 35%. These findings underscore the importance of considering design features in BWAS and emphasize that increasing sample size is not the only approach to improve the replicability of BWAS. | Make paid
A growing body of research suggests that changes in both structural and functional connectivity in the aging brain contribute to declines in cognitive functions such as response inhibition. In recent years, transcranial alternating current stimulation (tACS) has garnered substantial research interest as a potential tool for the modulation of functional connectivity. Here, we report the findings from a double-blind crossover study that investigated the effects of dual-site beta tACS over the right inferior frontal gyrus (rIFG) and pre-supplementary motor area (preSMA) on functional connectivity measured with electroencephalography and response inhibition (stop-signal task performance) of healthy young (n = 18, aged 18-34 years) and older (n =15, aged 61-79 years) adults. Two tACS conditions were administered in separate sessions: in-phase tACS, where electrical currents delivered to the rIFG and preSMA had a 0-degree phase difference, and anti-phase tACS, where currents had a 180-degree phase difference. Stop-signal task performance was assessed before and after tACS. We found significant improvements in response inhibition that were not due to the phase of the tACS applied. There were also no significant changes in rIFG-preSMA phase connectivity in either age group from in- or anti-phase tACS. Furthermore, we did not observe significant differences in rIFG-preSMA phase connectivity between successful and unsuccessful inhibition, which suggests that rIFG-preSMA phase-coupling might not underlie effective response inhibition. The results offer insight into the neurophysiology of response inhibition and contribute to the future development of non-pharmacological interventions aimed at alleviating age-related declines in cognitive function. | Make paid
Despite advances in prenatal diagnosis, it is still difficult to predict severity and outcomes of many congenital malformations. New patient-specific prenatal disease modelling may optimise personalised prediction. We and others have described the presence of mesenchymal stem cells in amniotic fluid (AFSC) that can generate induced pluripotent stem cells (iPSCs). The lengthy reprogramming processes, however, limits the ability to define individual phenotypes or plan prenatal treatment. Therefore, it would be advantageous if fetal stem cells could be obtained during pregnancy and expanded without reprogramming. Using single cell analysis, we characterised the cellular identities in amniotic fluid (AF) and identified viable epithelial stem/progenitor cells of fetal intestinal, renal and pulmonary origin. With relevance for prenatal disease modelling, these cells could be cultured to form clonal epithelial organoids manifesting small intestine, kidney and lung identity. To confirm this, we derived lung organoids from AF and tracheal fluid (TF) cells of Congenital Diaphragmatic Hernia (CDH) fetuses and found that they show differences to non-CDH controls and can recapitulate some pathological features of the disease. Amniotic Fluid Organoids (AFO) allow investigation of fetal epithelial tissues at clinically relevant developmental stages and may enable the development of therapeutic tools tailored to the fetus, as well as to predicting the effects of such therapies. | Make paid
In the last few years, several models trying to calculate the biological brain age have been proposed based on structural magnetic resonance imaging scans (T1-weighted MRIs, T1w) using multivariate methods and artificial intelligence. We developed and validated a convolutional neural network (CNN)-based biological brain age prediction model that uses only one T1w MRI pre-processing step to simplify implementation and increase accessibility in research settings. Our model only requires rigid image registration to the MNI space, which is an advantage compared to previous methods that require more pre-processing steps, such as feature extraction. We used a multicohort dataset of cognitively healthy individuals (age range = 32.0 - 95.7 yrs.) comprising 17296 MRIs for training and evaluation. We compared our model using hold-out (CNN1) and cross-validation (CNN2-4) approaches. To verify generalizability, we used two external datasets with different population and MRI scan characteristics to evaluate the model. To demonstrate its usability, we included the external dataset's images in the cross-validation training (CNN3). To ensure that our model used only the brain signal on the image, we also predicted brain age using skull-stripped images (CNN4). The trained models achieved a mean absolute error of 2.99, 2.67, 2.67, and 3.08 yrs. for the CNN1-4, respectively. The model's performance in the external dataset was in the typical range of mean absolute error (MAE) found in the literature for testing sets. Adding the external dataset to the training set (CNN3), overall, MAE is unaffected, but individual cohort MAE improves (2.25 to 5.63 years). Salience maps of predictions reveal that periventricular, temporal, and insular regions are the most important for age prediction. We provide indicators for using biological (predicted) brain age as a metric for age correction in neuroimaging studies as an alternative to the traditional chronological age. In conclusion, using different approaches, our CNN-based model showed good performance using only one T1w brain MRI pre-processing step. The proposed CNN model is made publicly available for the research community to be easily implemented and used to study aging and age-related disorders. | Make paid
Background: We aimed to estimate vaccine effectiveness (VE) against COVID-19 mortality, and to explore whether an increased risk of non-COVID-19 mortality exists in the weeks following a COVID-19 vaccine dose. Methods: National registries of causes of death, COVID-19 vaccination, specialized health care and long-term care reimbursements were linked by a unique person identifier using data from 1 January 2021 to 31 January 2022. We used Cox regression with calendar time as underlying time scale to, firstly, estimate VE against COVID-19 mortality after primary and first booster vaccination, per month since vaccination and, secondly, estimate risk of non-COVID-19 mortality in the 5 or 8 weeks following a first, second or first booster dose, adjusting for birth year, sex, medical risk group and country of origin. Results: VE against COVID-19 mortality was >90% for all age groups two months after completion of the primary series. VE gradually decreased thereafter, to around 80% at 7-8 months post-primary series for most groups, and around 60% for elderly receiving a high level of long-term care and for people aged 90+ years. Following a first booster dose, the VE increased to >85% in all groups. The risk of non-COVID-19 mortality was lower or similar in the 5 or 8 weeks following a first dose compared to no vaccination, as well as following a second dose compared to one dose and a booster compared to two doses, for all age and long-term care groups. Conclusion: At the population level, COVID-19 vaccination greatly reduced the risk of COVID-19 mortality and no increased risk of death from other causes was observed. | Make paid
Facial aging is the most visible manifestation of aging. People desire to look younger than others of the same chronological age. Hence, perceived age is often used as a visible marker of aging, while biological age, often estimated by methylation markers, is used as an objective measure of age. Multiple epigenetics-based clocks have been developed for accurate estimation of general biological age and the age of specific organs, including the skin. However, it is not clear whether the epigenetic biomarkers (CpGs) used in these clocks are drivers of aging processes or consequences of aging. In this proof-of-concept study, we integrate data from GWAS on perceived facial aging, and EWAS on CpGs measured in blood. By running EW Mendelian randomization, we identify hundreds of putative CpGs that are potentially causal to perceived facial aging with similar numbers of damaging markers that causally drive or accelerate facial aging and protective methylation markers that causally slow down or protect from aging. We further demonstrate that while candidate causal CpGs have little overlap with known epigenetics-based clocks, they affect genes or proteins with known functions in skin aging such as skin pigmentation, elastin, and collagen levels. Overall, our results suggest that blood methylation markers reflect facial aging processes, and thus can be used to quantify skin aging and develop anti-aging solutions that target the root causes of aging. | Make paid
Background: Diets high in saturated fat and sugar, termed western diets, have been associated with several negative health outcomes, including increased risk for neurodegenerative disease. Parkinson s Disease (PD) is the second most prevalent neurodegenerative disease and is characterized by the progressive death of dopaminergic neurons in the brain. We build upon previous work characterizing the impact of high sugar diets in Caenorhabditis elegans to mechanistically evaluate the relationship between high sugar diets and dopaminergic neurodegeneration. Results: Non-developmental high glucose and fructose diets led to increased lipid content and shorter lifespan and decreased reproduction. However, in contrast to previous reports, we found that non-developmental chronic high-glucose and high-fructose diets did not induce dopaminergic neurodegeneration alone and were protective from 6-hydroxydopamine (6-OHDA) induced degeneration. Neither sugar altered baseline electron transport chain function, and both increased vulnerability to organism-wide ATP depletion when the electron transport chain was inhibited, arguing against energetic rescue as a basis for neuroprotection. The induction of oxidative stress by 6-OHDA is hypothesized to contribute to its pathology, and high sugar diets prevented this increase in the soma of the dopaminergic neurons. However, we did not find increased expression of antioxidant enzymes or glutathione levels. Instead, we found evidence suggesting alterations to dopamine transmission that could result in decreased 6-OHDA uptake. Conclusion: Our work uncovers a neuroprotective role for high sugar diets, despite concomitant decreases in lifespan and reproduction. Our results support the broader finding that ATP depletion alone is insufficient to induce dopaminergic neurodegeneration, whereas increased neuronal oxidative stress may drive degeneration. Finally, our work highlights the importance of evaluating lifestyle by toxicant interactions. | Make paid
In computational neuroscience, there has been an increased interest in developing machine learning algorithms that leverage brain imaging data to provide estimates of "brain age" for an individual. Importantly, the discordance between brain age and chronological age (referred to as "brain age gap") can capture accelerated aging due to adverse health conditions and therefore, can reflect increased vulnerability towards neurological disease or cognitive impairments. However, widespread adoption of brain age for clinical decision support has been hindered due to lack of transparency and methodological justifications in most existing brain age prediction algorithms. In this paper, we leverage coVariance neural networks (VNN) to propose an anatomically interpretable framework for brain age prediction using cortical thickness features. Specifically, our brain age prediction framework extends beyond the coarse metric of brain age gap in Alzheimer's disease (AD) and we make two important observations: (i) VNNs can assign anatomical interpretability to elevated brain age gap in AD by identifying contributing brain regions, (ii) the interpretability offered by VNNs is contingent on their ability to exploit specific eigenvectors of the anatomical covariance matrix. Together, these observations facilitate an explainable perspective to the task of brain age prediction. | Make paid
CObjective: To determine child restraint practices approximately 10 years after introduction of legislation requiring correct use of age-appropriate restraints for all children aged up to 7 years. Methods: A stratified cluster sample was constructed to collect observational data from children aged 0-12 years across the Greater Sydney region of NSW. Methods replicated those used in a similar 2008 study. Population weighted estimates for restraint practices were generated, and logistic regression used to examine associations between restraint type, and child age with correct use accounting for the complex sample. Results: Almost all children were appropriately restrained (99.3%, 95% CI 98.4-100). However, less than half were correctly restrained (No error = 27.3%, 95% CI 10.8-43.8, No serious error = 43.8%, 95% CI 35.0-52.7). For any error, the odds of error decreased by 39% per year of age (OR 0.61, 95% 0.46-0.81), and for serious error by 25% per year (OR 0.75 95% CI 0.60-0.93). Conclusion: The findings demonstrate a substantial increase in appropriate child restraint, but no real change in correct use. Implications for Public Health: Given the negative impact incorrect use has on crash protection, continuing high rates of incorrect use may reduce effectiveness of legislative change on injury reduction. | Make paid
INTRODUCTION: We tested the hypothesis that healthy diet protects against dementia because it slows the pace of biological aging. METHODS: We analyzed Framingham Offspring Cohort data ([≥]60y). We measured healthy diet using the Dietary Guideline for Americans (DGA, 3 visits 1991-2008), pace of aging using the DunedinPACE epigenetic clock (2005-2008), and incident dementia and mortality using records (compiled 2005-2018). RESULTS: Of n=1,525 included participants (mean age 69.7, 54% female), n=129 developed dementia and n=432 died over follow-up. Greater DGA adherence was associated with slower DunedinPACE and reduced risks for dementia and mortality. Slower DunedinPACE was associated with reduced risks for dementia and mortality. Slower DunedinPACE accounted for 15% of the DGA association with dementia and 39% of the DGA association with mortality. DISCUSSION: Findings suggest that slower pace of aging mediates part of the relationship of healthy diet with reduced dementia risk. Monitoring pace of aging may inform dementia prevention. | Make paid
Anemia in children remains a public health concern in developing countries. In Cambodia, the prevalence of anemia among children decreased slightly from 55.2% in 2014 to 49% in 2019. We examined descriptively temporal and geospatial trends of anemia and used logistic regression to analyze potential associations between individual and household characteristics and anemia among children aged 6-59 months using data from the Cambodia Demographic and Health Survey (CDHS) for 2005, 2010, and 2014. Survey weights were applied to account for the complex survey design of the CDHS. We used logistic regression to assess factors associated with anemia among children aged 6-59 months. The prevalence of anemia among children decreased from 62.2% in 2005 to 56.6% in 2014. The proportion of the Cambodian child population with anemia was highest in Pursat (84.3%) for 2005, Kampong Thom (67%) for 2010, and Preah Vihear and Steung Treng (68.6%) for 2014, respectively. Factors independently associated with increased odds of having anemia included children with mothers who were anemic (adjusted odds ratio (AOR) =1.77, 95% CI: 1.58 - 1.97); children who were male (AOR=1.20, 95% CI: 1.07 - 1.33), underweight (AOR=1.24, 95% CI: 1.14 - 1.57), stunted (AOR=1.24, 95% CI: 1.09 - 1.41), or had a recent episode of fever (AOR=1.16, 95% CI: 1.03 - 1.31). Children had decreased odds of having anemia if they were aged 12-23 months (AOR=0.68; 95% CI: 0.55 -0.86), 24-35 months (AOR=0.21; 95% CI: 0.17 - 0.26), 36-47 months (AOR=0.17; 95% CI: 0.13 - 0.21) or aged 48-59 months (AOR=0.15; 95% CI: 0.12 - 0.19) compared to infants; they were also less likely to have anemia if they were from a wealthier household (AOR=0.64; 95% CI: 0.50 - 0.84), and children who took drugs for the intestinal parasite were decreased by 14% (AOR = 0.86; 95% CI: 0.89-0.93) than those who did not take drugs. Anemia remains highly prevalent among children aged 6-59 months in Cambodia. Public health interventions and policies to alleviate anemia should be prioritized to address these factors. | Make paid
IntroductionDramatic increases in U.S. drug overdose deaths involving synthetic opioids, most prominently fentanyl, beginning around 2014 have driven a marked progression in national rates of overall drug overdose deaths, which sharply rose to unprecedented levels amid the COVID-19 pandemic. Disparities in U.S. drug overdose mortality burden by educational attainment have not been widely scrutinized during the fentanyl era of the drug overdose epidemic and its intersection with the COVID-19 pandemic. MethodsUtilizing restricted-use mortality data from the National Vital Statistics System and population estimates from the American Community Survey, we estimated annual national age-adjusted drug overdose mortality rates jointly stratified by educational attainment and sex for adults aged 25-64 from 2015 to 2021. State-level age-adjusted mortality rates were estimated in 2015 and 2021 to examine geographic trends in the cumulative evolution of disparities in drug overdose deaths by educational attainment over the course of the analysis period. ResultsOver 452,700 drug overdose deaths among U.S. adults aged 25-64 occurred from 2015 to 2021. For both men and women in this age range, age-adjusted mortality rates rose fastest among persons with at most a high school-level education, whereas little to no change in age-adjusted mortality rates was observed for Bachelors degree holders, widening pre-existing disparities in drug overdose mortality burden by educational attainment. During the analysis period, the difference in age-adjusted mortality rates between persons with at most a high school-level education and Bachelors degree holders, for both men and women, increased from less than 8-fold to approximately 13-fold. These disparities widened in nearly every state, and the widening accelerated after the onset of the COVID-19 pandemic. Among non-Bachelors degree holders, age-adjusted mortality rates increased markedly faster among men. ConclusionsThe widening disparities in drug overdose deaths by educational attainment are a likely indicator of a rapidly-increasing socioeconomic divide in drug overdose mortality more broadly. Policy strategies should address the upstream socioeconomic drivers of drug use and overdose, especially among men, and tailor interventions accordingly. | Make paid
Decline in protein homeostasis (proteostasis) is a hallmark of cellular aging and aging-related diseases. Maintaining a balanced proteostasis requires a complex network of molecular machineries that govern protein synthesis, folding, localization, and degradation. Under proteotoxic stress, misfolded proteins that accumulate in cytosol can be imported into mitochondria for degradation via 'mitochondrial as guardian in cytosol' (MAGIC) pathway. Here we report an unexpected role of yeast Gas1, a cell wall-bound glycosylphosphatidylinositol (GPI)-anchored {beta}-1,3-glucanosyltransferase, in differentially regulating MAGIC and ubiquitin-proteasome system (UPS). Deletion of Gas1 inhibits MAGIC but elevates polyubiquitination and UPS-mediated protein degradation. Interestingly, we found that Gas1 exhibits mitochondrial localization attributed to its C-terminal GPI anchor signal. But this mitochondria-associated GPI anchor signal is not required for mitochondrial import and degradation of misfolded proteins via MAGIC. By contrast, catalytic inactivation of Gas1 via the gas1E161Q mutation inhibits MAGIC but not its mitochondrial localization. These data suggest that the glucanosyltransferase activity of Gas1 is important for regulating cytosolic proteostasis. | Make paid
Background People with multiple long term conditions (MLTC) face health and social care challenges. This study aimed to classify people by MLTC and Social Care Need (SCN) into distinct clusters and quantify the association between derived clusters and care outcomes. Methods A cohort study was conducted using the English Longitudinal Study of Ageing (ELSA), including people with up to ten MLTC. Self-reported SCN was assessed through 13 measures of difficulty with activities of daily living, ten measures of mobility difficulties, and whether health status was limiting earning capability. Latent class analysis was performed to identify clusters. Multivariate logistic regression quantified associations between derived MLTC/SCN clusters, all-cause mortality, and nursing home admission. Results The cohort included 9171 people at baseline with a mean age of 66.3 years; 44.5% were males. Nearly 78.8% had two or more MLTC, the most frequent being hypertension, arthritis and cardiovascular disease. We identified five distinct clusters classified as high SCN/MLTC through to low SCN/MLTC clusters. The high SCN/MLTC included mainly women aged 70 to 79 years who were white and educated to the upper secondary level. This cluster was significantly associated with higher nursing home admission (OR = 8.97; 95% CI: 4.36 to 18.45). We found no association between clusters and all-cause mortality. Conclusions This results in five clusters with distinct characteristics that permit the identification of high risk groups who are more likely to have worse health outcomes, including nursing home admission. This can inform targeted preventative action to where it is most needed amongst those with MLTC. | Make paid
Objective: Although there has been a reduction in stunting (low height/length for age), the prevalence of malnutrition in Ethiopia is still high. Child growth patterns and estimates of stunting are needed to determine vulnerabilities and potential for recovery. We collected longitudinal data to determine the prevalence, incidence and reversal of stunting among children aged 0-24 months. Methods: We conducted a cohort study of 4,354 children between December 2018 and November 2020 in the Birhan maternal and child health cohort in North Shewa Zone, Amhara Ethiopia. Children who had their length measured at least once were included in this study. Results: Among the 4,354 children enrolled, 3,674 (84.4%) were included. Our findings indicate that median population-level length is consistently below global standards from birth to age two. Growth velocity was slowest compared to global standards during the neonatal period and after children reached six months of age. The observed prevalence of stunting was highest at age two (57.9%). Incidence of stunting increased over time and reversal was highest between the ages of birth to six months. We found substantial heterogeneity in anthropometric measurements, which we addressed by fitting modeled growth trajectories for each child. Conclusion: Overall, the evidence from this study highlights a chronically malnourished population with much of the burden driven by growth faltering during the neonatal periods as well as after 6 months of age. To end all forms of malnutrition, growth faltering in populations such as that in young children in Amhara, Ethiopia needs to be addressed. | Make paid
Aging is the largest risk factor for neurodegenerative disorders, and commonly associated with compromised cerebrovasculature and pericytes. However, we do not know how normal aging differentially impacts the vascular structure and function in different brain areas. Here we utilize mesoscale microscopy methods (serial two-photon tomography and light sheet microscopy) and in vivo imaging (wide field optical spectroscopy and two-photon imaging) to determine detailed changes in aged cerebrovascular networks. Whole-brain vascular tracing showed an overall ~10% decrease in vascular length and branching density, and light sheet imaging with 3D immunolabeling revealed increased arteriole tortuosity in aged brains. Vasculature and pericyte densities showed significant reductions in the deep cortical layers, hippocampal network, and basal forebrain areas. Moreover, in vivo imaging in awake mice identified delays in neurovascular coupling and disrupted blood oxygenation. Collectively, we uncover regional vulnerabilities of cerebrovascular network and physiological changes that can mediate cognitive decline in normal aging. | Make paid
Introduction: Vision and hearing loss are highly prevalent and have a significant impact on physical, psychological and social wellbeing. There is a need for accurate, contemporary national data on the prevalence, risk factors and impacts of vision and hearing loss in Australian adults. Objectives: The Australian Eye and Ear Health Survey (AEEHS) aims to determine the prevalence, risk factors and impacts of vision and hearing loss in Aboriginal and Torres Strait Islander people and non-Indigenous adults. Methods and analysis: The AEEHS is a population-based cross-sectional survey which will include 5,000 participants (3250 non-Indigenous aged 50 years or older and 1750 Aboriginal and Torres Strait Islander people aged 40 years or older) from 30 sites covering urban and rural/regional geographic areas, selected using a multi-stage, random cluster sampling strategy. Questionnaires will be administered to collect data on socio-demographic, medical, ocular and otological history. The testing battery includes assessment of blood pressure, blood sugar, anthropometry, presenting and unaided visual acuity, subjective or autorefraction, tonometry, slit lamp and dilated eye examination, ocular imaging including optical coherence tomography (OCT), OCT-angiography, retinal photography and visual fields examination. Audiometry, tympanometry and video otoscopy will also be performed. The primary outcomes will be age-standardised prevalence of cause-specific visual and hearing impairment. Secondary outcomes will be prevalence of non-blinding eye diseases (dry eye disease), patterns in health service utilisation, universal health coverage metrics, risk factors for vision and hearing impairment, and impact on quality of life. Ethics: The protocol for this study was approved by the University of Sydney Human Research Ethics Committee (HREC-2020/818) and Australian Institute of Aboriginal and Torres Strait Islander Studies (AIATSIS) Research Ethics Committee (HREC-EO303-20211008). Dissemination of results: Our findings will be disseminated through presentation at meetings and peer-reviewed publications. Findings will also be widely disseminated by project partners with the aim of improving public health policy directives and equitable service delivery to prevent avoidable vision and hearing impairment in Australia. | Make paid
BackgroundAs 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. PurposeThe 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. MethodA 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. ResultThe 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. ConclusionThe 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
Critical limb ischemia (CLI) occurs when blood flow is restricted through the arteries, resulting in ulcers, necrosis, and chronic wounds in the downstream extremities. The development of collateral arterioles (i.e. arteriogenesis), either by remodeling of pre-existing vascular networks or de novo growth of new vessels, can prevent or reverse ischemic damage, but it remains challenging to stimulate collateral arteriole development in a therapeutic context. Here, we show that a gelatin-based hydrogel, devoid of growth factors or encapsulated cells, promotes arteriogenesis and attenuates tissue damage in a murine CLI model. The gelatin hydrogel is functionalized with a peptide derived from the extracellular epitope of Type 1 cadherins. Mechanistically, these "GelCad" hydrogels promote arteriogenesis by recruiting smooth muscle cells to vessel structures in both ex vivo and in vivo assays. In a murine femoral artery ligation model of CLI, delivery of in situ crosslinking GelCad hydrogels was sufficient to restore limb perfusion and maintain tissue health for 14 days, whereas mice treated with gelatin hydrogels had extensive necrosis and autoamputated within 7 days. A small cohort of mice receiving the GelCad hydrogels were aged out to 5 months and exhibited no decline in tissue quality, indicating durability of the collateral arteriole networks. Overall, given the simplicity and off-the-shelf format of the GelCad hydrogel platform, we suggest it could have utility for CLI treatment and potentially other indications that would benefit from arteriole development. | Make paid
Alzheimers disease (AD) is a neurodegenerative disorder that primarily affects elderly individuals, and is characterized by hallmark neuronal pathologies including extracellular amyloid-{beta} (A{beta}) plaque deposition, intracellular tau tangles, and neuronal death. However, recapitulating these age-associated neuronal pathologies in patient-derived neurons has remained a significant challenge, especially for late-onset AD (LOAD), the most common form of the disorder. Here, we applied the high efficiency microRNA-mediated direct neuronal reprogramming of fibroblasts from AD patients to generate cortical neurons in three-dimensional (3D) Matrigel and self-assembled neuronal spheroids. Our findings indicate that neurons and spheroids reprogrammed from both autosomal dominant AD (ADAD) and LOAD patients exhibited AD-like phenotypes linked to neurons, including extracellular A{beta} deposition, dystrophic neurites with hyperphosphorylated, K63-ubiquitin-positive, seed-competent tau, and spontaneous neuronal death in culture. Moreover, treatment with {beta}- or {gamma}-secretase inhibitors in LOAD patient-derived neurons and spheroids before A{beta} deposit formation significantly lowered A{beta} deposition, as well as tauopathy and neurodegeneration. However, the same treatment after the cells already formed A{beta} deposits only had a mild effect. Additionally, inhibiting the synthesis of age-associated retrotransposable elements (RTEs) by treating LOAD neurons and spheroids with the reverse transcriptase inhibitor, lamivudine, alleviated AD neuropathology. Overall, our results demonstrate that direct neuronal reprogramming of AD patient fibroblasts in a 3D environment can capture age-related neuropathology and reflect the interplay between A{beta} accumulation, tau dysregulation, and neuronal death. Moreover, miRNA-based 3D neuronal conversion provides a human-relevant AD model that can be used to identify compounds that can potentially ameliorate AD-associated pathologies and neurodegeneration. | Make paid
Alzheimer's disease (AD) is characterized by progressive neurodegeneration, but the specific events that cause cell death remain poorly understood. Death Induced by Survival gene Elimination (DISE) is a recently discovered powerful cell death mechanism mediated by short (s) RNAs including micro (mi) RNAs acting through the RNA induced silencing complex (RISC). G-rich 6mer seed sequences in the sRNAs (position 2-7) target hundreds of C-rich seed matches in genes essential for cell survival resulting in the simultaneous activation of multiple cell death pathways. Using Argonaute precipitation and RNAseq (Ago-RP-Seq) we analyzed RISC bound sRNAs (R-sRNAs) in in vitro cell line models and in the brains of two in vivo AD mouse models and aged mice. In cell line studies we find evidence for a contribution of RNAi to the cell death and DNA damage induced by toxic A{beta}42 oligomers. In addition, in AD mouse models and in the aging brain R-sRNAs RISC bound sRNAs show a shift to more toxic seeds. In contrast, in cells of "SuperAgers", individuals over age 80 who have superior memory performance, R-sRNAs are shifted to more nontoxic seeds, supporting a protective function of miRNAs. Cell death induced by A{beta}42 oligomers can be rescued by adding back protective miRNAs. Our data provide first evidence of a contribution of RNAi to the neurotoxicity and DNA damage seen in AD suggesting that increasing the levels of protective miRNAs in the brain or blocking the activity of toxic R-sRNAs could lead to a novel way of treating the disease. | Make paid
Abstract: Objective: To explore the effect of IOP on the refractive error in children and adolescents, and to analyze the correlation among IOP , AL and diopter of refraction. Methods: Conducting a cross-sectional study. A total of 3256 students (6511 pairs of eyes) aged between 4 and 15 in Jinniu district who presented for ocular health examination during October 2018 and October 2021 were selected, including 1735 boys (3470 eyes) and 1521 girls (3041 eyes).The differences between groups were analyzed by analysis of variance, correlation analysis by Pearson, data were analyzed by statistical software SPSS 25.0. Results: There were significant differences in SE, IOP and AL between each group (P < 0.001), whereas IOP, AL were positively correlated with SE, respectively. The average IOP of female (17.45plus-or-minus sign 2.56mmg) was higher than that of male (17.08 plus-or-minus sign 2.60mmg), while the mean AL of male (23.46 plus-or-minus sign 0.81 mm) was longer than that of female (22.91 plus-or-minus sign 0.83 mm).There was weak or no correlation between IOP and AL (r = 0.126, P < 0.001). No correlation was found between IOP and SE (r = 0.116, P < 0.001). Positive correlation between AL and SE (r = 0.632, P < 0.001) was noted. Conclusion: The increase of myopia degree in children at different ages is manifested by the increase of intraocular pressure and axial length, the increase of axial length is one of the main reasons affecting diopter.However, IOP may not directly lead to increase of myopia in children and adolescents within the range of normal IOP. | Make paid
Methylation of cytosines in the CG context (mCG) is the most abundant DNA modification in vertebrates that plays crucial roles in cellular differentiation and identity. After fertilisation, DNA methylation patterns inherited from parental gametes are remodelled into a state compatible with embryogenesis. In mammals, this is achieved through the global erasure and re-establishment of DNA methylation patterns. However, in non-mammalian vertebrates like zebrafish, no global erasure has been observed. To investigate the evolutionary conservation and divergence of DNA methylation remodelling in teleosts, we generated base resolution DNA methylome datasets of developing medaka and medaka-zebrafish hybrid embryos. In contrast to previous reports, we show that medaka display comparable DNA methylome dynamics to zebrafish with high gametic mCG levels (sperm: ~90%; egg: ~75%), and adoption of a paternal-like methylome during early embryogenesis, with no signs of prior DNA methylation erasure. We also demonstrate that non-canonical DNA methylation (mCH) reprogramming at TGCT tandem repeats is a conserved feature of teleost embryogenesis. Lastly, we find remarkable evolutionary conservation of DNA methylation remodelling patterns in medaka-zebrafish hybrids, indicative of compatible DNA methylation maintenance machinery in far-related teleost species. Overall, these results suggest strong evolutionary conservation of DNA methylation remodelling pathways in teleosts, which is distinct from the global DNA methylome erasure and reestablishment observed in mammals. | Make paid
Age-related cognitive impairment is not expressed uniformly across cognitive domains. Cognitive functions that rely on brain areas that undergo substantial neuroanatomical changes with age often show age-related impairment, while those that rely on brain areas with minimal age-related change typically do not. The common marmoset has grown in popularity as a model for neuroscience research, but robust cognitive phenotyping, particularly as a function of age and across multiple cognitive domains, is lacking. This presents a major limitation for the development and evaluation of the marmoset as a model of cognitive aging, and leaves open the question of whether they exhibit age-related cognitive impairment that is restricted to some cognitive domains, as in humans. In this study, we characterized stimulus-reward association learning and cognitive flexibility in young adults to geriatric marmosets using a Simple Discrimination and a Serial Reversal task, respectively. We found that aged marmosets show transient impairment in learning-to-learn but have conserved ability to form stimulus-reward associations. Furthermore, aged marmosets have impaired cognitive flexibility driven by susceptibility to proactive interference. Since these impairments are in domains critically dependent on the prefrontal cortex, our findings support prefrontal cortical dysfunction as a prominent feature of neurocognitive aging. This work positions the marmoset as a key model for understanding the neural underpinnings of cognitive aging. | Make paid
Breast cancer in young (<40 years) is associated with a higher frequency of aggressive tumor types and poor prognosis. It remains unclear if there is an underlying age-related biology that contributes to the unfavorable outcome. We aim to investigate the relationship between age and breast cancer biology, with emphasis on proliferation. Clinico-pathologic information, immunohistochemical markers, and follow-up data were obtained for all patients aged <50 (Bergen cohort-1; n=355) and compared to previously obtained information on patients aged 50-69 (Bergen cohort-2; n=540), who participated in the Norwegian Breast Cancer Screening Program. Data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC) was applied for validation and for analyses of gene expression signatures. Young breast cancer patients presented more aggressive tumor features such as hormone receptor negativity, HER2 positivity, lymph-node metastasis, the HER2-enriched and triple negative subtypes, and shorter survival. Age <40 was significantly associated with features of stemness and higher proliferation (by Ki67), also in molecular subsets. Ki67 showed weaker prognostic value in young patients. We point to aggressive phenotypes, increased tumor cell proliferation and stem-like features in breast cancer of the young. Hence, tumors of young breast cancer patients may have a unique biology, also when accounting for screen/interval differences, that may open for new clinical opportunities, stratifying treatment by age. | Make paid
Many studies have investigated the connection between the rate of change in diverse molecular markers and maximum lifespan across species. We describe a framework to address doubts that the rate of change in any biomarker displays a trivial inverse relation to lifespan. We leverage this framework on two comprehensive methylation datasets. The first connects the rate of change in blood methylation to the lifespan of 93 dog breeds. The second associates the rate of change in distinct chromatin states with the maximum lifespan of 125 mammalian species. We show how methylation levels in selected chromatin states shift with age across the lifespan. Our research reveals three significant outcomes: First, a reciprocal relationship exists between the rate of methylation change in bivalent promoter regions and maximum lifespan. Second, the association between age and average methylation within these bivalent promoter regions bears no relation to maximum lifespan. Third, the rate of methylation change in young animals is related to that in old animals. Our mathematical derivations draw connections between these findings. A substantial part of our mathematical framework for analyzing maximum lifespan can be applied to other molecular assessments as well. Overall, our study demonstrates that epigenetic aging rates in specific chromatin states exhibit an inverse relationship with maximum lifespan. | Make paid
Injury to adult mammalian central nervous system (CNS) axons results in limited regeneration. Rodent studies have revealed a developmental switch in CNS axon regenerative ability, yet whether this is conserved in humans is unknown. Using human fibroblasts from 8 gestational-weeks to 72 years-old, we performed direct reprogramming to transdifferentiate fibroblasts into induced neurons (Fib-iNs), avoiding pluripotency which restores cells to an embryonic state. We found that early gestational Fib-iNs grew longer neurites than all other ages, mirroring the developmental switch in regenerative ability in rodents. RNA-sequencing and screening revealed ARID1A as a developmentally-regulated modifier of neurite growth in human neurons. These data suggest that age-specific epigenetic changes may drive the intrinsic loss of neurite growth ability in human CNS neurons during development. | Make paid
The twenties are typically considered the prime reproductive years for women. However, in today's modern world, many women are choosing to delay family planning, resulting in an increase in females in their forties seeking fertility treatment. Although in vitro fertilization (IVF) with donated oocytes and preimplantation genetic testing may help to address the impact of maternal age, the success rate for IVF treatment in this age group is still significantly lower. While endometrial changes, such as abnormal endometrial thickness, inflammatory background, and altered hormone response signaling, are associated with aging, little is known about the molecular features of endometrial aging and their impact on the ability to support embryo implantation. To better understand age-specific changes, we performed endometrial transcriptome profiling of young and advanced-age females, undergoing hormonal replacement therapy (HRT) before frozen embryo transfer, followed by immunohistology analysis and single-cell-based deconvolution. Here, we identified 491 differentially expressed genes pointing to the effect of aging on decidualization, cell signaling, inflammation and endometrial receptivity. Our results indicate that p16INK4a may be involved in cellular senescence and the suppression of metabolic and inflammatory processes essential for endometrial preparation for embryo implantation. We have also shown that the proportion of ciliated cells along with ciliary processes is affected by endometrial aging. These findings have important implications for future strategies aimed at improving infertility treatment in women of advanced reproductive age. | Make paid
Background The ability to predict future risk of cancer development in non-malignant biopsies is poor. Cellular senescence has been associated with cancer as either a barrier mechanism restricting autonomous cell proliferation or a tumor-promoting microenvironmental mechanism that secretes pro-inflammatory paracrine factors. With most work done in non-human models and the heterogenous nature of senescence the precise role of senescent cells in the development of cancer in humans is not well understood. Further, more than one million non-malignant breast biopsies are taken every year that could be a major source of risk-stratification for women. Methods We applied single cell deep learning senescence predictors based on nuclear morphology to histological images of 4,411 H&E-stained breast biopsies from healthy female donors. Senescence was predicted in the epithelial, stromal, and adipocyte compartments using predictor models trained on cells induced to senescence by ionizing radiation (IR), replicative exhaustion (RS), or antimycin A, Atv/R and doxorubicin (AAD) exposures. To benchmark our senescence-based prediction results we generated 5-year Gail scores, the current clinical gold standard for breast cancer risk prediction. Findings We found significant differences in adipocyte-specific IR and AAD senescence prediction for the 86 out of 4,411 healthy women who developed breast cancer an average 4.8 years after study entry. Risk models demonstrated that individuals in the upper median of scores for the adipocyte IR model had a higher risk (OR=1.71 [1.10-2.68], p=0.019), while the adipocyte AAD model revealed a reduced risk (OR=0.57 [0.36-0.88], p=0.013). Individuals with both adipocyte risk factors had an OR of 3.32 ([1.68-7.03], p<0.001). Alone, 5-year Gail scores yielded an OR of 2.70 ([1.22-6.54], p=0.019). When combining Gail scores with our adipocyte AAD risk model, we found that individuals with both of these risk predictors had an OR of 4.70 ([2.29-10.90], p<0.001). Interpretation Assessment of senescence with deep learning allows considerable prediction of future cancer risk from non-malignant breast biopsies, something that was previously impossible to do. Furthermore, our results suggest an important role for microscope image-based deep learning models in predicting future cancer development. Such models could be incorporated into current breast cancer risk assessment and screening protocols. Funding This study was funded by the Novo Nordisk Foundation (#NNF17OC0027812), and by the National Institutes of Health (NIH) Common Fund SenNet program (U54AG075932). | Make paid