Background: Falls in the older population are a major public health concern. While many physiological and environmental factors have been associated with fall risk, muscle mitochondrial energetics has not yet been investigated. Methods: In this analysis, 835 Study of Muscle, Mobility and Aging (SOMMA) participants aged 70-94 were surveyed for recurrent falls (2+) after one year. Skeletal muscle energetics were assessed at baseline in vivo using 31P Magnetic Resonance Spectroscopy (MRS) (ATPmax) and ex vivo by High Resolution Respirometry (HRR) of permeabilized muscle fibers from the vastus lateralis (MaxOXPHOS). Results: SOMMA participants who reported recurrent falls (12%) had a slower 400m walk gait speed compared to those with 0-1 falls (1.0 +/- 0.2 vs. 1.1 +/- 0.2, p<.001) and took a greater number of medication in the 30 days before their baseline visit (5.6 +/- 4.4 vs. 4.2 +/- 3.4, p<0.05). MaxOXPHOS was significantly lower in those who reported recurrent falls (p=0.008) compared to those with one or fewer falls, but there was no significant difference in ATPmax (p=0.369). Neither muscle energetics measure was significantly associated with total number of falls or injurious falls, but recurrent falls were significantly higher with lower MaxOXPHOS (RR=1.33, 95% CI= 1.02-1.73, p=0.033). However, covariates accounted for the increased risk. Conclusions: Ex vivo maximal muscle mitochondrial energetics were lower in older adults who experienced recurrent falls, but covariates accounted for its association with recurrent fall risk, suggesting this hallmark of aging may not be directly implicated in the complex etiology of falls. | Make paid
Background: A quality diet and an active lifestyle are both important cornerstones of cardiovascular disease (CVD) prevention. However, despite their interlinked effects on metabolic health, the two behaviours are rarely jointly considered, particularly within the context of CVD prevention. We examined the independent, interactive and joint associations of diet and physical activity with CVD hospitalisation, CVD mortality and all-cause mortality. Methods: CVD-free Australian participants aged 45-74 years reported physical activity, diet and sociodemographic and lifestyle characteristics at baseline (2006-09) and follow-up (2012-15), and data were linked to hospitalisation and death registries (31/03/2019 for CVD hospitalisation and all-cause mortality and 08/12/2017 for CVD mortality). Diet quality was categorised as low, medium and high based on meeting dietary recommendations. Physical activity was operationalised as 1) total moderate-to-vigorous physical activity (MVPA) as per guidelines and 2) the composition of MVPA as the ratio of vigorous-intensity physical activity (VPA) to total MVPA. We used a left-truncated cause-specific Cox proportional hazards model using time-varying covariates. Results: During a median of 10.7 years of follow-up, 6,581 participants were admitted to the hospital for CVD and 6,586 died from all causes (879 from CVD during 9.3 years). A high-quality diet was associated with a 17% lower risk of all-cause mortality than low-quality, and the highest MVPA category (compared with the lowest) was associated with 44% and 48% lower risks of CVD and all-cause mortality. Multiplicative interactions between diet and physical activity were non-significant. For all outcomes, the lowest risk combinations involved a high-quality diet and the highest MVPA categories. Accounting for total MVPA, some VPA was associated with further risk reduction of CVD hospitalisation and all-cause mortality. Conclusion: For CVD prevention and longevity, one should adhere to both a healthy diet and an active lifestyle and incorporate some VPA when possible. | Make paid
Several triage systems have been developed, but little is known about their performance in low-resource settings. Evaluating and comparing novel triage systems to existing triage scales provides essential information about their added value, reliability, safety, and effectiveness before adoption. This prospective observational study included children aged < 15 years who presented to the emergency departments of two public hospitals in Kenya between February and December 2021. We compared the performance of Emergency Triage Assessment and Treatment (ETAT) guidelines and Smart Triage (ST) models (ST-only model, ST model with independent triggers, and recalibrated ST model with independent triggers) in categorizing children into emergency, priority, and non-urgent triage categories. We visualized changes in classification of participants using Sankey diagrams. 5618 children were enrolled, and the majority (3113, 55.4%) were aged between one and five years of age. Overall admission and mortality rates were 7% and 0.9%, respectively. ETAT classified less children, 513 (9.2%), into the emergency category compared to 790 (14.1%), 1163 (20.8%) and 1161 (20.7%) by the ST-only model, ST model with independent triggers and recalibrated model with independent triggers, respectively. ETAT also classified more children, 3089 (55.1%), into the non-urgent triage category compared to 2442 (43.6%), 2097 (37.4%) and 2617 (46.7%) for the respective ST models. ETAT classified 191/395 (48.4%) of admitted patients as emergency compared to more than half by all the ST models. ETAT and the ST-only model classified 25/49 (51%) children who died as emergencies, while the ST models with independent triggers classified 39/49 (79.6%) children as emergencies. Smart Triage shows potential for identifying critically ill children in low-resource settings, particularly when combined with independent triggers. Additionally, it performs comparably to ETAT. Evaluation of Smart Triage in other contexts and comparison to other triage systems is required. | Make paid
The age-related decline in muscle mitochondrial energetics contributes to the loss of mobility in older adults. Women experience a higher prevalence of mobility impairment compared to men, but it is unknown whether sex-specific differences in muscle energetics underlie this disparity. In the Study of Muscle, Mobility and Aging (SOMMA), muscle energetics were characterized using in vivo phosphorus-31 magnetic resonance spectroscopy and high-resolution respirometry of vastus lateralis biopsies in 773 participants (56.4% women, age 70-94 years). A Short Physical Performance Battery score [≤] 8 was used to define lower-extremity mobility impairment. Muscle mitochondrial energetics were lower in women compared to men (e.g. Maximal Complex I&II OXPHOS: Women=55.06 +/- 15.95; Men=65.80 +/- 19.74; p<0.001) and in individuals with mobility impairment compared to those without (e.g., Maximal Complex I&II OXPHOS in women: SPPB[≥]9=56.59 +/- 16.22; SPPB[≤]8=47.37 +/- 11.85; p<0.001). Muscle energetics were negatively associated with age only in men (e.g., Maximal ETS capacity: R=-0.15, p=0.02; age/sex interaction, p=0.04), resulting in muscle energetics measures that were significantly lower in women than men in the 70-79 age group but not the 80+ age group. Similarly, the odds of mobility impairment were greater in women than men only in the 70-79 age group (70-79 age group, ORage-adjusted=1.78, 95% CI=1.03, 3.08, p=0.038; 80+ age group, ORage-adjusted=1.05, 95% CI=0.52, 2.15, p=0.89). Accounting for muscle energetics attenuated up to 75% of the greater odds of mobility impairment in women. Women had lower muscle mitochondrial energetics compared to men, which largely explain their greater odds of lower-extremity mobility impairment. | Make paid
Age and longevity are key parameters for demography and life-history evolution of organisms. In clonal species, a widespread life history among animals, plants, algae and fungi, the sexually produced offspring (the genet) grows indeterminately by producing iterative modules, or ramets. The age of large genets often remains elusive, while estimates based on their spatial extent as proxy for age are unreliable. Here, we present a method for age estimation using a molecular clock based on the accumulation of fixed somatic genetic variation (SoGV) that segregates among ramets of the same genet. Using a stochastic model of a generic clonal organism, we demonstrate that the accumulation of fixed SoGV via somatic genetic drift will approach linearity after a short lag phase, and is determined by the mitotic mutation rate, without direct dependence on asexual generation time. The lag phase decreased with lower stem cell population size (N), number of founder cells for the formation of new modules (N0), and the ratio of symmetric vs. asymmetric stem cell divisions. We apply the somatic genetic clock to the clonal plant model Zostera marina (eelgrass) and show that linearity is approached within a few years. Taking advantage of two long-term cultivation experiments for Z. marina (4 and 17 years respectively) as calibration points, we find genet ages up to 1,403 years in a global data set of 20 eelgrass populations. The somatic genetic clock is applicable to any multicellular clonal species where a small number of founder cells are recruited to form new ramets, opening novel research avenues to study longevity and hence, demography and population dynamics of clonal species. | Make paid
In mice, zygotic genome activation (ZGA) is initiated at the late-one-cell stage, accompanied by an extensive incorporation of the histone variant H3.3 into the parental genomes. However, it is unclear how H3.3 engages in the onset of ZGA. Here, using the H3.3B-HA-tagged mouse model, we found that the paternal and maternal genomes are activated asynchronously. Paternally expressed H3.3 begins deposition on the zygotic genome at the early two-cell stage, whereas the deposition of maternally expressed H3.3 is delayed until the four-cell stage. Oocyte-stored maternal H3.3 (mH3.3) is crucial for cleavage development and minor ZGA. Deposition of mH3.3 on the paternal genome occurs globally during the protamine-to-histone transition but shows preferential enrichment at CpG-rich TSSs after the initial round of DNA replication. Depletion of mH3.3 can lead to a loss of H3K27ac, resulting in minor ZGA failure and early embryonic arrest. Mechanistically, mH3.3 deposition on the sperm genome removes repressive histone modifications, promotes the establishment of active histone modifications, and in turn enables the initiation of minor ZGA from the paternal genome. Our study highlights the pivotal role of mH3.3 in paternal genome reprogramming and minor ZGA initiation. | Make paid
The impact of host diversity on the genotypic and phenotypic evolution of broad-spectrum pathogens is a remaining issue. Here, we used populations of the plant pathogen Ralstonia pseudosolanacearum that were experimentally evolved on five types of host plants, either belonging to different botanical families or differing in their susceptibility or resistance to the pathogen. We investigated whether changes in transcriptomic profiles dissociated from genetic changes could occur during the process of host adaptation, and whether transcriptomic reprogramming was dependent on host type. Genomic and transcriptomic variations were established for 31 evolved clones that showed a better fitness in their experimental host than the ancestral clone. Few genomic polymorphisms were detected in these clones, but significant transcriptomic variations were observed, with a high number of differentially expressed genes (DEGs). In a very clear way, a group of genes belonging to the network of regulation of the bacterial virulence such as efpR, efpH or hrpB, among others, were deregulated in several independent evolutionary lineages and appeared to play a key role in the transcriptomic rewiring observed in evolved clones. A double hierarchical clustering based on the 400 top DEGs for each clone revealed two major patterns of gene deregulation that depend on host genotype, but not on host susceptibility or resistance to the pathogen. This work therefore highlights the existence of two major evolutionary paths that result in a significant reorganization of gene expression during adaptive evolution and underscore clusters of co-regulated genes associated to bacterial adaptation on different host lines. | Make paid
INTRODUCTION: Discovery of the associations between brain structural connectivity and clinical and demographic variables can help to better understand the vulnerability and resilience of the brain architecture to neurodegenerative diseases and to discover biomarkers.METHODS: We used four diffusion-MRI databases, three related to Alzheimer's disease, to exploratorily correlate structural connections between 85 brain regions with non-MRI variables, while stringently correcting the significance values for multiple testing and ruling out spurious correlations via careful visual inspection. We repeated the analysis with brain connectivity augmented with multi-synaptic neural pathways.RESULTS: We found 85 and 101 significant relationships with direct and augmented connectivity, respectively, which were generally stronger for augmented connectivity. Age was consistently linked to decreased connectivity, and healthier clinical scores were generally linked to increased connectivity.DISCUSSION: Our findings help to elucidate which structural brain networks are affected in Alzheimer's disease and aging and highlight the importance of including indirect connections. | Make paid
Objectives: To explore the experience of accessing Long COVID community rehabilitation from the perspectives of people with Long COVID and General Practitioners (GPs). Design: Qualitative descriptive study employing one-to-one semi-structured virtual interviews analysed using the framework method. Setting: Four NHS Scotland territorial health boards. Participants: Eleven people with Long COVID (1 male, 10 female; aged 40-65 [mean 53], and 13 GPs (5 male, 8 female). Results: Four key themes were identified: i) The lived experience of Long COVID; ii) The challenges of an emergent and complex chronic condition; iii) Systemic challenges for Long COVID service delivery, and iv) Perceptions and experiences of Long COVID and its management, including rehabilitation. Conclusions: There are several patient, GP, and service-level barriers to accessing community rehabilitation for Long COVID. There is a need for greater understanding by the public, GPs, and other potential referrers of the role of community rehabilitation professionals in the management of Long COVID. There is also a need for community rehabilitation services to be well promoted and accessible to the people with Long COVID for whom they may be appropriate. Service providers need to consider availability and accessibility of Long COVID rehabilitation and ensure adequate interprofessional communication and collaboration to enhance the experience for people with Long COVID. | Make paid
Background: Advanced HIV (AHD) in young people living with HIV (YLHIV) is an increasingly pressing public health issue. Despite global progress in early HIV testing and reducing HIV-related deaths over the past decade, many YLHIV, especially in sub-Saharan Africa, continue to experience HIV disease progression. This study provides an overview of the prevalence, clinical manifestations, and factors associated with AHD in YLHIV seeking medical services in a major hospital in Sierra Leone. Methods: We used a cross-sectional design to collect data from YLHIV aged 15 to 24 years at a major hospital in Sierra Leone. Data was collected between September 2022 and March 2023. AHD was defined as (i) CD4+ below 200 cells/mm3 or (ii) WHO clinical stage 3 or 4. Logistic regression models determined the association between observable independent characteristics and AHD. The statistical significance level was set at 0.05 for all statistical tests. Results: About 40% (231/574) YLHIV were recruited; 70.6% (163/231) were inpatients, and 29.4% (68/231) were outpatients. The mean age was approximately 21.6 years (SD 2.43). The overall prevalence of AHD in YLHIV was 42.9% (99/231); 51.5% (35/68) of outpatients, while 39.3% (64/163) inpatients had AHD. Age of inpatients (OR, 1.23; 95% CI, 1.00,1.52; p= 0.047) was associated with a higher risk of AHD. Female sex (OR, 0.51; 95% CI, 0.28, 0.94; p= 0.030), higher education (OR, 0.27; 95% CI, 0.10, 0.78; p= 0.015), and higher BMI (OR, 0.10; 95% CI, 0.01, 0.77; p= 0.028) were at lower risk of AHD. Common conditions diagnosed in this population are tuberculosis (13.58%), hepatitis B (6.13%), Kaposi sarcoma (3.07%), and esophageal candidiasis (2.45%). Conclusion: We reported a high prevalence of AHD among YLHIV in a national referral Hospital in a low-income country in West Africa. This emphasizes the need to strengthen public health measures and policies that address the challenges of access to HIV services. | Make paid
Oxidative stress is considered a contributor to declining muscle function and mobility during aging; however, the underlying molecular mechanisms remain poorly described. We hypothesized that greater levels of cysteine (Cys) oxidation on muscle proteins are associated with decreased measures of mobility. Herein, we applied a novel redox proteomics approach to measure reversible protein Cys oxidation in vastus lateralis muscle biopsies collected from 56 subjects in the Study of Muscle, Mobility and Aging (SOMMA), a community-based cohort study of individuals aged 70 years and older. We tested whether levels of Cys oxidation on key muscle proteins involved in muscle structure and contraction were associated with muscle function (leg power and strength), walking speed, and fitness (VO2 peak on cardiopulmonary exercise testing) using linear regression models adjusted for age, sex, and body weight. Higher oxidation levels of select nebulin Cys sites were associated with lower VO2 peak, while greater oxidation of myomesin-1, myomesin-2, and nebulin Cys sites was associated with slower walking speed. Higher oxidation of Cys sites in key proteins such as myomesin-2, alpha-actinin-2, and skeletal muscle alpha-actin were associated with lower leg power and strength. We also observed an unexpected correlation (r = 0.48) between a higher oxidation level of 8 Cys sites in alpha-actinin-3 and stronger leg power. Despite this observation, the results generally support the hypothesis that Cys oxidation of muscle proteins impair muscle power and strength, walking speed, and cardiopulmonary fitness with aging. | Make paid
Purpose: This study aimed to assess the accessibility of social protection programs for individuals with disabilities in Bangladesh and identify factors at the individual, household, and community levels influencing this accessibility. Methods: We analyzed data from 4,293 respondents in the 2021 National Survey on Persons with Disabilities. We categorized participation in social protection programs as follows: no assistance (0), support received within six months (1), and support received beyond six months (2). Explanatory variables were considered at individual, household, and community levels. A multilevel multinomial logistic regression model assessed associations, with two age groups: 0-17 and 18+. Results: Only 38% reported inclusion in social protection programs within six months, rising to 48% for support beyond six months. Disability allowances were the most common, followed by old age allowances and VGD/VGF assistance. Inclusion was likelier for older, unmarried, widowed, divorced, or separated individuals with disabilities. Conversely, those with higher education, wealthier households, and residing in Dhaka division were less likely to be included. Among children aged 0-17, multiple disabilities increased the likelihood of inclusion. Conclusion: These findings underscore the urgent need for more comprehensive and inclusive social protection policies and programs to support the well-being of individuals with disabilities in Bangladesh. | Make paid
Abstract Objective To assess the feasibility of identifying markers of health-seeking behaviour and healthcare access in UK electronic health records (EHR), for identifying populations at risk of poor health outcomes, and adjusting for confounding in epidemiological studies. Design Cross sectional observational study using the Clinical Practice Research Datalink (CPRD) Aurum pre-linked to Hospital Episode Statistics. Setting Individual level routine clinical data from 13 million patients across general practices (GPs) and secondary data in England. Participants Individuals aged =>66 years on 01/09/2019. Main outcome measures We used the Theory of Planned Behaviour (TPB) model and the literature to iteratively develop criteria for markers selection. Based on this we selected 15 markers: those that represented uptake of public health interventions, markers of active healthcare access/use and markers of lack of access/underuse. We calculated the prevalence of each marker using relevant lookback periods prior to index date (01/09/2019) and compared to national estimates. We assessed the correlation coefficients (phi) between markers with inferred hierarchical clustering. Results We included 1,991,284 individuals (mean age: 75.9 and 54.0% females). The prevalence of markers ranged from <0.1% (low-value prescriptions) to 92.6% (GP visits), and most were in line with national estimates; e.g., 73.3% for influenza vaccination in the 2018/2019 season, compared to 72.4% in national estimates. Screening markers e.g., abdominal aortic aneurysm screening were under-recorded even in age-eligible groups (54.3% in 65 to 69 year-olds vs 76.1% in national estimates in men). Overall, marker correlations were low (<0.5) and clustered into groups according to underlying determinants from the TPB model. Conclusion Overall, markers of health-seeking behaviour and healthcare access can be identified in UK EHRs. The generally low correlations between different markers of health-seeking behaviour and healthcare access suggest a range of variables are needed to capture different determinants of healthcare use. | Make paid
Social stress experienced in childhood is associated with adverse health later in life. Mitochondrial function has been implicated as a mechanism for how stressful life events get under the skin to influence physical wellbeing. Using data from the Study of Muscle, Mobility and Aging (n=879, 59% women), linear models examined whether adverse childhood events (i.e., physical abuse) were associated with two measures of skeletal muscle mitochondrial energetics in older adults: (1) maximal adenosine triphosphate production (ATPmax) and (2) maximal state 3 respiration (Max OXPHOS). Forty-five percent of the sample reported experiencing 1+ adverse child-hood event. After adjustment, each additional event was associated with -0.07 SD (95% CI= -0.12, -0.01) lower ATPmax. No association was observed with Max OXPHOS. Adverse child-hood events are associated with lower ATP production in later life. Findings indicate that mitochondrial function may be a mechanism in understanding how early social stress influences health in later life. | Make paid
Yield of harvestable organs is a complex function of photosynthetic output, and sink-strength and timing of competing carbon sinks. In potato (Solanum tuberosum) the effect of tuber onset timing and post-tuberization canopy senescence on growth dynamics and tuber fresh weight are poorly understood. To advance our understanding we compared above- and belowground traits of wildtype plants (WT) with StSP6A, i.e., tuberigen, knockdown plants (SP6Ai) and developed simple computational models to aid interpretation of results. We find that SP6Ai results in a delay of approximately 2 weeks in tuber onset, yet has a 4-to-5-week delayed canopy senescence. Together this results in a prolonged tuber growth phase, with reduced synchronization in tuber onset and a resulting increased variance in tuber sizes, while overall final tuber fresh weight remains similar. Using a leaf and tuber growth model comparing various leaf senescence mechanisms, we find that resource competition, and not a shared signal for tuberization and senescence, is able to explain how delayed tuberization leads to further delayed senescence. Our results point to a role for resource competition in the correlated timing of tuber onset and canopy senescence, as well as a leading role for StSP6A in tuber onset synchronization and tuber size uniformity. | Make paid
Canopy temperature (CT) is often interpreted as representing leaf activity traits such as photosynthetic rates, gas exchange rates, or stomatal conductance. Accordingly, CT measurements may provide a basis for high throughput assessments of the productivity of wheat canopies during early grain filling, which would allow distinguishing functional from dysfunctional stay-green. However, whereas the usefulness of CT as a fast surrogate measure of sustained vigor under soil drying is well established, its potential to quantify leaf activity traits under high-yielding conditions is less clear. To better understand sensitivity limits of CT measurements under high yielding conditions, we generated within-genotype variability in stay-green functionality by means of differential short-term pre-anthesis canopy shading that modified the sink:source balance. We quantified the effects of these modifications on stay-green properties through a combination of gold standard physiological measurements of leaf activity and newly developed methods for organ-level senescence monitoring based on timeseries of high-resolution imagery and deep-learning-based semantic image segmentation. In parallel, we monitored CT by means of a pole-mounted thermal camera that delivered continuous, ultra-high temporal resolution CT data. Our results show that differences in leaf activity stemming from differences in stay-green functionality translate into measurable differences in CT in the absence of major confounding factors. Differences amounted to approximately 0.8 degrees C and 1.5 degrees C for a very high-yielding source-limited genotype, and a medium-yielding sink-limited genotype, respectively. The gradual nature of the effects of shading on CT during the stay-green phase underscore the importance of a high measurement frequency and a time-integrated analysis of CT, whilst modest effect sizes confirm the importance of restricting screenings to a limited range of morphological and phenological diversity. | Make paid
Background: Effective detection of early lung disease in cystic fibrosis (CF) is critical to understanding early pathogenesis and evaluating early intervention strategies. We aimed to compare ability of several proposed sensitive functional tools to detect early CF lung disease as defined by CT structural disease in school aged children. Methods: 50 CF subjects (mean+/-SD 11.2+/-3.5y, range 5-18y) with early lung disease (FEV1>/=70% predicted: 95.7+/-11.8%) performed spirometry, Multiple breath washout (MBW, including trapped gas assessment), oscillometry, cardiopulmonary exercise testing (CPET) and simultaneous spirometer-directed low-dose CT imaging. CT data were analysed using well-evaluated fully quantitative software for bronchiectasis and air trapping (AT). Results: CT bronchiectasis and AT occurred in 24% and 58% of patients, respectively. Of the functional tools, MBW detected the highest rates of abnormality: Scond 82%, MBWTG RV 78%, LCI 74%, MBWTG IC 68% and Sacin 51%. CPET VO2peak detected slightly higher rates of abnormality (9%) than spirometry (FEV1/FVC 8%, FEF25-75 8%, FEV1 2%). For oscillometry AX (14%) performed better than Rrs (2%) whereas Xrs and R5-19 failed to detect any abnormality. LCI and Scond correlated with bronchiectasis (r=0.55-0.64, p<0.001) and AT (r=0.73-0.74, p<0.001). MBW-assessed trapped gas was detectable in 92% of subjects and concordant with CT-assessed AT in 74%. Conclusions: Significant structural and functional deficits occur in early CF lung disease, as detected by CT and MBW. For MBW, additional utility, beyond that offered by LCI, was suggested for Scond and MBW-assessed gas trapping. Our study reinforces the complementary nature of these tools and the limited utility of conventional oscillometry and CPET in this setting. | Make paid
Abdominal aortic aneurysm (AAA) is a degenerative vascular disease impacting aging populations with a high mortality upon rupture. There are no effective medical therapies to prevent AAA expansion and rupture. We previously demonstrated the role of the monocyte chemoattractant protein-1 (MCP-1)/C-C chemokine receptor type 2 (CCR2) axis in rodent AAA pathogenesis via positron emission tomography/computed tomography (PET/CT) using CCR2 targeted radiotracer 64Cu-DOTA-ECL1i. We have since translated this radiotracer into patients with AAA. CCR2 PET showed intense radiotracer uptake along the AAA wall in patients while little signal was observed in healthy volunteers. AAA tissues collected from individuals scanned with 64Cu-DOTA-ECL1i and underwent open-repair later demonstrated more abundant CCR2+ cells compared to non-diseased aortas. We then used a CCR2 inhibitor (CCR2i) as targeted therapy in our established male and female rat AAA rupture models. We observed that CCR2i completely prevented AAA rupture in male rats and significantly decreased rupture rate in female AAA rats. PET/CT revealed substantial reduction of 64Cu-DOTA-ECL1i uptake following CCR2i treatment in both rat models. Characterization of AAA tissues demonstrated decreased expression of CCR2+ cells and improved histopathological features. Taken together, our results indicate the potential of CCR2 as a theranostic biomarker for AAA management. | Make paid
Human immunodeficiency virus (HIV) is associated with persistent immune activation and dysfunction in people with HIV despite treatment with antiretroviral therapy (ART). Modulation of the immune system may be driven by: low-level HIV replication, co-pathogens, gut dysbiosis /translocation, altered lipid profiles, and ART toxicities. In addition, perinatally acquired HIV (PHIV) and lifelong ART may alter the development and function of the immune system. Our preliminary data and published literature suggest reprogramming innate immune cells may accelerate aging and increase the risk for future end-organ complications, including cardiovascular disease (CVD). The exact mechanisms, however, are currently unknown. Natural killer (NK) cells are a highly heterogeneous cell population with divergent functions. They play a critical role in HIV transmission and disease progression in adults. Recent studies suggest the important role of NK cells in CVDs; however, little is known about NK cells and their role in HIV-associated cardiovascular risk in PHIV adolescents. Here, we investigated NK cell subsets and their potential role in atherogenesis in PHIV adolescents compared to HIV-negative adolescents in Uganda. Our data suggest, for the first time, that activated NK subsets in PHIV adolescents may contribute to atherogenesis by promoting plasma oxidized low-density lipoprotein (Ox-LDL) uptake by vascular macrophages. | Make paid
Abstract Background. The geroscience hypothesis posits that aging biological processes contribute to many age-related deficits, including the accumulation of multiple chronic diseases. Though only one facet of mitochondrial function, declines in muscle mitochondrial bioenergetic capacities may contribute to this increased susceptibility to multimorbidity. Methods. The Study of Muscle, Mobility and Aging (SOMMA) assessed ex vivo muscle mitochondrial energetics in 764 older adults (mean age =76.4, 56.5% women, 85.9% non-Hispanic white) by high-resolution respirometry of permeabilized muscle fibers. We estimated the proportional odds ratio (POR [95%CI]) for the likelihood of greater multimorbidity (four levels: 0 conditions, N=332; 1 condition, N=299; 2 conditions, N=98; or 3+ conditions, N=35) from an index of 11 conditions, per SD decrement in muscle mitochondrial energetic parameters. Distribution of conditions allowed for testing the associations of maximal muscle energetics with some individual conditions. Results. Lower oxidative phosphorylation supported by fatty acids and/or complex-I and -II linked carbohydrates (e.g., Max OXPHOSCI+CII) was associated with a greater multimorbidity index score (POR=1.32[1.13,1.54]) and separately with diabetes mellitus (OR=1.62[1.26,2.09]), depressive symptoms (OR=1.45[1.04,2.00]) and possibly chronic kidney disease (OR=1.57[0.98,2.52]) but not significantly with other conditions (e.g., cardiac arrhythmia, chronic obstructive pulmonary disease). Conclusions. Lower muscle mitochondrial bioenergetic capacities was associated with a worse composite multimorbidity index score. Our results suggest that decrements in muscle mitochondrial energetics may contribute to a greater global burden of disease and is more strongly related to some conditions than others. | Make paid
Background: Cognitive impairment is the most common and disabling manifestation of post-acute sequelae of SARS-CoV-2. There is an urgent need for the application of more stringent methods for evaluating cognitive outcomes in research studies. Objective: To determine whether cognitive decline emerges with the onset of COVID-19 and whether it is more pronounced in patients with Post-Acute Sequelae of SARS-CoV-2 or severe COVID-19. Methods: This longitudinal cohort study compared the cognitive performance of 276 patients with COVID-19 to that of 217 controls across four neuroinflammation or vascular disease-sensitive domains of cognition using data collected both before and after the pandemic starting in 2015. Results: The mean age of the COVID-19 group was 56.04 (SD=6.6) years, while that of the control group was 58.1 (SD=7.3) years. Longitudinal models indicated a significant decline in cognitive throughput ((B=-0.168, P=.001) following COVID-19, after adjustment for pre-COVID-19 functioning, demographics, and medical factors. The effect sizes were large; the observed changes in throughput were equivalent to 10.6 years of normal aging and a 59.8% increase in the burden of mild cognitive impairment. Cognitive decline worsened with coronavirus disease 2019 severity and was concentrated in participants reporting post-acute sequelae of SARS-CoV-2. Conclusion: COVID-19 was most likely associated with the observed cognitive decline, which was worse among patients with PASC or severe COVID-19. Monitoring patients with post-acute sequelae of SARS-CoV-2 for declines in the domains of processing speed and visual working memory and determining the long-term prognosis of this decline are therefore warranted. | Make paid
Aging and cellular senescence are increasingly recognized as key contributors to pulmonary fibrosis. However, our understanding in the context of scleroderma associated interstitial lung disease (SSc-ILD) is limited. To investigate, we leveraged previously established lung aging and cell-specific senescence signatures to determine their presence and potential relevance to SSc-ILD. We performed a gene expression meta-analysis of lung tissue from 38 SSc-ILD and 18 healthy controls and found markers (GDF15, COMP, CDKN2A) and pathways (p53) of senescence were significantly increased in SSc-ILD. When probing the established aging and cellular senescence signatures, we found epithelial and fibroblast senescence signatures had a 3.6-fold and 3.7-fold enrichment respectively in the lung tissue of SSc-ILD and that lung aging genes (CDKN2A, FRZB, PDE1A, NAPI12) were increased in SSc-ILD. These signatures were also enriched in SSc skin and associated with degree of skin involvement (limited vs. diffuse cutaneous). To further support these findings, we examined telomere length (TL), a surrogate for aging, in lung tissue and found independent of age, SSc-ILD had significantly shorter telomeres than controls in type II alveolar cells in the lung. TL in SSc-ILD was comparable to idiopathic pulmonary fibrosis, a disease of known aberrant aging. Taken together, this study provides novel insight into the possible mechanistic effects of accelerated aging and aberrant cellular senescence in SSc-ILD pathogenesis. | Make paid
Background: Accelerated brain aging has been observed across multiple psychiatric disorders. Blood markers of neuronal injury such as Neurofilament Light (NfL) may therefore represent biomarkers of accelerated brain aging in these disorders. The current study aimed to examine whether relationships between age and plasma NfL were increased in individuals with primary psychiatric disorders compared to healthy individuals. Methods: Plasma NfL was analysed in major depressive disorder (MDD, n = 42), bipolar affective disorder (BPAD, n = 121), treatment-resistant schizophrenia (TRS, n = 82), a large reference normative control group (n= 1,926) and a locally-acquired HC sample (n = 59). A general linear model was used to examine diagnosis by age interactions on NfL z-scores using the large normative HC sample as a reference group. Significant results were then validated using the locally-acquired HC sample. Results: a GLM identified a significant age by diagnosis interaction for TRS vs HCs and BPAD vs HCs. Post hoc analyses revealed a positive correlation between NfL levels and age among individuals with TRS, whereas a negative correlation was found among individuals with BPAD. However, only the TRS findings were validated using the locally-acquired HC sample. Conclusions: These findings add to the growing literature supporting the notion of accelerated brain ageing in schizophrenia-spectrum disorders. | Make paid
Benign prostatic hyperplasia (BPH) is characterized by excessive cell proliferation and inflammation and affects most aging men. The development of new therapies for BPH requires a deeper understanding of the underlying pathophysiology and cellular components of BPH. Here, we characterize at single cell resolution the cellular states of BPH and identify cell populations enriched in BPH that contribute to cell proliferation and inflammation. Single-cell RNA-sequencing was performed on prostate tissue from 15 patients undergoing holmium laser enucleation of the prostate for treatment of BPH. Clustering and differential expression analysis on aligned single cell RNA-seq data was performed to annotate all cell types. Pseudotime, gene set enrichment, gene ontology, and ligand-receptor analyses were performed. 16,234 cells were analyzed and specific stromal, epithelial, and immune subgroups were found to be strongly associated with inflammation. A rare luminal subgroup was identified and pseudotime analysis indicated this luminal subgroup was more closely related to club and basal cells. Using a gene set derived from epithelial stem cells, we found that this luminal subgroup had a significantly higher stem cell signature score than all other epithelial subgroups, suggesting this subgroup is a luminal precursor state. Ligand-receptor interactions between stromal, epithelial, and immune cells were explored with CellPhoneDB. Unique interactions highlighting MIF, a pro-inflammatory cytokine that promotes epithelial cell growth and inflammation in the prostate, were found between fibroblasts and the progenitor luminal subgroup. This luminal subgroup also interacted with neutrophils and macrophages through MIF. Our single-cell profiling of BPH provides a roadmap for inflammation-linked cell subgroups and highlights a novel luminal progenitor subgroup interacting with other cell groups via MIF that may contribute to the inflammation and cell proliferation phenotype associated with BPH. | Make paid
Sugar sweetened beverage consumption has been suggested as a risk factor for asthma symptoms in children. We examined whether the UK Soft Drinks Industry Levy (SDIL), announced in March 2016 and implemented in April 2018, was associated with changes in National Health Service hospital admission rates for asthma in children. We conducted interrupted time series analyses (2012 - 2020) to measure changes in monthly incidence rates of hospital admissions for asthma. Sub-analysis was by age-group (5-9, 10-14, 15-18 years) and neighbourhood deprivation quintiles. Estimated changes were relative to counterfactual scenarios where SDIL was neither announced, nor implemented. Compared to the counterfactual scenario there was an overall relative reduction in incidence rates of hospital admissions of 20.9% (95%CI: 29.6-12.2), 22 months post-SDIL. Reductions were similar across age-groups and deprivation quintiles with relative reductions of 24.3% (95%CI: 29.6-12.2) in children aged 10-14 years, and reductions of 23.2% (95%CI 33.4-13.1) in children living in the middle deprivation quintile. These findings provide evidence that the implementation of a tax intended to reduce childhood obesity in the UK preceded a potentially significant collateral public health benefit in the form of reduced hospital admissions for childhood asthma. | Make paid
Background: Cardiopulmonary exercise testing (CPET), the gold-standard method to quantify cardiorespiratory fitness (CRF), is not always feasible due to cost, access, and burden. The usual-paced 400m long-distance corridor walk (LDCW), a measure of mobility among older adults, may provide an alternate method to assess CRF among populations unable to complete maximal intensity testing. The purpose of this study was to develop and validate an estimating equation to estimate VO2peak from average 400m walking speed (WS) among participants in the Study of Muscle, Mobility and Aging (SOMMA). Methods: At baseline, participants (N=820, 76.2{+/-}4.9 years, 58% Women, 86% Non-Hispanic White) completed a 400m LDCW (400m WS=400m/completion time in seconds) and symptom-limited maximal CPET (Modified Balke Protocol). VO2peak (mL/kg/min) was considered the highest 30-second average oxygen consumption during CPET. Other covariates included: age, sex, race, physical activity (7-day wrist-worn accelerometer), physical function (Short Physical Performance Battery, range 0-12), perceived physical fatigability (Pittsburgh Fatigability Scale, range 0-50), and Borg Rating of Perceived Exertion (RPE, range 6-20) at completion of the 400m LDCW. Stepwise linear regression was used. Internal validation was completed using data-splitting method (70%; 30%). Results: Mean VO2peak was 20.2{+/-}4.8 mL/kg/min and mean 400m WS was 1.06{+/-}0.2 m/s. Each 0.05 m/s increment in 400m WS was associated with a 0.40 mL/kg/min higher VO2peak after adjustment for covariates. An estimating equation including 400m WS, age, sex, race, and RPE was developed. Internal validation showed low overall bias (-0.26) and strong correlation (r = 0.71) between predicted and measured VO2peak values. Bland-Altman plot and regression analyses indicated predicted VO2peak was an acceptable alternative, despite mean underestimation of 4.53 mL/kg/min among those with CPET VO2peak [≥]25 mL/kg/min. Conclusions: Usual-paced 400m LDCW strongly correlates with direct measures of cardiorespiratory fitness during CPET in older adults with lower fitness and can be used to test both fitness and function. | Make paid
Background: Skeletal muscle energetics decline with age, and physical activity (PA) has been shown to counteract these declines in older adults. Yet, many studies were based on self-reported PA or structured exercise interventions. We examined the associations of objective daily PA and sedentary behavior (SB) with skeletal muscle energetics and also compared with self-reported PA and SB. We also explored the extent to which PA would attenuate the associations of age with muscle energetics. Methods: Among the Study of Muscle, Mobility and Aging (SOMMA) enrolled older adults, 810 (mean age=76{+/-}5, 58% women) had maximal muscle oxidative capacity measured ex vivo via high-resolution respirometry of permeabilized myofibers (maxOXPHOS) and in vivo by 31Phosphorus magnetic resonance spectroscopy (ATPmax). Objective PA was measured using the wrist-worn ActiGraph GT9X over 7-days to capture sedentary behavior (SB), light, and moderate-to-vigorous PA (MVPA). Self-reported SB, MVPA, and all exercise-related PA were assessed with The Community Healthy Activities Model Program for Seniors questionnaire. Linear regression models with progressive covariate adjustments evaluated the associations between SB, PA and muscle energetics, and the attenuation of the age / muscle energetic association by PA. Results: Every 30 minutes more objective MVPA was associated with 0.65 pmol/s*mg higher maxOXPHOS and 0.012 mM/sec higher ATPmax, after adjustment for age, site/technician and sex. More time spent in objective light+MVPA was significantly associated with higher ATPmax, but not maxOXPHOS. In contrast, every 30 minutes spent in objective SB was associated with 0.43 pmol/s*mg lower maxOXPHOS and 0.004 mM/sec lower ATPmax. Only associations with ATPmax held after further adjusting for socioeconomic status, body mass index, lifestyle factors and multimorbidities. Self-reported MVPA and all exercise-related activities, but not SB, yielded similar associations with maxOXPHOS and ATPmax. Lastly, age was only significantly associated with muscle energetics in men. Adjusting for objective time spent in MVPA attenuated the age association with ATPmax by nearly 60% in men. Conclusion: More time spent in daily PA, especially MVPA, were associated with higher muscle energetics. Interventions that increase higher intensity activity might offer potential therapeutic interventions to slow the age-related decline in muscle energetics. Our work also emphasizes the importance of taking PA into consideration when evaluating associations related to skeletal muscle energetics. | Make paid
Background Assessing well-being can be tricky due to its subjective nature which may result in inaccurate or incomplete evaluations. This is particularly challenging in measuring male well-being, as traditional gender roles and expectations often discourage normalising discussions about mens health concerns. Studies reveal notable obstacles in the way men perceive, behave, and hold beliefs about their health and well-being which may result in underreporting of health issues among men. A gender-specific measurement of well-being for men is therefore essential and merits further examination. Methods This study aims to validate a male well-being instrument in the context of Malaysian men using confirmatory factor analysis (CFA). An online cross-sectional survey involving a total of 651 Malaysian men aged 18 and above was conducted utilising a 33-item male well-being instrument developed in a preliminary study. Results The analysis resulted in a satisfactory 24-item model with six dimensions: self-confidence (4 items); family/close relationships adaptation (5 items); physical health (3 items); living environment adaptation (4 items); autonomy and agency (4 items); and economic stability (4 items). There were high correlations among the 24 items. The internal consistency reliability was robust, with no floor or ceiling effects. These results represented equivalence and consistency among the responses to items, suggesting that the items were homogenous in measuring Malaysian male well-being. Conclusions This study confirms the suitability of a 24-item instrument measuring male well-being in Malaysia. The instrument may possibly be used in similar Asian cultures as it achieved strong reliability, structural validity and construct validity that fulfilled goodness-of-fit criteria. | Make paid
Objectives: To explore the experience of accessing Long COVID community rehabilitation from the perspectives of people with Long COVID and General Practitioners (GPs). Design: Qualitative descriptive study employing one-to-one semi-structured virtual interviews analysed using the framework method. Setting: Four NHS Scotland territorial health boards. Participants: Eleven people with Long COVID (1 male, 10 female; aged 40-65 [mean 53], and 13 GPs (5 male, 8 female). Results: Four key themes were identified: i) The lived experience of Long COVID; ii) The challenges of an emergent and complex chronic condition; iii) Systemic challenges for Long COVID service delivery, and iv) Perceptions and experiences of Long COVID and its management, including rehabilitation. Conclusions: There are several patient, GP, and service-level barriers to accessing community rehabilitation for Long COVID. There is a need for greater understanding by the public, GPs, and other potential referrers of the role of community rehabilitation professionals in the management of Long COVID. There is also a need for community rehabilitation services to be well promoted and accessible to the people with Long COVID for whom they may be appropriate. Service providers need to consider availability and accessibility of Long COVID rehabilitation and ensure adequate interprofessional communication and collaboration to enhance the experience for people with Long COVID. | Make paid
After their transition from water to land around 450 million years ago, plants colonized new habitats facing unprecedented pathogenic microbes. That expansion was mostly supported by a growing anatomical complexity based on the acquisition of developmental innovations, such as roots, stomata and vascular tissue. Despite several of those innovations became central for the interaction between plants and their associated microbes, little is known about their impact on plant immune programs and on the diversification of infection strategies of their pathogens. A paradigmatic case is the close relationship between plant vasculature and viruses. Vascular tissues provide a unique cellular environment for viral replication and existence, besides constituting a fast track for viral systemic spread throughout the plant. Since most of our knowledge about plant-virus interactions come from studies in vascular plants, we here present a comparative study to contribute to the understanding of the evolution of plant- virus interactions by molecularly characterizing the interplay between the bryophyte Marchantia polymorpha and viruses. Virome analysis of Marchantia plants shows that they are primarily associated with RNA viruses in natural settings. Additional molecular characterization of the interaction between Marchantia and tobacco mosaic virus (TMV) show conserved basic processes with vascular plants and divergent features. Viral infection triggers an extensive transcriptional reprogramming in Marchantia encompassing broad range defence responses, inhibition of cell cycle and photosynthesis and a sustained wound response that prevents further viral movement. Additionally, infected plants show premature aging and organ maturation. Notably, we found that some core responses that occur in infected areas in Marchantia, were described to be restricted to vascular tissues in Nicotiana, suggesting that evolutionary appearance of developmental innovations that became central in plants-virus interactions resulted in re-routing of defence responses. Finally, we uncover the conserved role of a transcription factor interacting with the TMV silencing suppressor p126 in specifically abrogating TMV infection. | Make paid