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Abstract It has been hypothesized that ultraviolet (UV) radiation can lead to depletion of plasma folate and B12 vitamin, but few studies have investigated effects of other parameters of solar and geomagnetic activity (SGA). We investigated the association between four SGA parameters—interplanetary magnetic field (IMF), sunspot number (SSN), Kp index, and ground shortwave solar radiation (SWR)—and three plasma B-complex vitamins—folate, B6, and B12—in 910 participants from the Normative Aging Study (NAS) between 1998 and 2017. Mixed-effects regression models were used for 1- to 28-moving day averages of SGA exposure, adjusted for covariates. We compared the impact of SGA in individuals under higher and lower B-complex supplementation (> or

Psychological stress remains an important risk factor for morbidity and mortality throughout the life course. However, there have been counterintuitive findings reported in previous studies of older persons that examine the relationships of perceived psychological stress with DNA methylation-based markers of aging, which also serve as predictors of morbidity and mortality (epigenetic age/clocks). We aimed to replicate and expand findings from existing work by examining relationships of self-reported stress with nine epigenetic clocks: Hannum, Horvath, Intrinsic, Extrinsic, SkinBloodClock, PhenoAge, GrimAge, DNAm Telomere Length, and Pace of Aging. We analyzed data from 607 male participants (mean age 73.2 years) of the VA Normative Aging Study with one to two study visits from 1999 to 2007 (observations = 956). Stress was assessed via the 14-item Perceived Stress Scale (PSS). Epigenetic age was calculated from DNA methylation measured in leukocytes with the HumanMethylation450 BeadChip. In linear mixed effects models adjusted for demographic/lifestyle/health factors, a standard deviation (sd) increase in PSS was associated with Horvath (β = −0.35-years, 95%CI: −0.61, −0.09, P = 0.008) and Intrinsic (β = −0.40-years, 95%CI: −0.67, −0.13, P = 0.004) epigenetic age deceleration. However, in models limited to participants with the highest levels of stress (≥75th-percentile), Horvath (β = 2.29-years, 95%CI: 0.16, 4.41, P = 0.04) and Intrinsic (β = 2.06-years, 95%CI: −0.17, 4.28, P = 0.07) age acceleration associations were observed. Our results reinforce the complexity of psychological stress and epigenetic aging relationships and lay a foundation for future studies that explore longitudinal relationships with other adult stress metrics and factors that can influence stress such as resilience measures.

Background: While the health effects of air pollution and temperature are widely studied, the molecular effects are poorly understood. Extracellular microRNAs (ex-miRNAs) have the potential to serve as diagnostic or prognostic biomarkers and/or to act as intercellular signaling molecules that mediate the effects of environmental exposures on health outcomes. Methods: We examined the relationship between short-term exposure to air pollution and ambient temperature and the ex-miRNA profiles of participants in the Normative Aging Study (NAS) from 1999 to 2015. Our exposures were defined as same-day, two-day, three-day, one-week, two-week, and three-week moving averages of PM2.5, NO2, O3, and temperature which were derived from high-resolution spatio-temporal models. The ex-miRNA profiles of the subjects were obtained during follow-up visits. We analyzed the data using a longitudinal quantile regression model adjusted for individual covariates, batch effects, and time trends. We adjusted for multiple comparisons using a false discovery rate (FDR) correction. Ex-miRNAs that were significantly associated with exposures were further investigated using pathway analyses. Results: We found that all the examined exposures were associated with changes in ex-miRNA profiles in our study, particularly PM2.5 which was responsible for most of the statistically significant results. We found 110 statistically significant exposure-outcome relationships that revealed associations with the levels of 52 unique ex-miRNAs. Pathway analyses showed these ex-miRNAs have been linked to target mRNAs, genes, and biological mechanisms that could affect virtually every organ system, and as such may be linked to multiple clinical disease presentations such as cardiovascular disease, respiratory disease, and neurological disease. Conclusions: Air pollution and temperature exposures were significantly associated with alterations in the ex-miRNA profiles of NAS subjects with possible biological consequences.

Traditional approaches to understanding metabolomics in mental illness have focused on investigating a single disorder or comparisons between diagnoses, but a growing body of evidence suggests substantial mechanistic overlap in mental disorders that could be reflected by the metabolome. In this study, we investigated associations between global plasma metabolites and abnormal scores on the depression, anxiety, and phobic anxiety subscales of the Brief Symptom Inventory (BSI) among 405 older males who participated in the Normative Aging Study (NAS). Our analysis revealed overlapping and distinct metabolites associated with each mental health dimension subscale and four metabolites belonging to xenobiotic, carbohydrate, and amino acid classes that were consistently associated across all three symptom dimension subscales. Furthermore, three of these four metabolites demonstrated a higher degree of alteration in men who reported poor scores in all three dimensions compared to men with poor scores in only one, suggesting the potential for shared underlying biology but a differing degree of perturbation when depression and anxiety symptoms co-occur. Our findings implicate pathways of interest relevant to the overlap of mental health conditions in aging veterans and could represent clinically translatable targets underlying poor mental health in this high-risk population.

Abstract Background Long-term exposures to air pollution has been reported to be associated with inflammation and oxidative stress. However, the underlying metabolic mechanisms remain poorly understood. Objectives We aimed to determine the changes in the blood metabolome and thus the metabolic pathways associated with long-term exposure to outdoor air pollution and ambient temperature. Methods We quantified metabolites using mass-spectrometry based global untargeted metabolomic profiling of plasma samples among men from the Normative Aging Study (NAS). We estimated the association between long-term exposure to PM2.5, NO2, O3, and temperature (annual average of central site monitors) with metabolites and their associated metabolic pathways. We used multivariable linear mixed-effect regression models (LMEM) while simultaneously adjusting for the four exposures and potential confounding and correcting for multiple testing. As a reduction method for the intercorrelated metabolites (outcome), we further used an independent component analysis (ICA) and conducted LMEM with the same exposures. Results Men (N = 456) provided 648 blood samples between 2000 and 2016 in which 1158 metabolites were quantified. On average, men were 75.0 years and had an average body mass index of 27.7 kg/m2. Almost all men (97%) were not current smokers. The adjusted analysis showed statistically significant associations with several metabolites (58 metabolites with PM2.5, 15 metabolites with NO2, and 6 metabolites with temperature) while no metabolites were associated with O3. One out of five ICA factors (factor 2) was significantly associated with PM2.5. We identified eight perturbed metabolic pathways with long-term exposure to PM2.5 and temperature: glycerophospholipid, sphingolipid, glutathione, beta-alanine, propanoate, and purine metabolism, biosynthesis of unsaturated fatty acids, and taurine and hypotaurine metabolism. These pathways are related to inflammation, oxidative stress, immunity, and nucleic acid damage and repair. Conclusions Using a global untargeted metabolomic approach, we identified several significant metabolites and metabolic pathways associated with long-term exposure to PM2.5, NO2 and temperature. This study is the largest metabolomics study of long-term air pollution, to date, the first study to report a metabolomic signature of long-term temperature exposure, and the first to use ICA in the analysis of both.

This study investigated the associations between solar and geomagnetic activity and circulating biomarkers of systemic inflammation and endothelial activation in the Normative Aging Study (NAS) cohort. Mixed effects models with moving day averages from day 0 to day 28 were used to study the associations between solar activity (sunspot number (SSN), interplanetary magnetic field (IMF)), geomagnetic activity (planetary K index (Kp index), and various inflammatory and endothelial markers. Biomarkers included intracellular adhesion molecule-1 (sICAM-1), vascular cell adhesion molecule-1 (sVCAM-1), C-reactive protein (CRP), and fibrinogen. After adjusting for demographic and meteorological variables, we observed significant positive associations between sICAM-1 and sVCAM-1 concentrations and solar and geomagnetic activity parameters: IMF, SSN, and Kp. Additionally, a negative association was observed between fibrinogen and Kp index and a positive association was observed for CRP and SSN. These results demonstrate that solar and geomagnetic activity might be upregulating endothelial activation and inflammation.

Background: Measures to quantify changes in the pace of biological aging in response to intervention are needed to evaluate geroprotective interventions for humans. Previously, we showed that quantification of the pace of biological aging from a DNA-methylation blood test was possible (Belsky et al., 2020). Here, we report a next-generation DNA-methylation biomarker of Pace of Aging, DunedinPACE (for Pace of Aging Calculated from the Epigenome). Methods: We used data from the Dunedin Study 1972–1973 birth cohort tracking within-individual decline in 19 indicators of organ-system integrity across four time points spanning two decades to model Pace of Aging. We distilled this two-decade Pace of Aging into a single-time-point DNA-methylation blood-test using elastic-net regression and a DNA-methylation dataset restricted to exclude probes with low test-retest reliability. We evaluated the resulting measure, named DunedinPACE, in five additional datasets. Results: DunedinPACE showed high test-retest reliability, was associated with morbidity, disability, and mortality, and indicated faster aging in young adults with childhood adversity. DunedinPACE effect-sizes were similar to GrimAge Clock effect-sizes. In analysis of incident morbidity, disability, and mortality, DunedinPACE and added incremental prediction beyond GrimAge. Conclusions: DunedinPACE is a novel blood biomarker of the pace of aging for gerontology and geroscience. Funding: This research was supported by US-National Institute on Aging grants AG032282, AG061378, AG066887, and UK Medical Research Council grant MR/P005918/1.

Background Since solar activity and related geomagnetic disturbances modulate autonomic nervous system activity, we hypothesized that these events would be associated with blood pressure (BP). Methods and Results We studied 675 elderly men from the Normative Aging Study (Boston, MA) with 1949 BP measurements between 2000 and 2017. Mixed‐effects regression models were used to investigate the association of average 1‐day (ie, day of BP measurement) to 28‐day interplanetary magnetic field intensity, sunspot number, and a dichotomized measure of global geomagnetic activity (Kp index) in 4‐day increments with diastolic and systolic BP. We adjusted for meteorological conditions and other covariates associated with BP, and in additional models adjusted for ambient air pollutants (particulate matter with an aerodynamic diameter ≤2.5 µm, black carbon, and particle number) and ambient particle radioactivity. There were positive associations between interplanetary magnetic field, sunspot number, and Kp index and BP that were greatest with these exposures averaged over 16 through 28 days before BP measurement. An interquartile range increase of 16‐day interplanetary magnetic field and sunspot number and higher Kp index were associated with a 2.5 (95% CI, 1.7‒3.2), 2.8 (95% CI, 2.1‒3.4), and 1.7 (95% CI, 0.8‒2.5) mm Hg increase, respectively, for diastolic BP as well as a 2.1 (95% CI, 0.7‒3.6), 2.7 (95% CI, 1.5‒4.0), and 0.4 (95% CI, −1.2 to 2.1) mm Hg increase, respectively, for systolic BP. Associations remained after adjustment for ambient air pollutants and ambient particle radioactivity. Conclusions Solar activity and solar‐driven geomagnetic disturbances were positively associated with BP, suggesting that these natural phenomena influence BP in elderly men.

Background: The metabolomic signatures of short- and long-term exposure to PM2.5 have been reported and linked to inflammation and oxidative stress. However, little is known about the relative contribution of the specific PM2.5 species (hence sources) that drive these metabolomic signatures. Objectives: We aimed to determine the relative contribution of the different species of PM2.5 exposure to the perturbed metabolic pathways related to changes in the plasma metabolome. Methods: We performed mass-spectrometry based metabolomic profiling of plasma samples among men from the Normative Aging Study to identify metabolic pathways associated with PM2.5 species. The exposure windows included short-term (one, seven-, and thirty-day moving average) and long-term (one year moving average). We used linear mixed-effect regression with subject-specific intercepts while simultaneously adjusting for PM2.5, NO2, O3, temperature, relative humidity, and covariates and correcting for multiple testing. We also used independent component analysis (ICA) to examine the relative contribution of patterns of PM2.5 species. Results: Between 2000 and 2016, 456 men provided 648 blood samples, in which 1158 metabolites were quantified. We chose 305 metabolites for the short-term and 288 metabolites for the long-term exposure in this analysis that were significantly associated (p-value

Background: Exploring the associations of air pollution and weather variables with blood leukocyte distribution is critical to understand the impacts of environmental exposures on the human immune system. Objectives: As previous analyses have been mainly based on data from cell counters, which might not be feasible in epidemiologic studies including large populations of long-stored blood samples, we aimed to expand the understanding of this topic by employing the leukocyte distribution estimated by DNA methylation profiles. Methods: We measured DNA methylation profiles in blood samples using Illumina HumanMethylation450 BeadChip from 1519 visits of 774 Caucasian males participating in the Normative Aging Study. Leukocyte distribution was estimated using Houseman's and Horvath's algorithms. Data on air pollution exposure, temperature, and relative humidity within 28 days before each blood draw was obtained. Results: After fully adjusting for potential covariates, PM2.5, black carbon, particle number, carbon monoxide, nitrogen dioxide, sulfur dioxide, temperature, and relative humidity were associated with the proportions of at least one subtype of leukocytes. Particularly, an interquartile range-higher 28-day average exposure of PM2.5 was associated with 0.147-, 0.054- and 0.101-unit lower proportions (z-scored) of plasma cells, naïve CD8+ T cells, and natural killers, respectively, and 0.059- and 0.161-unit higher proportions (z-scored) of naïve CD4+ T cells and CD8+ T cells, respectively. Conclusions: Our study suggests that short-term air pollution exposure, temperature, and relative humidity are associated with leukocyte distribution. Our study further provides a successful attempt to use epigenetic patterns to assess the influences of environmental exposures on human immune profiles. Keywords: Air pollution, Weather variations, DNA methylation, Leukocyte distribution, Epigenetic epidemiology, Environmental health

Abstract Background Most research into myocardial infarctions (MIs) have focused on preventative efforts. For survivors, the occurrence of an MI represents a major clinical event that can have long-lasting consequences. There has been little to no research into the molecular changes that can occur as a result of an incident MI. Here, we use three cohorts to identify epigenetic changes that are indicative of an incident MI and their association with gene expression and metabolomics. Results Using paired samples from the KORA cohort, we screened for DNA methylation loci (CpGs) whose change in methylation is potentially indicative of the occurrence of an incident MI between the baseline and follow-up exams. We used paired samples from the NAS cohort to identify 11 CpGs which were predictive in an independent cohort. After removing two CpGs associated with medication usage, we were left with an “epigenetic fingerprint” of MI composed of nine CpGs. We tested this fingerprint in the InCHIANTI cohort where it moderately discriminated incident MI occurrence (AUC = 0.61, P = 6.5 × 10−3). Returning to KORA, we associated the epigenetic fingerprint loci with cis-gene expression and integrated it into a gene expression-metabolomic network, which revealed links between the epigenetic fingerprint CpGs and branched chain amino acid (BCAA) metabolism. Conclusions There are significant changes in DNA methylation after an incident MI. Nine of these CpGs show consistent changes in multiple cohorts, significantly discriminate MI in independent cohorts, and were independent of medication usage. Integration with gene expression and metabolomics data indicates a link between MI-associated epigenetic changes and BCAA metabolism.

BackgroundCollectively, an estimated 5% of the population have a genetic disease. Many of them feature characteristics that can be detected by facial phenotyping. Face2Gene CLINIC is an online app for facial phenotyping of patients with genetic syndromes. DeepGestalt, the neural network driving Face2Gene, automatically prioritizes syndrome suggestions based on ordinary patient photographs, potentially improving the diagnostic process. Hitherto, studies on DeepGestalt’s quality highlighted its sensitivity in syndromic patients. However, determining the accuracy of a diagnostic methodology also requires testing of negative controls. ObjectiveThe aim of this study was to evaluate DeepGestalt's accuracy with photos of individuals with and without a genetic syndrome. Moreover, we aimed to propose a machine learning–based framework for the automated differentiation of DeepGestalt’s output on such images. MethodsFrontal facial images of individuals with a diagnosis of a genetic syndrome (established clinically or molecularly) from a convenience sample were reanalyzed. Each photo was matched by age, sex, and ethnicity to a picture featuring an individual without a genetic syndrome. Absence of a facial gestalt suggestive of a genetic syndrome was determined by physicians working in medical genetics. Photos were selected from online reports or were taken by us for the purpose of this study. Facial phenotype was analyzed by DeepGestalt version 19.1.7, accessed via Face2Gene CLINIC. Furthermore, we designed linear support vector machines (SVMs) using Python 3.7 to automatically differentiate between the 2 classes of photographs based on DeepGestalt's result lists. ResultsWe included photos of 323 patients diagnosed with 17 different genetic syndromes and matched those with an equal number of facial images without a genetic syndrome, analyzing a total of 646 pictures. We confirm DeepGestalt’s high sensitivity (top 10 sensitivity: 295/323, 91%). DeepGestalt’s syndrome suggestions in individuals without a craniofacially dysmorphic syndrome followed a nonrandom distribution. A total of 17 syndromes appeared in the top 30 suggestions of more than 50% of nondysmorphic images. DeepGestalt’s top scores differed between the syndromic and control images (area under the receiver operating characteristic [AUROC] curve 0.72, 95% CI 0.68-0.76; P

Background: Access to healthcare delivery programs and systems is a primary correlate to the overall health and well-being of Veterans and the general population. Participation in clinical research is a gateway to novel therapies that are intended to address current global health issues. Meeting or exceeding recruitment goals in clinical research is one of the key determinants of the timely and successful completion of a study. The travel and time burdens experienced by study participants are often considered barriers to their enrollment into clinical research. The Department of Veterans Affairs (VA) Cooperative Studies Program (CSP) established a consortium of nine VA medical centers (VAMCs) called the Network of Dedicated Enrollment Sites (NODES). The NODES program provides study site-level expertise and innovative approaches that address challenges to clinical research execution. In alignment with our mission, our program developed an approach to increase study participant access to clinical research through implementing “Mobile Recruitment (MoRe)” units. This manuscript describes the utility and challenges associated with employing this strategy to address three common barriers to clinical research participation: 1) research participant travel burden, 2) participant access to study opportunities, and 3) low participant enrollment. Methods: A plan to introduce the Mobile Recruitment (MoRe) unit as a recruitment strategy was piloted for a high-volume, observational cohort study and mega biobank in the VA health care system, the “Million Veteran Program (MVP)”. MoRe is a recruitment strategy for CSP research integrating mobile technology and atypical research recruitment locations. Recruitment locations include primary or main VA hospitals and their assigned VA Community-Based Outpatient Clinics (CBOCs). Each Node site (n = 9) received components of the MoRe unit including a laptop, printer, portable cart with storage space, cooler/ice packs for specimen storage and transport. Each site's usage of these components varied based on its respective needs. Activities focused on both VA main facilities and CBOC facilities for recruitment. Results: Seven of the nine Node sites compared the effectiveness of the MoRe unit on MVP study enrollment outcomes over three-time points: pre-intervention period, intervention period, and post-intervention period. The utilization of MoRe in the intervention period demonstrated a 36.9% increase in enrollment compared to the previous six months (pre-intervention period). There was a 2% enrollment increase at the six-month post-intervention period as compared to the intervention period. When comparing the pre-intervention period to the post-intervention period (duration of eighteen months), enrollment increased by 38.9%. Conclusion: Five of the seven sites experienced an increase in enrollment during the intervention and post-intervention periods. The two sites without an increase in enrollment experienced various extenuating factors. Characteristics of sites using MoRe included the ability to utilize a smaller, unconventional space, i.e. not a traditional clinical research exam space for recruitment. MoRe was utilized in hospital laboratory space, CBOCs, primary care clinics, and other subspecialty clinics that allowed recruitment activities but did not have dedicated space to offer the research teams for that purpose. This initiative successfully demonstrated the benefit of deploying the unit, proving its utility in cases in where there was a lack of space or alternative workstations for research activities. The implementation of MoRe by NODES as a recruitment strategy for MVP may be transferable to other VA clinical research studies, as well as to other healthcare settings executing similar clinical research activities.

Biological aging is the gradual, progressive decline in system integrity that occurs with advancing chronological age, causing morbidity and disability. Measurements of the pace of aging are needed as surrogate endpoints in trials of therapies designed to prevent disease by slowing biological aging. We report a blood-DNA-methylation measure that is sensitive to variation in pace of biological aging among individuals born the same year. We first modeled change-over-time in 18 biomarkers tracking organ-system integrity across 12 years of follow-up in n = 954 members of the Dunedin Study born in 1972–1973. Rates of change in each biomarker over ages 26–38 years were composited to form a measure of aging-related decline, termed Pace-of-Aging. Elastic-net regression was used to develop a DNA-methylation predictor of Pace-of-Aging, called DunedinPoAm for Dunedin(P)ace(o)f(A)ging(m)ethylation. Validation analysis in cohort studies and the CALERIE trial provide proof-of-principle for DunedinPoAm as a single-time-point measure of a person’s pace of biological aging.

DNA methylation is an epigenetic regulator of gene transcription, which has been found to be both metastable and variable within human cohort studies. Currently, few studies have been done to identify metastable DNA methylation biomarkers associated with longitudinal lung function decline in humans. The identification of such biomarkers is important for screening vulnerable populations. We hypothesized that quantifiable blood-based DNA methylation alterations would serve as metastable biomarkers of lung function decline and aging, which may help to discover new pathways and/or mechanisms related to pulmonary pathogenesis. Using linear mixed models, we performed an Epigenome Wide Association Study (EWAS) between DNA methylation at CpG dinucleotides and longitudinal lung function (FVC, FEV1, FEF25–75%) decline and aging with initial discovery in the Normative Aging Study, and replication in the Cooperative Health Research in the Region of Augsburg cohort. We identified two metastable epigenetic loci associated with either poor lung function and aging, cg05575921 (AHRR gene), or lung function independently of aging, cg06126421 (IER3 gene). These loci may inform basic mechanisms associated with pulmonary function, pathogenesis, and aging. Human epigenomic variation, may help explain features of lung function decline and related pathophysiology not attributable to DNA sequence alone, such as accelerated pulmonary decline in smokers, former smokers, and perhaps non-smokers. Our EWAS across two cohorts, therefore, will likely have implications for the human population, not just the elderly.

Sonia Benammar,1,2 Alix Pantel,3,4 Fabien Aujoulat,5 Messaoud Benmehidi,1,2 René Courcol,6,7 Jean-Philippe Lavigne,3,4 Sara Romano-Bertrand,5,8 Hélène Marchandin3,5 1Department of Microbiology, University Hospital Center Touhami Benflis, Batna, Algeria; 2Department of Medicine, University Batna 2, Batna, Algeria; 3Department of Microbiology, Nîmes University Hospital, Nîmes, France; 4Faculty of Medicine, National Institute of Health and Medical Research, INSERM U1047, University of Montpellier, Nîmes, France; 5HydroSciences Montpellier, CNRS, IRD, University of Montpellier, University Hospital of Montpellier-Nîmes, Montpellier, France; 6Faculty of Medicine, University of Lille, Lille, France; 7Department of Bacteriology, Institute of Microbiology, Lille University Hospital, Lille, France; 8Department of Infection Control, Montpellier University Hospital, Montpellier, France Purpose: Vancomycin-resistant Enterococcus (VRE) faecium (VREfm) are highly resistant bacteria emerging worldwide and rarely studied using molecular tools in Algeria since their first report in 2006. The aim of the study was to investigate healthcare-associated infections (HAIs) involving the first VRE in Batna University Hospital, Algeria, and characterize isolates using molecular tools.Patients and methods: Medical charts were reviewed for patients with VREfm. van genes were detected by multiplex polymerase chain reaction (PCR), and strains were characterized by automated repetitive sequence-based PCR (rep-PCR), multiplex rep-PCR, pulsed-field gel electrophoresis (PFGE), and multilocus sequence typing (MLST).Results: During a 6-month period, VREfm infections occurred in four patients hospitalized in three wards. The four isolates were E. faecium vanA belonging to the hospital-adapted clonal complex 17. PCR-based methods did not discriminate the isolates but MLST and PFGE delineated a subgroup of three VREfm of identical pulsotype and sequence type (ST) 80 (yet identified for five isolates in the international PubMLST database) while the fourth isolate was of ST789 (not previously identified for a VREfm) and displayed an unrelated pulsotype. The three genotypically related isolates were recovered in patients who underwent surgery in the same department, suggesting an outbreak for which the source and route of transmission remained unidentified.Conclusion: This first molecular epidemiology study of VRE in Algeria was useful in delimiting an outbreak involving three of the four HAI cases and revealed rarely encountered genotypes. Considering the threat and burden of VRE infections worldwide, particularly in the USA, and the late emergence in Algeria, our study supports the urgent need for improved and early adequate infection control measures to avoid VRE spread in North African hospitals. Keywords: outbreak, genotyping, MLST, rep-PCR, PFGE, molecular epidemiology

Valentina A Tesky,1 Theresa Köbe,2 A Veronica Witte,2,3 Agnes Flöel,2 Jan Philipp Schuchardt,4 Andreas Hahn,4 Johannes Pantel1 1Geriatric Medicine, Institute of General Practice, Goethe University, Frankfurt, Germany; 2Department of Neurology, Charité – University Medicine Berlin, Berlin, Germany; 3Department of Neurology, Max Planck Institute of Human Cognitive and Brain Sciences, University of Leipzig, Leipzig, Germany; 4Department of Nutrition Physiology and Human Nutrition, Gottfried Wilhelm Leibniz University, Hannover, Germany Abstract: AKTIVA-MCI is a program for patients with mild cognitive impairment (MCI) that aims to enhance participation in cognitively stimulating leisure activities. Participation in cognitively stimulating activities seems to be a potential strategy for people with MCI delaying cognitive decline for a while. In total, 35 MCI patients were enrolled in the pilot study of whom 29 completed the whole program (16 female, 71.1±7.5 years; Mini Mental Status Examination score: 28±2.2). Daily activity protocols were used to measure the frequency of participation in cognitively stimulating activities during the program (12 sessions). Additional standardized psychometric tests and questionnaires were used to assess cognition, mood, and subjective memory decline. Analyses of the daily activity protocols showed that during the intervention participants increased the frequency of several cognitively stimulating leisure activities. Comparison of pre-post data indicates no changes in cognitive status, mood, and subjective memory decline. These findings indicate that the program is suitable for patients with MCI. Keywords: older people, MCI, pilot study, intervention study, cognitively stimulating leisure activities, training program, daily activity protocols

Epigenetics: choose your DNA methylation probing tool wisely! Researchers who study human epigenetics need to carefully consider the platform used to measure genome-wide patterns of DNA methylation. A team led by Karin Michels and Andrea Baccarelli from Harvard University in Boston, Massachusetts, USA, empirically examined the strengths and weaknesses of two methylation profiling tools: Illumina’s Infinium BeadChip, which uses a microarray system to interrogate hundreds of thousands of methylation sites across the genome at single-nucleotide resolution; and a high-throughput sequencing-based approach known as rapid multiplexed reduced representation bisulfite sequencing, or rmRRBS. The former did a better job at reading methylation in protein-coding and mitochondrial-related genes, while the latter required less input DNA and covered more methylation sites across the genome. The authors conclude that a scientist’s platform preference should depend on the nature of his or her investigation.

Although there is growing evidence that exposure to ambient particulate matter is associated with global DNA methylation and gene-specific methylation, little is known regarding epigenome-wide changes in DNA methylation in relation to particles and, especially, particle components. Using the Illumina Infinium HumanMethylation450 BeadChip, we examined the relationship between one-year moving averages of PM2.5 species (Al, Ca, Cu, Fe, K, Na, Ni, S, Si, V, and Zn) and DNA methylation at 484,613 CpG probes in a longitudinal cohort that included 646 subjects. Bonferroni correction was applied to adjust for multiple comparisons. Bioinformatics analysis of the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment was also performed. We observed 20 Bonferroni significant (P-value < 9.4× 10−9) CpGs for Fe, 8 for Ni, and 1 for V. Particularly, methylation at Schlafen Family Member 11 (SLFN11) cg10911913 was positively associated with measured levels of all 3 species. The SLFN11 gene codes for an interferon-induced protein that inhibits retroviruses and sensitizes cancer cells to DNA-damaging agents. Bioinformatics analysis suggests that gene targets may be relevant to pathways including cancers, signal transduction, and cell growth and death. Ours is the first study to examine the epigenome-wide association between ambient particles species and DNA methylation. We found that long-term exposures to specific components of ambient particle pollution, especially particles emitted during oil combustion, were associated with methylation changes in genes relevant to immune responses. Our findings provide insight into potential biologic mechanisms on an epigenetic level.

Background: Whole-body and thoracic ionizing radiation exposure are both associated with the development of renal dysfunction. However, whether low-level environmental radiation from air pollution affects renal function remains unknown. Objectives: We investigated the association of particle radioactivity (PR) with renal function defined by the estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD) in the Normative Aging Study. Methods: This longitudinal analysis included 2491 medical visits from 809 white males enrolled between 1999 and 2013. The eGFR was calculated using the CKD-EPI and MDRD equations, and CKD cases were identified as those with an eGFR

Previous studies have suggested increased risk of respiratory diseases and mortality following short-term exposures to ionizing radiation. However, the short-term respiratory effects of low-level environmental radiation associated with air pollution particles have not been considered. Although ambient particulate matter (PM) has been reproducibly linked to decreased lung function and to increased respiratory related morbidity, the properties of PM promoting its toxicity are uncertain. As such, we evaluated whether lung function was associated with exposures to radioactive components of ambient PM, referred to as particle radioactivity (PR). For this, we performed a repeated-measures analysis of 839 men to examine associations between PR exposure and lung function using mixed-effects regression models, adjusting for potential confounders. We examined whether PR-lung function associations changed after adjusting for PM2.5 (particulate matter≤2.5 μm) or black carbon, and vice versa. PR was measured by the USEPA's radiation monitoring network. We found that higher PR exposure was associated with a lower forced vital capacity (FVC) and forced expiratory volume in 1 second (FEV1). An IQR increase in 28-day PR exposure was associated with a 2.4% lower FVC [95% confidence interval (CI): 1.4, 3.4% p

Biological measures of aging are important for understanding the health of an aging population, with epigenetics particularly promising. Previous studies found that tumor tissue is epigenetically older than its donors are chronologically. We examined whether blood Δage (the discrepancy between epigenetic and chronological ages) can predict cancer incidence or mortality, thus assessing its potential as a cancer biomarker. In a prospective cohort, Δage and its rate of change over time were calculated in 834 blood leukocyte samples collected from 442 participants free of cancer at blood draw. About 3–5 years before cancer onset or death, Δage was associated with cancer risks in a dose-responsive manner (P = 0.02) and a one-year increase in Δage was associated with cancer incidence (HR: 1.06, 95% CI: 1.02–1.10) and mortality (HR: 1.17, 95% CI: 1.07–1.28). Participants with smaller Δage and decelerated epigenetic aging over time had the lowest risks of cancer incidence (P = 0.003) and mortality (P = 0.02). Δage was associated with cancer incidence in a ‘J-shaped’ manner for subjects examined pre-2003, and with cancer mortality in a time-varying manner. We conclude that blood epigenetic age may mirror epigenetic abnormalities related to cancer development, potentially serving as a minimally invasive biomarker for cancer early detection.

Background Bone lead offers a better method over blood lead measurement to discern long‐term lead exposure and accumulation. We examined the risk of resistant hypertension based on bone lead levels in a prospective cohort study of NAS (Normative Aging Study). Methods and Results Participants had clinic data on hypertension (systolic blood pressure, diastolic blood pressure, and antihypertension medication), lead (blood, bone‐patella, bone‐tibia), and demographic and confounding variables. Cases of resistant hypertension were identified by meeting criteria for: (1) inadequate systolic blood pressure (>140 mm Hg) or diastolic blood pressure (>90 mm Hg) while taking 3 medications or (2) requiring >4 medications for blood pressure control. A modified Poisson regression was used for model analysis. Of the 475 participants, 97 cases of resistant hypertension (20.4%) were identified. Among the cases of resistant hypertension, the median tibia and patella lead levels were 20 μg/g and 25 μg/g, respectively, while median tibia and patella lead levels were 20 μg/g and 27.5 μg/g, respectively, in participants without resistant hypertension. Tibia lead demonstrated a significant association with resistant hypertension (relative risk, 1.19; 95% confidence interval, 1.01–1.41 [P=0.04]) per interquartile range increase in tibia lead (13–28.5 μg/g). Patella lead was not associated with resistant hypertension (relative risk, 1.10; 95% confidence interval, 0.92–1.31 [P=0.31]) per interquartile range increase in patella lead (18–40 μg/g). Blood lead levels were not significantly associated with resistant hypertension (relative risk, 1.11; 95% confidence interval, 0.88–1.40 [P=0.38]). Conclusions Tibia lead represents a novel risk factor for resistant hypertension. Our study demonstrates an increased association between tibia lead and resistant hypertension status, with an increased risk of 19% per 1 interquartile range increase in tibia lead.

BackgroundThe cardiovascular effects of low‐level environmental radiation exposures are poorly understood. Although particulate matter (PM) has been linked to cardiovascular morbidity and mortality, and elevated blood pressure (BP), the properties promoting its toxicity remain uncertain. Addressing a knowledge gap, we evaluated whether BP increased with higher exposures to radioactive components of ambient PM, herein referred to as particle radioactivity (PR). Methods and ResultsWe performed a repeated‐measures analysis of 852 men to examine associations between PR exposure and BP using mixed‐effects regression models. As a surrogate for PR, we used gross β activity, measured by the US Environmental Protection Agency's radiation monitoring network. Higher PR exposure was associated with increases in both diastolic BP and systolic BP, for exposures from 1 to 28 days. An interquartile range increase in 28‐day PR exposure was associated with a 2.95–mm Hg increase in diastolic BP (95% confidence interval, 2.25–3.66; P

Background: Accelerated telomere shortening may cause cancer via chromosomal instability, making it a potentially useful biomarker. However, publications on blood telomere length (BTL) and cancer are inconsistent. We prospectively examined BTL measures over time and cancer incidence. Methods: We included 792 Normative Aging Study participants with 1–4 BTL measurements from 1999 to 2012. We used linear mixed-effects models to examine BTL attrition by cancer status (relative to increasing age and decreasing years pre-diagnosis), Cox models for time-dependent associations, and logistic regression for cancer incidence stratified by years between BTL measurement and diagnosis. Findings: Age-related BTL attrition was faster in cancer cases pre-diagnosis than in cancer-free participants (pdifference = 0.017); all participants had similar age-adjusted BTL 8–14 years pre-diagnosis, followed by decelerated attrition in cancer cases resulting in longer BTL three (p = 0.003) and four (p = 0.012) years pre-diagnosis. Longer time-dependent BTL was associated with prostate cancer (HR = 1.79, p = 0.03), and longer BTL measured ≤4 years pre-diagnosis with any (OR = 3.27, p

The underlying mechanisms of the association between ambient temperature and cardiovascular morbidity and mortality are not well understood, particularly for daily temperature variability. We evaluated if daily mean temperature and standard deviation of temperature was associated with heart rate-corrected QT interval (QTc) duration, a marker of ventricular repolarization in a prospective cohort of older men.This longitudinal analysis included 487 older men participating in the VA Normative Aging Study with up to three visits between 2000-2008 (n = 743). We analyzed associations between QTc and moving averages (1-7, 14, 21, and 28 days) of the 24-hour mean and standard deviation of temperature as measured from a local weather monitor, and the 24-hour mean temperature estimated from a spatiotemporal prediction model, in time-varying linear mixed-effect regression. Effect modification by season, diabetes, coronary heart disease, obesity, and age was also evaluated.Higher mean temperature as measured from the local monitor, and estimated from the prediction model, was associated with longer QTc at moving averages of 21 and 28 days. Increased 24-hr standard deviation of temperature was associated with longer QTc at moving averages from 4 and up to 28 days; a 1.9°C interquartile range increase in 4-day moving average standard deviation of temperature was associated with a 2.8 msec (95%CI: 0.4, 5.2) longer QTc. Associations between 24-hr standard deviation of temperature and QTc were stronger in colder months, and in participants with diabetes and coronary heart disease.In this sample of older men, elevated mean temperature was associated with longer QTc, and increased variability of temperature was associated with longer QTc, particularly during colder months and among individuals with diabetes and coronary heart disease. These findings may offer insight of an important underlying mechanism of temperature-related cardiovascular morbidity and mortality in an older population.

Air pollution has been associated with increased systemic inflammation markers. We developed a new pathway analysis approach to investigate whether gene variants within relevant pathways (oxidative stress, endothelial function, and metal processing) modified the association between particulate air pollution and fibrinogen, C-reactive protein (CRP), intercellular adhesion molecule-1 (ICAM-1), and vascular cell adhesion molecule-1 (VCAM-1). Our study population consisted of 822 elderly participants of the Normative Aging Study (1999-2011). To investigate the role of biological mechanisms and to reduce the number of comparisons in the analysis, we created pathway-specific scores using gene variants related to each pathway. To select the most appropriate gene variants, we used the least absolute shrinkage and selection operator (Lasso) to relate independent outcomes representative of each pathway (8-hydroxydeoxyguanosine for oxidative stress, augmentation index for endothelial function, and patella lead for metal processing) to gene variants. A high genetic score corresponds to a higher allelic risk profile. We fit mixed-effects models to examine modification by the genetic score of the weekly air pollution association with the outcome. Among participants with higher genetic scores within the oxidative stress pathway, we observed significant associations between particle number and fibrinogen, while we did not find any association among participants with lower scores (p(interaction) = 0.04). Compared to individuals with low genetic scores of metal processing gene variants, participants with higher scores had greater effects of particle number on fibrinogen (p(interaction) = 0.12), CRP (p(interaction) = 0.02), and ICAM-1 (pinteraction = 0.08). This two-stage penalization method is easy to implement and can be used for large-scale genetic applications.

Abstract This manuscript summarizes current thinking on the value and promise of evolving circulating tumor cell (CTC) technologies for cancer patient diagnosis, prognosis, and response to therapy, as well as accelerating oncologic drug development. Moving forward requires the application of the classic steps in biomarker development–analytical and clinical validation and clinical qualification for specific contexts of use. To that end, this review describes methods for interactive comparisons of proprietary new technologies, clinical trial designs, a clinical validation qualification strategy, and an approach for effectively carrying out this work through a public-private partnership that includes test developers, drug developers, clinical trialists, the US Food & Drug Administration (FDA) and the US National Cancer Institute (NCI).

Abstract Background As cell-free circulating DNA exists predominantly as mono- and oligonucleosomes, the focus of the current study was to examine the interplay of circulating nucleosomes, DNA, proteases and caspases in blood of patients with benign and malignant breast diseases. Methods The concentrations of cell-free DNA and nucleosomes as well as the protease and caspase activities were measured in serum of patients with benign breast disease (n = 20), primary breast cancer (M0, n = 31), metastatic breast cancer (M1, n = 32), and healthy individuals (n = 28) by PicoGreen, Cell Death Detection ELISA, Protease Fluorescent Detection Kit and Caspase-Glo®3/7 Assay, respectively. Results Patients with benign and malignant tumors had significantly higher levels of circulating nucleic acids in their blood than healthy individuals (p = 0.001, p = 0.0001), whereas these levels could not discriminate between benign and malignant lesions. Our analyses of all serum samples revealed significant correlations of circulating nucleosome with DNA concentrations (p = 0.001), nucleosome concentrations with caspase activities (p = 0.008), and caspase with protease activities (p = 0.0001). High serum levels of protease and caspase activities associated with advanced tumor stages (p = 0.009). Patients with lymph node-positive breast cancer had significantly higher nucleosome levels in their blood than node-negative patients (p = 0.004). The presence of distant metastases associated with a significant increase in serum nucleosome (p = 0.01) and DNA levels (p = 0.04), and protease activities (p = 0.008). Conclusion Our findings demonstrate that high circulating nucleic acid concentrations in blood are no indicators of a malignant breast tumor. However, the observed changes in apoptosis-related deregulation of proteolytic activities along with the elevated serum levels of nucleosomes and DNA in blood are linked to breast cancer progression.

Abstract Background Reconstructive surgery of the facial nerve is not daily routine for most head and neck surgeons. The published experience on strategies to ensure optimal functional results for the patients are based on small case series with a large variety of surgical techniques. On this background it is worthwhile to develop a standardized approach for diagnosis and treatment of patients asking for facial rehabilitation. Conclusion A standardized approach is feasible: Patients with chronic facial palsy first need an exact classification of the palsy's aetiology. A step-by-step clinical examination, if necessary MRI imaging and electromyographic examination allow a classification of the palsy's aetiology as well as the determination of the severity of the palsy and the functional deficits. Considering the patient's desire, age and life expectancy, an individual surgical concept is applicable using three main approaches: a) early extratemporal reconstruction, b) early reconstruction of proximal lesions if extratemporal reconstruction is not possible, c) late reconstruction or in cases of congenital palsy. Twelve to 24 months after the last step of surgical reconstruction a standardized evaluation of the therapeutic results is recommended to evaluate the necessity for adjuvant surgical procedures or other adjuvant procedures, e.g. botulinum toxin application. Up to now controlled trials on the value of physiotherapy and other adjuvant measures are missing to give recommendation for optimal application of adjuvant therapies.

Abstract Background The aim of the current study was to analyze the involvement of methyl-CpG binding proteins (MBDs) and histone modifications on the regulation of CD44, Cyclin D2, GLIPR1 and PTEN in different cellular contexts such as the prostate cancer cells DU145 and LNCaP, and the breast cancer cells MCF-7. Since global chromatin changes have been shown to occur in tumours and regions of tumour-associated genes are affected by epigenetic modifications, these may constitute important regulatory mechanisms for the pathogenesis of malignant transformation. Methods In DU145, LNCaP and MCF-7 cells mRNA expression levels of CD44, Cyclin D2, GLIPR1 and PTEN were determined by quantitative RT-PCR at the basal status as well as after treatment with demethylating agent 5-aza-2'-deoxycytidine and/or histone deacetylase inhibitor Trichostatin A. Furthermore, genomic DNA was bisulfite-converted and sequenced. Chromatin immunoprecipitation was performed with the stimulated and unstimulated cells using antibodies for MBD1, MBD2 and MeCP2 as well as 17 different histone antibodies. Results Comparison of the different promoters showed that MeCP2 and MBD2a repressed promoter-specifically Cyclin D2 in all cell lines, whereas in MCF-7 cells MeCP2 repressed cell-specifically all methylated promoters. Chromatin immunoprecipitation showed that all methylated promoters associated with at least one MBD. Treatment of the cells by the demethylating agent 5-aza-2'-deoxycytidine (5-aza-CdR) caused dissociation of the MBDs from the promoters. Only MBD1v1 bound and repressed methylation-independently all promoters. Real-time amplification of DNA immunoprecipitated by 17 different antibodies showed a preferential enrichment for methylated lysine of histone H3 (H3K4me1, H3K4me2 and H3K4me3) at the particular promoters. Notably, the silent promoters were associated with unmodified histones which were acetylated following treatment by 5-aza-CdR. Conclusions This study is one of the first to reveal the histone code and MBD profile at the promoters of CD44, Cyclin D2, GLIPR1 and PTEN in different tumour cells and associated changes after stimulation with methylation inhibitor 5-aza-CdR.

Abstract Background Metastasis is the leading cause of cancer-related death. Bone marrow (BM) is a frequent site for the settlement of disseminated tumor cells which occurs years before overt metastases signal incurability. Methods Here we describe a new method to assess the initial stage of metastasis development in cancer patients. By immunomagnetic selection with HER2/neu and EpCAM as catcher antigens single disseminated tumor cells can be enriched from BM samples. To examine whether the immunomagnetic enrichment technique may change gene expression in the selected tumor cells, we performed differential expression profiling with the breast cancer cell lines MCF-7 and BT474 as models. The profiles were performed using 1.2 Cancer Arrays (Clontech) containing 1176 cDNAs that can be grouped into different functional categories, such as signal transduction, cell cycle, adhesion, cytoskeleton plasticity, growth factors and others. Results The reproducibility of the gene expression profiling between duplicate cDNA-array experiments was assessed by two independent experiments with MCF-7 breast cancer cells. Scatter blot analysis revealed a good reproducibility of the cDNA array analysis (i.e. less than 10% difference in the gene expression between the arrays). Subsequent comparative cDNA-array analyses of immunobead-selected and unselected MCF-7 and BT474 cancer cells indicated that the antibody incubation during the immunomagnetic selection procedure did not considerably alter the gene expression profile. Conclusion The described method offers an excellent tool for the enrichment of micrometastatic tumor cells in BM without largely changing the gene expression pattern of these cells.

Abstract Close vital signs monitoring is crucial for the clinical management of patients with dengue. We investigated performance of a non-invasive wearable utilising photoplethysmography (PPG), to provide real-time risk prediction in hospitalised individuals. We performed a prospective observational clinical study in Vietnam between January 2020 and October 2022: 153 patients were included in analyses, providing 1353 h of PPG data. Using a multi-modal transformer approach, 10-min PPG waveform segments and basic clinical data (age, sex, clinical features on admission) were used as features to continuously forecast clinical state 2 h ahead. Prediction of low-risk states (17,939/80,843; 22.1%), defined by NEWS2 and mSOFA

Abstract We investigate the possible production of a MeV-scale sterile fermion through the up-scattering of neutrinos on nuclei and atomic electrons at different facilities. We consider a phenomenological model that adds a new fermion to the particle content of the Standard Model and we allow for all possible Lorentz-invariant non-derivative interactions (scalar, pseudoscalar, vector, axial-vector and tensor) of neutrinos with electrons and first-generation quarks. We first explore the sensitivity of the DUNE experiment to this scenario, by simulating elastic neutrino-electron scattering events in the near detector. We consider both options of a standard and a tau-optimized neutrino beams, and investigate the impact of a mobile detector that can be moved off-axis with respect to the beam. Next, we infer constraints on the typical coupling, new fermion and mediator masses from elastic neutrino-electron scattering events induced by solar neutrinos in two current dark matter direct detection experiments, XENONnT and LZ. Under the assumption that the new mediators couple also to first-generation quarks, we further set constraints on the up-scattering production of the sterile fermion using coherent elastic neutrino-nucleus scattering data from the COHERENT experiment. Moreover, we set additional constraints assuming that the sterile fermion may decay within the detector. We finally compare our results and discuss how these facilities are sensitive to different regions of the relevant parameter space due to kinematics arguments and can hence provide complementary information on the up-scattering production of a sterile fermion.

Purpose This study aimed to verify participation and performance in all road and trail-based races in Switzerland over two decades (1999–2019). Methods This is a secondary data-based study. We used 1,149,182 race records (788,818 from men and 360,364 from women) from 407,944 unique finishers of the 5 km, 10 km, half-marathon, marathon, and ultra-marathon races in Switzerland, between 1999 and 2019. Data included the athletes’ genders, ages, race distances, and types of races (road or trail). The mento- women ratio was calculated and box plots were used to present differences according to gender, age groups, and race distances in both terrains. Differences between the groups were calculated. Results The men-to-women ratio has generally decreased in all race distances over the years. Runners competing in roadbased races were faster than those in a trail run in all distances. Men had faster finish times than women independent of age, except those competing in 10 km trail races. In road-based races, the men-to-women ratio was higher among older marathoners, while for trail runs, a higher men-to-women ratio was shown for older half-marathoners and participants in 10 km races. For 5 km, 10 km, half-marathon, and ultra-marathon races, a decrease in running speed differences was shown until the age of 50 years. Conclusions In Switzerland, most of the runners competed in road-based races, but the interest in trail running has increased. The men-to-women ratio declined over time, which could show an increase in the interest of women to participate in endurance activities.

Despite ongoing efforts, the relationship between groin strength and injury remains unclear. The challenge of accurately predicting injuries presents an opportunity for researchers to develop prevention strategies to reduce the occurrence of such injuries. Consequently, this issue requires further investigation to obtain insights into effective mitigation strategies. In 120 male soccer players, the maximum isometric strength of the hip muscle groups was measured, and the strength ratios were calculated. Previous injury and anthropometric data were registered. Injury data were collected following the FIFA/UEFA consensus. k-nearest neighbor (k-NN) was used to predict the incidence of injury, while the significant predictive variables of the k-NN algorithm were fitted into a multivariate logistic regression model (LR) to analyze the likelihood of players sustaining a groin injury. The LR model determined two variables as significant predictors of groin injury. Players were less likely to sustain a groin injury by 76% for each decrease of the adductor/abductor isometric strength ratio in the non-dominant limb (OR = 0.238, CI 95% = [(0.098–0.572]). Players with a history of previous injury had a 67% greater risk of sustaining an injury (OR = 0.333, CI 95% = [(0.1068–1.038]). Isometric hip adductor and abductor strength imbalances of the non-dominant lower limb and a history of previous injury were risk factors for groin injury in soccer players.

Marathon sports events and those who participate in them have grown over the last years, reflecting notably an augmentation of women and master runners’ participation. The aim of the present narrative review was to briefly present the results of studies on anthropometric, physiological, and training characteristics, as well as predictors of performance, in marathon runners. It was observed that performance was better in runners with a small body weight, body mass index, body fat percentage, and rate of endomorphy. Regarding physiology, an increased maximal oxygen uptake, anaerobic threshold, and improved running economy could result in a faster race time. The training variables that could predict performance involved weekly training volume (distance) and intensity (running speed), as well as history of training (years). A combination of these three broad categories of characteristics may offer an approximate estimation of the race speed considering that other aspects (e.g., nutrition, biomechanics, and motivation) influence race performance, too. In summary, the findings of the present study provided an overview of the anthropometric, physiological, and training characteristics associated with marathon race times; thus, optimization of any of these characteristics would be expected to improve the race time.

Abstract Genome-wide association studies (GWAS) have revolutionized our understanding of the genetic architecture of complex traits and diseases. GWAS summary statistics have become essential tools for various genetic analyses, including meta-analysis, fine-mapping, and risk prediction. However, the increasing number of GWAS summary statistics and the diversity of software tools available for their analysis can make it challenging for researchers to select the most appropriate tools for their specific needs. This systematic review aims to provide a comprehensive overview of the currently available software tools and databases for GWAS summary statistics analysis. We conducted a comprehensive literature search to identify relevant software tools and databases. We categorized the tools and databases by their functionality, including data management, quality control, single-trait analysis, and multiple-trait analysis. We also compared the tools and databases based on their features, limitations, and user-friendliness. Our review identified a total of 305 functioning software tools and databases dedicated to GWAS summary statistics, each with unique strengths and limitations. We provide descriptions of the key features of each tool and database, including their input/output formats, data types, and computational requirements. We also discuss the overall usability and applicability of each tool for different research scenarios. This comprehensive review will serve as a valuable resource for researchers who are interested in using GWAS summary statistics to investigate the genetic basis of complex traits and diseases. By providing a detailed overview of the available tools and databases, we aim to facilitate informed tool selection and maximize the effectiveness of GWAS summary statistics analysis.

Abstract The majority of participants in Ironman triathlon races are age group athletes. We have extensive knowledge about recreational athletes’ training and competition participation. Nonetheless, Ironman age group triathletes must achieve fast race times to qualify for the Ironman World Championship in Hawaii. They can, therefore, benefit from knowing where the fastest Ironman racecourses in the world are. The aim of the present study was to investigate where the fastest Ironman racecourses for age group triathletes are located in the world. Data from 677,702 Ironman age group finishers’ records (544,963 from men and 132,739 from women) originating from 228 countries and participating in 444 events across 66 different Ironman race locations between 2002 and 2022 were analyzed. Data was analyzed through traditional descriptive statistics and with machine learning regression models. Four algorithms were tested (Random Forest Regressor, XG Boost Regressor, Cat Boot Regressor, and Decision Tree Regressor). The models used gender, age group, country of origin, environmental factors (average air and water temperatures), and the event location as independent variables to predict the final overall race time. Despite the majority of successful Ironman age group triathletes originating from the USA (274,553), followed by athletes from the United Kingdom (55,410) and Canada (38,264), these countries exhibited average overall race times that were significantly slower compared to the fastest countries. Most of the triathletes competed in Ironman Wisconsin (38,545), followed by Ironman Florida (38,157) and Ironman Lake Placid (34,341). The fastest overall race times were achieved in Ironman Copenhagen (11.68 ± 1.38 h), followed by Ironman Hawaii (11.72 ± 1.86 h), Ironman Barcelona (11.78 ± 1.43 h), Ironman Florianópolis (11.80 ± 1.52 h), Ironman Frankfurt (12.03 ± 1.38 h) and Ironman Kalmar (12.08 ± 1.47 h). The fastest athletes originated from Belgium (11.48 ± 1.47 h), followed by athletes from Denmark (11.59 ± 1.40 h), Switzerland (11.62 ± 1.49 h), Austria (11.68 ± 1.50), Finland (11.68 ± 1.40 h) and Germany (11.74 ± 15.1 h). Flat running and cycling courses were associated with faster overall race times. Three of the predictive models identified the ‘country’ and ‘age group’ variables as the most important predictors. Environmental characteristics showed the lowest influence regarding the other variables. The origin of the athlete was the most predictive variable whereas environmental characteristics showed the lowest influence. Flat cycling and flat running courses were associated with faster overall race times. The fastest overall race times were achieved mainly in European races such as Ironman Copenhagen, Ironman Hawaii, Ironman Barcelona, Ironman Florianópolis, Ironman Frankfurt and Ironman Kalmar. The fastest triathletes originated from European countries such as Belgium, Denmark, Switzerland, Austria, Finland, and Germany.

Abstract Given the ubiquity of exploration in everyday life, researchers from many disciplines have developed methods to measure exploratory behaviour. There are therefore many ways to quantify and measure exploration. However, it remains unclear whether the different measures (i) have convergent validity relative to one another, (ii) capture a domain general tendency, and (iii) capture a tendency that is stable across time. In a sample of 678 participants, we found very little evidence of convergent validity for the behavioural measures (Hypothesis 1); most of the behavioural measures lacked sufficient convergent validity with one another or with the self-reports. In psychometric modelling analyses, we could not identify a good fitting model with an assumed general tendency to explore (Hypothesis 2); the best fitting model suggested that the different behavioural measures capture behaviours that are specific to the tasks. In a subsample of 254 participants who completed the study a second time, we found that the measures had stability across an 1 month timespan (Hypothesis 3). Therefore, although there were stable individual differences in how people approached each task across time, there was no generalizability across tasks, and drawing broad conclusions about exploratory behaviour from studies using these tasks may be problematic. The Stage 1 protocol for this Registered Report was accepted in principle on 2nd December 2022 https://doi.org/10.6084/m9.figshare.21717407.v1 . The protocol, as accepted by the journal, can be found at https://doi.org/10.17605/OSF.IO/64QJU .

Abstract Assessing fertilized human embryos is crucial for in vitro fertilization, a task being revolutionized by artificial intelligence. Existing models used for embryo quality assessment and ploidy detection could be significantly improved by effectively utilizing time-lapse imaging to identify critical developmental time points for maximizing prediction accuracy. Addressing this, we develop and compare various embryo ploidy status prediction models across distinct embryo development stages. We present BELA, a state-of-the-art ploidy prediction model that surpasses previous image- and video-based models without necessitating input from embryologists. BELA uses multitask learning to predict quality scores that are thereafter used to predict ploidy status. By achieving an area under the receiver operating characteristic curve of 0.76 for discriminating between euploidy and aneuploidy embryos on the Weill Cornell dataset, BELA matches the performance of models trained on embryologists’ manual scores. While not a replacement for preimplantation genetic testing for aneuploidy, BELA exemplifies how such models can streamline the embryo evaluation process.

Nitrogen indices could be used to evaluate organic and inorganic fertilization because they provide quantitative measures of nitrogen availability in the soil, allowing for a more accurate assessment of nutrient-management practices and optimization of crop yields. This study investigates the impact of different fertilization types and salinity on various soil parameters in fenugreek (Trigonella foenum-graecum L.) cultivation and nitrogen indices. A field experiment was established at the Agricultural University of Athens during the cropping period of 2018–2019 (CP I), 2019–2020 (CP II), and 2020–2021 (CP III) in a split-plot design with two main salinity treatments (high salinity, HS, and conventional salinity, CS) and five fertilization treatments (biocyclic–vegan humus soil (BHS), manure (FYM), compost (COMP), inorganic fertilization (11–15–15), and the control (C). The Nitrogen Balance Intensity (NBI) was statistically significantly affected by the factors of fertilization (p ≤ 0.01) and salinity (p ≤ 0.001) for CP I. The maximum NUEcrop value was recorded in the FYM treatment (0.83 ± 0.04) and the minimum in the COMP treatment (0.64 ± 0.04). Physiological efficiency (PE) was not significantly affected by any treatment for CP III. The fertilization factor significantly affected the NUEsoil index (p ≤ 0.001) for all three CPs. For CP I, the highest Nitrogen Uptake Efficiency (NUpE) value was recorded in the BHS treatment (27.08 ± 7.31) and the lowest in the C treatment (13.22 ± 7.31). There were no significant differences in CP I and CP II NUEbalance values among the NPK, BHS, and FYM treatments. These findings underscore the potential of organic fertilizers in addressing the global nitrogen challenge and promoting environmentally sustainable farming practices.

This study harnesses EEG signals to enable the real-time control of servo motors, utilizing the OpenBCI Community Dataset to identify and assess brainwave patterns related to motor imagery tasks. Specifically, the dataset includes EEG data from 52 subjects, capturing electrical brain activity while participants imagined executing specific motor tasks. Each participant underwent multiple trials for each motor imagery task, ensuring a diverse and comprehensive dataset for model training and evaluation. A deep neural network model comprising convolutional and bidirectional long short-term memory (LSTM) layers was developed and trained using k-fold cross-validation, achieving a notable accuracy of 98%. The model’s performance was further compared against recurrent neural networks (RNNs), multilayer perceptrons (MLPs), and Τransformer algorithms, demonstrating that the CNN-LSTM model provided the best performance due to its effective capture of both spatial and temporal features. The model was deployed on a Python script interfacing with an Arduino board, enabling communication with two servo motors. The Python script predicts actions from preprocessed EEG data to control the servo motors in real-time. Real-time performance metrics, including classification reports and confusion matrices, demonstrate the seamless integration of the LSTM model with the Arduino board for precise and responsive control. An Arduino program was implemented to receive commands from the Python script via serial communication and control the servo motors, enabling accurate and responsive control based on EEG predictions. Overall, this study presents a comprehensive approach that combines machine learning, real-time implementation, and hardware interfacing to enable the precise and real-time control of servo motors using EEG signals, with potential applications in the human–robot interaction and assistive technology domains.

Abstract CTNNB1 syndrome is a rare monogenetic disorder caused by CTNNB1 de novo pathogenic heterozygous loss-of-function variants that result in cognitive and motor disabilities. Treatment is currently lacking; our study addresses this critical need. CTNNB1 encodes β-catenin which is essential for normal brain function via its dual roles in cadherin-based synaptic adhesion complexes and canonical Wnt signal transduction. We have generated a Ctnnb1 germline heterozygous mouse line that displays cognitive and motor deficits, resembling key features of CTNNB1 syndrome in humans. Compared with wild-type littermates, Ctnnb1 heterozygous mice also exhibit decreases in brain β-catenin, β-catenin association with N-cadherin, Wnt target gene expression, and Na/K ATPases, key regulators of changes in ion gradients during high activity. Consistently, hippocampal neuron functional properties and excitability are altered. Most important, we identify a highly selective inhibitor of glycogen synthase kinase (GSK)3α,β that significantly normalizes the phenotypes to closely meet wild-type littermate levels. Our data provide new insights into brain molecular and functional changes, and the first evidence for an efficacious treatment with therapeutic potential for individuals with CTNNB1 syndrome.

Abstract Background Affective responses are increasingly recognized as potentially effective intervention targets that may facilitate exercise and physical activity behavior change. While emerging correlational evidence suggests that more pleasant affective responses are associated with higher participation and adherence, experimental evidence remains scarce. In light of this, we conducted a preregistered, pragmatic, single-blinded, superiority randomized controlled trial with two parallel groups, with the goal of determining the impact of an individualized exercise-intensity prescription targeting pleasure on exercise frequency. Methods Forty-seven non-regular exercisers were randomized into two groups. For both groups, the intervention consisted of three exercise sessions based on the Frequency-Intensity-Time-Type (FITT) principle. However, the experimental group also received an individualized intensity prescription based on prior assessment of preference for and tolerance of exercise intensity, as well as instructions emphasizing the promotion of pleasure as a basis for self-regulating exercise intensity. The primary outcome was gymnasium attendance over an eight-week follow-up period. Secondary outcomes were affective valence and arousal, post-exercise enjoyment, core affective exercise experiences, and anticipated and remembered affect. Results Forty-six participants were retained for analysis (Mage = 32.00; SD = 8.62 years; 56.5% female). Compared to the control group, the experimental group exhibited 77% higher session attendance (14.35 vs. 8.13 sessions) over the eight-week follow-up period (group main effect p = 0.018, η2 p = 0.120; Cohen’s d ranged from 0.28 to 0.91 during follow-up). Also, the experimental group reported higher levels of pleasure during the intervention sessions (for all group main effects, p

Focusing on elastic neutrino–electron scattering events, we explore the prospect of constraining new physics beyond the Standard Model at the DUNE Near Detector (ND). Specifically, we extract the attainable sensitivities for motivated scenarios such as neutrino generalized interactions (NGIs), the sterile neutrino dipole portal and unitarity violation. We furthermore examine the impact of the τ-optimized flux at the DUNE-ND and compare our results with those obtained using the standard CP-optimized flux. We find that our present analysis is probing a previously unexplored region of the parameter space, complementing existing results from cosmological observations and terrestrial experiments.

Abstract Backstroke has been thoroughly investigated in the context of sports science. However, we have no knowledge about the nationalities of the fastest age group backstroke swimmers. Therefore, the present study intended to investigate the nationalities of the fastest backstroke swimmers. For all World Masters Championships held between 1986 and 2024, the year of competition, the first and last name, the age, and the age group, and both the stroke and the distance were recorded for each swimmer. Descriptive data were presented using mean, standard deviation, maximum and minimum values, and confidence intervals. The top ten race times for each swimming distance and sex were identified for descriptive purposes. Nationalities were then grouped into six categories: the top five nationalities with the most appearances in the backstroke swimming top ten times by distance each year and one group consisting of all other nationalities. The Kruskal–Wallis test compared nationality differences, followed by Bonferroni-adjusted pairwise comparisons to identify specific distinctions. Between 1986 and 2024, most age group backstroke swimmers (39.6%) competed in the 50 m event (11,964, 6206 women, and 5,758 men), followed by the 100 m event (32.3%, n = 9764, 5157 women, and 4607 men), and the 200 m event (28.1%, n = 8483, 4511 women, and 3,972 men). Germany had the highest number of top ten female swimmers in the 50 m backstroke distance. Brazil had the highest number of top ten male swimmers in the same distance. The USA had the highest number of female and male swimmers among the top ten in the 100 m and 200 m backstroke distances. Germany and Great Britain were the only countries with swimmers in the top ten for all female backstroke distances. Brazil, the USA, Italy, and Germany were the countries that had swimmers in the top ten for all male backstroke distances. In summary, the fastest backstroke age group swimmers originated from Germany, Brazil, USA, Great Britain, and Italy, where differences between the sexes and race distances exist.

Abstract This EEG study aims at dissecting the differences in the activation of neural generators between borderline personality disorder patients with court-ordered measures (BDL-COM) and healthy controls in visual perspective taking. We focused on the distinction between mentalizing (Avatar) and non-mentalizing (Arrow) stimuli as well as self versus other-perspective in the dot perspective task (dPT) in a sample of 15 BDL-COM cases and 54 controls, all of male gender. BDL-COM patients showed a late and diffuse right hemisphere involvement of neural generators contrasting with the occipitofrontal topography observed in controls. For Avatars only and compared to controls, the adoption of Self perspective involved a lower EEG activity in the left inferior frontal, right middle temporal cortex and insula in BDL-COM patients prior to 80 ms post-stimulus. When taking the Other-perspective, BDL-COM patients also showed a lower activation of superior frontal, right inferior temporal and fusiform cortex within the same time frame. The beta oscillation power was significantly lower in BDL-COM patients than controls between 400 and 1300 ms post stimulus in the Avatar-Other condition. These results indicate that BDL-COM patients display both altered topography of EEG activation patterns and reduced abilities to mobilize beta oscillations during the treatment of mentalistic stimuli in dPT.

Abstract In hybrid automatic insulin delivery (HAID) systems, meal disturbance is compensated by feedforward control, which requires the announcement of the meal by the patient with type 1 diabetes (DM1) to achieve the desired glycemic control performance. The calculation of insulin bolus in the HAID system is based on the amount of carbohydrates (CHO) in the meal and patient-specific parameters, i.e. carbohydrate-to-insulin ratio (CR) and insulin sensitivity-related correction factor (CF). The estimation of CHO in a meal is prone to errors and is burdensome for patients. This study proposes a fully automatic insulin delivery (FAID) system that eliminates patient intervention by compensating for unannounced meals. This study exploits the deep reinforcement learning (DRL) algorithm to calculate insulin bolus for unannounced meals without utilizing the information on CHO content. The DRL bolus calculator is integrated with a closed-loop controller and a meal detector (both previously developed by our group) to implement the FAID system. An adult cohort of 68 virtual patients based on the modified UVa/Padova simulator was used for in-silico trials. The percentage of the overall duration spent in the target range of 70–180 mg/dL was $$71.2\%$$ 71.2 % and $$76.2\%$$ 76.2 % , $$180$$ > 180 mg/dL was $$26.7\%$$ 26.7 % and $$21.1\%$$ 21.1 % , respectively, for the FAID system and HAID system utilizing a standard bolus calculator (SBC) including CHO misestimation. The proposed algorithm can be exploited to realize FAID systems in the future.

African swine fever is one of the most serious threats to the world pig industry due to high infectivity and mortality rates among pigs. To date, no effective means of active prevention of the infection have been developed. The only effective method of control is passive monitoring of the spread of the pathogen among the population of domestic and wild pigs, detection of infected animals and their depopulation. The study analyzes the spread of African swine fever in Ukraine from 2012 to 2024 and compares it with the countries that share a common border – Poland, Romania, Hungary, Slovakia and Moldova. In Ukraine, the first outbreaks were recorded in 2012 in Zaporizhzhia region among domestic pigs. In total, 619 outbreaks were detected during the study period: 482 among domestic pigs and 137 among wild pigs. The largest number of outbreaks was recorded in Odesa (64), Poltava (54), Mykolaiv (52) and Kyiv (46) regions. In Eastern European countries, African swine fever was detected later: in Poland – since 2014 (1304 among domestic and 17871 among wild pigs), Romania – since 2017 (6729 and 3649, respectively), Hungary and Slovakia – since 2018 (0 and 7875; 72 and 3645). In Moldova, the first outbreak was in 2020 (39 among domestic and 45 among wild pigs). The highest total number of outbreaks was recorded in Poland (19175), mainly among wild boars (93.2%). In Hungary, all detected cases involved wild animals. The analysis revealed a statistically significant difference in the number of African swine fever outbreaks between the analyzed countries. There is also a difference in the number of outbreaks within the analyzed time period. If we analyze the number of cases since 2018, there is no statistically significant difference. Prevention and control of African swine fever are complicated by the circulation of the pathogen among wild boars, non-compliance with biosecurity measures by owners of small pig farms and the movement of infected animals. Comprehensive monitoring with early detection of outbreaks and timely destruction of infected animals plays a key role.