Healthcare use attributable to COVID-19: a propensity-matched national electronic health records cohort study of 249,390 people in Wales, UK

Background: To determine the extent and nature of changes associated with COVID-19 infection in terms of healthcare utilisation, this study observed healthcare contact 1 to 4 and 5 to 24 weeks following a COVID-19 diagnosis compared to propensity-matched controls. Methods: Two hundred forty nine thousand three hundred ninety Welsh individuals with a positive reverse transcription–polymerase chain reaction (RT-PCR) test were identified from data from national PCR test results. After elimination criteria, 98,600 positive individuals were matched to test negative and never tested controls using propensity matching. Cohorts were split on test location. Tests could be taken in either the hospital or community. Controls were those who had tested negative in their respective environments. Survival analysis was utilised for first clinical outcomes which are grouped into primary and secondary. Primary outcomes include post-viral-illness and fatigue as an indication of long-COVID. Secondary outcomes include clinical terminology concepts for embolism, respiratory conditions, mental health conditions, fit notes, or hospital attendance. Increased instantaneous risk for positive individuals was quantified using hazard ratios (HR) from Cox regression, while absolute risk (AR) and relative risk were quantified using life table analysis. Results: Analysis was conducted using all individuals and stratified by test location. Cases are compared to controls from the same test location. Fatigue (HR: 1.77, 95% CI: 1.34–2.25, p = < 0.001) and embolism (HR: 1.50, 95% CI: 1.15–1.97, p = 0.003) were more likely to occur in all positive individuals in the first 4 weeks; however, anxiety and depression (HR: 0.83, 95% CI: 0.73–0.95, p = 0.007) were less likely. Positive individuals continued to be more at risk of fatigue (HR: 1.47, 95% CI: 1.24–1.75, p = < 0.001) and embolism (HR: 1.51, 95% CI: 1.13–2.02, p = 0.005) after 4 weeks. All positive individuals are also at greater risk of post-viral illness (HR: 4.57, 95% CI: 1.77–11.80, p = 0.002). Despite statistical association between testing positive and several conditions, life table analysis shows that only a small minority of the study population were affected. Conclusions: Community COVID-19 disease is associated with increased risks of post-viral-illness, fatigue, embolism, and respiratory conditions. Despite elevated risks, the absolute healthcare burden is low. Subsequently, either very small proportions of people experience adverse outcomes following COVID-19 or they are not presenting to healthcare

Methylome of human skeletal muscle after acute & chronic resistance exercise training, detraining & retraining

DNA methylation is an important epigenetic modification that can regulate gene expression following environmental encounters without changes to the genetic code. Using Infinium MethylationEPIC BeadChip Arrays (850,000 CpG sites) we analysed for the first time, DNA isolated from untrained human skeletal muscle biopsies (vastus lateralis) at baseline (rest) and immediately following an acute (single) bout of resistance exercise. In the same participants, we also analysed the methylome following a period of muscle growth (hypertrophy) evoked via chronic (repeated bouts-3 sessions/wk) resistance exercise (RE) (training) over 7-weeks, followed by complete exercise cessation for 7-weeks returning muscle back to baseline levels (detraining), and finally followed by a subsequent 7-week period of RE-induced hypertrophy (retraining). These valuable methylome data sets described in the present manuscript and deposited in an open-access repository can now be shared and re-used to enable the identification of epigenetically regulated genes/ networks that are modified after acute anabolic stimuli and hypertrophy, and further investigate the phenomenon of epigenetic memory in skeletal muscle

Mechanical loading of bioengineered skeletal muscle in vitro recapitulates gene expression signatures of resistance exercise in vivo.

Understanding the role of mechanical loading and exercise in skeletal muscle (SkM) is paramount for delineating the molecular mechanisms that govern changes in muscle mass. However, it is unknown whether loading of bioengineered SkM in vitro adequately recapitulates the molecular responses observed after resistance exercise (RE) in vivo. To address this, the transcriptional and epigenetic (DNA methylation) responses were compared after mechanical loading in bioengineered SkM in vitro and after RE in vivo. Specifically, genes known to be upregulated/hypomethylated after RE in humans were analyzed. Ninety-three percent of these genes demonstrated similar changes in gene expression post-loading in the bioengineered muscle when compared to acute RE in humans. Furthermore, similar differences in gene expression were observed between loaded bioengineered SkM and after programmed RT in rat SkM tissue. Hypomethylation occurred for only one of the genes analysed (GRIK2) post-loading in bioengineered SkM. To further validate these findings, DNA methylation and mRNA expression of known hypomethylated and upregulated genes post-acute RE in humans were also analyzed at 0.5, 3, and 24 h post-loading in bioengineered muscle. The largest changes in gene expression occurred at 3 h, whereby 82% and 91% of genes responded similarly when compared to human and rodent SkM respectively. DNA methylation of only a small proportion of genes analyzed (TRAF1, MSN, and CTTN) significantly increased post-loading in bioengineered SkM alone. Overall, mechanical loading of bioengineered SkM in vitro recapitulates the gene expression profile of human and rodent SkM after RE in vivo. Although some genes demonstrated differential DNA methylation post-loading in bioengineered SkM, such changes across the majority of genes analyzed did not closely mimic the epigenetic response to acute-RE in humans

Genetic variation at mouse and human ribosomal DNA influences associated epigenetic states

Background Ribosomal DNA (rDNA) displays substantial inter-individual genetic variation in human and mouse. A systematic analysis of how this variation impacts epigenetic states and expression of the rDNA has thus far not been performed. Results Using a combination of long- and short-read sequencing, we establish that 45S rDNA units in the C57BL/6J mouse strain exist as distinct genetic haplotypes that influence the epigenetic state and transcriptional output of any given unit. DNA methylation dynamics at these haplotypes are dichotomous and life-stage specific: at one haplotype, the DNA methylation state is sensitive to the in utero environment, but refractory to post-weaning influences, whereas other haplotypes entropically gain DNA methylation during aging only. On the other hand, individual rDNA units in human show limited evidence of genetic haplotypes, and hence little discernible correlation between genetic and epigenetic states. However, in both species, adjacent units show similar epigenetic profiles, and the overall epigenetic state at rDNA is strongly positively correlated with the total rDNA copy number. Analysis of different mouse inbred strains reveals that in some strains, such as 129S1/SvImJ, the rDNA copy number is only approximately 150 copies per diploid genome and DNA methylation levels are < 5%. Conclusions Our work demonstrates that rDNA-associated genetic variation has a considerable influence on rDNA epigenetic state and consequently rRNA expression outcomes. In the future, it will be important to consider the impact of inter-individual rDNA (epi)genetic variation on mammalian phenotypes and diseases

Childhood outcomes in children with and without cardiac echogenic foci: An electronic birth cohort study in Wales, UK

There is uncertainty about outcomes associated with cardiac echogenic foci (CEF) seen at the midtrimester ultrasound scan because of limited population-based follow-up data. This can lead to unnecessary invasive testing and significant parental anxiety. We analysed data from a cohort study, The Welsh Study of Mothers and Babies, to examine whether children with CEF had more adverse outcomes during childhood compared with children without CEF. Children born between 1 January 2009 and 31 December 2011 were followed until 31 January 2018, migration out of Wales, or death. The primary outcome was cardiac hospital admissions, defined a priori by an expert steering group. Secondary outcomes included congenital cardiac anomalies, and hospital admissions for other causes. There was no evidence of an association between isolated CEF and cardiac hospital admissions (hazard ratio 0.87, 95% confidence interval [CI] 0.33–2.25, p value 0.768), or with congenital cardiac anomalies. There was a small increased risk of a respiratory admission with isolated CEF (hazard ratio 1.27, 95% CI 1.04–1.54, p value 0.020). Further research is needed on features of CEF, such as location or number, to fully understand the clinical significance of these findings

Healthcare use attributable to COVID-19: a propensity-matched national electronic health records cohort study of 249,390 people in Wales, UK

Background: To determine the extent and nature of changes associated with COVID-19 infection in terms of healthcare utilisation, this study observed healthcare contact 1 to 4 and 5 to 24 weeks following a COVID-19 diagnosis compared to propensity-matched controls. Methods: Two hundred forty nine thousand three hundred ninety Welsh individuals with a positive reverse transcription–polymerase chain reaction (RT-PCR) test were identified from data from national PCR test results. After elimination criteria, 98,600 positive individuals were matched to test negative and never tested controls using propensity matching. Cohorts were split on test location. Tests could be taken in either the hospital or community. Controls were those who had tested negative in their respective environments. Survival analysis was utilised for first clinical outcomes which are grouped into primary and secondary. Primary outcomes include post-viral-illness and fatigue as an indication of long-COVID. Secondary outcomes include clinical terminology concepts for embolism, respiratory conditions, mental health conditions, fit notes, or hospital attendance. Increased instantaneous risk for positive individuals was quantified using hazard ratios (HR) from Cox regression, while absolute risk (AR) and relative risk were quantified using life table analysis. Results: Analysis was conducted using all individuals and stratified by test location. Cases are compared to controls from the same test location. Fatigue (HR: 1.77, 95% CI: 1.34–2.25, p = &lt; 0.001) and embolism (HR: 1.50, 95% CI: 1.15–1.97, p = 0.003) were more likely to occur in all positive individuals in the first 4 weeks; however, anxiety and depression (HR: 0.83, 95% CI: 0.73–0.95, p = 0.007) were less likely. Positive individuals continued to be more at risk of fatigue (HR: 1.47, 95% CI: 1.24–1.75, p = &lt; 0.001) and embolism (HR: 1.51, 95% CI: 1.13–2.02, p = 0.005) after 4 weeks. All positive individuals are also at greater risk of post-viral illness (HR: 4.57, 95% CI: 1.77–11.80, p = 0.002). Despite statistical association between testing positive and several conditions, life table analysis shows that only a small minority of the study population were affected. Conclusions: Community COVID-19 disease is associated with increased risks of post-viral-illness, fatigue, embolism, and respiratory conditions. Despite elevated risks, the absolute healthcare burden is low. Subsequently, either very small proportions of people experience adverse outcomes following COVID-19 or they are not presenting to healthcare

Is cosmology consistent?

We perform a detailed analysis of the latest CMB measurements (including BOOMERaNG, DASI, Maxima and CBI), both alone and jointly with other cosmological data sets involving, e.g., galaxy clustering and the Lyman Alpha Forest. We first address the question of whether the CMB data are internally consistent once calibration and beam uncertainties are taken into account, performing a series of statistical tests. With a few minor caveats, our answer is yes, and we compress all data into a single set of 24 bandpowers with associated covariance matrix and window functions. We then compute joint constraints on the 11 parameters of the ``standard'' adiabatic inflationary cosmological model. Out best fit model passes a series of physical consistency checks and agrees with essentially all currently available cosmological data. In addition to sharp constraints on the cosmic matter budget in good agreement with those of the BOOMERaNG, DASI and Maxima teams, we obtain a heaviest neutrino mass range 0.04-4.2 eV and the sharpest constraints to date on gravity waves which (together with preference for a slight red-tilt) favors ``small-field'' inflation models.Comment: Replaced to match accepted PRD version. 14 pages, 12 figs. Tiny changes due to smaller DASI & Maxima calibration errors. Expanded neutrino and tensor discussion, added refs, typos fixed. Combined CMB data, window and covariance matrix at http://www.hep.upenn.edu/~max/consistent.html or from [email protected]

Genetic variation at mouse and human ribosomal DNA influences associated epigenetic states

Background: Ribosomal DNA (rDNA) displays substantial inter-individual genetic variation in human and mouse. A systematic analysis of how this variation impacts epigenetic states and expression of the rDNA has thus far not been performed. Results: Using a combination of long- and short-read sequencing, we establish that 45S rDNA units in the C57BL/6J mouse strain exist as distinct genetic haplotypes that influence the epigenetic state and transcriptional output of any given unit. DNA methylation dynamics at these haplotypes are dichotomous and life-stage specific: at one haplotype, the DNA methylation state is sensitive to the in utero environment, but refractory to post-weaning influences, whereas other haplotypes entropically gain DNA methylation during aging only. On the other hand, individual rDNA units in human show limited evidence of genetic haplotypes, and hence little discernible correlation between genetic and epigenetic states. However, in both species, adjacent units show similar epigenetic profiles, and the overall epigenetic state at rDNA is strongly positively correlated with the total rDNA copy number. Analysis of different mouse inbred strains reveals that in some strains, such as 129S1/SvImJ, the rDNA copy number is only approximately 150 copies per diploid genome and DNA methylation levels are < 5%. Conclusions: Our work demonstrates that rDNA-associated genetic variation has a considerable influence on rDNA epigenetic state and consequently rRNA expression outcomes. In the future, it will be important to consider the impact of inter-individual rDNA (epi)genetic variation on mammalian phenotypes and diseases

Galaxy and Cluster Biasing from Local Group Dynamics

Comparing the gravitational acceleration induced on the Local Group of galaxies by different tracers of the underline density field we estimate, within the linear gravitational instability theory and the linear biasing ansatz, their relative bias factors. Using optical SSRS2 galaxies, IRAS (PSCz) galaxies and Abell/ACO clusters, we find b_{O,I} ~ 1.21 +- 0.06 and b_{C,I} ~ 4.3 +- 0.8, in agreement with other recent studies. Finally, there is an excellent one-to-one correspondence of the PSCz and Abell/ACO cluster dipole profiles, once the latter is rescaled by b_{C,I}, out to at least ~150 h^{-1} Mpc.Comment: 7 pages, 5 figures, accepted for publication in MNRA

The Comparative Methylome and Transcriptome After Change of Direction Compared to Straight Line Running Exercise in Human Skeletal Muscle.

The methylome and transcriptome signatures following exercise that are physiologically and metabolically relevant to sporting contexts such as team sports or health prescription scenarios (e.g., high intensity interval training/HIIT) has not been investigated. To explore this, we performed two different sport/exercise relevant high-intensity running protocols in five male sport team members using a repeated measures design of: (1) change of direction (COD) versus; (2) straight line (ST) running exercise with a wash-out period of at least 2 weeks between trials. Skeletal muscle biopsies collected from the vastus lateralis 30 min and 24 h post exercise, were assayed using 850K methylation arrays and a comparative analysis with recent (subject-unmatched) sprint and acute aerobic exercise meta-analysis transcriptomes was performed. Despite COD and ST exercise being matched for classically defined intensity measures (speed × distance and number of accelerations/decelerations), COD exercise elicited greater movement (GPS-Playerload), physiological (HR), metabolic (lactate) as well as central and peripheral (differential RPE) exertion measures compared with ST exercise, suggesting COD exercise evoked a higher exercise intensity. The exercise response alone across both conditions evoked extensive alterations in the methylome 30 min and 24 h post exercise, particularly in MAPK, AMPK and axon guidance pathways. COD evoked a considerably greater hypomethylated signature across the genome compared with ST exercise, particularly at 30 min post exercise, enriched in: Protein binding, MAPK, AMPK, insulin, and axon guidance pathways. Comparative methylome analysis with sprint running transcriptomes identified considerable overlap, with 49% of genes that were altered at the expression level also differentially methylated after COD exercise. After differential methylated region analysis, we observed that VEGFA and its downstream nuclear transcription factor, NR4A1 had enriched hypomethylation within their promoter regions. VEGFA and NR4A1 were also significantly upregulated in the sprint transcriptome and meta-analysis of exercise transcriptomes. We also confirmed increased gene expression of VEGFA, and considerably larger increases in the expression of canonical metabolic genes PPARGC1A (that encodes PGC1-α) and NR4A3 in COD vs. ST exercise. Overall, we demonstrate that increased physiological/metabolic load via COD exercise in human skeletal muscle evokes considerable epigenetic modifications that are associated with changes in expression of genes responsible for adaptation to exercise