Proton pump inhibitors and dementia risk: Evidence from a cohort study using linked routinely collected national health data in Wales, UK

Objectives: Proton pump inhibitors (PPIs) are commonly prescribed for prevention and treatment of gastrointestinal conditions or for gastroprotection from other drugs. Research suggests they are linked to increased dementia risk. We use linked national health data to examine the association between PPI use and the development of incident dementia. Methods and findings: A population-based study using electronic health-data from the Secure Anonymised Information Linkage (SAIL) Databank, Wales (UK) from 1999 to 2015. Of data available on 3,765,744 individuals, a cohort who had ever been prescribed a PPI was developed (n=183,968) for people aged 55 years and over and compared to non-PPI exposed individuals (131,110). Those with prior dementia, mild-cognitive-impairment or delirium codes were excluded. Confounding factors included comorbidities and/or drugs associated with them. Comorbidities might include head injury and some examples of medications include antidepressants, antiplatelets and anticoagulants. These commonly prescribed drugs were investigated as it was not feasible to explore all drugs in this study. The main outcome was a diagnosis of incident dementia. Cox proportional hazard regression modelling was used to calculate the Hazard ratio (HR) of developing dementia in PPI-exposed compared to unexposed individuals while controlling for potential confounders. The mean age of the PPI exposed individuals was 69.9 years and 39.8% male while the mean age of the unexposed individuals was 72.1 years and 41.1% male. The rate of PPI usage was 58.4% (183,968) and incident dementia rate was 11.8% (37,148/315,078). PPI use was associated with decreased dementia risk (HR: 0.67, 95% CI: 0.65 to 0.67, p<0.01). Conclusions: This study, using large-scale, multi-centre health-data was unable to confirm an association between PPI use and increased dementia risk. Previously reported links may be associated with confounders of people using PPI’s, such as increased risk of cardiovascular disease and/or depression and their associated medications which may be responsible for any increased risk of developing dementia

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

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

Graded reductions in pre-exercise muscle glycogen impair exercise capacity but do not augment cell skeletal muscle signalling: implication for CHO periodisation

We examined the effects of graded muscle glycogen on exercise capacity and modulation of skeletal muscle signalling pathways associated with the regulation of mitochondrial biogenesis. In a repeated measures design, eight males completed a sleep-low, train-low model comprising an evening glycogen depleting cycling protocol followed by an exhaustive exercise capacity test (8 x 3 min at 80% PPO, followed by 1 min efforts at 80% PPO until exhaustion) the subsequent morning. Following glycogen depleting exercise, subjects ingested a total of 0 g kg-1 (L-CHO), 3.6 g kg-1 (M-CHO) or 7.6 g kg-1 (H-CHO) of carbohydrate during a 6 h period prior to sleeping, such that exercise was commenced the next morning with graded (P < 0.05) muscle glycogen concentrations (Mean ± SD) (L-CHO: 88 ± 43, M-CHO: 185 ± 62, H-CHO: 278 ± 47 mmol kg-1 dw). Despite differences (P < 0.05) in exercise capacity at 80% PPO between trials (L-CHO: 18 ± 7, M-CHO: 36 ± 3, H-CHO: 44 ± 9 min) exercise induced comparable AMPKThr172 phosphorylation (~4 fold) and PGC-1α mRNA expression (~5 fold) post- and 3 h post-exercise, respectively. In contrast, exercise nor CHO availability affected the phosphorylation of p38MAPKThr180/Tyr182, CaMKIIThr268 or mRNA expression of p53, Tfam, CPT-1, CD36 or PDK4. Data demonstrate that when exercise is commenced with muscle glycogen below 300 mmol kg-1 dw, further graded reductions of 100 mmol kg-1 dw impair exercise capacity but do not augment skeletal muscle cell signaling

Student loneliness through the pandemic : how, why and where?

Loneliness has emerged as a problem for individuals and society. A group whose loneliness has recently grown in severity and visibility is students in higher education. Complementing media reports and surveys of students’ lockdown loneliness, this paper presents qualitative research findings on students loneliness during the COVID-19 pandemic. It explores the how, why and where of student loneliness through research co-produced with undergraduate and postgraduate students. Student-researchers investigated loneliness as a function of relationships and interactions through self-interviews and peer interviews (n = 46) and through objects, chosen by participants to represent their experiences of lockdown. This research led to three conclusions, each with a geographical focus. First, as the spaces in which students live and study were fragmented, interactions and relationships were disrupted. Second, students struggled to put down roots in their places of study. Without a sense of belonging—to the city and institution where they studied, and the neighbourhood and accommodation where they lived—they were more likely to experience loneliness. Third, many students were unable to progress through life transitions associated with late adolescence including leaving home, learning social skills, forming sexual relationships and emerging into adulthood. Those facing bigger changes such as bereavement struggled to process these events and spoke of feeling ‘neither here nor there’—in limbo. But students displayed resilience, finding ways to cope with and mitigate their loneliness. Their coping strategies speak to the efforts of policymakers and practitioners—including those in universities, government, health and wellbeing services, and accommodation services—who are seeking ways to tackle students' (and other peoples') loneliness

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

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

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