Interactions of short-term and chronic treadmill training with aging of the left ventricle of the heart

With aging, there is a decline in cardiac function accompanying increasing risk of arrhythmias. These effects are likely to be mechanistically associated with age-associated changes in calcium regulation within cardiac myocytes. Previous studies suggest that lifelong exercise can potentially reduce age-associated changes in the heart. Although exercise itself is associated with changes in cardiac function, little is known about the interactions of aging and exercise with respect to myocyte calcium regulation. To investigate this, adult (12 months) and old (24 months) C57/Bl6 mice were trained using moderate-intensity treadmill running. In response to 10 weeks’ training, comparable cardiac hypertrophic responses were observed, although aging independently associated with additional cardiac hypertrophy. Old animals also showed increased L- and T-type calcium channels, the sodium–calcium exchange, sarcoendoplasmic reticulum calcium ATPase, and collagen (by 50%, 92%, 66%, 88%, and 113% respectively). Short-term exercise training increased D-type and T-type calcium channels in old animals only, whereas an increase in sodium–calcium exchange was seen only in adult animals. Long-term (12 months) training generally opposed the effects of aging. Significant hypertrophy remained in long-term trained old animals, but levels of sarcoendoplasmic reticulum calcium ATPase, sodium–calcium exchange, and collagen were not significantly different from those found in the adult trained animals

Increasing precipitation variability on daily-to-multiyear timescales in a warmer world

This is the final version. Available on open access from the American Association for the Advancement of Science via the DOI in this recordData and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper, supplementary materials, and/or linked repositories. The GPCP precipitation data is acquired from https://climatedataguide.ucar.edu/climate-data/gpcp-daily-global precipitation-climatology-project. The IMERG precipitation data is acquired from https://gpm.nasa.gov/data/directory. For the HadGEM3-GC3.05 PPE simulations, two-dimensional fields can be accessed from https://catalogue.ceda.ac.uk/uuid/f1a2fc3c120f400396a92f5de84d596a, and post-processed three dimensional fields can be accessed from https://doi.org/10.7910/DVN/GHWGG0.The hydrological cycle intensifies under global warming with precipitation increases. How the increased precipitation varies temporally at a given location has vital implications for regional climates and ecosystem services. Based on ensemble climate model projections under a high emission scenario, here we show that approximately two-thirds of land on Earth will face a “wetter and more variable” hydroclimate on daily to multiyear timescales. This means wider swings between wet and dry extremes. Such an amplification of precipitation variability is particularly prominent over climatologically wet regions, with percentage increases in variability more than twice those in mean precipitation. Thermodynamic effects, linked to increased moisture availability, increase precipitation variability uniformly everywhere. It is the dynamic effects (negative) linked to weakened circulation variability that make precipitation variability changes strongly region dependent. The increase in precipitation variability poses a new challenge to the climate resilience of infrastructures and human society.National Natural Science Foundation of ChinaChina Postdoctoral Science FoundationInternational Partnership Program of Chinese Academy of SciencesUK–China Research Innovation Partnership Fun

Light smoking at base-line predicts a higher mortality risk to women than to men; evidence from a cohort with long follow-up

BACKGROUND: There is conflicting evidence as to whether smoking is more harmful to women than to men. The UK Cotton Workers’ Cohort was recruited in the 1960s and contained a high proportion of men and women smokers who were well matched in terms of age, job and length of time in job. The cohort has been followed up for 42 years. METHODS: Mortality in the cohort was analysed using an individual relative survival method and Cox regression. Whether smoking, ascertained at baseline in the 1960s, was more hazardous to women than to men was examined by estimating the relative risk ratio women to men, smokers to never smoked, for light (1–14), medium (15–24), heavy (25+ cigarettes per day) and former smoking. RESULTS: For all-cause mortality relative risk ratios were 1.35 for light smoking at baseline (95% CI 1.07-1.70), 1.15 for medium smoking (95% CI 0.89-1.49) and 1.00 for heavy smoking (95% CI 0.63-1.61). Relative risk ratios for light smoking at baseline for circulatory system disease was 1.42 (95% CI 1.01 to 1.98) and for respiratory disease was 1.89 (95% CI 0.99 to 3.63). Heights of participants provided no explanation for the gender difference. CONCLUSIONS: Light smoking at baseline was shown to be significantly more hazardous to women than to men but the effect decreased as consumption increased indicating a dose response relationship. Heavy smoking was equally hazardous to both genders. This result may help explain the conflicting evidence seen elsewhere. However gender differences in smoking cessation may provide an alternative explanation

The contribution of smoking-attributable mortality to differences in mortality and life expectancy among US African-American and white adults, 2000-2019

Background: The role of smoking in racial disparities in mortality and life expectancy in the United States has been examined previously, but up-to-date estimates are generally unavailable, even though smoking prevalence has declined in recent decades. Objective: We estimate the contribution of smoking-attributable mortality to observed differences in mortality and life expectancy for US African-American and white adults from 2000-2019. Methods: The indirect Preston-Glei-Wilmoth method was used with national vital statistics and population data and nationally representative never-smoker lung cancer death rates to estimate the smoking-attributable fraction (SAF) of deaths in the United States by sex-race group from 2000-2019. Mortality rates without smoking-attributable mortality were used to estimate life expectancy at age 50 (e_50) by group during the period. Results: African-American men had the highest estimated SAF during the period, beginning at 26.4Š (95Š CI:25.0Š-27.8Š) in 2000 and ending at 12.1Š (95Š CI:11.4Š-12.8Š) in 2019. The proportion of the difference in e_50 for white and African-American men that was due to smoking decreased from 27.7Š to 14.8Š. For African-American and white women, the estimated differences in e_50 without smoking-attributable mortality were similar to observed differences. Conclusions: Smoking continues to contribute to racial disparities in mortality and life expectancy among men in the United States. Contribution: We present updated estimates of the contribution of smoking to mortality differences in the United States using nationally representative data sources

P20-19 LB. Extensive HLA-driven viral diversity following a single-source HIV-1 outbreak in rural China

Background: High rates of mutation in HIV infected individual allow the virus to adapt rapidly in vivo to selective forces such as anti-retroviral therapy (ART) and host immune pressure. This provides an opportunity to determine the relative contribution of different components of the immune response to HIV-1 infection in driving viral diversity, which may also facilitate assessment of their role in controlling viral replication. It is accepted that HIV-1-specific cytotoxic T-lymphocytes (CTL) may drive the selection of viral variants that can escape T-cell recognition but the extent of this selective pressure has been controversial. Methods: Two digit HLA typing; ELISPOT assay; HIV-1 sequence analysis; HIV sequence clustering and phylogenetic analysis of HLA associations using the neighbour-joining method, S-Plus 8.0, “Partitioning around medoids” (PAM) method and Stratification analysis by Mantel-Haenszel tests Results: Here we describe the consequences of HLA-associated selection on viral diversity in the main targets of T-cell recognition following an outbreak of HIV-1 in a cohort of 258 former plasma donors in rural China. The surprising finding that all the donors appear to have been infected with the same strain of clade B HIV-1 ensured that the analysis was not confounded by “founder effect”. At least 32.63% (232/711) of the mutations in the gag, pol and nef genes leading to amino acid substitutions were associated with class I HLA molecules: of these, 27.16% (63/232) were found within or close to known CD8+ T-cell epitopes. Conclusion: Taken together our data confirm that CD8+ T-cell pressure has a major impact on HIV-1 viral diversity and represent an important element of viral control in the infected host

Management and treatment of children, young people and adults with systemic lupus erythematosus: British Society for Rheumatology guideline scope

\ua9 The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.The objective of this guideline is to provide up-to-date, evidence-based recommendations for the management of SLE that builds upon the existing treatment guideline for adults living with SLE published in 2017. This will incorporate advances in the assessment, diagnosis, monitoring, non-pharmacological and pharmacological management of SLE. General approaches to management as well as organ-specific treatment, including lupus nephritis and cutaneous lupus, will be covered. This will be the first guideline in SLE using a whole life course approach from childhood through adolescence and adulthood. The guideline will be developed with people with SLE as an important target audience in addition to healthcare professionals. It will include guidance related to emerging approved therapies and account for National Institute for Health and Care Excellence Technology Appraisals, National Health Service England clinical commissioning policies and national guidance relevant to SLE. The guideline will be developed using the methods and rigorous processes outlined in ‘Creating Clinical Guidelines: Our Protocol’ by the British Society for Rheumatology

Randomised controlled trial of GM-CSF in critically ill patients with impaired neutrophil phagocytosis

Background. Critically ill patients with impaired neutrophil phagocytosis have significantly increased risk of nosocomial infection. Granulocyte-macrophage colony-stimulating factor (GM-CSF) improves phagocytosis by neutrophils ex vivo. This study tested the hypothesis that GM-CSF improves neutrophil phagocytosis in critically ill patients in whom phagocytosis is known to be impaired Methods. This was a multi-centre, phase 2a randomised, placebo-controlled clinical trial Using a personalised medicine approach, only critically ill patients with impaired neutrophil phagocytosis were included. Patients were randomised 1:1 to subcutaneous GM-CSF (3 microgrammws/kg/day) or placebo, once daily for 4 days. The primary outcome measure was neutrophil phagocytosis 2 days after initiation of GM-CSF. Secondary outcomes included neutrophil phagocytosis over time, neutrophil functions other than phagocytosis, monocyte HLA-DR expression, and safety. Results. Thirty-eight patients were recruited from 5 intensive care units (17 randomised to GM-CSF). Mean neutrophil phagocytosis at day 2 was 57.2% (SD 13.2%) in the GM-CSF group and 49.8% (13.4%) in the placebo group, p=0.73. The proportion of patients with neutrophil phagocytosis >50% at day 2, and monocyte HLA-DR, appeared significantly higher in the GM-CSF group. Neutrophil functions other than phagocytosis did not appear significantly different between the groups. The most common adverse event associated with GM-CSF was pyrexia. Conclusions. GM-CSF did not improve mean neutrophil phagocytosis at day 2, but was safe and appeared to increase the proportion of patients with adequate phagocytosis. The study suggests proof of principle for a pharmacological effect on neutrophil function in a subset of critically ill patients.This work was funded by a grant from the Medical Research Council (G1100233), with additional support from the National Institute for Health Research (NIHR) Newcastle Biomedical Research Centre. It was sponsored by Newcastle Universit

Activation of the hypothalamic-pituitary-adrenal axis by exogenous and endogenous GDF15.

An acute increase in the circulating concentration of glucocorticoid hormones is essential for the survival of severe somatic stresses. Circulating concentrations of GDF15, a hormone that acts in the brain to reduce food intake, are frequently elevated in stressful states. We now report that GDF15 potently activates the hypothalamic-pituitary-adrenal (HPA) axis in mice and rats. A blocking antibody to the GDNF-family receptor α-like receptor completely prevented the corticosterone response to GDF15 administration. In wild-type mice exposed to a range of stressful stimuli, circulating levels of both corticosterone and GDF15 rose acutely. In the case of Escherichia coli or lipopolysaccharide injections, the vigorous proinflammatory cytokine response elicited was sufficient to produce a near-maximal HPA response, regardless of the presence or absence of GDF15. In contrast, the activation of the HPA axis seen in wild-type mice in response to the administration of genotoxic or endoplasmic reticulum toxins, which do not provoke a marked rise in cytokines, was absent in Gdf15 -/- mice. In conclusion, consistent with its proposed role as a sentinel hormone, endogenous GDF15 is required for the activation of the protective HPA response to toxins that do not induce a substantial cytokine response. In the context of efforts to develop GDF15 as an antiobesity therapeutic, these findings identify a biomarker of target engagement and a previously unrecognized pharmacodynamic effect, which will require monitoring in human studies

Hypoxia shapes the immune landscape in lung injury and promotes the persistence of inflammation

Hypoxemia is a defining feature of acute respiratory distress syndrome (ARDS), an often-fatal complication of pulmonary or systemic inflammation, yet the resulting tissue hypoxia, and its impact on immune responses, is often neglected. In the present study, we have shown that ARDS patients were hypoxemic and monocytopenic within the first 48 h of ventilation. Monocytopenia was also observed in mouse models of hypoxic acute lung injury, in which hypoxemia drove the suppression of type I interferon signaling in the bone marrow. This impaired monopoiesis resulted in reduced accumulation of monocyte-derived macrophages and enhanced neutrophil-mediated inflammation in the lung. Administration of colony-stimulating factor 1 in mice with hypoxic lung injury rescued the monocytopenia, altered the phenotype of circulating monocytes, increased monocyte-derived macrophages in the lung and limited injury. Thus, tissue hypoxia altered the dynamics of the immune response to the detriment of the host and interventions to address the aberrant response offer new therapeutic strategies for ARDS