Higher risk of upper respiratory tract infection post marathon running: when physical exercise becomes a threat to the immune system.

Background: Several studies have reported that marathon runners have a higher risk of upper respiratory tract infections (URTI) post marathon than non-exercising controls. However, other studies did not find a higher risk of URTI in the same participants before and after a marathon, precluding a conclusive consensus. Besides the between-subjects effects, another important confounding factor in these results is the different pre and post follow-up time to track URTI. Objectives: Identify by meta-analysis whether a marathon Running increases the risk of URTI, adjusting the follow-up time to track URTI. Data sources: We searched for articles using MEDLINE (PubMed), Embase, Scopus, Web of Science, the Cochrane Library, and EBSCOhost, combining the marathon and respiratory infection descriptor synonyms, on 1st December 2022. Eligibility criteria: The PICOS framework included human population, comparison between pre and post marathon running, of URTI symptoms (assessed from one to 4 weeks), in noncontrolled intervention studies. Data Synthesis: Because follow-up was longer before the marathon in many studies, we adjusted the number of subjects with infections before marathon to the equivalent post-marathon follow-up duration. There was 18% higher incidence of URTI post-marathon (OR 1.18 95%CI [1.05-1.33], p= 0.005) in a very consistent meta-analysis (I2 = 0%, p = 0.69), with no risk of publication bias (Egger test p-value = 0.82) for the 7 studies included. The main issues with quality of the studies were bias in measuring the outcome, bias in classification of intervention (participation in the marathon) and time-varying confounding (corrected for analysis), and therefore the quality of evidence was moderate (GRADE approach = 3). Limitations: The need for follow-up time adjustment is a limitation, since the number of URTI recorded could be different if the original studies had used the same follow-up time pre and post marathon. The subjectivity of the URTI assessments is another limitation in this field. Conclusions: There is an increased risk of URTI post marathon running and research on this topic to understand mechanisms might support runners to find efficient interventions to reduce this risk. Protocol: Protocol registration on in the International Prospective Register of Systematic Reviews (PROSPERO): CRD42022380991.

Severe thermal and major traumatic injury results in elevated plasma concentrations of total heme that are associated with poor clinical outcomes and systemic immune suppression.

Background: Traumatic and thermal injuries result in a state of systemic immune suppression, yet the mechanisms that underlie its development are poorly understood. Released from injured muscle and lysed red blood cells, heme is a damage associated molecular pattern with potent immune modulatory properties. Here, we measured plasma concentrations of total heme in over 200 traumatic and thermally-injured patients in order to examine its relationship with clinical outcomes and post-injury immune suppression. Methods: Blood samples were collected from 98 burns (≥15% total body surface area) and 147 traumatically-injured (injury severity score ≥8) patients across the ultra-early (≤1 hour) and acute (4-72 hours) post-injury settings. Pro-inflammatory cytokine production by lipopolysaccharide (LPS) challenged whole blood leukocytes was studied, and plasma concentrations of total heme, and its scavengers haptoglobin, hemopexin and albumin measured, alongside the expression of heme-oxygenase-1 (HO-1) in peripheral blood mononuclear cells (PBMCs). LPS-induced tumour necrosis factor-alpha (TNF-α) production by THP-1 cells and monocytes following in vitro heme treatment was also examined. Results: Burns and traumatic injury resulted in significantly elevated plasma concentrations of heme, which coincided with reduced levels of hemopexin and albumin, and correlated positively with circulating levels of pro and anti-inflammatory cytokines. PBMCs isolated from trauma patients 4-12 and 48-72 hours post-injury exhibited increased HO-1 gene expression. Non-survivors of burn injury and patients who developed sepsis, presented on day 1 with significantly elevated heme levels, with a difference of 6.5 µM in heme concentrations corresponding to a relative 52% increase in the odds of post-burn mortality. On day 1 post-burn, heme levels were negatively associated with ex vivo LPS-induced TNF-α and interleukin-6 production by whole blood leukocytes. THP-1 cells and monocytes pre-treated with heme exhibited significantly reduced TNF-α production following LPS stimulation. This impairment was associated with decreased gene transcription, reduced activation of extracellular signal-regulated kinase 1/2 and an impaired glycolytic response. Conclusions: Major injury results in elevated plasma concentrations of total heme that may contribute to the development of endotoxin tolerance and increase the risk of poor clinical outcomes. Restoration of the heme scavenging system could be a therapeutic approach by which to improve immune function post-injury.

Accelerated aging of skeletal muscle and the immune system in patients with chronic liver disease.

Patients with chronic liver disease (CLD) often present with significant frailty, sarcopenia, and impaired immune function. However, the mechanisms driving the development of these age-related phenotypes are not fully understood. To determine whether accelerated biological aging may play a role in CLD, epigenetic, transcriptomic, and phenotypic assessments were performed on the skeletal muscle tissue and immune cells of CLD patients and age-matched healthy controls. Accelerated biological aging of the skeletal muscle tissue of CLD patients was detected, as evidenced by an increase in epigenetic age compared with chronological age (mean +2.2 ± 4.8 years compared with healthy controls at -3.0 ± 3.2 years, p = 0.0001). Considering disease etiology, age acceleration was significantly greater in both the alcohol-related (ArLD) (p = 0.01) and nonalcoholic fatty liver disease (NAFLD) (p = 0.0026) subgroups than in the healthy control subgroup, with no age acceleration observed in the immune-mediated subgroup or healthy control subgroup (p = 0.3). The skeletal muscle transcriptome was also enriched for genes associated with cellular senescence. Similarly, blood cell epigenetic age was significantly greater than that in control individuals, as calculated using the PhenoAge (p < 0.0001), DunedinPACE (p < 0.0001), or Hannum (p = 0.01) epigenetic clocks, with no difference using the Horvath clock. Analysis of the IMM-Age score indicated a prematurely aged immune phenotype in CLD patients that was 2-fold greater than that observed in age-matched healthy controls (p < 0.0001). These findings suggested that accelerated cellular aging may contribute to a phenotype associated with advanced age in CLD patients. Therefore, therapeutic interventions to reduce biological aging in CLD patients may improve health outcomes.

DYNamic Assessment of Multi-Organ level dysfunction in patients recovering from COVID-19: DYNAMO COVID-19.

We evaluated the impacts of COVID-19 on multi-organ and metabolic function in patients following severe hospitalised infection compared to controls. Patients (n = 21) without previous diabetes, cardiovascular or cerebrovascular disease were recruited 5-7 months post-discharge alongside controls (n = 10) with similar age, sex and body mass. Perceived fatigue was estimated (Fatigue Severity Scale) and the following were conducted: oral glucose tolerance (OGTT) alongside whole-body fuel oxidation, validated magnetic resonance imaging and spectroscopy during resting and supine controlled exercise, dual-energy X-ray absorptiometry, short physical performance battery (SPPB), intra-muscular electromyography, quadriceps strength and fatigability, and daily step-count. There was a greater insulin response (incremental area under the curve, median (inter-quartile range)) during the OGTT in patients [18,289 (12,497-27,448) mIU/min/L] versus controls [8655 (7948-11,040) mIU/min/L], P < 0.001. Blood glucose response and fasting and post-prandial fuel oxidation rates were not different. This greater insulin resistance was not explained by differences in systemic inflammation or whole-body/regional adiposity, but step-count (P = 0.07) and SPPB scores (P = 0.004) were lower in patients. Liver volume was 28% greater in patients than controls, and fat fraction adjusted liver T1, a measure of inflammation, was raised in patients. Patients displayed greater perceived fatigue scores, though leg muscle volume, strength, force-loss, motor unit properties and post-exercise muscle phosphocreatine resynthesis were comparable. Further, cardiac and cerebral architecture and function (at rest and on exercise) were not different. In this cross-sectional study, individuals without known previous morbidity who survived severe COVID-19 exhibited greater insulin resistance, pointing to a need for physical function intervention in recovery.

A combination nutritional supplement reduces DNA methylation age only in older adults with a raised epigenetic age.

An increase in systemic inflammation (inflammaging) is one of the hallmarks of aging. Epigenetic (DNA methylation) clocks can quantify the degree of biological aging and this can be reversed by lifestyle and pharmacological intervention. We aimed to investigate whether a multi-component nutritional supplement could reduce systemic inflammation and epigenetic age in healthy older adults.We recruited 80 healthy older participants (mean age ± SD: 71.85 ± 6.23; males = 31, females = 49). Blood and saliva were obtained pre and post a 12-week course of a multi-component supplement, containing: Vitamin B3, Vitamin C, Vitamin D, Omega 3 fish oils, Resveratrol, Olive fruit phenols and Astaxanthin. Plasma GDF-15 and C-reactive protein (CRP) concentrations were quantified as markers of biological aging and inflammation respectively. DNA methylation was assessed in whole blood and saliva and used to derive epigenetic age using various clock algorithms.No difference between the epigenetic and chronological ages of participants was observed pre- and post-treatment by the blood-based Horvath or Hannum clocks, or the saliva-based InflammAge clock. However, in those with epigenetic age acceleration of ≥ 2 years at baseline, a significant reduction in epigenetic age (p = 0.015) and epigenetic age acceleration (p = 0.0058) was observed post-treatment using the saliva-based InflammAge clock. No differences were observed pre- and post-treatment in plasma GDF-15 and CRP, though participants with CRP indicative of an elevated cardiovascular disease risk (hsCRP ≥ 3µg/ml), had a reduction in CRP post-supplementation (p = 0.0195).Our data suggest a possible benefit of combined nutritional supplementation in individuals with an accelerated epigenetic age and inflammaging.

Relaxation of mitochondrial hyperfusion in the diabetic retina via N6-furfuryladenosine confers neuroprotection regardless of glycaemic status.

The recovery of mitochondrial quality control (MQC) may bring innovative solutions for neuroprotection, while imposing a significant challenge given the need of holistic approaches to restore mitochondrial dynamics (fusion/fission) and turnover (mitophagy and biogenesis). In diabetic retinopathy, this is compounded by our lack of understanding of human retinal neurodegeneration, but also how MQC processes interact during disease progression. Here, we show that mitochondria hyperfusion is characteristic of retinal neurodegeneration in human and murine diabetes, blunting the homeostatic turnover of mitochondria and causing metabolic and neuro-inflammatory stress. By mimicking this mitochondrial remodelling in vitro, we ascertain that N6-furfuryladenosine enhances mitochondrial turnover and bioenergetics by relaxing hyperfusion in a controlled fashion. Oral administration of N6-furfuryladenosine enhances mitochondrial turnover in the diabetic mouse retina (Ins2Akita males), improving clinical correlates and conferring neuroprotection regardless of glycaemic status. Our findings provide translational insights for neuroprotection in the diabetic retina through the holistic recovery of MQC.

Influence of scar age, laser type and laser treatment intervals on paediatric burn scars: a systematic review and meta-analysis.

Background: Laser therapy has emerged to play a valuable role in the treatment of paediatric burn scars; however, there is heterogeneity in the literature, particularly concerning optimal timing for initiation of laser therapy. This study aims to investigate the effect of factors such as scar age, type of laser and laser treatment interval on burn scar outcomes in children by meta-analysis of previous studies. Methods: A literature search was conducted across seven databases in May 2022 to understand the effects of laser therapy on burn scar outcomes in paediatric patients by metanalysis of standardized mean difference (SMD) between pre- and post-laser intervention. Meta-analyses were performed using the Comprehensive Meta-Analysis software version 4.0. Fixed models were selected when there was no significant heterogeneity, and the random effects model was selected for analysis when significant heterogeneity was identified. For all analyses, a p-value < 0.05 was considered significant. Results: Seven studies were included in the meta-analysis with a total of 467 patients. Laser therapy significantly improved Vancouver Scar Scale (VSS)/Total Patient and Observer Scar Assessment Scale (Total POSAS), vascularity, pliability, pigmentation and scar height of burn scars. Significant heterogeneity was found between the studies and thus subgroup analyses were performed. Early laser therapy (<12 months post-injury) significantly improved VSS/POSAS scores compared to latent therapy (>12 months post-injury) {SMD -1.97 [95% confidence interval (CI) = -3.08; -0.87], p < 0.001 vs -0.59 [95%CI = -1.10; -0.07], p = 0.03} as well as vascularity {SMD -3.95 [95%CI = -4.38; -3.53], p < 0.001 vs -0.48 [95%CI = -0.66; -0.30], p < 0.001}. Non-ablative laser was most effective, significantly reducing VSS/POSAS, vascularity, pliability and scar height outcomes compared to ablative, pulse dye laser and a combination of ablative and pulse dye laser. Shorter treatment intervals of <4 weeks significantly reduced VSS/POSAS and scar height outcomes compared to intervals of 4 to 6 weeks. Conclusions: Efficacy of laser therapy in the paediatric population is influenced by scar age, type of laser and interval between laser therapy application. The result of this study particularly challenges the currently accepted initiation time for laser treatment. Significant heterogeneity was observed within the studies, which suggests the need to explore other confounding factors influencing burn scar outcomes after laser therapy.

Association of Epigenetic Age and Outcome in Critically Ill Patients.

OBJECTIVES: DNA methylation can be used to determine an individual's biological age, as opposed to chronological age, an indicator of underlying health status. This study aimed to assess epigenetic age in critically ill patients with and without sepsis to determine if higher epigenetic age is associated with admission diagnosis or mortality. DESIGN: Secondary analysis of whole blood DNA methylation data generated from a nested case-control study of critically ill septic and nonseptic patients. SETTING: Four tertiary care hospitals in Canada. INTERVENTIONS: None. PATIENTS: Critically ill patients with and without sepsis. MEASUREMENTS AND MAIN RESULTS: Epigenetic age was derived from DNA methylation data using the Hannum and PhenoAge algorithms and deviation from the patient's chronological age in years was determined. Of the 66 patients with sepsis, 34 were male (51.5%), the mean age was 65.03 years and 25 patients (37.8%) died before discharge. Of the 68 nonseptic patients, 47 were male (69.1%), the mean age was 64.92 years and 25 (36.7%) died before discharge. Epigenetic age calculated using the PhenoAge algorithm showed a significant age acceleration of 4.97 years in septic patients (p = 0.045), but no significant acceleration in nonseptic patients. Epigenetic age calculated using the Hannum algorithm showed no significant acceleration in the septic or nonseptic patients. Similarly, in the combined septic and nonseptic cohorts, nonsurvivors showed an epigenetic age acceleration of 7.62 years (p = 0.004) using the PhenoAge algorithm while survivors showed no significant age acceleration. Survivor status was not associated with age acceleration using the Hannum algorithm. CONCLUSIONS: In critically ill patients, epigenetic age acceleration, as calculated by the PhenoAge algorithm, was associated with sepsis diagnosis and mortality.

Accelarated immune ageing is associated with COVID-19 disease severity.

BACKGROUND: The striking increase in COVID-19 severity in older adults provides a clear example of immunesenescence, the age-related remodelling of the immune system. To better characterise the association between convalescent immunesenescence and acute disease severity, we determined the immune phenotype of COVID-19 survivors and non-infected controls. RESULTS: We performed detailed immune phenotyping of peripheral blood mononuclear cells isolated from 103 COVID-19 survivors 3-5 months post recovery who were classified as having had severe (n = 56; age 53.12 ± 11.30 years), moderate (n = 32; age 52.28 ± 11.43 years) or mild (n = 15; age 49.67 ± 7.30 years) disease and compared with age and sex-matched healthy adults (n = 59; age 50.49 ± 10.68 years). We assessed a broad range of immune cell phenotypes to generate a composite score, IMM-AGE, to determine the degree of immune senescence. We found increased immunesenescence features in severe COVID-19 survivors compared to controls including: a reduced frequency and number of naïve CD4 and CD8 T cells (p < 0.0001); increased frequency of EMRA CD4 (p < 0.003) and CD8 T cells (p < 0.001); a higher frequency (p < 0.0001) and absolute numbers (p < 0.001) of CD28-ve CD57+ve senescent CD4 and CD8 T cells; higher frequency (p < 0.003) and absolute numbers (p < 0.02) of PD-1 expressing exhausted CD8 T cells; a two-fold increase in Th17 polarisation (p < 0.0001); higher frequency of memory B cells (p < 0.001) and increased frequency (p < 0.0001) and numbers (p < 0.001) of CD57+ve senescent NK cells. As a result, the IMM-AGE score was significantly higher in severe COVID-19 survivors than in controls (p < 0.001). Few differences were seen for those with moderate disease and none for mild disease. Regression analysis revealed the only pre-existing variable influencing the IMM-AGE score was South Asian ethnicity ([Formula: see text] = 0.174, p = 0.043), with a major influence being disease severity ([Formula: see text] = 0.188, p = 0.01). CONCLUSIONS: Our analyses reveal a state of enhanced immune ageing in survivors of severe COVID-19 and suggest this could be related to SARS-Cov-2 infection. Our data support the rationale for trials of anti-immune ageing interventions for improving clinical outcomes in these patients with severe disease.

Duke Activity Status Index and Liver Frailty Index predict mortality in ambulatory patients with advanced chronic liver disease: A prospective, observational study.

BACKGROUND: There remains a lack of consensus on how to assess functional exercise capacity and physical frailty in patients with advanced chronic liver disease (CLD) being assessed for liver transplantation (LT). Aim To investigate prospectively the utility of the Duke Activity Status Index (DASI) and Liver Frailty Index (LFI) in ambulatory patients with CLD. AIM: To investigate prospectively the utility of the Duke Activity Status Index (DASI) and Liver Frailty Index (LFI) in ambulatory patients with CLD. METHODS: We recruited patients from outpatient clinics at University Hospitals Birmingham, UK (2018-2019). We prospectively collated the DASI and LFI to identify the prevalence of, respectively, functional capacity and physical frailty, and to evaluate their accuracy in predicting overall and pre-LT mortality. RESULTS: We studied 307 patients (57% male; median age 54 years; UKELD 52). Median DASI score was 28.7 (IQR 16.2-50.2), mean LFI was 3.82 (SD = 0.72), and 81% were defined either 'pre-frail' or 'frail'. Female sex and hyponatraemia were significant independent predictors of both DASI and LFI. Age and encephalopathy were significant independent predictors of LFI, while BMI significantly predicted DASI. DASI and LFI were significantly related to overall (HR 0.97, p = 0.001 [DASI], HR 2.04, p = 0.001 [LFI]) and pre-LT mortality (HR 0.96, p = 0.02 [DASI], HR 1.94, p = 0.04 [LFI]). CONCLUSIONS: Poor functional exercise capacity and physical frailty are highly prevalent among ambulatory patients with CLD who are being assessed for LT. The DASI and LFI are simple, low-cost tools that predict overall and pre-LT mortality. Implementation of both should be considered in all outpatients with CLD to highlight those who may benefit from targeted nutritional and exercise interventions.

Senescent cell-derived extracellular vesicles as potential mediators of innate immunosenescence and inflammaging.

Ageing is accompanied by a decline in immune function (immunosenescence), increased inflammation (inflammaging), and more senescent cells which together contribute to age-related disease and infection susceptibility. The innate immune system is the front-line defence against infection and cancer and is also involved in the removal of senescent cells, so preventing innate immunosenescence and inflammaging is vital for health in older age. Extracellular vesicles (EVs) modulate many aspects of innate immune function, including chemotaxis, anti-microbial responses, and immune regulation. Senescent cell derived EVs (SEVs) have different cargo to that of non-senescent cell derived EVs, suggesting alterations in EV cargo across the lifespan may influence innate immune function, possibly contributing to immunosenescence and inflammaging. Here we review current understanding of the potential impact of miRNAs, lipids and proteins, found in higher concentrations in SEVs, on innate immune functions and inflammation to consider whether SEVs are potential influencers of innate immunosenescence and inflammaging. Furthermore, senolytics have demonstrated an ability to return plasma EV content closer to that of non-senescent EVs, therefore the potential use of senotherapeutics (senolytics and senostatics) to ameliorate the effects of SEVs on immunosenescence and inflammaging is also considered as a possible strategy for extending health-span in older adults.