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Aim Experiments have indicated that skin perfusion in mice is sensitive to reductions in environmental O2 availability. Specifically, a reduction in skin-surface PO2 attenuates transcutaneous O2 diffusion, and hence epidermal O2 supply. In response, epidermal HIF-1 α expression increases and facilitates initial cutaneous vasoconstriction and subsequent nitric oxide-dependent vasodilation. Here, we investigated whether the same mechanism exists in humans. Methods In a first experiment, eight males rested twice for 8 h in a hypobaric chamber. Once, barometric pressure was reduced by 50%, while systemic oxygenation was preserved by O2-enriched (42%) breathing gas (HypoxiaSkin), and once barometric pressure and inspired O2 fraction were normal (Control1). In a second experiment, nine males rested for 8 h with both forearms wrapped in plastic bags. O2 was expelled from one bag by nitrogen flushing (AnoxiaSkin), whereas the other bag was flushed with air (Control2). In both experiments, skin blood flux was assessed by laser Doppler on the dorsal forearm, and HIF-1 α expression was determined by immunohistochemical staining in forearm skin biopsies. Results Skin blood flux during HypoxiaSkin and AnoxiaSkin remained similar to the corresponding Control trial ( P = 0.67 and P = 0.81). Immunohistochemically stained epidermal HIF-1 α was detected on 8.2 ± 6.1 and 5.3 ± 5.7% of the analysed area during HypoxiaSkin and Control1 ( P = 0.30) and on 2.3 ± 1.8 and 2.4 ± 1.8% during AnoxiaSkin and Control2 ( P = 0.90) respectively. Conclusion Reductions in skin-surface PO2 do not affect skin perfusion in humans. The unchanged epidermal HIF-1 α expression suggests that epidermal O2 homoeostasis was not disturbed by HypoxiaSkin/AnoxiaSkin, potentially due to compensatory increases in arterial O2 extraction. [ABSTRACT FROM AUTHOR]

The present study investigated whether exercise induces the expression of PGC-1α splice variants in human skeletal muscle and the possible influence of metabolic perturbation on this response. The subjects exercised one leg for 45 min with restricted blood flow (R-leg), followed by 45 min of exercise using the other leg at the same absolute workload but with normal blood flow (NR-leg). This ischemic model (R-leg) has been shown previously to induce a greater metabolic perturbation and enhance the expression of PGC-1α beyond that observed in the NR-leg. Cultured human myotubes were used to test suggested exercise-induced regulatory stimuli of PGC-1α. We showed, for the first time, that transcripts from both the canonical promoter (PGC-1α-a) and the proposed upstream-located promoter (PGC-1α-b) are present in human skeletal muscle. Both transcripts were upregulated after exercise in the R-leg, but the fold change increase of PGC-1α-b was much greater than that of PGC-1a-a. No differences were observed between the two conditions regarding the marker for calcineurin activation, MCIP1, or p38 phosphorylation. AMPK phosphorylation increased to a greater extent in the R-leg, and AICAR stimulation of cultured human myotubes induced the expression of PGC-1α-a and PGC-1α-b. AICAR combined with norepinephrine yielded an additive effect on the PGC-1α-b expression only. Our results indicate clearly that exercise can activate an upstream promoter in humans and support AMPK as a major regulator of transcripts from the canonical PGC-1α promoter and the involvement of β-adrenergic stimulation in combination with AMPK in the regulation of PGC-1α-b. [ABSTRACT FROM AUTHOR]

Background: The goal of the study was to assess the potential of the vascular endothelial growth factor receptor (VEGFR)-2-targeting carbon-11 labeled (R)-N-(4-bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-3-piperidinyl)methoxy)-4-quinazolineamine ((R)-[11C]PAQ) as a positron emission tomography (PET) imaging biomarker for evaluation of the efficacy of anticancer drugs in preclinical models.Methods: MMTV-PyMT mice were treated with vehicle alone (VEH), murine anti-VEGFA antibody (B20-4.1.1), and paclitaxel (PTX) in combination or as single agents. The treatment response was measured with (R)-[11C]PAQ PET as standardized uptake value (SUV)mean, SUVmax relative changes at the baseline (day 0) and follow-up (day 4) time points, and magnetic resonance imaging (MRI)-derived PyMT mammary tumor volume (TV) changes. Expression of Ki67, VEGFR-2, and CD31 in tumor tissue was determined by immunohistochemistry (IHC). Non-parametric statistical tests were used to evaluate the relation between (R)-[11C]PAQ radiotracer uptake and therapy response biomarkers.Results: The (R)-[11C]PAQ SUVmax in tumors was significantly reduced after 4 days in the B20-4.1.1/PTX combinational and B20-4.1.1 monotherapy groups (p < 0.0005 and p < 0.003, respectively). No significant change was observed in the PTX monotherapy group. There was a significant difference in the SUVmax change between the VEH group and B20-4.1.1/PTX combinational group, as well as between the VEH group and the B20-4.1.1 monotherapy group (p < 0.05). MRI revealed significant decreases in TV in the B20-4.1.1/PTX treatment group (p < 0.005) but not the other therapy groups. A positive trend was observed between the (R)-[11C]PAQ SUVmax change and TV reduction in the B20-4.1.1/PTX group. Statistical testing showed a significant difference in the blood vessel density between the B20-4.1.1/PTX combinational group and the VEH group (p < 0.05) but no significant difference in the Ki67 positive signal between treatment groups.Conclusions: The results of this study are promising. However, additional studies are necessary before (R)-[11C]PAQ can be approved as a predictive radiotracer for cancer therapy response. [ABSTRACT FROM AUTHOR]

Introduction: The COVID-19 pandemic has resulted in a post-infectious syndrome designated as long-COVID or post-COVID condition (PCC) that presents with numerous symptoms including fatigue and myalgias. This study evaluated myopathic electromyography (EMG) findings in non-hospitalized PCC patients in relation to symptom severity, quality of life (QoL), and physical function., Methods: Twenty-nine PCC patients with persistent symptoms ≥ 3 months after laboratory-confirmed SARS-CoV-2 infection, without hospitalization or comorbidities, were included. EMG, nerve conduction studies (NCS), and quantitative sensory testing (QST) were performed. Symptom severity was measured with visual analog scales, QoL with validated questionnaires, and physical function with the 6-min walk test, cardiopulmonary exercise testing, handgrip strength, and isokinetic dynamometry., Results: Myopathic findings on EMG were present in 62% of PCC patients (n = 18). Symptom severity (muscle pain and fatigue) and QoL (physical function and fatigue) were similar between patients with and without myopathic EMG findings. The 6-min walk test (457 ± 81 vs. 459 ± 86 m) and peak VO 2 (29 ± 9 vs. 28 ± 6 mL/kg/min) were similar between patients with and without myopathic EMG findings. Handgrip strength (32 [29-43] vs. 33 [29-50] kg) and quadriceps muscle strength (136 [111-191] vs. 136 [114-184] Nm) were comparable between the groups. NCS and QST results were normal in all patients., Discussion: Myopathic findings on EMG are common in PCC patients, but no significant differences in symptom severity, QoL, or physical function were found between those with and without myopathic EMG findings. Myopathic EMG changes in PCC patients should be interpreted with caution, considering the overall clinical context., (© 2024 The Author(s). Muscle & Nerve published by Wiley Periodicals LLC.)

Background: Longitudinal studies investigating hormone therapy in transgender individuals are rare and often limited to 1- to 2-year follow-up periods., Objectives and Methods: We examined changes in body composition, muscle volumes, and fat distribution as well as muscle strength, arterial stiffness, and cardiometabolic biomarkers in both transgender men (TM; n = 17, age 25 ± 5 years) and transgender women (TW; n = 16, age 28 ± 5 years) at baseline and after 1 and 5-6 years of hormone therapy in a longitudinal prospective cohort design. Whole-body and regional fat and muscle volumes were analyzed using magnetic resonance imaging, and blood samples were taken., Results: Skeletal muscle size increased in TM (21% after 6 years) and decreased in TW (7% after 5 years). Muscle strength increased 18% after 6 years in TM (p = 0.003) but was statistically unchanged in TW. Muscle fat infiltration changed (p < 0.05) almost completely toward the affirmed sex phenotype after 1 year of therapy in both TM and TW. The most notable changes in fat volume distribution were that TW increased total adiposity but decreased visceral fat volume, whereas TM showed increased visceral fat (70%) and liver fat but relatively stable total adipose tissue levels. Although arterial stiffness and blood pressure did not change, there was a significant increase in triglyceride and LDL cholesterol levels and a decrease in HDL levels in TM after 6 years., Conclusion: These unique longitudinal data underscore the importance of continued clinical monitoring of the long-term health effects of gender-affirming hormone therapy in both TW and, perhaps especially, TM., (© 2024 The Author(s). Journal of Internal Medicine published by John Wiley & Sons Ltd on behalf of Association for Publication of The Journal of Internal Medicine.)

Introduction: Doxorubicin is a chemotherapeutic drug used to treat various cancers. Exercise training (ET) can attenuate some cardiotoxic effects of doxorubicin (DOX) in tumor-free animals. However, the ET effects on cardiac function and glucose metabolism in DOX-treated breast cancer models remain unclear., Objectives: This study investigated ET-induced structural, functional, vascular, oxidative stress, and plausible glucose uptake alterations of the left ventricle (LV) in a murine breast cancer model during DOX treatment., Methods: Female FVB/N-mice were divided to tumor-free groups with or without voluntary wheel-running ET and those inoculated subcutaneously with mammary tumor-derived I3TC-cells with or without exercise or DOX treatment (5 mg/kg/week). Mice underwent 2-[ 18 F]fluoro-2-deoxy-D-glucose positron emission tomography and echocardiography after two and four DOX-doses. The cardiac histology, oxidative stress, maximal metabolic enzyme activities, and mitochondrial respiration were analyzed., Results: DOX increased LV glucose uptake (LVGU) and mitochondrial uncoupling and decreased running activity, LV-weight, and ejection fraction (EF). In DOX-treated group ET blunted the increase in LVGU, increased LV-weight and EF, and lowered LV lactate dehydrogenase activity. DOX-treated exercised mice did not differ from tumor-bearing group without DOX in LVGU or from the tumor-free ET-group in LV-weight or EF whereas unexercised DOX-treated group did. ET also increased LV citrate synthase activity in tumor-bearing animals. There was an inverse association between LVGU and EF and LV-weight., Conclusion: In a murine breast cancer model, voluntary ET moderated DOX-induced cardiotoxicities such as increased LVGU, LV-atrophy and decreased EF. This suggests that ET might benefit patients with cancer undergoing doxorubicin treatment by mitigating cardiotoxicity., Competing Interests: Declarations. Ethics approval and consent to participate: All animal experiments were performed in compliance with the European Union directive 2010/EU/63 on the protection of animals used for scientific purposes and were approved by the national Project Authorization Board in Finland (license number: ESAVI/26508/2021). Consent for publication: Not applicable. Competing interests: The authors declare that they have no competing interests. Antti Saraste discloses speaker fees or consultancy fees from Abbott, Astra Zeneca, BMS, Janssen and Pfizer. Anu Autio discloses current employment in MSD Finland., (© 2025. The Author(s).)

Purpose: To evaluate the cost utility of a 9-month supervised exercise program for patients with metastatic breast cancer (mBC), compared with control (usual care, supplemented with general activity advice and an activity tracker). Evidence on the cost-effectiveness of exercise for patients with mBC is essential for implementation in clinical practice and is currently lacking., Methods: A cost-utility analysis was performed alongside the multinational PREFERABLE-EFFECT randomized controlled trial, conducted in 8 centers across Europe and Australia. Patients with mBC (N = 357) were randomly assigned to either a 9-month, twice-weekly, supervised exercise group (EG) or control group (CG). Costs of the exercise program were calculated through a bottom-up approach. Other health care resource use, productivity losses, and quality of life were collected using country-adapted, self-reported questionnaires. Analyses were conducted from a societal perspective with a time horizon of 9 months. Costs were collected and reported in 2021 Euros (€1 = $1.18 US dollars)., Results: Compared with the CG, EG resulted in a quality-adjusted life-year (QALY) gain of 0.013 (95% CI, -0.02 to 0.05) over a 9-month period. The mean costs of the exercise program were €1,696 per patient with one-on-one supervision (scenario 1) and €609 with one-on-four supervision (scenario 2). These costs were offset by savings in health care and productivity costs, resulting in mean total cost differences of -€163 (scenario 1) and -€1,249 (scenario 2) in favor of EG. The probability of supervised exercise being cost-effective was 65% in scenario 1 and 91% in scenario 2 at a willingness-to-pay threshold of €20,000 per QALY., Conclusion: Exercise for patients with mBC increases quality of life, decreases costs, and is likely to be cost-effective. Group-based supervision is expected to have even higher cost-savings. Our positive findings can inform reimbursement of supervised exercise interventions for patients with mBC.

Introduction: The aim of this prospective cohort study was to investigate the associations between changes in cardiorespiratory fitness (CRF) and the risk of colorectal and prostate cancer in men., Methods: Data from men who completed a health assessment both in military conscription in youth and an occupational health profile assessment (HPA) later in life were used. CRF was assessed as estimated V̇O 2max , using a cycle ergometer fitness test at both time points. We linked the assessment data to national register data on colorectal and prostate cancer incidence, and hazard ratios and confidence intervals were estimated using Cox proportional hazard regression., Results: 139,764 men with a mean age of 18 (SD 0.6) at conscription and 43 (SD 8.9) at HPA were included. The average time between the two assessments was 25.9 (SD 9.0) years and mean follow-up time following HPA test was 10.0 (SD 5.6) years for prostate and colorectal cancer. Annual percentage change in relative and absolute V̇O 2max from conscription to HPA was inversely associated with the risk of colorectal cancer incidence, hazard ratio of 0.83 (95% CI [0.72-0.94]) and 0.88 (95% CI [0.79-0.99]), respectively. These associations were driven by data from individuals in the lowest and moderate level fitness tertials at conscription. Change in CRF was not associated with prostate cancer incidence risk., Conclusions: Changes in, not only level of, CRF from youth to adulthood are related to colorectal cancer incidence risk and therefore, improving CRF should be considered as an important colorectal cancer risk reduction strategy., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

The heart depends critically on continuous blood supply, but it is unknown whether cancer itself affects myocardial blood flow (MBF). This study investigated MBF in cancer patients and cardiac morphology in a cancer mice model. MBF was quantified with [ 15 O]H 2 O positron emission tomography at rest in recently diagnosed breast cancer patients and age-matched female controls, and additionally during 10-min exercise in the cancer patients. Cardiac morphological changes were analyzed with a breast cancer mouse model and control mice without tumors. Resting MBF was similar in cancer patients and controls. MBF increased significantly during exercise in cancer patients, and exercising MBF correlated positively with cancer grade. In the mouse model, cancer did not affect heart weight, cardiomyocyte size, myocardial capillary density, or capillary-to-myocyte size ratio. Thus, resting MBF in humans or myocardial capillarity in mice appears not to be affected by breast cancer. The exercise-induced MBF increase in cancer patients with higher histologic grade requires further investigations., Competing Interests: The authors declare no competing interests., (© 2024 The Author(s).)

Physical exercise both during and after curative cancer treatment has been shown to reduce side effects. Evidence in the metastatic cancer setting is scarce, and interventions that improve health-related quality of life (HRQOL) are much needed for patients with metastatic breast cancer (MBC). The multinational randomized controlled PREFERABLE-EFFECT trial assessed the effects of exercise on fatigue and HRQOL in patients with MBC. In total, 357 patients with MBC and a life expectancy of ≥6 months but without unstable bone metastases were recruited at eight study centers across five European countries and Australia. Participants were randomly assigned (1:1) to usual care (control group, n = 179) or a 9-month supervised exercise program (exercise group, n = 178). Intervention effects on physical fatigue (European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire (QLQ)-FA12 scale) and HRQOL (EORTC QLQ-C30 summary score) were determined by comparing the change from baseline to 3, 6 (primary timepoint) and 9 months between groups using mixed models for repeated measures, adjusted for baseline values of the outcome, line of treatment (first or second versus third or higher) and study center. Exercise resulted in significant positive effects on both primary outcomes. Physical fatigue was significantly lower (-5.3 (95% confidence interval (CI), -10.0 to -0.6), Bonferroni-Holm-adjusted P = 0.027; Cohen's effect size, 0.22) and HRQOL significantly higher (4.8 (95% CI, 2.2-7.4), Bonferroni-Holm-adjusted P = 0.0003; effect size, 0.33) in the exercise group than in the control group at 6 months. Two serious adverse events occurred (that is, fractures), but both were not related to bone metastases. These results demonstrate that supervised exercise has positive effects on physical fatigue and HRQOL in patients with MBC and should be recommended as part of supportive care.ClinicalTrials.gov Identifier: NCT04120298 ., (© 2024. The Author(s).)

Several metabolites have been shown to have independent and at times unexpected biological effects outside of their metabolic pathways. These include succinate, lactate, fumarate, and 2-hydroxyglutarate. 2-Hydroxybutyrate (2HB) is a byproduct of endogenous cysteine synthesis, produced during periods of cellular stress. 2HB rises acutely after exercise; it also rises during infection and is also chronically increased in a number of metabolic disorders. We show here that 2HB inhibits branched-chain aminotransferase enzymes, which in turn triggers a SIRT4-dependent shift in the compartmental abundance of protein ADP-ribosylation. The 2HB-induced decrease in nuclear protein ADP-ribosylation leads to a C/EBPβ-mediated transcriptional response in the branched-chain amino acid degradation pathway. This response to 2HB exposure leads to an improved oxidative capacity in vitro. We found that repeated injection with 2HB can replicate the improvement to oxidative capacity that occurs following exercise training. Together, we show that 2-HB regulates fundamental aspects of skeletal muscle metabolism., Competing Interests: BW, ML, EM, PC, VE, CB, CA, SS, EM, PK, JR, HR, JL, RJ No competing interests declared, (© 2023, Wadsworth et al.)

The protocol predefined aim of this study is to assess sustained effects of the OptiTrain trial on several health outcomes, 5 years after the baseline assessment. The OptiTrain study was a prospective, randomised controlled trial with 240 patients with breast cancer undergoing adjuvant chemotherapy that compared the effects of 16 weeks of two exercise programs, RT-HIIT and AT-HIIT, with usual care (UC). After a 5-year follow-up, eligible participants were evaluated for the primary outcome of cancer-related fatigue (CRF) and secondary outcomes including quality of life, symptoms, muscle strength, cardiorespiratory fitness, body mass, physical activity, and sedentary behavior. Statistical analysis was conducted using linear mixed models adjusted for baseline values. Tumour profile and menopausal status were additionally adjusted for CRF. Mean differences (MD), 95% confidence intervals (CIs), and standardized effect sizes (ES) were reported. At the 5-year follow-up, there were no statistically significant differences in total CRF between the intervention groups and the UC group. RT-HIIT reported significantly reduced pain sensitivity at the gluteus MD = 79.00 (95% CI 10.17, 147.83, ES = 0.55) compared to UC. Clinically meaningful differences for an increase in cognitive CRF and cardiorespiratory fitness were observed for the AT-HIIT versus UC group, and for lower limb strength for the RT-HIIT versus UC group, albeit without statistical significance. Engaging in targeted exercise during adjuvant chemotherapy for breast cancer provides short-term benefits in reducing fatigue and maintaining physical function. However, our 5-year follow-up indicates that these effects are limited in the long term. This underscores the need to support breast cancer survivors maintain their PA levels throughout their survivorship journey., (© 2024. The Author(s).)

Background: Mobilization of certain immune cells may improve the ability of the immune system to combat tumor cells, but the effect of acute exercise on mobilizing immune cells has been sparsely investigated in cancer patients. Therefore, we examined how acute exercise influences circulating immune cells in breast cancer patients., Methods: Nineteen newly diagnosed breast cancer patients aged 36-68 performed 30 minutes of moderate-intensity exercise with a cycle ergometer. Blood samples were collected at various time points: at rest, at 15 (E15) and 30 minutes (E30) after onset of the exercise, and at 30 and 60 minutes post-exercise. We analyzed several immune cell subsets using flow cytometry., Results: Acute exercise increased the number of total leukocytes, neutrophils, lymphocytes, monocytes, basophils, total T-cells, CD4 + T-cells, T helper (Th) 2-cells, Th 17-cells, CD8 + T-cells, CD4 - CD8 - T-cells, CD56 + natural killer (NK) cells, and CD14 - CD16 + monocytes. Many of the changes were transient. Proportions of NK-cells and CD8 + T-cells increased, while the proportion of myeloid derived suppressor cells (MDSCs) reduced, and proportion of regulatory T-cells remained unchanged by exercise. Several associations were detected between cell mobilizations and disease state. For instance, tumor size correlated negatively with NK cell mobilization at E15, and progesterone receptor positivity correlated negatively with CD8 + T-cell mobilization., Conclusion: The findings show that the proportions of CD8 + T-cells and NK cells increased and the proportion of MDSCs proportion decreased in breast cancer patients after 30-minute exercise, suggesting a change in the profile of circulating immune cells towards more cytotoxic/anti-tumorigenic. The mobilization of some immune cells also appears to be related to the disease state., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Koivula, Lempiäinen, Neuvonen, Norha, Hollmén, Sundberg, Rundqvist, Minn, Rinne and Heinonen.)

Introduction: The possible beneficial effects of physical activity during doxorubicin treatment of breast cancer need further investigation as many of the existing studies have been done on non-tumor-bearing models. Therefore, in this study, we aim to assess whether short-term voluntary wheel-running exercise during doxorubicin treatment of breast cancer-bearing mice could induce beneficial cardiac effects and enhance chemotherapy efficacy. Methods: Murine breast cancer I3TC cells were inoculated subcutaneously to the flank of female FVB mice ( n = 16) that were divided into exercised and non-exercised groups. Two weeks later, doxorubicin treatment was started via intraperitoneal administration (5 mg/kg weekly for 3 weeks). Organs were harvested a day after the last dose. Results: The tumor volume over time was significantly different between the groups, with the exercising group having lower tumor volumes. The exercised group had increased body weight gain, tumor apoptosis, capillaries per cardiomyocytes, and cardiac lactate dehydrogenase activity compared to the unexercised group, but tumor blood vessel density and maturation and tumor and cardiac HIF1-α and VEGF-A levels did not differ from those of the non-exercised group. Discussion: We conclude that even short-term light exercise such as voluntary wheel running exercise can decrease the subcutaneous mammary tumor growth, possibly via increased tumor apoptosis. The increase in cardiac capillaries per cardiomyocytes may also have positive effects on cancer treatment outcomes., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Uurasmaa, Ricardo, Autio, Heinonen, Rundqvist and Anttila.)

T cells must adapt to variations in tissue microenvironments; these adaptations include the degree of oxygen availability. The hypoxia-inducible factor (HIF) transcription factors control much of this adaptation, and thus regulate many aspects of T cell activation and function. The HIFs are in turn regulated by oxygen-dependent hydroxylases: both the prolyl hydroxylases (PHDs) which interact with the VHL tumour suppressor and control HIF turnover, and the asparaginyl hydroxylase known as the Factor inhibiting HIF (FIH), which modulates HIF transcriptional activity. To determine the role of this latter factor in T cell function, we generated T cell-specific FIH knockout mice. We found that FIH regulates T cell fate and function in a HIF-dependent manner and show that the effects of FIH activity occur predominantly at physiological oxygen concentrations. T cell-specific loss of FIH boosts T cell cytotoxicity, augments T cell expansion in vivo , and improves anti-tumour immunotherapy in mice. Specifically inhibiting FIH in T cells may therefore represent a promising strategy for cancer immunotherapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Bargiela, Cunha, Veliça, Krause, Brice, Barbieri, Gojkovic, Foskolou, Rundqvist and Johnson.)

Importance: Many patients with post-COVID condition (PCC) experience persistent fatigue, muscle pain, and cognitive problems that worsen after exertion (referred to as postexertional malaise). Recommendations currently advise against exercise in this population to prevent symptom worsening; however, prolonged inactivity is associated with risk of long-term health deterioration., Objective: To assess postexertional symptoms in patients with PCC after exercise compared with control participants and to comprehensively investigate the physiologic mechanisms underlying PCC., Design, Setting, and Participants: In this randomized crossover clinical trial, nonhospitalized patients without concomitant diseases and with persistent (≥3 months) symptoms, including postexertional malaise, after SARS-CoV-2 infection were recruited in Sweden from September 2022 to July 2023. Age- and sex-matched control participants were also recruited., Interventions: After comprehensive physiologic characterization, participants completed 3 exercise trials (high-intensity interval training [HIIT], moderate-intensity continuous training [MICT], and strength training [ST]) in a randomized order. Symptoms were reported at baseline, immediately after exercise, and 48 hours after exercise., Main Outcomes and Measures: The primary outcome was between-group differences in changes in fatigue symptoms from baseline to 48 hours after exercise, assessed via the visual analog scale (VAS). Questionnaires, cardiopulmonary exercise testing, inflammatory markers, and physiologic characterization provided information on the physiologic function of patients with PCC., Results: Thirty-one patients with PCC (mean [SD] age, 46.6 [10.0] years; 24 [77%] women) and 31 healthy control participants (mean [SD] age, 47.3 [8.9] years; 23 [74%] women) were included. Patients with PCC reported more symptoms than controls at all time points. However, there was no difference between the groups in the worsening of fatigue in response to the different exercises (mean [SD] VAS ranks for HIIT: PCC, 29.3 [19.5]; controls, 28.7 [11.4]; P = .08; MICT: PCC, 31.2 [17.0]; controls, 24.6 [11.7]; P = .09; ST: PCC, 31.0 [19.7]; controls, 28.1 [12.2]; P = .49). Patients with PCC had greater exacerbation of muscle pain after HIIT (mean [SD] VAS ranks, 33.4 [17.7] vs 25.0 [11.3]; P = .04) and reported more concentration difficulties after MICT (mean [SD] VAS ranks, 33.0 [17.1] vs 23.3 [10.6]; P = .03) compared with controls. At baseline, patients with PCC showed preserved lung and heart function but had a 21% lower peak volume of oxygen consumption (mean difference: -6.8 mL/kg/min; 95% CI, -10.7 to -2.9 mL/kg/min; P < .001) and less isometric knee extension muscle strength (mean difference: -37 Nm; 95% CI, -67 to -7 Nm; P = .02) compared with controls. Patients with PCC spent 43% less time on moderate to vigorous physical activity (mean difference, -26.5 minutes/d; 95% CI, -42.0 to -11.1 minutes/d; P = .001). Of note, 4 patients with PCC (13%) had postural orthostatic tachycardia, and 18 of 29 (62%) showed signs of myopathy as determined by neurophysiologic testing., Conclusions and Relevance: In this study, nonhospitalized patients with PCC generally tolerated exercise with preserved cardiovascular function but showed lower aerobic capacity and less muscle strength than the control group. They also showed signs of postural orthostatic tachycardia and myopathy. The findings suggest cautious exercise adoption could be recommended to prevent further skeletal muscle deconditioning and health impairment in patients with PCC., Trial Registration: ClinicalTrials.gov Identifier: NCT05445830.

Objectives: To examine the associations between changes in cardiorespiratory fitness (CRF) in adulthood and prostate cancer incidence and mortality., Methods: In this prospective study, men who completed an occupational health profile assessment including at least two valid submaximal CRF tests, performed on a cycle ergometer, were included in the study. Data on prostate cancer incidence and mortality were derived from national registers. HRs and CIs were calculated using Cox proportional hazard regression with inverse probability treatment weights of time-varying covariates., Results: During a mean follow-up time of 6.7 years (SD 4.9), 592 (1%) of the 57 652 men were diagnosed with prostate cancer, and 46 (0.08%) died with prostate cancer as the primary cause of death. An increase in absolute CRF (as % of L/min) was associated with a reduced risk of prostate cancer incidence (HR 0.98, 95% CI 0.96 to 0.99) but not mortality, in the fully adjusted model. When participants were grouped as having increased (+3%), stable (±3%) or decreased (-3%) CRF, those with increased fitness also had a reduced risk of prostate cancer incidence compared with those with decreased fitness (HR 0.65, 95% CI 0.49 to 0.86), in the fully adjusted model., Conclusion: In this study of employed Swedish men, change in CRF was inversely associated with risk of prostate cancer incidence, but not mortality. Change in CRF appears to be important for reducing the risk of prostate cancer., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

The skeletal muscle and the immune system are heavily affected by the space environment. The crosstalk between these organs, although established, is not fully understood. This study determined the nature of immune cell changes in the murine skeletal muscle following (hindlimb) unloading combined with an acute session of irradiation (HLUR). Our findings show that 14 days of HLUR induces a significant increase of myeloid immune cell infiltration in skeletal muscle., (© 2023. The Author(s).)

Importance: Cardiorespiratory fitness (CRF) levels appear to be an important risk factor for cancer incidence and death., Objectives: To examine CRF and prostate, colon, and lung cancer incidence and mortality in Swedish men, and to assess whether age moderated any associations between CRF and cancer., Design, Setting, and Participants: A prospective cohort study was conducted in a population of men who completed an occupational health profile assessment between October 1982 and December 2019 in Sweden. Data analysis was performed from June 22, 2022, to May 11, 2023., Exposure: Cardiorespiratory fitness was assessed as maximal oxygen consumption, estimated using a submaximal cycle ergometer test., Main Outcomes and Measures: Data on prostate, colon, and lung cancer incidence and mortality were derived from national registers. Hazard ratios (HRs) and 95% CIs were calculated using Cox proportional hazards regression., Results: Data on 177 709 men (age range, 18-75 years; mean [SD] age, 42 [11] years; mean [SD] body mass index, 26 [3.8]) were analyzed. During a mean (SD) follow-up time of 9.6 (5.5) years, a total of 499 incident cases of colon, 283 of lung, and 1918 of prostate cancer occurred, as well as 152 deaths due to colon cancer, 207 due to lung cancer, and 141 deaths due to prostate cancer. Higher levels of CRF (maximal oxygen consumption as milliliters per minute per kilogram) were associated with a significantly lower risk of colon (HR, 0.98, 95% CI, 0.96-0.98) and lung cancer (HR, 0.98; 95% CI, 0.96-0.99) incidence, and a higher risk of prostate cancer incidence (HR, 1.01; 95% CI, 1.00-1.01). Higher CRF was associated with a lower risk of death due to colon (HR, 0.98; 95% CI, 0.96-1.00), lung (HR, 0.97; 95% CI, 0.95-0.99), and prostate (HR, 0.95; 95% CI, 0.93-0.97) cancer. After stratification into 4 groups and in fully adjusted models, the associations remained for moderate (>35-45 mL/min/kg), 0.72 (0.53-0.96) and high (>45 mL/min/kg), 0.63 (0.41-0.98) levels of CRF, compared with very low (<25 mL/min/kg) CRF for colon cancer incidence. For prostate cancer mortality, associations remained for low (HR, 0.67; 95% CI, 0.45-1.00), moderate (HR, 0.57; 95% CI, 0.34-0.97), and high (HR, 0.29; 95% CI, 0.10-0.86) CRF. For lung cancer mortality, only high CRF (HR, 0.41; 95% CI, 0.17-0.99) was significant. Age modified the associations for lung (HR, 0.99; 95% CI, 0.99-0.99) and prostate (HR, 1.00; 95% CI, 1.00-1.00; P < .001) cancer incidence, and for death due to lung cancer (HR, 0.99; 95% CI, 0.99-0.99; P = .04)., Conclusions and Relevance: In this cohort of Swedish men, moderate and high CRF were associated with a lower risk of colon cancer. Low, moderate, and high CRF were associated with lower risk of death due to prostate cancer, while only high CRF was associated with lower risk of death due to lung cancer. If evidence for causality is established, interventions to improve CRF in individuals with low CRF should be prioritized.