AIM:Indoles are tryptophan (Trp)-derived metabolites that are produced by the gut microbiota and may influence the gut-microbiota-brain axis in multiple sclerosis (MS). Indole-3-lactate (ILA) is reduced in persons with MS and improves MS clinical scores in animal models via its anti-inflammatory remyelinating properties. The ILA/indole-3-acetate (IAA) (ILA/AA) index is considered a neuroprotection index. Physical exercise and diet can modify gut microbiota and indole metabolism. METHODS:This secondary analysis of a randomized control trial aimed to assess the effects of acute and chronic exercise on serum indoles in relapsing-remitting MS (RRMS). Thirty-one RRMS patients (≥ 70% session attendance) completed a 10 week multimodal functional training (60 min, 3×/week) vs. a waitlist control group. Blood samples were collected at baseline and compared to a matched healthy control group, and after 10 weeks for the assessment of chronic effects. Additionally, acute effects of a single bout of exercise were assessed with a blood sample before, during, and immediately after one interim training session. Serum indole concentrations were measured using LC-MS/MS. RESULTS:Baseline indole levels in RRMS patients differed from those of matched healthy controls, and reduced ILA levels were observed. The 10 week intervention increased the ILA/IAA index, while a single exercise bout induced an increase in both ILA and ILA/IAA. CONCLUSION:Multimodal functional training over 10 weeks led to an improved ILA/IAA index suggesting a neuroprotective shift in gut microbiota composition, and a single bout acutely increases the circulating level of ILA. STUDY REGISTRATION NUMBER:DRKS00017091.

The positive effect of exercise on the immune system is widely acknowledged, but the molecular response of immune cells to exercise remains largely unknown. Here, we perform mass-spectrometry-based proteomic analysis on peripheral blood mononuclear cells (PBMC) at a depth of >6000 proteins. Comparing high-intensity interval exercise (HIIE) and moderate-intensity continuous exercise (MICE), matched for time and workload, we identify versatile changes in the proteomic makeup of PBMCs and reveal profound alterations, related to effector function and immune cell activation pathways within one hour following exercise. These changes are more pronounced after HIIE compared to MICE and occur despite identical immune cell mobilization patterns between the two exercise conditions. We further identify an immunoproteomic signature that effectively predicts cardiorespiratory fitness, thus allowing insights into potential exercise-triggered adaptations and immunological health benefits that are mediated by exercise. This study provides a reliable data resource that expands our knowledge on how exercise modulates the immune system, and delivers biological evidence supporting the WHO 2020 guidelines, which highlight exercise intensity as a relevant factor to maintain health.

Determining physiological stress at high resolution is crucial across diverse settings to enable informed decision-making in the context of health and disease. Saliva-based targeted multi-omics testing provides a powerful, non-invasive method to quantify physiological stress and circadian dynamics at high-frequency. In a laboratory crossover trial with 24-hour sampling comprising 413 saliva samples, we demonstrate high analytical reliability, distinct molecular individuality, and robust acute and delayed responses to physical exercise across proteins, metabolites, and lipids. Moreover, we present the most comprehensive existing dataset describing 24-hour molecular kinetics across these three omics layers. Leveraging this controlled setting, we applied machine learning to single-timepoint saliva samples to accurately predict recent physical exercise both immediately after and 24 hours later. Next, we translated this analytical framework to a real-world longitudinal setting of elite football players monitored over 16 months, comprising over 12,000 saliva samples. Despite increased biological and contextual variability, the model retained robust discrimination between exercise and rest on the following day. Based on prediction probabilities, we introduce a saliva-based internal strain metric, that captures internal load and can be harnessed to monitor physical exercise and recovery. Model robustness was further supported through out-of-sample validation using previously unseen observations. Our findings demonstrate that saliva-based targeted multi-omics reliably captures physical exercise and recovery states in both laboratory and real-world environments, providing a scalable framework for monitoring physical performance. This non-invasive approach holds broad potential for physiological monitoring and can serve as a blueprint for health- and disease-related contexts.

Cancer survivors frequently experience cancer-related cognitive impairment (CRCI), but the contributions of different anti-cancer therapies remain unclear. Patients with breast or gynaecological cancer were recruited before any anti-cancer treatment. Cognitive function was assessed by objective and subjective measures pre-treatment (T0), post-treatment (T1), and 1 year after T1 (T2). Objective measures include Hopkins Verbal Learning Test-Revised (HVLT-R), Trail Making Test (TMT), Controlled Oral Word Association Test (COWA), and Mnemonic Similarity Task (MST). Subjective measures include Functional Assessment of Cancer Therapy-Cognitive scale (FACT-Cog) and European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30). Linear mixed models were performed. Patients (n = 234) were of age 55.4 ± 11.6 years. At T1, chemotherapy was associated with worse visual searching and motor speed (TMT-A: β = 0.36, 95% CI: 0.03-0.69), perceived global function (FACT-Cog Global Function: β = -0.39, 95% CI: -0.67 to -0.11), and cognitive function (EORTC QLQ-C30: β = -0.50, 95% CI: -0.82 to -0.18) compared to endocrine therapy. At T2, endocrine therapy was associated with poorer verbal learning and memory performance (HVLT-R total recall: β = -0.40, 95% CI: -6 to -0.03) and higher perceived cognitive impairments (FACT-Cog PCI: β = 0.34, 95% CI: 0.05-0.63). In conclusion, CRCI may occur during certain types of chemotherapy but appears to ameliorate over time. Ongoing endocrine therapy may have longer-lasting impact on cognitive function. Appropriate counselling for informed decision making and good supportive care is needed.

BACKGROUND AND OBJECTIVES:Kynurenine pathway (KP) metabolites modulate inflammatory activity and neuronal viability. The consequences of KP imbalance partly resemble the molecular mechanisms of multiple sclerosis (MS). An improved understanding of KP imbalance and its relevance in MS requires holistic approaches beyond single-metabolite investigations. Thus, we aimed to explore the presence of KP metabolite patterns in MS and to evaluate their relevance in relation to participant characteristics and clinical measures. METHODS:In this multinational cross-sectional analysis, we determined serum concentrations of KP metabolites in persons with MS and healthy individuals using targeted metabolomics (LC-MS/MS). Analyses were conducted between March 24, 2022, and August 9, 2024. The source studies were conducted in Denmark, Germany, and Switzerland. All participants were aged 18 years or older and free of acute or chronic diseases besides MS. Persons with MS had mild to moderate disease severity (Expanded Disability Status Scale [EDSS] score ≤6.5). Following the investigation of individual metabolites, we explored KP metabolite patterns using exploratory factor analysis. Associations between KP metabolite patterns and participant characteristics, MS symptoms, and MRI metrics were investigated using correlation analyses, proportional odds regression, and multiple linear regression. RESULTS:The MS cohort included 353 participants (67.1% female) with a mean (SD) age of 46.1 (12.4) years. The mean (SD) EDSS score was 3.1 (1.8). The healthy control (HC) cohort included 111 participants (53.2% female) with a mean (SD) age of 45.7 (16.6) years. Persons with MS showed 2 distinct KP metabolite patterns: an inflammation-driven neurotoxic pattern (NeuroTox) and a neuroprotective pattern (NeuroPro). Greater NeuroTox was associated with a higher EDSS score, older age, and higher body fat percentage. Greater NeuroPro was associated with a lower EDSS score and higher cardiorespiratory fitness. DISCUSSION:Using a data-driven approach, we demonstrate the presence of 2 KP metabolite patterns, NeuroTox and NeuroPro, in MS. Greater NeuroTox and lower NeuroPro were both associated with greater disease severity. Future studies need to investigate the KP metabolite patterns across the MS disability spectrum and may use comparable approaches to investigate whether KP imbalance follows similar or disease-specific patterns in diseases other than MS. TRIAL REGISTRATION INFORMATION:NCT03322761, NCT02661555, NCT04762342, NCT04356248, DRKS00017091, DRKS00031445, DRKS00028792, DRKS00029105.

Low skeletal muscle mass and strength are common in patients with metastatic breast cancer (mBC) and have been associated with treatment toxicities and poor prognosis. The PREFERABLE-EFFECT study (NCT04120298) investigated exercise effects on body composition, muscle strength, and functional performance (secondary outcomes) in patients with mBC. Patients with mBC (n = 357) were randomized to a 9-month supervised aerobic, resistance and balance exercise program (EX) or control. Body composition (subset n = 66), lower body strength (subset n = 126), handgrip strength and functional performance were assessed at baseline, 3 and 6 months. Changes between groups were compared using linear mixed models for repeated measures. EX significantly increased whole body lean mass at 3 months (between-group difference = 0.79 kg, 95

Abstract Background The beneficial effects of exercise in cancer patients are increasingly understood, whereas the inclusion of structured oncological exercise as a standard of care remains a challenge. Herein, we evaluate the innovative, supervised Oncological Exercise Therapy (OTT) integrated into the standard of clinical care and report patient characteristics, exercise participation and attendance, and effects on patient-reported outcomes (PROs) and physical performance. Methods An observational study was conducted to analyze patient and exercise cohort data collected between 2012 and 2020 on the OTT. Cancer patients were encouraged to attend the personalized OTT intervention for a minimum of three months. Demographic, medical and treatment-related patient data were documented at enrollment. Exercise attendance was measured up to one year after enrollment, and exercise efficacy was evaluated between 6 and 24 weeks of exercise and included strength and endurance assessments and PROs on quality of life, fatigue, and psychosocial distress. Results Most of the n = 1660 enrolled patients (median age: 54 years [18–86]) were female (70%), diagnosed with breast cancer (40%), without metastasis (80%) and were receiving anticancer treatment (65%). One-third (32%) exercised for an average of 19 ± 10 sessions in a 19-week (± 13 weeks) period. Only 1% of patients reached the recommended average of ≥ 2 weekly sessions on the OTT. Older age and shorter travel distance were associated with increased exercise attendance. Exercise improved strength and endurance performance and PROs, indicating more pronounced effects in patients with greater exercise attendance. Conclusions Innovative exercise programs can be established as standard of cancer care in hospital settings. These real-world data suggest a beneficial effect of exercise in cancer patients on PROs and physical outcomes, with more pronounced effects in patients with greater exercise attendance. Therefore, strategies to increase exercise attendance appear crucial to maximize benefits derived from real-world exercise interventions in cancer patients.

Kynurenine pathway imbalance is a characteristic feature of multiple sclerosis (MS). Serum kynurenines contribute to latent factors reflecting a neurotoxic (NeuroTox) or neuroprotective pattern (NeuroPro). Previous single-metabolite studies show a favorable modulation of the kynurenine pathway by acute exercise, characterized by increased neuroprotective kynurenic acid. This study aims to investigate the acute and chronic effects of different exercise modalities on NeuroTox and NeuroPro. In this pooled analysis of randomized controlled trials, we followed four subcohorts of our previous work, in which we identified NeuroTox and NeuroPro. Serum concentrations of kynurenines were quantified by liquid chromatography-tandem mass spectrometry. Pattern stability was assessed by repeating exploratory factor analysis (EFA). Acute effects of a single session of combined strength-focused exercise (CE; FunTraiMS study) and chronic effects of exercise interventions, including CE (10 weeks; FunTraiMS study) and endurance exercise (3 weeks; HIITMS study and 24 weeks; EMSES and EXBRAIN studies), were evaluated using linear mixed-effects models. The four subcohorts included 273 participants (67.0% female; mean (SD) age: 44.5 (10.6) years). Repeated EFA resulted in similar factor loadings of serum kynurenines across subcohorts. CE induced an acute increase in NeuroPro (0.421, 95% CI [0.216, 0.626], p < 0.001) in FunTraiMS. Twenty-four-week endurance exercise induced a chronic decrease in NeuroTox (-0.432, 95% CI [-0.786, -0.080], p = 0.019) in EXBRAIN. NeuroTox and NeuroPro are temporally stable constructs. NeuroPro shows acute responsiveness to strength-focused exercise. NeuroTox may be chronically diminished by endurance exercise. Determinants and the clinical relevance of changes in NeuroTox and NeuroPro warrant further investigation.

BACKGROUND:Low circulating concentrations of B vitamins are linked to various chronic and neurodegenerative diseases. Notably, pyridoxal 5'-phosphate (vitamin B6) deficiency is linked to altered inflammatory responses and cellular immune function, both critical in multiple sclerosis (MS). Nevertheless, most MS research has focused on folate (vitamin B9) and vitamin B12, leaving other B vitamins understudied. OBJECTIVES:This secondary analysis investigated B-vitamin serum concentrations and related metabolites across MS phenotypes (primary progressive MS, relapsing-remitting MS, and secondary progressive MS) and disease severity levels. Additionally, the impact of endurance exercise on B-vitamin concentrations was investigated. METHODS:In total, 106 individuals with MS participated in a randomized controlled trial, including different endurance exercise conditions. Serum B-vitamin concentrations were analyzed in 99 participants before and after 3 wk of intervention. Before analysis, participants were dichotomized to 1 of the 2 disability groups based on their expanded disability status scale (EDSS) score: EDSS≥4.5 (n = 47, EDSS: 5.86 ± 0.56) and EDSS<4 (n = 52, EDSS: 3.59 ± 0.83). RESULTS:Higher EDSS scores were associated with lower pyridoxal 5'-phosphate (vitamin B-6) concentrations (rs: -0.32; 95% CI: -0.49, -0.12; P = 0.011), with the EDSS≥4.5 group also showing lower baseline pyridoxal 5'-phosphate (vitamin B6) concentrations (β: -0.18; 95% CI: -0.30, -0.07; P = 0.007) than the EDSS<4 group. Significant time × EDSS group interactions were evident for pyridoxal 5'-phosphate (vitamin B6; β: 0.05; 95% CI: 0.02, 0.08; P = 0.011), pyridoxal (vitamin B6; β: 0.05; 95% CI: 0.02, 0.09; P = 0.005), and riboflavin (vitamin B2; β: 0.06; 95% CI: 0.02, 0.09; P = 0.008), showing increases in these vitamers in the EDSS≥4.5 group postexercise. N1-Methylnicotinamide (vitamin B3; β: -0.11; 95% CI: -0.15, -0.06; P < 0.001) decreased in both groups over time. CONCLUSIONS:Disease severity is associated with distinct B-vitamin profiles in individuals with MS, although endurance exercise appears to modify specific B-vitamin concentrations. This trial was registered at clinicaltrials.gov as NCT04356248.

Nicotinamide adenine dinucleotide (NAD+) coenzymes are the central electron carriers in biological energy metabolism. Low NAD+ levels are proposed as a hallmark of ageing and several diseases, which has given rise to therapeutic strategies that aim to tackle these conditions by boosting NAD+ levels. As a lifestyle factor with preventive and therapeutic effects, exercise increases NAD+ levels across various tissues, but so far human trials are mostly focused on skeletal muscle. Given that immune cells are mobilized and redistributed in response to acute exercise, we conducted two complementary trials to test the hypothesis that a single exercise session alters NAD+ metabolism of peripheral blood mononuclear cells (PBMCs). In a randomized crossover trial (DRKS00017686) with 24 young adults (12 female) we show that acute exercise increases gene expression and protein abundance of several key NAD+ metabolism enzymes with high conformity between high-intensity interval training (HIIT) and moderate-intensity continuous training (MICT). In a longitudinal exercise trial (DRKS00029105) with 12 young adults (6 female) we confirm these results and reveal that - similar to skeletal muscle - NAD+ salvage is pivotal for PBMCs in response to exercise. Nicotinamide phosphoribosyltransferase (NAMPT), the rate-limiting enzyme of NAD+ salvage pathway, displayed a pronounced increase in gene expression during exercise, which was accompanied by elevated intracellular NAD+ levels and reduced serum levels of the NAD+ precursor nicotinamide. These results demonstrate that acute exercise triggers NAD+ biosynthesis of human PBMCs with potential implications for immunometabolism, immune effector function, and immunological exercise adaptions.

AIM:Recent pre-clinical evidence suggests that the tryptophan metabolite 3-hydroxyanthranilic acid (3-HAA) and the related enzyme activity along the kynurenine metabolic pathway (KP) are associated with lifespan extension. We aimed to translate these findings into humans and expose exercise training as a potential non-pharmacological intervention to modulate this metabolic hub. METHODS:To explore whether recent pre-clinical findings might also be of relevance for humans, we analyzed the evolutionary conservation of KYNU and HAAO, the two core KP enzymes associated with 3-HAA. In a cross-sectional analysis of young-to-middle-aged adults (N = 84), we examined potential associations of serum 3-HAA and its precursor anthranilic acid with age. We then investigated whether 26 weeks of endurance exercise (increasing intensity (INC) during the intervention period (n = 17) vs. conventional moderate continuous training (CON) matched for energy expenditure (n = 17)) impacted 3-HAA levels, related metabolic ratios, and other KP metabolites. RESULTS:We demonstrate that the core KP enzymes associated with 3-HAA are evolutionarily conserved in humans. Serum 3-HAA and its precursor anthranilic acid were consistently associated with age in young-to-middle-aged adults. Both exercise modes tested induced an increase in 3-HAA levels of 134% (p < 0.001) and 85% (p < 0.001) compared with baseline, respectively, without a significant time*group interaction effect. CONCLUSION:We translate the association between systemic 3-HAA levels and age from animal models into humans and highlight longer-term exercise training as an efficient strategy to boost systemic 3-HAA levels in middle-aged adults. Our findings open promising research avenues concerning the mediating role of 3-HAA in training adaptations, health, and longevity.

BACKGROUND:The biological foundation of changes in mental state after acute exercise is not yet understood, but it may be related to immunological alterations. The study investigated the hypothesis that the exercise-induced mobilization in circulating immune cells and cellular inflammation markers are associated with changes in the subjective mental state. As a secondary aim, the study investigated, wether the effects of the circulating immune cells are sex-dependent. METHODS:In a randomized cross-over trial, 24 young healthy adults (eight female; age 25.75 ± 4.35 years) completed a single exercise bout until exhaustion on a cycle ergometer and a passive control session. Outcomes were assessed immediately before, after the session, and 1 h, 3 h, 24 h, and 48 h after the session and comprise cell counts of leukocytes, lymphocytes, neutrophils and platelets, and the inflammation markers neutrophil-to-lymphocyte-ratio, platelet-to-lymphocyte-ratio and systemic-immune-inflammation-index as blood-based parameters, and subjective mental state measured using the Multidimensional-Mood-Questionnaire (MDMQ, subdomains mood, energetic arousal, calmness). RESULTS:There were significant time*group effects for all blood-based parameters (p < 0.001) and significant main effects of time for the MDMQ mood (p < 0.001) and energetic arousal (p = 0.008). No significant sex-dependent differences were obeserved. Within the intervention group, MDMQ energetic arousal showed significant correlations with lymphocytes (rrm=-0.41, p < 0.001), platelets (rrm=-0.28, p = 0.002), NLR (rrm=0.28, p = 0.002), PLR (rrm=0.33, p < 0.001), SII (rrm=0.269, p = 0.003) and MDMQ calmness showed significant correlations with leukocytes (rrm=-0.29, p = 0.002), lymphocytes (rrm=-0.36, p < 0.001), platelets (rrm=-0.30, p = 0.001), and PLR (rrm=0.25, p = 0.007). Within the control group, MDMQ mood showed significant correlations with lymphocytes (rrm=0.20, p = 0.031, NLR (rrm=-0.28, p = 0.002), PLR (rrm=-0.19, p = 0.033), SII (rrm=-0.24, p = 0.008) and MDMQ calmness showed significant correlations with PLR (rrm=-0.23, p = 0.011), SII (rrm=-0.20, p = 0.029). Fisher´s z-test revealed no significant difference between the correlations of the groups. CONCLUSION:Acute exhaustive exercise affects immune cells, inflammation markers, and the subjective mental state regardless of sex. The correlation between blood-based parameters and the MDMQ appears to be robust and indicates relevant psychoneuroimmune associations in the human body. However, the acute exercise intervention used in this study does not influence this association. CLINICAL TRIAL REGISTRATION NUMBER:DRKS00028792.

Background and ObjectivesKynurenine pathway (KP) metabolites modulate inflammatory activity and neuronal viability. The consequences of KP imbalance partly resemble the molecular mechanisms of multiple sclerosis (MS). An improved understanding of KP imbalance and its relevance in MS requires holistic approaches beyond single-metabolite investigations. Thus, we aimed to explore the presence of KP metabolite patterns in MS and to evaluate their relevance in relation to participant characteristics and clinical measures.MethodsIn this multinational cross-sectional analysis, we determined serum concentrations of KP metabolites in persons with MS and healthy individuals using targeted metabolomics (LC-MS/MS). Analyses were conducted between March 24, 2022, and August 9, 2024. The source studies were conducted in Denmark, Germany, and Switzerland. All participants were aged 18 years or older and free of acute or chronic diseases besides MS. Persons with MS had mild to moderate disease severity (Expanded Disability Status Scale [EDSS] score <= 6.5). Following the investigation of individual metabolites, we explored KP metabolite patterns using exploratory factor analysis. Associations between KP metabolite patterns and participant characteristics, MS symptoms, and MRI metrics were investigated using correlation analyses, proportional odds regression, and multiple linear regression.ResultsThe MS cohort included 353 participants (67.1% female) with a mean (SD) age of 46.1 (12.4) years. The mean (SD) EDSS score was 3.1 (1.8). The healthy control (HC) cohort included 111 participants (53.2% female) with a mean (SD) age of 45.7 (16.6) years. Persons with MS showed 2 distinct KP metabolite patterns: an inflammation-driven neurotoxic pattern (NeuroTox) and a neuroprotective pattern (NeuroPro). Greater NeuroTox was associated with a higher EDSS score, older age, and higher body fat percentage. Greater NeuroPro was associated with a lower EDSS score and higher cardiorespiratory fitness.DiscussionUsing a data-driven approach, we demonstrate the presence of 2 KP metabolite patterns, NeuroTox and NeuroPro, in MS. Greater NeuroTox and lower NeuroPro were both associated with greater disease severity. Future studies need to investigate the KP metabolite patterns across the MS disability spectrum and may use comparable approaches to investigate whether KP imbalance follows similar or disease-specific patterns in diseases other than MS.Trial Registration InformationNCT03322761, NCT02661555, NCT04762342, NCT04356248, DRKS00017091, DRKS00031445, DRKS00028792, DRKS00029105.

Exercise-driven alterations of the immune system are a key mechanism in the prevention and treatment of various diseases. Here, we performed mass spectrometry-based proteomics analysis on peripheral blood mononuclear cells (PBMCs) at a depth of >6000 proteins. Comparing time- and workload-matched high-intensity interval exercise (HIIE) and moderate-intensity continuous exercise (MICE) we discover versatile changes in the proteomic makeup of PBMCs and reveal profound alterations related to effector function and immune cell activation pathways within one hour after exercise. These changes were more pronounced after HIIE compared to MICE and occurred despite identical immune cell mobilization patterns between the two exercise conditions. We further identify an immunoproteomic signature that effectively predicts cardiorespiratory fitness. This study provides a reliable data resource that expands our knowledge on how exercise modulates the immune system, and delivers biological evidence supporting the WHO 2020 guidelines, which highlight exercise intensity as a relevant factor to maintain health. ### Competing Interest Statement The authors have declared no competing interest. ### Clinical Trial DRKS00017686 ### Funding Statement This study received internal funding by the German Sport University Cologne. ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB of the German Sport University Cologne gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes All data produced in the present work are contained in the manuscript or available online.

Functional exercise training focuses on enhancing the body’s capacity for everyday movements by targeting a combination of strength, stability, balance, coordination, and flexibility. More flexible and less standardized exercise approaches, such as functional exercise training, may offer further benefits on improving symptoms in persons with MS (pwMS), but they have been less investigated. This review aims to provide a comprehensive overview of the existing literature on the effects of functional exercise training on functional outcomes (mobility, walking capacity, balance, and proprioception), physical (strength and endurance) and physiological performance measures, as well as patient-reported outcomes (Quality of Life, Fatigue) in pwMS. The systematic review was conducted according to the PRISMA guidelines. Literature searches were conducted in Medline (PubMed) and Cochrane CENTRAL (inception to 19th February 2025). We included studies investigating the effects of functional exercise training on any outcome in adult pwMS. The quality and reporting were evaluated using the Tool for the assEssment of Study qualiTy and reporting in EXercise (TESTEX). A total of 19 studies were included in the review, ranging from smaller pilot studies to larger randomized controlled trials. Interventions lasted between six and 16 weeks. Results of the studies included in this review were highly heterogeneous. Some of the included studies have demonstrated improvements in mobility, short and long walking capacity, balance, strength, and endurance measures as well as on quality of life and fatigue. Adherence to training was poorly reported. Functional exercise training for pwMS is a comprehensive approach to achieving functional improvements, strength gains, and improved endurance simultaneously, thereby promoting beneficial health effects. In future, a clear definition of functional exercise training is required, research should focus on the consistent reporting of treatment adherence, and investigate the long-term effects of functional exercise training in pwMS. PROSPERO registration number: CRD42023448077.

Background A vegan diet is frequently associated with a health-conscious lifestyle and has become increasingly adopted by athletes. However, empirical evidence regarding its impact on athletic performance and health—particularly in young female athletes—remains limited. This study aimed to investigate the effects of a vegan dietary pattern on health markers, immune function, body composition, and physical performance. Methods In a 12-week randomized controlled two-arm trial, 22 young female athletes were assigned to follow either a vegan or an omnivorous diet. Blood samples, body composition, and performance metrics were assessed at baseline and at four-week intervals. A certified nutritionist and medical personnel supervised the intervention. Results Significant between-group differences were found in total energy intake, macronutrient distribution, and micronutrient consumption. The vegan group consumed significantly less energy (p = 0.011), protein (p = 0.007), essential amino acids (p = 0.010) including L-leucine (p = 0.005), calcium (p = 0.002), and vitamin B12 (p < 0.001), but had higher intakes of carbohydrates (p = 0.011), sugar (p = 0.028), and iron (p = 0.004). While no significant differences were observed in lipid profile, liver and kidney function, or sex hormones, a significant group difference was observed for iron concentration after 12 weeks (p = 0.019). In terms of body composition, the vegan group showed a significant reduction in body weight (p < 0.001) and BMI (p = 0.004), with no differences in fat-free mass, skeletal muscle mass, or fat mass. Performance measures revealed a significant decrease in 1-RM squat performance in the vegan group (p = 0.031), along with group differences at weeks 4 (p < 0.05 and 8 (p < 0.05) in relative squat performance. A significant difference in squat jump performance was also noted at week 4 (p < 0.05). Conclusion A non-matched vegan diet may impair strength-related performance and reduce iron status in young female athletes, underscoring the need for carefully structured nutritional planning to ensure adequate energy as well as macro- and micronutrient intake. German Clinical Trials Register (DRKS00031633)

ABSTRACT Background Cancer‐related cognitive impairment (CRCI) is a frequent and burdensome problem that is still insufficiently understood and managed. We investigated subjective and objective measures of CRCI, as recommended by the International Cancer and Cognition Task Force (ICCTF) in cancer patients prior to systemic or radiation therapy with respect to potential influencing or associated psychosocial, demographic, or lifestyle factors. Methods Female patients with breast or gynecological tumors (n = 239, mean age = 55.5, SD = 11.6) prior to any systemic or radiation therapy completed validated subjective (FACT‐Cog: perceived cognitive impairment [PCI], perceived cognitive ability [PCA], impact on quality of life [IQoL]) and objective measures of CRCI (Trail Making Test [TMT‐A and ‐B], Controlled Oral Word Association Test [COWA], and Hopkins Verbal Learning Test‐Revised [HVLT‐R]). Association with cross‐sectionally assessed age, body mass index, education, smoking, alcohol intake, sleep problems, social support, anxiety, and pain was investigated using multiple linear regression models. Results A quarter (25.1%) of patients showed indication for CRCI based on the PCI score. Subjective and objective CRCI measures showed no or only weak correlations, also when adjusting for age and education (partial Spearman correlations with each other, all |r| ≤ 0.21). Anxiety, sleep problems, and pain were significantly associated with low subjective cognitive function (PCI, PCA, and IQoL). Poor objective cognitive values (TMT, COWA, and HVLT‐R) were mainly determined by higher age and lower education. Conclusions Cancer‐related cognitive impairment is not solely (chemo‐)therapy‐induced but may be triggered or influenced by anxiety, sleep problems, and pain. Addressing these issues early in the treatment phase could potentially alleviate perceived CRCI. The ICCTF‐recommended neuropsychological tests do not adequately capture this CRCI prior to systemic or radiation therapy, but could serve as complementary tools to monitor cognitive changes over time, independent of psychosocial influences.

Background: Multiple Sclerosis (MS) represents a neuroinflammatory autoimmune disease characterized by the predominance of circulating T cell subsets with proinflammatory characteristics and increased central nervous system (CNS)-homing potential. Substantial evidence confirms various beneficial effects of chronic exercise interventions in MS, but it is unknown how long-term multi-modal intense exercise affects MS-associated lymphocytes that are commonly targeted by medication in persons with relapsing remitting MS (pwRRMS). Methods: A total of 45 participants with defined RRMS were randomized to either the exercise (n = 22) or passive waitlist-control group (n = 23). A 10-week intervention consisting of progressive resistance and strength-endurance exercises was applied (3x/week & agrave; 60 min). Blood was drawn before (T-1) and after (T-2) the intervention period. Flow cytometry was used for phenotyping lymphocyte subsets. Results: Relative protein expression of CD49d within CD8(+) T cells, quantified via mean fluorescence intensity (MFI), is significantly associated with the Expanded Disability Status Scale (p = 0.007, r = 0.440), decreased in the exercise group (p = 0.001) only, and was significantly lower in the exercise compared to the control group at T-2 (p < 0.001). T helper (Th) 17 cell frequency decreased only in the exercise group (p < 0.001). CD8(+)CD20(+) T cell frequency was significantly lower in the exercise compared to the control group at T-2 (p = 0.003), without showing significant time effects. Conclusion: The 10-week multimodal exercise intervention mainly affected circulating T cells harboring a pathophysiological phenotype in MS. The findings of a decreased frequency of pathogenic Th17 cells and the reduced CNS-homing potential of CD8(+) T cells, indicated by reduced CD49d MFI, substantiate the positive effects of exercise on cellular biomarkers involved in disease activity and progression in MS. To confirm exercise-mediated beneficial effects on both disease domains, clinical endpoints (i.e., relapse rate, lesion formation, EDSS score) should be assessed together with these cellular and molecular markers in studies with a larger sample size and a duration of six to twelve months or longer.

Acute exercise increases energy demand in skeletal muscle and releases metabolic intermediates into circulation, yet the serum kinetics of exercise-mobilized metabolites remain poorly characterized. By applying high-frequency serial blood sampling and targeted metabolomics in a longitudinal exercise trial with 12 young, healthy adults (6 females, 6 males), we assessed temporal alterations in energy-related metabolites during acute aerobic exercise and after 1 h of recovery. We provide evidence for 42 exercise-responsive metabolites, including end products of glycolysis, tricarboxylic acid cycle intermediates, ketone bodies, and amino acids. Overall, the observed metabolic alterations closely resembled skeletal muscle energy metabolism, thereby refining fundamental principles of exercise biochemistry through detailed serum kinetics, including novel, so far uncharacterized responses in systemic energy homeostasis and interorgan crosstalk.NEW & NOTEWORTHY In our study, we provide detailed serum kinetics of energy-related metabolites during acute aerobic exercise and after 1 h of recovery. Semantic interpretation of our results against the backdrop of fundamental principles of exercise biochemistry indicate that serum metabolites mirror skeletal muscle energy metabolism, thus providing new insights into systemic energy homeostasis and interorgan crosstalk.