Heart transplant recipients exhibit reduced exercise tolerance and persistently diminished aerobic capacity despite exercise training. Exercise tolerance depends on integrated oxygen transport and utilization, which are impaired in heart transplant recipients. We synthesize evidence supporting that the combined effects of impaired pulmonary gas exchange, reduced haemoglobin concentration, heart denervation, chronic calcineurin inhibition, decreased muscle capillary density, and detraining from limited physical activity contribute to: (1) reduced pulmonary diffusion and alveolar ventilation-perfusion mismatch that contribute to hypoxemia and increased ventilatory demand; (2) impaired convective oxygen delivery due to anaemia and to heart denervation that limits cardiac output; (3) deficits in endothelial function and reduced muscle capillarization that contribute to diminished convective and diffusive oxygen transport within skeletal muscle. Using Wagner's model, which describes oxygen transport from the atmosphere to muscle mitochondrion, we develop the hypothesis that the persistent reduction in aerobic capacity in heart transplant recipients reflects the combined and interactive effects of impaired convective oxygen transport and reduced muscle oxygen diffusive capacity, rather than a single dominant limitation. This basis generates testable physiological targets for interventions aimed at improving functional capacity after transplantation.

Exogenous ketosis induced by ketone ester (KE) ingestion has attracted growing interest as a potential strategy to enhance physiological tolerance to reduced O2 availability. Reported benefits arise largely from KE-induced hyperventilation, which can improve systemic and tissue oxygenation during altitude exposure and hypoxic exercise, potentially complemented by favourable effects on cellular bioenergetics. Whether these responses translate to breath-hold diving, however, remains unknown. Breath-hold performance is constrained by the integrated effects of progressive hypoxaemia, CO2 accumulation, acid-base disturbance, altered cerebrovascular regulation and chemoreflex-mediated respiratory drive. Because ventilation ceases during apnoea, interventions that alter pre-apnoeic acid-base status or CO2 signalling might modify the chemical, neural and perceptual stimuli underlying the urge to breathe without slowing O2 depletion. Safety therefore depends not only on preserving cerebral O2 delivery, but also on maintaining the chemoreflex and perceptual warning signals that ordinarily precede hypoxic loss of consciousness. This review evaluates whether the established physiological effects of KE are mechanistically compatible with the unique demands of apnoea, focusing on acid-base regulation, CO2-dependent cerebrovascular control, autonomic integration and training-related adaptations in elite freedivers, including reduced chemoreflex sensitivity and enhanced cortical control of respiratory drive. We propose that benefits observed during maintained ventilation might not translate to breath-hold diving and could create a mechanistic mismatch with uncertain consequences for performance and safety. Direct apnoea-specific studies are required to determine whether KE supplementation is beneficial, neutral or harmful.

Abortion aetiology is critically linked to increased myometrial contractions and maternal psychological stress. Given the limited efficacy of current therapies such as progesterone, investigating novel therapeutic interventions is essential. Melatonin exerts reproductive benefits. Agomelatine stands out as an agent that exerts antidepressant effects through serotonin receptor (5-HT2C) antagonism in addition to its potent melatonergic activity. Furthermore, agomelatine inhibits myometrial contractions. In this context, this study investigates agomelatine's therapeutic potential in an abortion model across behavioural, biochemical and histological parameters. Eighty female Sprague-Dawley rats were randomized into eight groups: control, sham, abortion, melatonin (M), agomelatine (A), progesterone (P) and combinations (MP, AP). Following pregnancy (Day 0), oral treatments were administered daily for 14 days. Abortion was induced via mifepristone on Day 11. Depressive-like behaviours were assessed using a forced swimming test on Day 13. The next day, rats were sacrificed for serum hormone analysis and uterine histological evaluation. The forced swimming test showed shorter immobility time in the AP group compared to the abortion group. An enzyme-linked immunosorbent Assay revealed lower serum prostaglandin F2α level in the AP group and lower serum oxytocin levels in the M, A, MP and AP groups versus the abortion group. Histologically, M, A, P, MP and AP groups exhibited higher scores for complete fetus, decidual congestion, decidual inflammation and cytotrophoblast-syncytiotrophoblast cells compared to the abortion group. Additionally, the abortion group showed higher decidual necrosis than controls. In conclusion, agomelatine-containing protocols demonstrated restorative effects in abortion across behavioural, biochemical and histological parameters. These effects of agomelatine provide a new perspective on the currently limited options for treatment of abortion.

Sedentary behaviour is increasingly recognized as a risk factor for systemic disorders; however, its effects on male reproductive health and penile tissue integrity remain insufficiently understood. Furthermore, the therapeutic role of whole-body vibration (WBV) has not been investigated. This study evaluated the effects of sedentary behaviour on testicular and penile tissues and examined whether WBV could attenuate these alterations. We hypothesized that sedentary behaviour would impair spermatogenesis and penile tissue integrity, whereas WBV would attenuate these effects. Thirty-two male Wistar rats were randomized into four groups (n = 8/group): Control, Sedentary, Sedentary+WBV and WBV. Sedentary conditions were induced for 28 days via a reduced-cage model, with daily WBV application (45 Hz, 3 mm). Serum testosterone, sperm parameters, testicular histology and penile smooth muscle-to-collagen ratio were assessed. Sedentary behaviour impaired spermatogenesis, with lower Johnsen scores (P = 0.008), reduced sperm concentration (P = 0.006) and motility (P < 0.001), and increased morphological abnormalities (P < 0.001). It also reduced the penile smooth muscle-to-collagen ratio (P < 0.001), indicating adverse structural remodelling in erectile tissue. In sedentary animals, WBV attenuated several alterations, preserving sperm quality and cavernosal smooth muscle content. However, WBV alone impaired spermatogenesis and increased sperm morphological abnormalities in non-sedentary animals. Serum testosterone levels did not differ significantly. In conclusion, prolonged sedentary behaviour impaired male reproductive indices and induced adverse structural remodelling of penile tissue in male rats. WBV showed context-dependent effects, attenuating alterations under sedentary conditions while showing adverse associations in non-sedentary animals. These findings warrant further translational investigation into the context-dependent effects of WBV on male reproductive and penile tissues.

Epilepsy is characterized by the occurrence of at least two unprovoked seizures occurring more than 24 h apart, reflecting a predisposition to recurrent epileptic events. The role of dietary amino acids (AAs) in epilepsy is not clearly understood. To the best of our knowledge, this study is the first to investigate the link between the odds of developing epilepsy and dietary AA patterns. This cross-sectional study, derived from the Prospective Epidemiologic Research Studies in Iran (PERSIAN) Sabzevar Cohort Study, included 112 individuals diagnosed with prevalent epilepsy and 3951 participants without epilepsy. Dietary intake was estimated using a validated semi-quantitative food frequency questionnaire. Principal component analysis was applied to identify two distinct dietary AA patterns: one predominantly derived from animal sources and the other from plant food sources. Participants with epilepsy were more likely to be male, have lower levels of education, be married, be unemployed and also to exhibit lower intakes of all assessed AAs. In the fully adjusted model, no significant association was observed between the animal AA pattern and the odds of having epilepsy (odds ratio (OR) (Q4 vs. Q1): 0.62, 95% CI: 0.35-1.08, P = 0.094), although the P-value for trend across quartiles was statistically significant (Ptrend = 0.002). By contrast, higher adherence to the plant AA pattern was associated with 63% lower odds of having epilepsy (OR (Q4 vs. Q1): 0.37, 95% CI: 0.20-0.67, P = 0.001). The P-value for trend across quartiles was significant (Ptrend = 0.001). In conclusion, greater adherence to the plant-based AA pattern was associated with lower odds of having epilepsy. These findings may inform dietary strategies, but prospective studies are needed to determine whether these associations reflect a causal relationship.

Acute mountain sickness (AMS) affects many individuals ascending to high altitude annually, carrying potential morbidity and mortality risks (e.g., high-altitude cerebral oedema). The objective of this pilot study was to record overnight pulse oximetry during ascent to 4554 m and determine whether: (1) extracted overnight biomarkers had any relationship to AMS; and (2) AMS at 4554 m could be predicted by oximetry biomarkers using classification models trained/validated on overnight data from lower altitudes. Twenty lowlanders (five females, 36.8 ± 18.5 years old) completed a 4 day ascent to 4554 m, where AMS status was determined by clinical examination. Oximetry was recorded continuously each night, with >40 biomarkers extracted and compared between AMS and non-AMS. Exploratory classification models (5-fold cross-validation) were tested for nightly data with a systematic approach to feature selection. Model performances were evaluated based on predictions of AMS at 4554 m. A significant effect of ascent was observed for many overnight biomarkers; however, no effect of AMS status was evident, nor were any differences observed between AMS and non-AMS for any overnight biomarkers during ascent. AMS at 4554 m was most accurately predicted from overnight recordings collected at 2600 m (accuracy, 100%; true positive rate, 100%) and 3647 m (accuracy, 80%; true positive rate, 90.9%) using k-nearest neighbour and support vector machine classification models. Biomarkers were extracted from overnight oximetry recordings, with limited differences observed between AMS and non-AMS. In conclusion, AMS at 4554 m can be predicted from overnight oximetry using machine learning; however, these preliminary findings need confirmation in a larger cohort, with additional investigation into the most clinically relevant biomarkers.

The separation of measured arterial pressure into a reservoir pressure and an excess pressure was introduced over 20 years ago as a heuristic hypothesis. Since then it has gained some traction through epidemiological studies that show that various measures of reservoir and excess pressure are independent risk factors for cardiovascular disease. We demonstrate that a two-time asymptotic analysis of the 1-D conservation equations in each artery coupled with the separation of the arteries into inviscid and viscid arteries, based on their resistance or drag coefficients, results in a formal derivation of the reservoir pressure. The most important result of this analysis is that flow in the arteries can be considered quasi-steady during every interval on the slow time scale. The slow-time conservation equations involve a drag coefficient that models the effect of viscosity on the flow. We separate the arteries into the larger inviscid arteries where viscosity is negligible and the smaller viscid arteries where it is not. The slow time pressure in the inviscid arteries is shown to be spatially uniform but varying in time. We identify this pressure as the reservoir pressure. Dynamic analysis using mass and energy conservation in the inviscid arteries shows that the reservoir pressure accounts for the storage of potential energy by the distension of the elastic inviscid arteries during early systole and its release during late systole and diastole. This analysis thus provides a formal derivation of the reservoir pressure and ascribes its physical meaning.

Volumetric muscle loss (VML) is a traumatic skeletal muscle injury characterized by chronic functional impairments in the affected muscle and adjacent uninjured bone. Rehabilitative strategies aimed at restoring limb function following VML, including voluntary running, have shown limited efficacy and in some cases have been detrimental. One potential explanation is disproportional loading of the uninjured contralateral limb during running, but evaluation of unilateral weight-bearing following VML has not been explored. This study was designed to evaluate if the limited response to rehabilitation following VML could be explained by limb loading asymmetry. Twelve-week-old C57Bl/6J mice (n = 24; equal males/females) were randomized to three groups: Naïve-Run, VML, and VML-Run. Two weeks post-VML, mice in running groups were provided free access to wheels for 6 weeks. Weight-bearing asymmetry was assessed before injury and biweekly thereafter. Terminally at ∼20 weeks of age, in vivo muscle function was evaluated, and muscles and bones were saved for analyses. Prior to injury, no difference in weight-bearing asymmetry was observed across groups. VML-injured mice exhibited similar weight-bearing asymmetries prior to running. Following 6 weeks of running, VML-Run mice regained weight-bearing symmetry comparable to Naïve-Run. Despite this, remaining muscle function remained persistently impaired following VML injury. Collectively this works suggests that voluntary running promotes favourable weight-bearing adaptations following VML, but does not improve muscle function or the mechanical properties of the adjacent bone.

Muscle strength is a key predictor of physical functioning, yet the influence of patient and treatment factors on muscle properties in young people with cerebral palsy is not fully known. We explored whether medial gastrocnemius properties vary by age, ambulatory status and spasticity treatment (botulinum toxin or selective dorsal rhizotomy). In this exploratory cross-sectional study, microbiopsies of the medial gastrocnemius were obtained from 16 children (6-17 years of age) with cerebral palsy. Outcomes included muscle thickness, collagen content, myofibre cross-sectional area, capillaries, myofibres with centrally located nuclei, lipid area, satellite cell density and myosin heavy chain myofibre type. Myofibre cross-sectional area (P = 0.02) and myofibres with centrally located nuclei (P = 0.02) were positively correlated with age. Non-ambulatory individuals had smaller myofibre cross-sectional area (P = 0.02). The number of botulinum toxin injections was associated with more capillary contacts per myofibre (P = 0.04). Selective dorsal rhizotomy was not associated with any statistically significant findings. Preliminary data suggest that gastrocnemius muscle properties might vary across patient factors and spasticity treatment history. Confirmatory prospective studies with matched control groups are needed to evaluate properly the effects of age, ambulatory status, botulinum toxin and selective dorsal rhizotomy.

Liver cirrhosis imposes a substantial global burden, with complications driving high mortality. Diet is pivotal in managing liver disease progression and cirrhosis-related death. This study investigated associations between total fat intake, specific dietary fatty acid subclasses and all-cause mortality in cirrhotic patients. In this prospective cohort study, 121 ambulatory patients with recently diagnosed cirrhosis (≤6 months) were enrolled. Baseline dietary intake was evaluated via a validated 168-item semi-quantitative food frequency questionnaire. Participants were categorized into tertiles by total fat and fatty acid subclasses: saturated (SFA), monounsaturated (MUFA), polyunsaturated (PUFA), omega-3 and omega-6 fatty acids. Cox proportional hazards models computed hazard ratios (HRs) and 95% confidence intervals (CIs), adjusted sequentially for age, sex, energy intake, BMI, smoking, alcohol use, cirrhosis aetiology, MELD score and Child-Pugh class. During the 60-month follow-up, 50 deaths (41.3%) occurred. In fully adjusted models, highest versus lowest tertiles of total fat intake (HR = 6.69; 95% CI: 1.37-13.34; P-trend = 0.017), SFA intake (HR = 8.2; 95% CI: 1.33-20.53; P-trend = 0.014) and PUFA-6 intake (HR = 5.24; 95% CI: 1.1-26.44; P-trend = 0.014) were independently associated with significantly elevated mortality risk. No significant associations were observed for MUFA, total PUFA or PUFA-3 intake. Kaplan-Meier analyses confirmed significantly reduced 5-year survival with higher total fat (log-rank P = 0.003) and SFA intake (log-rank P < 0.001). In this exploratory prospective cohort study, higher intakes of total fat, saturated fatty acids and omega-6 polyunsaturated fatty acids were associated with increased all-cause mortality among patients with cirrhosis. These preliminary findings are hypothesis-generating and require confirmation in larger, adequately powered prospective studies.