Infantile epileptic spasms syndrome (IESS) is characterized by epileptic spasms (ES) in infants and hypsarrhythmia on EEG. High-frequency oscillations (HFOs), defined as oscillatory events at >80 Hz, reflect rapid spatiotemporal dynamics of cortical activity and might serve as novel biomarkers for epilepsy. In this study, we investigated the association among hypsarrhythmia, ES and scalp HFOs in IESS, focusing on their spatiotemporal and morphological characteristics. We analysed scalp EEG recordings from 22 paediatric patients with IESS (12 males; age range, 0-12 years), classified into four groups: hypsarrhythmia with ES; hypsarrhythmia without ES; multifocal interictal epileptiform discharges (IED); and non-multifocal IED. The proportions of EEG recordings with at least one detected scalp HFO differed significantly among the groups, being 100.0% in hypsarrhythmia with ES, 90.9% in hypsarrhythmia without ES, 36.0% in multifocal IED and 29.4% in non-multifocal IED (P < 0.001). Age-adjusted odds ratios [95% confidence intervals] for high HFO detection rates were significantly greater in the hypsarrhythmia groups than in the IED groups (with ES, 24.66 [4.86-125.10], P < 0.001; and without ES, 8.38 [1.94-36.20], P = 0.004). Receiver operating characteristic analysis showed that scalp HFO detection rates discriminated ES activity with an area under the curve of 0.92, 100% sensitivity and 77.4% specificity. Compared with the IED groups, the hypsarrhythmia groups exhibited lower-frequency HFOs, with the lowest HFO frequencies being observed in the hypsarrhythmia with ES group. These findings suggest that the spatiotemporal and morphological characteristics of scalp HFOs might provide complementary multidimensional biomarkers for hypsarrhythmia and assessing ictal states in IESS.

The striatum is a brain region within the basal ganglia that plays a crucial role in generating behaviour and mediating perception. The tail striatum (TS) is a poorly understood striatal domain with predominantly sensory functions. Recent evidence supports that abnormal TS dopamine transmission in dopaminergic disease contributes to sensory symptoms by dysregulating TS medium spiny neurons (MSNs). Importantly, the ventral TS is segregated into medial, intermediate and lateral divisions in which TS-MSNs express D1 and D2 dopamine receptors unevenly, but the functional significance of this is unclear. We aimed to gain insight into the functional significance of this organisation and to investigate how TS-MSNs are modulated by dopamine. We used whole-cell patch clamping in rat (P45-55, both sexes) brain slices to conduct the first in-depth electrophysiological characterisation of TS-MSNs and compared them across divisions. The adjacent dorsolateral striatum (DLS) was included for comparison. We also investigated how bath-applied dopamine and selective dopamine agonists SKF38393 and quinpirole modulate MSNs in each region. We found that TS-MSNs are electrophysiologically distinct from DLS-MSNs, reflecting the established functional differences between these domains. TS-MSNs were more depolarised than DLS-MSNs at rest and had lower rheobase. We also identified functional heterogeneity across the TS divisions. The intermediate division had higher rheobase than the medial or lateral divisions. At rheobase, lateral division TS-MSNs showed higher firing frequencies than medial or intermediate division TS-MSNs. Finally, TS-MSNs showed weaker modulation by dopamine, SKF38393 and quinpirole than DLS-MSNs, which was also uneven across divisions. These data provide a novel electrophysiological characterisation of TS-MSNs, showing they are functionally distinct from DLS-MSNs and heterogeneous across divisions, which could have implications for dopaminergic diseases.

High-altitude hypoxia elicits several profound physiological responses, including substantial increases in muscle sympathetic nerve activity (MSNA); however, the association of this heightened MSNA with cardiovascular and cerebrovascular haemodynamics remains unclear in lowlanders and indigenous highlander populations. We hypothesized that at high altitude resting MSNA would be associated with resting cardiovascular and cerebrovascular haemodynamics in lowlanders (n = 26), and Sherpa (n = 8) and Andean (n = 23) indigenous highlanders. Data were retrospectively analysed from two separate high-altitude expeditions to Nepal (2016; 5050 m) and Peru (2018; 4300 m). We assessed resting MSNA via radial or peroneal microneurography, and measured S p O 2 , heart rate, mean arterial pressure, brachial artery blood flow and endothelial function, and internal carotid and vertebral artery diameter, velocity, and blood flow. Resting MSNA demonstrated limited, population-specific associations with vascular haemodynamics. Lowlanders showed the most consistent relationships, including positive associations between MSNA and heart rate, vertebral artery diameter and blood flow, and internal carotid artery velocity, while Sherpa and Andean highlanders showed few systemic or cerebrovascular associations with MSNA. No relationship was observed between MSNA and S p O 2 , brachial artery blood flow or endothelial function across populations. Sensitivity analysis confirmed that most directional relationships were robust to the removal of influential participants, although some associations, including the negative relationship between MSNA and brachial artery blood flow in Sherpa, were attenuated. These data highlight that single time-point, resting MSNA may have limited predictive value for cardiovascular and cerebrovascular haemodynamics at high altitude within these specific populations; however, these data should be interpreted with caution, given the small cross-sectional sample sizes.

During glucose uptake into muscle, GLUT-4 can translocate with stimulus from insulin or muscle contraction via exercise, but some exercise-intolerant populations are unable to benefit from improved glycaemic control. We investigated how passive movement training (PMT) and passive movement training with blood flow restriction (PMT+BFR) could be used as an alternative method. The effects on blood lactate and insulin were also investigated. Eleven healthy males (26.9 ± 8.3 years, 25.7 ± 2.1 kg/m[2]) undertook a crossover trial of three 150-min treatments, control (CTRL), PMT and PMT+BFR, on three separate study visits, separated by ≥24 h. Each participant arrived fasted and consumed a standardised high-carbohydrate meal (522 kcal, 112.5 g carbohydrate). The PMT protocol involved 30 min of intermittent bilateral knee extension/flexion (1 min:1 min work/rest) at an angular velocity of 180°/s through an 80° range of motion. PMT+BFR used a pressure calibrated at 80% arterial occlusion. Blood glucose and lactate were measured every 5 min, with insulin at 0, 30 and 60 min. Acute changes in muscle thickness were recorded using ultrasound pre- and post-intervention. There were no significant differences between the treatment groups for mean glucose (CTRL: 4.59 ± 0.48, PMT: 4.88 ± 0.82, PMT+BFR: 4.51 ± 0.90 mmol/L; P = 0.498). A statistically significant acute difference of muscle thickness (P = 0.00420) from pre- to post-treatment was detected in PMT+BFR. While PMT did not improve postprandial glycaemia with or without BFR, the acute increase in muscle thickness after PMT+BFR suggests that it may be useful in other applications.

M. Bashir, A. Murtada, M. Jubouri, A. Bashir, I. Williams, and D. Bailey, "Surgery in Space: The Ultimate Frontier," Experimental Physiology (2025): EP092765, 10.1113/EP092765. The above article, published online on 10 June 2025 in Wiley Online Library (wileyonlinelibrary.com), has been retracted by the Physiological Society and John Wiley & Sons Ltd., with the agreement of all authors. Following publication, concerns were raised by a third party that one of the references in the article could not be verified. A subsequent investigation by the editors found that 12 out of 23 citations could not be substantiated as they were presented in the published article. As a result, The Physiological Society and John Wiley & Sons Ltd no longer have confidence in the article as a properly supported scholarly contribution and therefore agree that the article must be retracted.

Acute mountain sickness (AMS) is common after ascent to altitude, yet individual susceptibility remains difficult to predict and diagnosis relies on subjective report. Sleep disturbances and nocturnal hypoxaemia at altitude may provide insight, but their relationship to AMS is incompletely understood. In a sub-study of a randomized, placebo-controlled trial, 112 healthy, lowland-dwelling volunteers rapidly ascended to 3810 m. AMS was assessed using the 2018 Lake Louise Scoring System (LLSS); sleep scores were recorded separately. Overnight monitoring used the WatchPAT300 device to measure oxygen saturation, oxygen desaturation index, respiratory disturbance index, apnoea-hypopnoea index and inferred sleep stage. Thirty-eight participants (34%) developed AMS by the 2018 LLSS criteria. Compared with unaffected individuals, those with AMS had lower mean nocturnal S p O 2 , greater cumulative time with S p O 2 < 70%, and higher oxygen desaturation index and respiratory disturbance index on nights 2 and 3. Respiratory disturbance indices improved only in participants without AMS, while AMS-positive subjects demonstrated persistent reductions in estimated deep sleep, and higher self-reported sleep disturbance scores. A sensitivity analysis applying 1993 LLSS criteria identified 64 subjects (58%) with AMS, and strengthened between-group differences in nocturnal S p O 2 , but not respiratory indices. In exploratory multivariable analysis, cumulative time with S p O 2 < 70% and first-night sleep disturbance score at altitude remained independently associated with AMS. In summary, nocturnal hypoxaemia was associated with AMS status under both 2018 and 1993 criteria, while failure of respiratory index normalization and impaired sleep architecture are associated with AMS persistence, suggesting a longitudinal signal of failed acclimatization. These findings support further examination of sleep-related metrics in relation to AMS assessment.

Ramadan is a sacred religious practice observed by Muslims that involves abstaining from food and water from sunrise to sunset for 1 month. Prior work has reported that peak oxygen uptake (V ̇ O 2 peak) can decline during Ramadan in parallel with reduced physical activity. We investigated whether dietary nitrate supplementation could attenuate the decrease in V ̇ O 2 peak during 10 days of Ramadan fasting. In a randomized design, 21 healthy participants (13 females) were assigned to ingest 70 mL of beetroot juice (∼6.45 mmol nitrate; n = 10), twice a day for 10 days consecutively, or a non-supplement control (n = 11). The V ̇ O 2 peak was assessed by indirect calorimetry during a maximal cycle ergometer ramp test. After 10 days of Ramadan fasting, the change in body mass was not different between groups [change (∆), -0.91 ± 1.3 vs. -0.27 ± 1.2 kg (control vs. nitrate), P = 0.25], nor were the changes in resting systolic (P = 0.21) or diastolic (P = 0.53) blood pressure or urine specific gravity (P = 0.17). Subjective sleep quality declined over time in both groups (P < 0.01). Participants self-reported a decline (n = 17) or no change (n = 4) in regular physical activity, and the number of exercise bouts during the 10 days of Ramadan did not differ between groups (2.5 ± 2.0 vs. 3.3 ± 2.4, P = 0.44). Absolute V ̇ O 2 peak decreased in the control group compared with the dietary nitrate supplementation group (∆, -155 ± 168 vs. +67 ± 162 mL min[-1], P < 0.01), as did V ̇ O 2 peak relative to body mass (∆, -2.4 ± 2.5 vs. +0.3 ± 1.9 mL kg[-1] min[-1], P = 0.02) and peak power output (∆, -12 ± 16 vs. ∆+2 ± 10 W, P = 0.04). Dietary nitrate supplementation might represent a practical nutritional strategy to preserve aerobic capacity during Ramadan fasting.

A common misconception surrounding space exploration is that humanity's pursuit of interplanetary travel, such as missions to Mars, is an escape from Earth. In reality, this endeavour offers an invaluable opportunity to address critical biomedical challenges here at home. The extreme conditions of space, including microgravity, cosmic radiation and prolonged isolation, create a natural laboratory for studying human biology under stress, allowing us to explore the boundaries of human resilience. These exposures yield key insights into the biology of aging, the accelerated decline of physiological function and the early onset of chronic diseases. Among the organs most susceptible to environmental stress is the kidney, which is at high risk of failure during long-duration spaceflight. Its sensitivity makes it an ideal model for understanding how stress accelerates degeneration, both in space and on Earth. By studying kidney function alongside broader cellular processes, we can illuminate how stress drives aging and chronic disease. This is particularly exemplified by the process of cellular necrosis (unprogrammed cell death), which represents a key central node as recently demonstrated. Necrosis acts upstream of processes like cellular senescence and tissue degeneration, and is the mechanism through which multiple environmental factors erode resilience and drive the progression of chronic diseases like kidney disease. Following this exploration of how stress accelerates biological decline, we examine strategies that may protect against such damage, preventing disease and preserving physiological resilience. Pharmaceuticals, with their ability to modulate physiology transiently, are especially powerful in dynamic, real-world environments where stressors continually change. This 'chameleon effect' of pharmaceuticals offers the potential to uncouple biological trade-offs and enhance adaptive capacity to stress. Understanding these processes in the space environment provides an unprecedented opportunity, difficult to reproduce on Earth, to identify links between exposure and develop targeted interventions to enhance health and resilience on Earth.

High-altitude chronic hypoxia can induce excessive erythrocytosis (EE, defined as a haemoglobin concentration of ≥21 g/dL in men), leading to hyperviscosity and promoting endothelial dysfunction. We aimed to assess whether EE affects the retinal vascular phenotype and the ophthalmological vascular response to CO2. We conducted an ophthalmological cross-sectional study among highlanders permanently living at 5100 m (La Rinconada, Peru). The central retinal artery equivalent (CRAE), central retinal vein equivalent (CRVE) and retinal vessel tortuosity were measured using semi-automatic imaging software (VAMPIRE) from the diameters of the six largest arteries and veins on fundus images. Choroidal blood flow was assessed using laser Doppler flowmetry. Measurements were performed at rest and during a hypercapnic challenge (+10.1 ± 1.4 mmHg end-tidal CO2). Among the 62 included highlanders, 38 (61%) had EE. Compared with non-EE, highlanders with EE exhibited higher CRVE (278 ± 25 vs. 249 ± 24 µm, P < 0.001), with no other significant ophthalmological differences. Resting CRVE was significantly correlated (all P-values < 0.001) with haematocrit (r = 0.56), haemoglobin concentration (r = 0.65), blood volume (r = 0.55) and the arterial partial pressure of carbon dioxide (r = 0.46). Hypercapnia led to a moderate overall decrease in CRVE (-8.6 ± 22.0 µm, P = 0.02), without a specific effect of EE, and induced no other retinal vascular or choroidal blood flow changes in either group. We observed larger retinal vein diameters in EE highlanders compared with non-EE. Although hypercapnia is known to increase retinal vessel diameter in healthy lowlanders, it selectively decreased CRVE in highlanders, irrespective of EE status. These findings suggest a retinal vascular dysfunction in highlanders, probably induced by chronic exposure to severe hypoxia.

Nutrient sensing enables the body to detect and respond to nutrient availability through hormonal regulation. In this study, we examined nutrient-stimulated hormonal responses in children with severe acute malnutrition (SAM) compared with hospitalized (HC) and community (CC) child comparators. Basal and fed blood samples were collected from participants before and after consumption of a liquid meal. In the basal state, children with SAM showed significantly higher circulating concentrations of insulin, C-peptide, peptide tyrosine tyrosine (PYY), ghrelin, glucagon, glucagon-like peptide 1 (GLP-1) and glucagon like peptide 2 (GLP-2), in comparison to one or both comparators. After feeding, insulin, C-peptide, cholecystokinin, PYY and GLP-1 increased in all groups, indicating some level of preserved nutrient sensing. GLP-2 increased significantly in SAM and hospitalized children, and a reduction in ghrelin was observed in children with SAM. No significant changes were detected for glucagon, leptin or secretin in any group. Disordered responses, defined as zero or positive postprandial responses in ghrelin and zero or negative postprandial responses in the other hormones, were seen in all children. Significantly higher percentages of children with SAM had disordered responses compared with the non-malnourished children, particularly for insulin (23%) and C-peptide (16%), suggestive of altered pancreatic hormonal regulation in SAM. These findings highlight the need for improved nutritional interventions for affected children.

Polyendocrine metabolic ovarian syndrome [PMOS; previously known as polycystic ovary syndrome (PCOS)] is an endocrine condition affecting 10%-13% of women of reproductive age, with cardiometabolic, reproductive and psychological features. The PMOS guidelines have established recommendations for its management, which can include pharmacological, lifestyle and/or traditional medicines. The aim of this narrative review is to explore the pathophysiology, treatment recommendations and current evidence for lifestyle management for those with PMOS. Using the consolidated framework for implementation research (CFIR) and capability, opportunity, motivation and behaviour (COM-B) frameworks, this review identifies barriers and facilitators to implement lifestyle recommendations for PMOS, followed by strategies to support improvement in lifestyle management. There is limited high-quality evidence to support specific physical activity and dietary recommendations for those with PMOS. Underlying physiological mechanisms driving PMOS can impact energy expenditure, metabolism, appetite and satiety hormones, acting as barriers for weight and lifestyle-management strategies. Qualitative research suggests that implementation of lifestyle-management strategies from the PMOS guidelines has not been adopted. From a psychosocial perspective, those with PMOS often report that their health needs are not being met by health professionals. This might be related to a disproportionate focus on weight-focused care, inadequate lifestyle-management education for health professionals and inadequate support for people with PMOS to achieve lifestyle management. Working in partnership with those who have lived experience is crucial to translate the PMOS guidelines to improve health professional education, resources and adaption of lifestyle-management programmes to meet the needs of those with PMOS better.

Cancer cachexia, affecting up to 80% of patients with advanced cancer, is characterized by metabolic and inflammatory dysregulation driven by tumour- and host-derived factors. Although cytokines are central to cachexia pathogenesis, their circulating profiles and transcriptional relevance across models and sexes remain incompletely defined. We characterized plasma cytokines and skeletal muscle inflammatory signatures in multiple cachexia models, including Lewis Lung Carcinoma (LLC), Colon-26 (C26) and Apc[Min/+] mice. Animals were monitored for 4 weeks (LLC), 25 days (C26) or until ∼20 weeks of age (Apc[Min/+]) per model appropriate endpoints. Publicly available RNA-sequencing datasets from gastrocnemius (LLC) and tibialis anterior (C26 and Apc[Min/+]) muscles were integrated with plasma profiling using a Mouse Cytokine/Chemokine 32-Plex assay. To enhance accessibility and reproducibility, we developed an interactive Shiny application - thecachexiatlas/Cytokine Explorer - enabling dynamic visualization of cytokine levels, transcriptional signatures and phenotype correlations across models and sexes. Cytokine receptor encoding genes (Il6ra, Il4ra, Csf3, Osmr) and inflammatory pathways were consistently enriched in skeletal muscle of cachectic animals across models and sexes. Among circulating cytokines, granulocyte colony-stimulating factor (G-CSF) was uniquely elevated in all models and both sexes. Elevated G-CSF levels exhibited stronger negative correlations with tibialis anterior muscle mass than the commonly used cytokine interleukin (IL)-6, particularly when expressed as the ratio of G-CSF to the anti-inflammatory cytokine IL-13. The G-CSF:IL-13 ratio may represent a robust global biomarker of cachexia severity. The Cytokine Explorer Shiny app provides an open, interactive platform to facilitate hypothesis generation and advance research in cancer cachexia.

Pregnancy requires the coordinated maternal reorganization of lipid and endocrine pathways to sustain fetal growth and anticipate neonatal nutrition. Leptin, produced by adipose tissue and the placenta, acts as an integrative signal linking maternal energy status with trophoblast function and vascular adaptation, while cholesterol provides essential structural and hormonal substrates required for steroidogenesis and neurodevelopment. Emerging evidence indicates that leptin and cholesterol act as convergent regulators of metabolic and cardiovascular (CV) adaptation during pregnancy. We propose that excessive hyperleptinaemia and maternal hypercholesterolaemia, frequently coexisting, form a convergent axis that modulates placental signalling, alters the epigenetic regulation of lipid transporters and disrupts mitochondrial homeostasis. Mechanistically, this convergence operates through hepatic, epigenetic and renal pathways detailed throughout this review. Beyond the placenta, dysregulation of the leptin-cholesterol axis may extend to maternal organs central to CV homeostasis, particularly the kidney. Emerging evidence suggests that similar leptin-driven renal pathways may operate during pregnancy, amplifying vascular dysfunction and susceptibility to hypertensive complications. This perspective highlights the leptin-cholesterol axis as a mechanistic link connecting placental, kidney and CV pathways within the Developmental Origins of Health and Disease (DOHaD) paradigm, with potential implications for long-term cardiometabolic risk. This review integrates molecular, epigenetic and clinical evidence to emphasize lipoprotein-centred mechanisms, identify critical knowledge gaps and discuss translational opportunities for nutritional intervention, biomarker development and early-life preventive strategies.