Sports and Immunity, from the recreational to the elite athlete.

The pivotal role of the immune system in physical activity is well-established. While interactions are complex, they tend to constitute discrete immune responses. Moderate intensity exercise causes leukocytosis with a mild anti-inflammatory cytokine profile and immunoenhancement. Above a threshold of intensity, lactate-mediated IL-6 release causes a proinflammatory state followed by a depressed inflammatory state, which stimulates immune adaptation and longer term cardiometabolic enhancement. Exercise-related immune responses are modulated by sex, age and immunonutrition. At all ability levels, these factors collectively affect the immune balance between enhancement or overload and dysfunction. Excessive training, mental stress or insufficient recovery risks immune cell exhaustion and hypothalamic pituitary axis (HPA) stress responses causing immunodepression with negative impacts on performance or general health. Participation in sport provides additional immune benefits in terms of ensuring regularity, social inclusion, mental well-being and healthier life choices in terms of diet and reduced smoking and alcohol, thereby consolidating healthy lifestyles and longer term health. Significant differences exist between recreational and professional athletes in terms of inherent characteristics, training resilience and additional stresses arising from competition schedules, travel-related infections and stress. Exercise immunology examines the central role of immunity in exercise physiology and straddles multiple disciplines ranging from neuroendocrinology to nutrition and genetics, with the aim of guiding athletes to train optimally and safely. This review provides a brief outline of the main interactions of immunity and exercise, some influencing factors, and current guidance on maintaining immune health.

The Effect of Photobiomodulation on the Treatment of Hereditary Mitochondrial Diseases.

Introduction: Despite a wide variety of clinical presentations in hereditary Mitochondrial Diseases, muscle fatigue is a common theme and impairs a patient's quality of life and ability to function. Current treatments are only supportive and include nutritional supplementation and physical therapy. Photobiomodulation therapy (PBMT) using low-intensity, narrow spectrum light in the red/near infrared (NIR) range, from a low-level laser or light-emitting diode sources, enhances mitochondrial function in preclinical and clinical studies on a range of conditions. However, little research has been done on the effectiveness of photobiomodulation in hereditary mitochondrial disorders. Methods: We performed a scoping review of the evidence of the beneficial effects of photobiomodulation for treating the muscle-related symptoms of hereditary mitochondrial disease. Results: No studies regarding photobiomodulation in hereditary mitochondrial disease were identified. However, in other clinical conditions featuring acquired mitochondrial impairment, we identified studies that suggested improved function, although sample sizes were small in number and statistical power. Conclusion: There is emerging evidence of efficacy for PBMT for diseases involving acquired mitochondrial insufficiency. We identified no published research on PBMT in hereditary mitochondrial disease, but this review confirms a theoretical rationale for a positive effect and suggests further research.

The effects of physical activity on glutamate neurotransmission in neuropsychiatric disorders.

Physical activity (PA) is an effective way of increasing cognitive and emotional health and counteracting many psychiatric conditions. Numerous neurobiological models for depression have emerged in the past 30 years but many struggle to incorporate the effects of exercise. The hippocampus and pre-frontal cortex (PFC) containing predominantly glutamate neurotransmission, are the centres of changes seen in depression. There is therefore increasing interest in glutamatergic systems which offers new paradigms of understanding mechanisms connecting physical activity, stress, inflammation and depression, not explained by the serotonin theories of depression. Similar hippocampal glutamate dysfunction is observed in many other neuropsychiatric conditions. Excitatory glutamate neurones have high functionality, but also high ATP requirements and are therefore vulnerable to glucocorticoid or pro-inflammatory stress that causes mitochondrial dysfunction, with synaptic loss, culminating in depressed mood and cognition. Exercise improves mitochondrial function, angiogenesis and synaptogenesis. Within the glutamate hypothesis of depression, the mechanisms of stress and inflammation have been extensively researched, but PA as a mitigator is less understood. This review examines the glutamatergic mechanisms underlying depression and the evidence of physical activity interventions within this framework. A dynamic glutamate-based homeostatic model is suggested whereby stress, neuroinflammation and PA form counterbalancing influences on hippocampal cell functionality, which manifests as depression and other neuropsychiatric conditions when homeostasis is disrupted.

Emerging Evidence for the Widespread Role of Glutamatergic Dysfunction in Neuropsychiatric Diseases.

The monoamine model of depression has long formed the basis of drug development but fails to explain treatment resistance or associations with stress or inflammation. Recent animal research, clinical trials of ketamine (a glutamate receptor antagonist), neuroimaging research, and microbiome studies provide increasing evidence of glutamatergic dysfunction in depression and other disorders. Glutamatergic involvement across diverse neuropathologies including psychoses, neurodevelopmental, neurodegenerative conditions, and brain injury forms the rationale for this review. Glutamate is the brain's principal excitatory neurotransmitter (NT), a metabolic and synthesis substrate, and an immune mediator. These overlapping roles and multiple glutamate NT receptor types complicate research into glutamate neurotransmission. The glutamate microcircuit comprises excitatory glutamatergic neurons, astrocytes controlling synaptic space levels, through glutamate reuptake, and inhibitory GABA interneurons. Astroglia generate and respond to inflammatory mediators. Glutamatergic microcircuits also act at the brain/body interface via the microbiome, kynurenine pathway, and hypothalamus-pituitary-adrenal axis. Disruption of excitatory/inhibitory homeostasis causing neuro-excitotoxicity, with neuronal impairment, causes depression and cognition symptoms via limbic and prefrontal regions, respectively. Persistent dysfunction reduces neuronal plasticity and growth causing neuronal death and tissue atrophy in neurodegenerative diseases. A conceptual overview of brain glutamatergic activity and peripheral interfacing is presented, including the common mechanisms that diverse diseases share when glutamate homeostasis is disrupted.

An Intuitive Risk Communication Tool to Enhance Patient-Provider Partnership in Diabetes Consultation.

INTRODUCTION: This technology report introduces an innovative risk communication tool developed to support providers in communicating diabetes-related risks more intuitively to people with type 2 diabetes mellitus (T2DM). METHODS: The development process involved three main steps: (1) selecting the content and format of the risk message; (2) developing a digital interface; and (3) assessing the usability and usefulness of the tool with clinicians through validated questionnaires. RESULTS: The tool calculates personalized risk information based on a validated simulation model (United Kingdom Prospective Diabetes Study Outcomes Model 2) and delivers it using more intuitive risk formats, such as "effective heart age" to convey cardiovascular risks. Clinicians reported high scores for the usability and usefulness of the tool, making its adoption in routine care promising. CONCLUSIONS: Despite increased use of risk calculators in clinical care, this is the first time that such a tool has been developed in the diabetes area. Further studies are needed to confirm the benefits of using this tool on behavioral and health outcomes in T2DM populations.

Intravenous iron and chronic obstructive pulmonary disease: a randomised controlled trial.

BACKGROUND: Increased iron availability modifies cardiorespiratory function in healthy volunteers and improves exercise capacity and quality of life in patients with heart failure or pulmonary hypertension. We hypothesised that intravenous iron would produce improvements in oxygenation, exercise capacity and quality of life in patients with chronic obstructive pulmonary disease (COPD). METHODS: We performed a randomised, placebo-controlled, double-blind trial in 48 participants with COPD (mean±SD: age 69±8 years, haemoglobin 144.8±13.2 g/L, ferritin 97.1±70.0 µg/L, transferrin saturation 31.3%±15.2%; GOLD grades II-IV), each of whom received a single dose of intravenous ferric carboxymaltose (FCM; 15 mg/kg bodyweight) or saline placebo. The primary endpoint was peripheral oxygen saturation (SpO2) at rest after 1 week. The secondary endpoints included daily SpO2, overnight SpO2, exercise SpO2, 6 min walk distance, symptom and quality of life scores, serum iron indices, spirometry, echocardiographic measures, and exacerbation frequency. RESULTS: SpO2 was unchanged 1 week after FCM administration (difference between groups 0.8%, 95% CI -0.2% to 1.7%). However, in secondary analyses, exercise capacity increased significantly after FCM administration, compared with placebo, with a mean difference in 6 min walk distance of 12.6 m (95% CI 1.6 to 23.5 m). Improvements of ≥40 m were observed in 29.2% of iron-treated and 0% of placebo-treated participants after 1 week (p=0.009). Modified MRC Dyspnoea Scale score was also significantly lower after FCM, and fewer participants reported scores ≥2 in the FCM group, compared with placebo (33.3% vs 66.7%, p=0.02). No significant differences were observed in other secondary endpoints. Adverse event rates were similar between groups, except for hypophosphataemia, which occurred more frequently after FCM (91.7% vs 8.3%, p<0.001). CONCLUSIONS: FCM did not improve oxygenation over 8 weeks in patients with COPD. However, this treatment was well tolerated and produced improvements in exercise capacity and functional limitation caused by breathlessness. These effects on secondary endpoints require confirmation in future studies. TRIAL REGISTRATION NUMBER: ISRCTN09143837.

Chaos, mitochondria and type 2 diabetes; does type 2 diabetes arise from a metabolic dysrhythmia?

The increasing incidence of type 2 diabetes transcends all cultures, largely due to populations transitioning from traditional diets and manual occupations, to sedentary, calorific lifestyles. Excess calorie intake leads to intramuscular fat accumulation and insulin resistance. Physical inactivity causes underutilization of mitochondria causing dysfunction and inflammation. Both insulin resistance and mitochondrial dysfunction mechanisms are known to be closely related and to antagonise one another, although the precise nature of the relationship has eluded characterization. It is poorly understood why this mutual dysfunction progresses on to clinical diabetes in only some patients, why progression is often stepwise and why diabetes control only weakly predicts future cardiovascular disease in individuals. Clinical prediction in patients is therefore currently unsatisfactory and current linear assumptions require challenging. Cells contain networks of oscillating ionic fluxes. Cellular activity is characterised by complex patterns of fluctuation with sudden transitions between patterns. The non-linear nature of these oscillations is well characterised in neuronal activity, cardiac impulses and more recently mitochondria, but not previously in relation to diabetes. Cells under metabolic stress demonstrate complex fluctuations of mitochondrial distribution, coupling strength and synchronisation resulting in periodic or chaotic oscillations of function, causing accumulation of intracellular fat and excess reactive oxygen species (ROS), which exacerbates insulin resistance. Glucose, insulin and HbA1c in patients are also known to oscillate in complex patterns but the mechanisms and significance are largely unknown. Drawing on existing evidence and models from other diseases, a nonlinear, dynamical hypothesis of diabetes onset and progression is proposed. Insulin receptor pathways and mitochondria are treated as two populations of coupled, phase oscillators. Health or disease states depend on system stability or instability and reflect the balance of substrate supply and energy demand. The implication of this novel mechanism is that diabetes and the complications are not the consequence of a distinct pathological agent or pathway, but more an evolving dysrhythmia of normal cellular energetics systems, resulting from accumulated adverse lifestyle conditions. This hypothesis is proposed with the intention of stimulating research into non-linear dynamical constructs as an alternative to current linear models, to improve risk prediction and trajectory analysis in type 2 diabetes.

Risk attitudes of people with 'manageable' chronic disease: An analysis under prospect theory.

Health promotion interventions can be improved using methods from behavioural economics to identify and target specific decision-making biases at the individual level. In this context, prospect theory provides a suitable framework within which decision-making processes can be operationalised. Focusing on a trade-off between health outcomes and behaviour change incurred by chronic disease management (lifestyle change, or 'self-management'), we are the first to measure the risk attitudes and quantify the full utility function under prospect theory of a patient population. We conducted a series of hypothetical elicitations over health outcomes associated with different self-management behaviours from a population of individuals with or without 'manageable' chronic disease (n = 120). We observed risk aversion in both the gain and the loss domains, as well as significant loss aversion. There seems to be an age effect on risk attitudes in this context, with younger people being on average less risk averse than older people. Our work addresses a need to better understand these decision-making processes, so that behaviour change interventions tailored to specific patient populations can be improved.

Nudging people with Type 2 diabetes towards better self-management through personalized risk communication: A pilot randomized controlled trial in primary care.

OBJECTIVES: To assess the feasibility in routine primary care consultation and investigate the effect on risk recall and self-management of a new type of risk communication intervention based on behavioural economics ("nudge-based") for people with Type 2 diabetes mellitus (T2DM). METHODS: Forty adults with poorly controlled T2DM (HbA1c > 7.5%) were randomized to receive a personalized, nudge-based risk communication intervention (n = 20) or standard care (n = 20). Risk recall and self-management were evaluated at baseline and 12 weeks after the intervention. RESULTS: Both in terms of feasibility and acceptability, this new risk communication intervention was very satisfactory. Study retention rate after 12 weeks was very high (90%) and participants were highly satisfied with the intervention (4.4 out of 5 on the COMRADE scale). Although not powered to identify significant between-group effects, the intervention significantly improved risk recall after 12 weeks and intentions to make lifestyle changes (dietary behaviour) compared to standard care. CONCLUSIONS: This pilot study provides the first evidence of the feasibility of implementing in primary care a nudge-based risk communication intervention for people with T2DM. Based on the promising results observed, an adequately powered trial to determine the effectiveness of the intervention on long-term self-management is judged feasible. As a result of this feasibility study, some minor adaptations to the intervention and study methods that would help to facilitate a definitive trial are also reported.