Ketosis Suppression and Ageing (KetoSAge) Part 2: The Effect of Suppressing Ketosis on Biomarkers Associated with Ageing, HOMA-IR, Leptin, Osteocalcin, and GLP-1, in Healthy Females.

Metabolic dysfunctions are among the best documented hallmarks of ageing. Cardiovascular disease, Alzheimer's disease, cancer, type 2 diabetes mellitus, metabolic-dysfunction-associated steatosis liver disease, and fragility fractures are diseases of hyperinsulinaemia that reduce life and healthspan. We studied the effect of suppressing ketosis in 10 lean (BMI 20.5 kg/m2 ± 1.4), metabolically healthy, pre-menopausal women (age 32.3 ± 8.9 years) maintaining nutritional ketosis (NK) for an average of 3.9 years (± 2.3) who underwent three 21-day phases: nutritional ketosis (NK; P1), suppressed ketosis (SuK; P2), and returned to NK (P3). Ketosis suppression significantly increased insulin, 1.83-fold (p = 0.0006); glucose, 1.17-fold (p = 0.0088); homeostasis model assessment for insulin resistance (HOMA-IR), 2.13-fold (p = 0.0008); leptin, 3.35-fold (p = 0.0010); total osteocalcin, 1.63-fold (p = 0.0138); and uncarboxylated osteocalcin, 1.98-fold (p = 0.0417) and significantly decreased beta-hydroxybutyrate, 13.50-fold (p = 0.0012) and glucagon-like peptide-1 (GLP-1), 2.40-fold (p = 0.0209). Sustained NK showed no adverse health effects and may mitigate hyperinsulinemia. All biomarkers returned to basal P1 levels after removing the intervention for SuK, indicating that metabolic flexibility was maintained with long-term euketonaemia.

Ketosis Suppression and Ageing (KetoSAge): The Effects of Suppressing Ketosis in Long Term Keto-Adapted Non-Athletic Females.

Most studies on ketosis have focused on short-term effects, male athletes, or weight loss. Hereby, we studied the effects of short-term ketosis suppression in healthy women on long-standing ketosis. Ten lean (BMI 20.5 ± 1.4), metabolically healthy, pre-menopausal women (age 32.3 ± 8.9) maintaining nutritional ketosis (NK) for > 1 year (3.9 years ± 2.3) underwent three 21-day phases: nutritional ketosis (NK; P1), suppressed ketosis (SuK; P2), and returned to NK (P3). Adherence to each phase was confirmed with daily capillary D-beta-hydroxybutyrate (BHB) tests (P1 = 1.9 ± 0.7; P2 = 0.1 ± 0.1; and P3 = 1.9 ± 0.6 pmol/L). Ageing biomarkers and anthropometrics were evaluated at the end of each phase. Ketosis suppression significantly increased: insulin, 1.78-fold from 33.60 (± 8.63) to 59.80 (± 14.69) pmol/L (p = 0.0002); IGF1, 1.83-fold from 149.30 (± 32.96) to 273.40 (± 85.66) µg/L (p = 0.0045); glucose, 1.17-fold from 78.6 (± 9.5) to 92.2 (± 10.6) mg/dL (p = 0.0088); respiratory quotient (RQ), 1.09-fold 0.66 (± 0.05) to 0.72 (± 0.06; p = 0.0427); and PAI-1, 13.34 (± 6.85) to 16.69 (± 6.26) ng/mL (p = 0.0428). VEGF, EGF, and monocyte chemotactic protein also significantly increased, indicating a pro-inflammatory shift. Sustained ketosis showed no adverse health effects, and may mitigate hyperinsulinemia without impairing metabolic flexibility in metabolically healthy women.

Stimulation of the Pro-Resolving Receptor Fpr2 Reverses Inflammatory Microglial Activity by Suppressing NFκB Activity.

Neuroinflammation driven primarily by microglia directly contributes to neuronal death in many neurodegenerative diseases. Classical anti-inflammatory approaches aim to suppress pro-inflammatory mediator production, but exploitation of inflammatory resolution may also be of benefit. A key driver of peripheral inflammatory resolution, formyl peptide receptor 2 (Fpr2), is expressed by microglia, but its therapeutic potential in neurodegeneration remains unclear. Here, we studied whether targeting of Fpr2 could reverse inflammatory microglial activation induced by the potent bacterial inflammogen lipopolysaccharide (LPS). Exposure of murine primary or immortalised BV2 microglia to LPS triggered pro-inflammatory phenotypic change and activation of ROS production, effects significantly attenuated by subsequent treatment with the Fpr2 agonist C43. Mechanistic studies showed C43 to act through p38 MAPK phosphorylation and reduction of LPS-induced NFκB nuclear translocation via prevention of IκBα degradation. Here, we provide proof-of-concept data highlighting Fpr2 as a potential target for control of microglial pro-inflammatory activity, suggesting that it may be a promising therapeutic target for the treatment of neuroinflammatory disease.

Bio-Hacking Better Health-Leveraging Metabolic Biochemistry to Maximise Healthspan.

In the pursuit of longevity and healthspan, we are challenged with first overcoming chronic diseases of ageing: cardiovascular disease, hypertension, cancer, dementias, type 2 diabetes mellitus. These are hyperinsulinaemia diseases presented in different tissue types. Hyperinsulinaemia reduces endogenous antioxidants, via increased consumption and reduced synthesis. Hyperinsulinaemia enforces glucose fuelling, consuming 4 NAD+ to produce 2 acetyl moieties; beta-oxidation, ketolysis and acetoacetate consume 2, 1 and 0, respectively. This decreases sirtuin, PARPs and oxidative management capacity, leaving reactive oxygen species to diffuse to the cytosol, upregulating aerobic glycolysis, NF-kB and cell division signalling. Also, oxidising cardiolipin, reducing oxidative phosphorylation (OXPHOS) and apoptosis ability; driving a tumourigenic phenotype. Over time, increasing senescent/pathological cell populations occurs, increasing morbidity and mortality. Beta-hydroxybutyrate, an antioxidant, metabolite and signalling molecule, increases synthesis of antioxidants via preserving NAD+ availability and enhancing OXPHOS capacity. Fasting and ketogenic diets increase ketogenesis concurrently decreasing insulin secretion and demand; hyperinsulinaemia inhibits ketogenesis. Lifestyles that maintain lower insulin levels decrease antioxidant catabolism, additionally increasing their synthesis, improving oxidative stress management and mitochondrial function and, subsequently, producing healthier cells. This supports tissue and organ health, leading to a better healthspan, the first challenge that must be overcome in the pursuit of youthful longevity.

PEG hydrogel containing dexamethasone-conjugated hyaluronic acid reduces secondary injury and improves motor function in a rat moderate TBI model.

Traumatic brain injury (TBI) leads to long-term impairments in motor and cognitive function. TBI initiates a secondary injury cascade including a neuro-inflammatory response that is detrimental to tissue repair and limits recovery. Anti-inflammatory corticosteroids such as dexamethasone can reduce the deleterious effects of secondary injury; but challenges associated with dosing, administration route, and side effects have hindered their clinical application. Previously, we developed a hydrolytically degradable hydrogel (PEG-bis-AA/HA-DXM) composed of poly (ethylene) glycol-bis-(acryloyloxy acetate) (PEG-bis-AA) and dexamethasone-conjugated hyaluronic acid (HA-DXM) for local and sustained dexamethasone delivery. In this study, we evaluated the effect of locally applied PEG-bis-AA/HA-DXM hydrogel on secondary injury and motor function recovery after moderate controlled cortical impact (CCI) TBI. Hydrogel treatment significantly improved motor function evaluated by beam walk and rotarod tests compared to untreated rats over 7 days post-injury (DPI). We also observed that the hydrogel treatment reduced lesion volume, inflammatory response, astrogliosis, apoptosis, and increased neuronal survival compared to untreated rats at 7 DPI. These results suggest that PEG-bis-AA/HA-DXM hydrogels can mitigate secondary injury and promote motor functional recovery following moderate TBI.

Improving physiological relevance of cell culture: the possibilities, considerations, and future directions of the ex vivo coculture model.

In vitro models provide an important platform for the investigation of cellular growth and atrophy to inform, or extend mechanistic insights from, logistically challenging in vivo trials. Although these models allow for the identification of candidate mechanistic pathways, many models involve supraphysiological dosages, nonphysiological conditions, or experimental changes relating to individual proteins or receptors, all of which limit translation to human trials. To overcome these drawbacks, the use of ex vivo human plasma and serum has been used in cellular models to investigate changes in myotube hypertrophy, cellular protein synthesis, anabolic and catabolic markers in response to differing age, disease states, and nutrient status. However, there are currently no concurrent guidelines outlining the optimal methodology for this model. This review discusses the key methodological considerations surrounding the use of ex vivo plasma and serum with a focus in application to skeletal muscle cell lines (i.e., C2C12, L6, and LHCN-M2) and human primary skeletal muscle cells (HSMCs) as a means to investigate molecular signaling in models of atrophy and hypertrophy, alongside future directions.

The effects of gradual vs. rapid weight loss on serum concentrations of myokines and body composition in overweight and obese females.

Context: Research has shown the modulations of Follistatin (FST) and Myostatin (MST) following weight loss.Objective: We evaluated the effects of gradual weight loss (GWL) and rapid weight loss (RWL) on serum MST, FST, and body composition in overweight and obese females.Materials and methods: Thirty-six overweight and obese females successfully completed the study interventions: GWL (n = 18) or RWL (n = 18). Serum MST and FST concentrations, as well as anthropometric measurements, were collected at baseline and at the conclusion of each weight loss intervention.Results: MST concentration significantly (p < .05) decreased in the GWL; while FST concentration, body fat percentage and skeletal muscle mass significantly declined in both conditions. The loss in skeletal muscle mass was significantly greater in RWL relative to GWL.Discussion and conclusion: GWL was more effective than RWL in preserving skeletal muscle mass in overweight and obese females. Moreover, GWL leads to declines in MST concentrations.

What is the optimal strategy for managing primary care patients with an uncomplicated acute sore throat? Comparing the consequences of nine different strategies using a compilation of previous studies.

OBJECTIVE: Identifying optimal strategies for managing patients of any age with varying risk of acute rheumatic fever (ARF) attending for an apparently uncomplicated acute sore throat, also clarifying the role of point-of-care testing (POCT) for presence of group A beta-haemolytic Streptococcus (GABHS) in these settings. DESIGN: We compared outcomes of adhering to nine different strategies for managing these patients in primary healthcare. SETTING AND PARTICIPANTS: The nine strategies, similar to guidelines from several countries, were tested against two validation data sets being constructs from seven prior studies. MAIN OUTCOME MEASURES: The proportion of patients requiring a POCT, prescribed antibiotics, prescribed antibiotics having GABHS and finally having GABHS not prescribed antibiotics, if different strategies had been adhered to. RESULTS: In a scenario with high risk of ARF, adhering to existing guidelines would risk many patients ill from GABHS left without antibiotics. Hence, using a POCT on all of these patients minimised their risk. For low-risk patients, it is reasonable to only consider antibiotics if the patient has more than low pain levels despite adequate analgesia, 3-4 Centor scores (or 2-3 FeverPAIN scores or 3-4 McIsaac scores) and a POCT confirming the presence of GABHS. This would require testing only 10%-15% of patients and prescribing antibiotics to only 3.5%-6.6%. CONCLUSIONS: Patients with high or low risk for ARF needs to be managed very differently. POCT can play an important role in safely targeting the use of antibiotics for patients with an apparently uncomplicated acute sore throat.

Effects of Icelandic yogurt consumption and resistance training in healthy untrained older males.

Due to the important roles of resistance training and protein consumption in the prevention and treatment of sarcopenia, we assessed the efficacy of post-exercise Icelandic yogurt consumption on lean mass, strength and skeletal muscle regulatory factors in healthy untrained older males. Thirty healthy untrained older males (age = 68 ± 4 years) were randomly assigned to Icelandic yogurt (IR; n 15, 18 g of protein) or an iso-energetic placebo (PR; n 15, 0 g protein) immediately following resistance training (3×/week) for 8 weeks. Before and after training, lean mass, strength and skeletal muscle regulatory factors (insulin-like growth factor-1 (IGF-1), transforming growth factor-beta 1 (TGF-ß1), growth differentiation factor 15 (GDF15), Activin A, myostatin (MST) and follistatin (FST)) were assessed. There were group × time interactions (P < 0·05) for body mass (IR: Δ 1, PR: Δ 0·7 kg), BMI (IR: Δ 0·3, PR: Δ 0·2 kg/m2), lean mass (IR: Δ 1·3, PR: Δ 0·6 kg), bench press (IR: Δ 4, PR: 2·3 kg), leg press (IR: Δ 4·2, PR: Δ 2·5 kg), IGF-1 (IR: Δ 0·5, Δ PR: 0·1 ng/ml), TGF-ß (IR: Δ - 0·2, PR: Δ - 0·1 ng/ml), GDF15 (IR: Δ - 10·3, PR: Δ - 4·8 pg/ml), Activin A (IR: Δ - 9·8, PR: Δ - 2·9 pg/ml), MST (IR: Δ - 0·1, PR: Δ - 0·04 ng/ml) and FST (IR: Δ 0·09, PR: Δ 0·03 ng/ml), with Icelandic yogurt consumption resulting in greater changes compared with placebo. The addition of Icelandic yogurt consumption to a resistance training programme improved lean mass, strength and altered skeletal muscle regulatory factors in healthy untrained older males compared with placebo. Therefore, Icelandic yogurt as a nutrient-dense source and cost-effective supplement enhances muscular gains mediated by resistance training and consequently may be used as a strategy for the prevention of sarcopenia.

Preliminary Investigations Into the Effect of Exercise-Induced Muscle Damage on Systemic Extracellular Vesicle Release in Trained Younger and Older Men.

Background: Exercise-induced muscle damage (EIMD) results in transient muscle inflammation, strength loss, and muscle soreness and may cause subsequent exercise avoidance. Research has recently proven that skeletal muscle can also release extracellular vesicles (EVs) into the circulation following a bout of exercise. However, EV's potential role, including as a biomarker, in the response to eccentric resistance exercise stimulus remains unclear. Methods: Twelve (younger, n=7, 27.0±1.5years and older, n=5, 63.0±1.0years) healthy, physically active males, undertaking moderate, regular physical activity (3-5 times per week) performed a unilateral high intensity eccentric exercise protocol. Venous plasma was collected for assessment of EVs and creatine kinase (CK) prior to EIMD, immediately after EIMD, and 1-72h post-EIMD, and maximal voluntary isometric contraction (MVIC) and delayed onset muscle soreness (DOMS) were assessed at all time points, except 1 and 2h post-EIMD. Results: A significant effect of both time (p=0.005) and group (p<0.001) was noted for MVIC, with younger participants' MVIC being higher throughout. Whilst a significant increase was observed in DOMS in the younger group (p=0.014) and in the older group (p=0.034) following EIMD, no significant differences were observed between groups. CK was not different between age groups but was altered following the EIMD (main effect of time p=0.026), with increased CK seen immediately post-, at 1 and 2h post-EIMD. EV count tended to be lower in older participants at rest, relative to younger participants (p=0.056), whilst EV modal size did not differ between younger and older participants pre-EIMD. EIMD did not substantially alter EV modal size or EV count in younger or older participants; however, the alteration in EV concentration (ΔCount) and EV modal size (ΔMode) between post-EIMD and pre-EIMD negatively associated with CK activity. No significant associations were noted between MVIC or DOMS and either ΔCount or ΔMode of EVs at any time point. Conclusion: These findings suggest that profile of EV release, immediately following exercise, may predict later CK release and play a role in the EIMD response. Exercise-induced EV release profiles may therefore serve as an indicator for subsequent muscle damage.

High Intensity Interval Training (HIIT) as a Potential Countermeasure for Phenotypic Characteristics of Sarcopenia: A Scoping Review.

Background: Sarcopenia is defined as a progressive and generalized loss of skeletal muscle quantity and function associated predominantly with aging. Physical activity appears the most promising intervention to attenuate sarcopenia, yet physical activity guidelines are rarely met. In recent years high intensity interval training (HIIT) has garnered interested in athletic populations, clinical populations, and general population alike. There is emerging evidence of the efficacy of HIIT in the young old (i.e. seventh decade of life), yet data concerning the oldest old (i.e., ninth decade of life onwards), and those diagnosed with sarcopenic are sparse. Objectives: In this scoping review of the literature, we aggregated information regarding HIIT as a potential intervention to attenuate phenotypic characteristics of sarcopenia. Eligibility Criteria: Original investigations concerning the impact of HIIT on muscle function, muscle quantity or quality, and physical performance in older individuals (mean age ≥60 years of age) were considered. Sources of Evidence: Five electronic databases (Medline, EMBASE, Web of Science, Scopus, and the Cochrane Central Register of Controlled Trials [CENTRAL]) were searched. Methods: A scoping review was conducted using the Arksey and O'Malley methodological framework (2005). Review selection and characterization were performed by two independent reviewers using pretested forms. Results: Authors reviewed 1,063 titles and abstracts for inclusion with 74 selected for full text review. Thirty-two studies were analyzed. Twenty-seven studies had a mean participant age in the 60s, two in the 70s, and three in the 80s. There were 20 studies which examined the effect of HIIT on muscle function, 22 which examined muscle quantity, and 12 which examined physical performance. HIIT was generally effective in Improving muscle function and physical performance compared to non-exercised controls, moderate intensity continuous training, or pre-HIIT (study design-dependent), with more ambiguity concerning muscle quantity. Conclusions: Most studies presented herein utilized outcome measures defined by the European Working Group on Sarcopenia in Older People (EWGSOP). However, there are too few studies investigating any form of HIIT in the oldest old (i.e., ≥80 years of age), or those already sarcopenic. Therefore, more intervention studies are needed in this population.

Metabolic Phenotypes and Step by Step Evolution of Type 2 Diabetes: A New Paradigm.

Unlike bolus insulin secretion mechanisms, basal insulin secretion is poorly understood. It is essential to elucidate these mechanisms in non-hyperinsulinaemia healthy persons. This establishes a baseline for investigation into pathologies where these processes are dysregulated, such as in type 2 diabetes (T2DM), cardiovascular disease (CVD), certain cancers and dementias. Chronic hyperinsulinaemia enforces glucose fueling, depleting the NAD+ dependent antioxidant activity that increases mitochondrial reactive oxygen species (mtROS). Consequently, beta-cell mitochondria increase uncoupling protein expression, which decreases the mitochondrial ATP surge generation capacity, impairing bolus mediated insulin exocytosis. Excessive ROS increases the Drp1:Mfn2 ratio, increasing mitochondrial fission, which increases mtROS; endoplasmic reticulum-stress and impaired calcium homeostasis ensues. Healthy individuals in habitual ketosis have significantly lower glucagon and insulin levels than T2DM individuals. As beta-hydroxybutyrate rises, hepatic gluconeogenesis and glycogenolysis supply extra-hepatic glucose needs, and osteocalcin synthesis/release increases. We propose insulin's primary role is regulating beta-hydroxybutyrate synthesis, while the role of bone regulates glucose uptake sensitivity via osteocalcin. Osteocalcin regulates the alpha-cell glucagon secretory profile via glucagon-like peptide-1 and serotonin, and beta-hydroxybutyrate synthesis via regulating basal insulin levels. Establishing metabolic phenotypes aids in resolving basal insulin secretion regulation, enabling elucidation of the pathological changes that occur and progress into chronic diseases associated with ageing.

Strategic Ingestion of High-Protein Dairy Milk during a Resistance Training Program Increases Lean Mass, Strength, and Power in Trained Young Males.

BACKGROUND: We evaluated the effects of high-protein dairy milk ingestion on changes in body composition, strength, power, and skeletal muscle regulatory markers following 6 weeks of resistance training in trained young males. METHODS: Thirty resistance-trained young males (age: 27 ± 3 years; training experience: 15 ± 2 months) were randomly assigned to one of two groups: high-protein dairy milk (both whey and casein) + resistance training (MR; n = 15) or isoenergetic carbohydrate (maltodextrin 9%) + resistance training (PR; n = 15). Milk and placebo were ingested immediately post-exercise (250 mL; 30 g protein) and 30 min before sleep (250 mL; 30 g protein). Before and after 6 weeks of linear periodized resistance training (4 times/week), body composition (bioelectrical impedance), strength, power, and serum levels of skeletal muscle regulatory markers (insulin-like growth factor 1 (IGF-1), growth hormone, testosterone, cortisol, follistatin, myostatin, and follistatin-myostatin ratio) were assessed. RESULTS: The MR group experienced a significantly higher (p < 0.05) increase in lean mass, strength, and power (upper- and lower-body) than the PR group. Further, IGF-1, growth hormone, testosterone, follistatin, and follistatin-myostatin ratio were significantly increased, while cortisol and myostatin significantly decreased in the MR group than the PR group (p < 0.05). CONCLUSIONS: The strategic ingestion of high-protein dairy milk (post-exercise and pre-sleep) during 6 weeks of resistance training augmented lean mass, strength, power, and altered serum concentrations of skeletal muscle regulatory markers in trained young males compared to placebo.

Sprint interval training (SIT) reduces serum epidermal growth factor (EGF), but not other inflammatory cytokines in trained older men.

PURPOSE: The present study aimed to investigate the effect of age on circulating pro- and anti-inflammatory cytokines and growth factors. A secondary aim was to investigate whether a novel sprint interval training (SIT) intervention (3 × 20 s 'all out' static sprints, twice a week for 8 weeks) would affect inflammatory markers in older men. METHODS: Nine older men [68 (1) years] and eleven younger men [28 (2) years] comprised the younger group. Aerobic fitness and inflammatory markers were taken at baseline for both groups and following the SIT intervention for the older group. RESULTS: Interleukin (IL)-8, vascular endothelial growth factor (VEGF), and monocyte chemoattractant protein-1 (MCP-1) were unchanged for the older and younger groups at baseline (IL-8, p = 0.819; MCP-1, p = 0.248; VEGF, p = 0.264). Epidermal growth factor (EGF) was greater in the older group compared to the younger group at baseline [142 (20) pg mL-1 and 60 (12) pg mL-1, respectively, p = 0.001, Cohen's d = 1.64]. Following SIT, older men decreased EGF to 100 (12) pg mL-1 which was similar to that of young men who did not undergo training (p = 0.113, Cohen's d = 1.07). CONCLUSION: Older aerobically trained men have greater serum EGF than younger aerobically trained men. A novel SIT intervention in older men can shift circulating EGF towards trained younger concentrations. As lower EGF has previously been associated with longevity in C. elegans, the manipulative effect of SIT on EGF in healthy ageing in the human may be of further interest.

Improving antibiotics targeting using PCR point-of-care testing for group A streptococci in patients with uncomplicated acute sore throat.

BACKGROUND AND OBJECTIVES: Evidence supports some beneficial effects of antibiotics prescribed to patients with a sore throat and proven presence of group A streptococci (GAS). METHOD: A total of 283 patients were included from North and North-West Queensland, Australia, at their first presentation for uncomplicated acute sore throat. Patterns of antibiotic prescribing were explored before and after testing for GAS using a rapid point-of-care polymerase chain reaction (PCR) test. RESULTS: The results of the study showed the Australian Therapeutic Guidelines were often not adhered to. The PCR test reduced the proportion of patients prescribed antibiotics from 46% to 40%. The decision to prescribe antibiotics was changed in 30% of patients (P <0.001): before testing only 40% of patients prescribed antibiotics had a positive GAS PCR while this increased to 97% after testing. DISCUSSION: An easy-to-use point-of-care test to detect GAS allows better targeting of antibiotic prescribing in patients with an uncomplicated acute sore throat.

The effect of Omega-3 polyunsaturated fatty acid supplementation on exercise-induced muscle damage.

BACKGROUND: Exercise-induced muscle damage (EIMD) results in transient muscle inflammation, strength loss, muscle soreness and may cause subsequent exercise avoidance. Omega-3 (n-3) supplementation may minimise EIMD via its anti-inflammatory properties, however, its efficacy remains unclear. METHODS: Healthy males (n = 14, 25.07 ± 4.05 years) were randomised to 3 g/day n-3 supplementation (N-3, n = 7) or placebo (PLA, n = 7). Following 4 weeks supplementation, a downhill running protocol (60 min, 65% V̇O2max, - 10% gradient) was performed. Creatine kinase (CK), interleukin (IL)-6 and tumour necrosis factor (TNF)-α, perceived muscle soreness, maximal voluntary isometric contraction (MVIC) and peak power were quantified pre, post, and 24, 48 and 72 h post-EIMD. RESULTS: Muscle soreness was significantly lower in N-3 vs PLA group at 24 h post-EIMD (p = 0.034). IL-6 was increased in PLA (p = 0.009) but not in N-3 (p = 0.434) following EIMD, however, no significant differences were noted between groups. Peak power was significantly suppressed in PLA relative to pre-EIMD but not in N-3 group at 24 h post-EIMD. However, no significant difference in peak power output was observed between groups. MVIC, CK and TNF-α were altered by EIMD but did not differ between groups. CONCLUSION: N-3 supplementation for 4 weeks may successfully attenuate minor aspects of EIMD. Whilst not improving performance, these findings may have relevance to soreness-associated exercise avoidance.

Relationships between hyperinsulinaemia, magnesium, vitamin D, thrombosis and COVID-19: rationale for clinical management.

Risk factors for COVID-19 patients with poorer outcomes include pre-existing conditions: obesity, type 2 diabetes mellitus, cardiovascular disease (CVD), heart failure, hypertension, low oxygen saturation capacity, cancer, elevated: ferritin, C reactive protein (CRP) and D-dimer. A common denominator, hyperinsulinaemia, provides a plausible mechanism of action, underlying CVD, hypertension and strokes, all conditions typified with thrombi. The underlying science provides a theoretical management algorithm for the frontline practitioners.Vitamin D activation requires magnesium. Hyperinsulinaemia promotes: magnesium depletion via increased renal excretion, reduced intracellular levels, lowers vitamin D status via sequestration into adipocytes and hydroxylation activation inhibition. Hyperinsulinaemia mediates thrombi development via: fibrinolysis inhibition, anticoagulation production dysregulation, increasing reactive oxygen species, decreased antioxidant capacity via nicotinamide adenine dinucleotide depletion, haem oxidation and catabolism, producing carbon monoxide, increasing deep vein thrombosis risk and pulmonary emboli. Increased haem-synthesis demand upregulates carbon dioxide production, decreasing oxygen saturation capacity. Hyperinsulinaemia decreases cholesterol sulfurylation to cholesterol sulfate, as low vitamin D regulation due to magnesium depletion and/or vitamin D sequestration and/or diminished activation capacity decreases sulfotransferase enzyme SULT2B1b activity, consequently decreasing plasma membrane negative charge between red blood cells, platelets and endothelial cells, thus increasing agglutination and thrombosis.Patients with COVID-19 admitted with hyperglycaemia and/or hyperinsulinaemia should be placed on a restricted refined carbohydrate diet, with limited use of intravenous dextrose solutions. Degree/level of restriction is determined by serial testing of blood glucose, insulin and ketones. Supplemental magnesium, vitamin D and zinc should be administered. By implementing refined carbohydrate restriction, three primary risk factors, hyperinsulinaemia, hyperglycaemia and hypertension, that increase inflammation, coagulation and thrombosis risk are rapidly managed.