Metabolic Consequences of Anabolic Steroids, Insulin, and Growth Hormone Abuse in Recreational Bodybuilders: Implications for the World Anti-Doping Agency Passport.

BACKGROUND: Hormonal doping in recreational sports is a public-health concern. The World Anti-Doping Agency (WADA) promoted the creation of the Athlete Biological Passport, aiming to monitor athlete's biological variables over time to facilitate indirect detection of doping. Detection tests for anabolic androgenic steroids (AAS) and growth hormone (GH) are available while insulin abuse cannot be revealed. We have determined in recreational bodybuilders the metabolic effects associated with different patterns of hormone abuse. All analyses were conducted using Statistical Package for Social Sciences (SPSS) 21.0 software (SPSS Chicago, IL). RESULTS: We have assessed plasma concentrations of selected metabolic markers and fatty acid content in erythrocyte membranes of 92 male bodybuilders and in 45 healthy controls. Hormonal abuse was identified by anonymous questionnaires. 43% (%) of recruited bodybuilders regularly abused hormones, i.e., anabolic androgenic steroids (95%) often associated with GH (30%) and/or insulin (38%). HDL-cholesterol was lower in insulin and/or GH abusers. Alanine (ALT) and aspartic (AST) transaminases were greater in hormone abusing bodybuilders than in non-doping bodybuilders and controls. Insulin doping was selectively associated with increased plasma ALT-to-AST ratio. In erythrocyte membranes, elongase activity (i.e., stearic-to-palmitic ratio) was lower in insulin and/or growth hormone doping, whereas increased Δ-9 desaturase activity (i.e., palmitoleic-to-palmitic ratio) was selectively associated with insulin doping. CONCLUSIONS: In conclusion, our study demonstrates that insulin and GH abuse are characterized by multiple alterations of specific metabolic markers. Although further studies are needed to test whether longitudinal monitoring of selected metabolic marker such as muscle contraction time, HDL levels, ALT-AST ratio as well as the activities of selected enzymes (e.g. Δ-9 desaturase and elongase), could contribute to the detection of insulin and GH abuse in sport.

High-protein diet with excess leucine prevents inactivity-induced insulin resistance in women.

BACKGROUND AND AIMS: Muscle inactivity leads to muscle atrophy and insulin resistance. The branched-chain amino acid (BCAA) leucine interacts with the insulin signaling pathway to modulate glucose metabolism. We have tested the ability of a high-protein BCAA-enriched diet to prevent insulin resistance during long-term bed rest (BR). METHODS: Stable isotopes were infused to determine glucose and protein kinetics in the postabsorptive state and during a hyperinsulinemic-euglycemic clamp in combination with amino acid infusion (Clamp + AA) before and at the end of 60 days of BR in two groups of healthy, young women receiving eucaloric diets containing 1 g of protein/kg per day (n = 8) or 1.45 g of protein/kg per day enriched with 0.15 g/kg per day of BCAAs (leucine/valine/isoleucine = 2/1/1) (n = 8). Body composition was determined by Dual X-ray Absorptiometry. RESULTS: BR decreased lean body mass by 7.6 ± 0.3 % and 7.2 ± 0.8 % in the groups receiving conventional or high protein-BCAA diets, respectively. Fat mass was unchanged in both groups. At the end of BR, percent changes of insulin-mediated glucose uptake significantly (p = 0.01) decreased in the conventional diet group from 155 ± 23 % to 84 ± 10 % while did not change significantly in the high protein-BCAA diet group from 126 ± 20 % to 141 ± 27 % (BR effect, p = 0.32; BR/diet interaction, p = 0.01; Repeated Measures ANCOVA). In contrast, there were no BR/diet interactions on proteolysis and protein synthesis Clamp + AA changes in the conventional diet and the high protein-BCAA diet groups. CONCLUSION: A high protein-BCAA enriched diet prevented inactivity-induced insulin resistance in healthy women.

Lipoprotein(a) as a Risk Factor for Cardiovascular Diseases: Pathophysiology and Treatment Perspectives.

Cardiovascular disease (CVD) is still a leading cause of morbidity and mortality, despite all the progress achieved as regards to both prevention and treatment. Having high levels of lipoprotein(a) [Lp(a)] is a risk factor for cardiovascular disease that operates independently. It can increase the risk of developing cardiovascular disease even when LDL cholesterol (LDL-C) levels are within the recommended range, which is referred to as residual cardiovascular risk. Lp(a) is an LDL-like particle present in human plasma, in which a large plasminogen-like glycoprotein, apolipoprotein(a) [Apo(a)], is covalently bound to Apo B100 via one disulfide bridge. Apo(a) contains one plasminogen-like kringle V structure, a variable number of plasminogen-like kringle IV structures (types 1-10), and one inactive protease region. There is a large inter-individual variation of plasma concentrations of Lp(a), mainly ascribable to genetic variants in the Lp(a) gene: in the general po-pulation, Lp(a) levels can range from <1 mg/dL to >1000 mg/dL. Concentrations also vary between different ethnicities. Lp(a) has been established as one of the risk factors that play an important role in the development of atherosclerotic plaque. Indeed, high concentrations of Lp(a) have been related to a greater risk of ischemic CVD, aortic valve stenosis, and heart failure. The threshold value has been set at 50 mg/dL, but the risk may increase already at levels above 30 mg/dL. Although there is a well-established and strong link between high Lp(a) levels and coronary as well as cerebrovascular disease, the evidence regarding incident peripheral arterial disease and carotid atherosclerosis is not as conclusive. Because lifestyle changes and standard lipid-lowering treatments, such as statins, niacin, and cholesteryl ester transfer protein inhibitors, are not highly effective in reducing Lp(a) levels, there is increased interest in developing new drugs that can address this issue. PCSK9 inhibitors seem to be capable of reducing Lp(a) levels by 25-30%. Mipomersen decreases Lp(a) levels by 25-40%, but its use is burdened with important side effects. At the current time, the most effective and tolerated treatment for patients with a high Lp(a) plasma level is apheresis, while antisense oligonucleotides, small interfering RNAs, and microRNAs, which reduce Lp(a) levels by targeting RNA molecules and regulating gene expression as well as protein production levels, are the most widely explored and promising perspectives. The aim of this review is to provide an update on the current state of the art with regard to Lp(a) pathophysiological mechanisms, focusing on the most effective strategies for lowering Lp(a), including new emerging alternative therapies. The purpose of this manuscript is to improve the management of hyperlipoproteinemia(a) in order to achieve better control of the residual cardiovascular risk, which remains unacceptably high.

Epidemiology of atherosclerotic cardiovascular disease in polygenic hypercholesterolemia with or without high lipoprotein(a) levels.

Background and aims: Epidemiology of atherosclerotic cardiovascular disease might be different in patients with polygenic hypercholesterolemia plus high levels (≥30 mg/dl) of Lp(a) (H-Lpa) than in those with polygenic hypercholesterolemia alone (H-LDL). We compared the incidence of peripheral artery disease (PAD), coronary artery disease (CAD), and cerebrovascular disease (CVD) in patients with H-Lpa and in those with H-LDL. Methods: Retrospective analysis of demographics, risk factors, vascular events, therapy, and lipid profile in outpatient clinical data. Inclusion criteria was adult age, diagnosis of polygenic hypercholesterolemia, and both indication and availability for Lp(a) measurement. Results: Medical records of 258 patients with H-Lpa and 290 H-LDL were reviewed for occurrence of vascular events. The median duration of follow-up was 10 years (IQR 3-16). In spite of a similar reduction of LDL cholesterol, vascular events occurred more frequently, and approximately 7 years earlier (P = 0.024) in patients with H-Lpa than in H-LDL (HR 1.96 1.21-3.17, P = 0.006). The difference was around 10 years for acute events (TIA, Stroke, acute coronary events) and one year for chronic ones (P = 0.023 and 0.525, respectively). Occurrence of acute CAD was higher in H-Lpa men (HR 3.1, 95% CI 1.2-7.9, P = 0.007) while, among women, PAD was observed exclusively in H-Lpa subjects with smoking habits (P = 0.009). Conclusions: Patients with high Lp(a) levels suffer from a larger and earlier burden of the disease compared to those with polygenic hypercholesterolemia alone. These patients are at higher risk of CAD if they are men, and of PAD if they are women.

Early lean mass sparing effect of high-protein diet with excess leucine during long-term bed rest in women.

Muscle inactivity leads to muscle atrophy. Leucine is known to inhibit protein degradation and to promote protein synthesis in skeletal muscle. We tested the ability of a high-protein diet enriched with branched-chain amino acids (BCAAs) to prevent muscle atrophy during long-term bed rest (BR). We determined body composition (using dual energy x-ray absorptiometry) at baseline and every 2-weeks during 60 days of BR in 16 healthy young women. Nitrogen (N) balance was assessed daily as the difference between N intake and N urinary excretion. The subjects were randomized into two groups: one received a conventional diet (1.1 ± 0.03 g protein/kg, 4.9 ± 0.3 g leucine per day) and the other a high protein, BCAA-enriched regimen (1.6 ± 0.03 g protein-amino acid/kg, 11.4 ± 0.6 g leucine per day). There were significant BR and BR × diet interaction effects on changes in lean body mass (LBM) and N balance throughout the experimental period (repeated measures ANCOVA). During the first 15 days of BR, lean mass decreased by 4.1 ± 0.9 and 2.4 ± 2.1% (p < 0.05) in the conventional and high protein-BCAA diet groups, respectively, while at the end of the 60-day BR, LBM decreased similarly in the two groups by 7.4 ± 0.7 and 6.8 ± 2.4%. During the first 15 days of BR, mean N balance was 2.5 times greater (p < 0.05) in subjects on the high protein-BCAA diet than in those on the conventional diet, while we did not find significant differences during the following time intervals. In conclusion, during 60 days of BR in females, a high protein-BCAA diet was associated with an early protein-LBM sparing effect, which ceased in the medium and long term.

Golgi Complex form and Function: A Potential Hub Role Also in Skeletal Muscle Pathologies?

A growing number of disorders has been associated with mutations in the components of the vesicular transport machinery. The early secretory pathway consists of Endoplasmic Reticulum, numerous vesicles, and the Golgi Complex (GC), which work together to modify and package proteins to deliver them to their destination. The GC is a hub organelle, crucial for organization of the other secretory pathway components. As a consequence, GC's form and function are key players in the pathogenesis of several disorders. Skeletal muscle (SKM) damage can be caused by defective protein modifications and traffic, as observed in some Limb girdle muscular dystrophies. Interestingly, in turn, muscle damage in Duchenne dystrophic SKM cells also includes the alteration of GC morphology. Based on the correlation between GC's form and function described in non-muscle diseases, we suggest a key role for this hub organelle also in the onset and progression of some SKM disorders. An altered GC could affect the secretory pathway via primary (e.g., mutation of a glycosylation enzyme), or secondary mechanisms (e.g., GC mis-localization in Duchenne muscles), which converge in SKM cell failure. This evidence induces considering the secretory pathway as a potential therapeutic target in the treatment of muscular dystrophies.

Mechanism of action and therapeutic use of bempedoic acid in atherosclerosis and metabolic syndrome.

Bempedoic acid is a new cholesterol-lowering drug, which has recently received US FDA and EMA approval. This drug targets lipid and glucose metabolism as well as inflammation via downregulation of ATP-citrate lyase and upregulation of AMP-activated protein kinase (AMPK). The primary effect is the reduction of cholesterol synthesis in the liver and its administration is generally not associated to unwanted muscle effects. Suppression of hepatic fatty acid synthesis leads to decreased triglycerides and, possibly, improved non-alcoholic fatty liver disease. Bempedoic acid may decrease gluconeogenesis leading to improved insulin sensitivity, glucose metabolism, and metabolic syndrome. The anti-inflammatory action of bempedoic acid is mainly achieved via activation of AMPK pathway in the immune cells, leading to decreased plasma levels of C-reactive protein. Effects of bempedoic acid on atherosclerotic cardiovascular disease, type 2 diabetes and chronic liver disease have been assessed in randomized clinical trials but require further confirmation. Safety clinical trials in phase III indicate that bempedoic acid administration is generally well-tolerated in combination with statins, ezetimibe, or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors to achieve low-density lipoprotein cholesterol targets. The aim of this narrative review on bempedoic acid is to explore the underlying mechanisms of action and potential clinical targets, present existing evidence from clinical trials, and describe practical management of patients.

Candidate Biomarkers for the Detection of Serious Infections in Children: A Prospective Clinical Study.

Serious bacterial infections (SBI) in children are associated with considerable morbidity and mortality, and their early identification remains challenging. The role of laboratory tests in this setting is still debated, and new biomarkers are needed. This prospective, observational, single-center study aims to evaluate the diagnostic role of blood biomarkers in detecting SBI in children presenting with signs of systemic inflammatory response syndrome (SIRS). A panel of biomarkers was performed, including C-reactive protein (CRP), procalcitonin (PCT), white blood cell count (WBC), absolute neutrophil count (ANC), interleukin (IL)-6, IL-8, IL-10, human terminal complement complex (C5b-9), Plasmalemma-Vesicle-associated protein 1 (PV-1), Intercellular Adhesion Molecule-1 (ICAM-1), and Phospholipase A2 (PLA2). Among 103 patients (median age 2.9 years, 60% males), 39 had a diagnosis of SBI (38%). Significant predictors of SBI were CRP (p = 0.001) and ICAM-1 (p = 0.043). WBC (p = 0.035), ANC (p = 0.012) and ANC/WBC ratio (p = 0.015) were also significantly associated with SBI in children without pre-existing neutropenia. ROC curves, however, revealed suboptimal performance for all variables. Nevertheless, a model that combined CRP and ANC/WBC ratio had more in-depth diagnostic accuracy than either of the two variables. Overall, this study confirms the limited usefulness of blood biomarkers for the early diagnosis of SBI. WBC, ANC, ANC/WBC ratio, CRP, and ICAM-1 showed the best, albeit moderate, diagnostic accuracy.

Skeletal Muscle in Hypoxia and Inflammation: Insights on the COVID-19 Pandemic.

SARS-CoV-2 infection is often associated with severe inflammation, oxidative stress, hypoxia and impaired physical activity. These factors all together contribute to muscle wasting and fatigue. In addition, there is evidence of a direct SARS-CoV-2 viral infiltration into skeletal muscle. Aging is often characterized by sarcopenia or sarcopenic obesity These conditions are risk factors for severe acute COVID-19 and long-COVID-19 syndrome. From these observations we may predict a strong association between COVID-19 and decreased muscle mass and functions. While the relationship between physical inactivity, chronic inflammation, oxidative stress and muscle dysfunction is well-known, the effects on muscle mass of COVID-19-related hypoxemia are inadequately investigated. The aim of this review is to highlight metabolic, immunity-related and redox biomarkers potentially affected by reduced oxygen availability and/or muscle fatigue in order to shed light on the negative impact of COVID-19 on muscle mass and function. Possible countermeasures are also reviewed.

Are Baseline Levels of Gas6 and Soluble Mer Predictors of Mortality and Organ Damage in Patients with Sepsis? The Need-Speed Trial Database.

Soluble tyrosine kinase receptor Mer (sMer) and its ligand Growth arrest-specific protein 6 (Gas6) are predictors of mortality in patients with sepsis. Our aim is to clarify whether their measurement at emergency department (ED) presentation is useful in risk stratification. We re-analyzed data from the Need-Speed trial, evaluating mortality and the presence of organ damage according to baseline levels of sMer and Gas6. 890 patients were eligible; no association with 7- and 30-day mortality was observed for both biomarkers (p > 0.05). sMer and Gas6 levels were significantly higher in acute kidney injury (AKI) patients compared to non-AKI ones (9.8 [4.1-17.8] vs. 7.9 [3.8-12.9] ng/mL and 34.8 [26.4-47.5] vs. 29.8 [22.1-41.6] ng/mL, respectively, for sMer and Gas6), and Gas6 also emerged as an independent AKI predictor (odds ratio (OR) 1.01 [1.00-1.02]). Both sMer and Gas6 independently predicted thrombocytopenia in sepsis patients not treated with anticoagulants (OR 1.01 [1.00-1.02] and 1.04 [1.02-1.06], respectively). Moreover, sMer was an independent predictor of both prothrombin time-international normalized ratio (PT-INR) > 1.4 (OR 1.03 [1.00-1.05]) and sepsis-induced coagulopathy (SIC) (OR 1.05 [1.02-1.07]). An early measurement of the sMer and Gas6 plasma concentration could not predict mortality. However, the biomarkers were associated with AKI, thrombocytopenia, PT-INR derangement and SIC, suggesting a role in predicting sepsis-related organ damage.

Genetic Variants of Matrix Metalloproteinase and Sepsis: The Need Speed Study.

Many causal mechanisms in sepsis susceptibility are largely unknown and the functional genetic polymorphisms (GP) of matrix metalloproteinases (MMPs) and their natural tissue inhibitor of MMPs (TIMP1) could play a role in its development. GPs of MMPs and TIMP (namely MMP-1 rs1799750, MMP-3 rs3025058, MMP-8 rs11225395, MMP-9 rs2234681, and TIMP-1 rs4898) have been compared in 1058 patients with suspected sepsis to assess the association with susceptibility and etiology of sepsis. Prevalence of MMP8 rs11225395 G/G genotype was higher in sepsis patients than in those with non-infective Systemic Inflammatory Reaction Syndrome (35.6 vs. 26%, hazard ratio, HR 1.56, 95% C.I. 1.04-2.42, p = 0.032). G/G patients developed less hyperthermia (p = 0.041), even after stratification for disease severity (p = 0.003). Patients carrying the 6A allele in MMP3 rs3025058 had a higher probability of microbiologically-proven sepsis (HR 1.4. 95%C.I. 1.01-1.94, p = 0.044), particularly when due to virus (H.R. 2.14, 95% C.I. 1.06-4.31, p = 0.046), while MMP-1 G/G genotype patients carried a higher risk for intracellular bacteria (Chlamydia, Mycoplasma, and Legionella, H.R. 6.46, 95% C.I. 1.58-26.41, p = 0.003). Neither severity of sepsis at presentation, nor 30-day mortality were influenced by the investigated variants or their haplotype. MMP8 rs11225395 G/G carriers have lower temperature at presentation and a more than 50% increased susceptibility to sepsis. Among patients with sepsis, carriers of MMP1 rs1799750 G/G have an increased susceptibility for intracellular pathogen infections, while virus serology is more often positive in those with the MMP3 rs3025058 A/A genotype.

Remodeling of abdominal aortic aneurysm sac following endovascular aortic repair: association with clinical, surgical, and genetic factors.

After successful endovascular aortic repair (EVAR), abdominal aortic aneurysms (AAA) sac will undergo negative remodeling (i.e., shrinkage) as a measure of successful exclusion. Determinants of shrinkage after EVAR are not fully known. In 84 post-EVAR patients, time course of AAA diameter after repair and occurrence of endoleaks (ELs) have been correlated with clinical history, medications, anthropometric data, vascular anatomy, and matrix metalloprotease (MMP) genetic variants (namely MMP-1 rs1799750, MMP-3 rs35068180, MMP-9 rs2234681, rs917576, rs917577, MMP-12 rs652438, and TIMP1 rs4898). During follow-up, 41 ELs were detected in 37 patients (44%, 10.4 events/100 pt./y), accounting for AAA dilation or reduced shrinkage (P < .001). High-flow ELs (type 1 and/or 3) occurrence was associated with warfarin use, MMP9 rs17577 polymorphism, and unfavorable anatomy, while low-flow type 2 ELs occurred more often in TIMP1 rs4898 non-T carriers. In EL-free patients, AAA diameter decreased for the first three years, (-4, -3 and - 2 mm/year respectively) and remained stable thereafter. Shrinkage between two measurements (n = 120) was associated with smaller AAA diameter at the baseline, peripheral arterial disease (PAD), patients' older age at intervention, and G-/G- genotype in MMP1 rs1799750 (binary logistic regression, P = .0001). Aneurysmal sac shrinking occurs for few years after EVAR, only in patients without EL, and is related to older age, PAD, smaller aneurysm size and putative lower MMP1 expression while EL occurrence prevents such a remodeling and is mainly related to local-acting factors like unfavorable anatomy, anticoagulation, and MMP9 and TIMP1 genetic polymorphisms.

Statin-Associated Myopathy: Emphasis on Mechanisms and Targeted Therapy.

Hyperlipidemia is a major risk factor for cardiovascular morbidity and mortality. Statins are the first-choice therapy for dyslipidemias and are considered the cornerstone of atherosclerotic cardiovascular disease (ASCVD) in both primary and secondary prevention. Despite the statin-therapy-mediated positive effects on cardiovascular events, patient compliance is often poor. Statin-associated muscle symptoms (SAMS) are the most common side effect associated with treatment discontinuation. SAMS, which range from mild-to-moderate muscle pain, weakness, or fatigue to potentially life-threatening rhabdomyolysis, are reported by 10% to 25% of patients receiving statin therapy. There are many risk factors associated with patient features and hypolipidemic agents that seem to increase the risk of developing SAMS. Due to the lack of a "gold standard", the diagnostic test for SAMS is based on a clinical criteria score, which is independent of creatine kinase (CK) elevation. Mechanisms that underlie the pathogenesis of SAMS remain almost unclear, though a high number of risk factors may increase the probability of myotoxicity induced by statin therapy. Some of these, related to pharmacokinetic properties of statins and to concomitant therapies or patient characteristics, may affect statin bioavailability and increase vulnerability to high-dose statins.

Ruling Out Coronavirus Disease 2019 in Patients with Pneumonia: The Role of Blood Cell Count and Lung Ultrasound.

Coronavirus disease 2019 (COVID-19) is characterized by a distinctive blood leucocyte pattern and B-lines on lung ultrasound (LUS) as marker of alveolar-interstitial syndrome. We aimed to evaluate the accuracy of blood leucocyte count alone or in combination with LUS for COVID-19 diagnosis. We retrospectively enrolled consecutive patients diagnosed with community acquired pneumonia (CAP) at hospital admission to derive and validate cutoff values for blood cell count that could be predictive of COVID-19 before confirmation by the nucleic acid amplification test (NAAT). Cutoff values, generated and confirmed in inception (41/115, positive/negative patients) and validation (100/180, positive/negative patients) cohorts, were ≤17 and ≤10 cells/mm3 for basophils and eosinophils, respectively. Basophils and/or eosinophils below cutoff were associated with sensitivity of 98% (95%CI, 94-100) and negative likelihood ratio of 0.04 (95%CI, 0.01-0.11). In a subgroup of 265 subjects, the sensitivity of B-line on LUS was 15% lower (p < 0.001) than that of basophils and/or eosinophils below cutoff. The combination of B-lines with basophils and eosinophils below cutoff was associated with a moderate increase of the positive likelihood ratio: 5.0 (95%CI, 3.2-7.7). In conclusion, basophil and eosinophil counts above the generated cutoff virtually rule out COVID-19 in patients with CAP. Our findings can help optimize patient triage pending the NAAT results.

The Aging Muscle in Experimental Bed Rest: A Systematic Review and Meta-Analysis.

Background: Maintaining skeletal muscle mass and function in aging is crucial for preserving the quality of life and health. An experimental bed rest (BR) protocol is a suitable model to explore muscle decline on aging during inactivity. Objective: The purpose of this systematic review and meta-analysis was, therefore, to carry out an up-to-date evaluation of bed rest, with a specific focus on the magnitude of effects on muscle mass, strength, power, and functional capacity changes as well as the mechanisms, molecules, and pathways involved in muscle decay. Design: This was a systematic review and meta-analysis study. Data sources: We used PubMed, Medline; Web of Science, Google Scholar, and the Cochrane library, all of which were searched prior to April 23, 2020. A manual search was performed to cover bed rest experimental protocols using the following key terms, either singly or in combination: "Elderly Bed rest," "Older Bed rest," "Old Bed rest," "Aging Bed rest," "Aging Bed rest," "Bed-rest," and "Bedrest". Eligibility criteria for selecting studies: The inclusion criteria were divided into four sections: type of study, participants, interventions, and outcome measures. The primary outcome measures were: body mass index, fat mass, fat-free mass, leg lean mass, cross-sectional area, knee extension power, cytokine pattern, IGF signaling biomarkers, FOXO signaling biomarkers, mitochondrial modulation biomarkers, and muscle protein kinetics biomarkers. Results: A total of 25 studies were included in the qualitative synthesis, while 17 of them were included in the meta-analysis. In total, 118 healthy elderly volunteers underwent 5-, 7-, 10-, or 14-days of BR and provided a brief sketch on the possible mechanisms involved. In the very early phase of BR, important changes occurred in the skeletal muscle, with significant loss of performance associated with a lesser grade reduction of the total body and muscle mass. Meta-analysis of the effect of bed rest on total body mass was determined to be small but statistically significant (ES = -0.45, 95% CI: -0.72 to -0.19, P < 0.001). Moderate, statistically significant effects were observed for total lean body mass (ES = -0.67, 95% CI: -0.95 to -0.40, P < 0.001) after bed rest intervention. Overall, total lean body mass was decreased by 1.5 kg, while there was no relationship between bed rest duration and outcomes (Z = 0.423, p = 672). The meta-analyzed effect showed that bed rest produced large, statistically significant, effects (ES = -1.06, 95% CI: -1.37 to -0.75, P < 0.001) in terms of the knee extension power. Knee extension power was decreased by 14.65 N/s. In contrast, to other measures, meta-regression showed a significant relationship between bed rest duration and knee extension power (Z = 4.219, p < 0.001). Moderate, statistically significant, effects were observed after bed rest intervention for leg muscle mass in both old (ES = -0.68, 95% CI: -0.96 to -0.40, P < 0.001) and young (ES = -0.51, 95% CI: -0.80 to -0.22, P < 0.001) adults. However, the magnitude of change was higher in older (MD = -0.86 kg) compared to younger (MD = -0.24 kg) adults. Conclusion: Experimental BR is a suitable model to explore the detrimental effects of inactivity in young adults, old adults, and hospitalized people. Changes in muscle mass and function are the two most investigated variables, and they allow for a consistent trend in the BR-induced changes. Mechanisms underlying the greater loss of muscle mass and function in aging, following inactivity, need to be thoroughly investigated.

Impact of sedentarism due to the COVID-19 home confinement on neuromuscular, cardiovascular and metabolic health: Physiological and pathophysiological implications and recommendations for physical and nutritional countermeasures.

The COVID-19 pandemic is an unprecedented health crisis as entire populations have been asked to self-isolate and live in home-confinement for several weeks to months, which in itself represents a physiological challenge with significant health risks. This paper describes the impact of sedentarism on the human body at the level of the muscular, cardiovascular, metabolic, endocrine and nervous systems and is based on evidence from several models of inactivity, including bed rest, unilateral limb suspension, and step-reduction. Data form these studies show that muscle wasting occurs rapidly, being detectable within two days of inactivity. This loss of muscle mass is associated with fibre denervation, neuromuscular junction damage and upregulation of protein breakdown, but is mostly explained by the suppression of muscle protein synthesis. Inactivity also affects glucose homeostasis as just few days of step reduction or bed rest, reduce insulin sensitivity, principally in muscle. Additionally, aerobic capacity is impaired at all levels of the O2 cascade, from the cardiovascular system, including peripheral circulation, to skeletal muscle oxidative function. Positive energy balance during physical inactivity is associated with fat deposition, associated with systemic inflammation and activation of antioxidant defences, exacerbating muscle loss. Importantly, these deleterious effects of inactivity can be diminished by routine exercise practice, but the exercise dose-response relationship is currently unknown. Nevertheless, low to medium-intensity high volume resistive exercise, easily implementable in home-settings, will have positive effects, particularly if combined with a 15-25% reduction in daily energy intake. This combined regimen seems ideal for preserving neuromuscular, metabolic and cardiovascular health.

Hypernatremia and moderate-to-severe hyponatremia are independent predictors of mortality in septic patients at emergency department presentation: A sub-group analysis of the need-speed trial.

STUDY OBJECTIVE: Early risk stratification of septic patients presenting to the emergency department (ED) is challenging. The aim of the study was to evaluate the prognostic role of plasmatic sodium level (PNa+) derangements at ED presentation in septic patients. METHODS: According to PNa+ at ED presentation patients were divided in eunatremic (136-145 mEq/L), hypernatremic (>145 mEq/L) and hyponatremic (<136 mEq/L). Hyponatremic patients were subsequently divided in mild (130-135 mEq/L), moderate (125-129 mEq/L) and severe (<125 mEq/L). 7 and 30-day mortality was evaluated according to PNa+ derangements and the degree of hyponatremia. The same analysis was then performed only in respiratory tract infection-related (RTI-r) sepsis patients. RESULTS: 879 septic patients were included in this analysis, 40.3% had hyponatremia, 5.7% hypernatremia. Hypernatremia showed higher mortality rates at both endpoints compared to eunatremia and hyponatremia (p<0.0001 for both). Eunatremia and mild hyponatremia were compared vs. moderate-to-severe hyponatremia showing a significant difference in terms of 7 and 30-day survival (p = 0.004 and p = 0.007, respectively). The Cox proportional model identified as independent predictors of 7 and 30-day mortality moderate-to-severe hyponatremia (HR 4.89[2.38-10.03] and 1.79[1.07-3.01], respectively) and hypernatremia (HR 3.52[1.58-7.82] and 2.14[1.17-3.92], respectively). The same analysis was performed in patients with respiratory tract infection-related sepsis (n = 549), with similar results. CONCLUSION: Both hypernatremia and moderate-to-severe hyponatremia at ED presentation independently predict mortality in septic patients, allowing early risk stratification and suggesting more aggressive therapeutic strategies.

The Integration of qSOFA with Clinical Variables and Serum Biomarkers Improves the Prognostic Value of qSOFA Alone in Patients with Suspected or Confirmed Sepsis at ED Admission.

BACKGROUND: The prognostic value of quick sepsis-related organ failure assessment (qSOFA) outside intensive care units has been criticized. Therefore, we aimed to improve its ability in predicting 30-day all-cause mortality, and in ruling out the cases at high risk of death among patients with suspected or confirmed sepsis at emergency department (ED) admission. METHODS: This study is a secondary analysis of a prospective multicenter study. We built three predictive models combining qSOFA with the clinical variables and serum biomarkers that resulted in an independent association with 30-day mortality, in both 848 undifferentiated patients (Group 1) and in 545 patients definitively diagnosed with sepsis (Group 2). The models reaching the highest negative predictive value (NPV) with the minimum expenditure of biomarkers in Group 1 and in Group 2 were validated in two cohorts of patients initially held out due to missing data. RESULTS: In terms of the area under the receiver-operating characteristic curve, all six models significantly exceeded qSOFA in predicting prognosis. An "extended" qSOFA (eqSOFA1) in Group 1 and an eqSOFA2 integrated with C-reactive protein and mid-regional proadrenomedullin (eqSOFA2+CRP+MR-proADM) in Group 2 reached the best NPV (0.94 and 0.93, respectively) and ease of use. eqSOFA1 and eqSOFA2+CRP+MR-proADM performed equally well in both the inception and validation cohorts. CONCLUSIONS: We have derived and validated two prognostic models that outweigh qSOFA in predicting mortality and in identifying the low risk of death among patients with suspected or confirmed sepsis at ED admission.