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Exercise facilitates cerebral lactate uptake, likely by increasing arterial lactate concentration and hence the diffusion gradient across the blood brain barrier. However, non-specific β-adrenergic blockade by propranolol has previously reduced the arterio-jugular venous lactate difference (AVLac) during exercise, suggesting β-adrenergic control of cerebral lactate uptake. Alternatively, we hypothesize that propranolol reduces cerebral lactate uptake by decreasing arterial lactate concentration. To test that hypothesis, we evaluated cerebral lactate uptake taking changes in arterial concentration into account. Nine healthy males performed incremental cycling exercise to exhaustion with and without intravenous propranolol (18.7 ± 1.9 mg). Lactate concentration was determined in arterial and internal jugular venous blood at the end of each workload. To take changes in arterial lactate into account we calculated the fractional extraction (FELac) defined as AVLac divided by the arterial lactate concentration. Arterial lactate concentration was reduced by propranolol at any workload (p-1 during maximal exercise without and with propranolol, respectively. While AVLac and FELac increased during exercise (both P < 0.05), they were both unaffected by propranolol at any workload (P = 0.68 and P = 0.26) or for any given arterial lactate concentration (P = 0.78 and P = 0.22). These findings support that, while propranolol may reduce cerebral lactate uptake, this effect reflects the propranolol-induced reduction in arterial lactate concentration and not inhibition of a β-adrenergic mechanism within the brain. We hence conclude that cerebral lactate uptake during exercise is directly driven by the increasing arterial concentration with work rate.

Background People living with HIV (PLWH) have low levels of physical activity. Using the social ecological model to understand perceptions, facilitators and barriers of physical activity in this population is of importance for developing contextualised interventions to improve physical activity in PLWH. Method This was a qualitative sub-study conducted between august and November 2019 as part of a cohort study on diabetes and associated complications in HIV infected in Mwanza, Tanzania. Sixteen in-depth interviews and three focus groups with nine participants in each were conducted. The interviews and focus groups were audio recorded, transcribed and translated into English. The social ecological model was considered during the coding and interpretation of the results. Transcripts were discussed, coded and analyzed using deductive content analysis. Results Forty-three PLWH aged 23–61 years participated in this study. The findings showed that most PLWH perceived physical activity as beneficial to their health. However, their perceptions of physical activity were rooted within existing gender stereotypes and roles in the community. Running and playing football were perceived as activities for men while household chores activities were for women. Further, men were perceived to do more physical activity than women. For women, household chores and income-generating activities were perceived as sufficient physical activity. Social support and engagement of family members and friends in physical activity were reported as facilitators of physical activity. Reported barriers of physical activity were lack of time, money, availability of physical activity facilities and social support groups, and poor information on physical activity from health care providers in HIV clinics. Human-immunodeficiency virus (HIV) HIV infection was not perceived by PLWH as a barrier for doing physical activity but most family members did not support them to do physical activity, fearing that it might worsen their condition. Conclusion The findings demonstrated differing perceptions, facilitators and barriers of physical activity among PLWH. Interventions addressing awareness, gender stereotypes and roles related to physical activity from individual to community level are needed. Supportive environment and infrastructures are needed to improve physical activity levels in PLWH in Tanzania.

Background: Observed associations of high-protein diets with changes in insulin resistance are inconclusive.Objectives: We aimed to assess associations of changes in both reported and estimated protein (PRep; PEst) and energy intake (EIRep; EIEst) with changes in HOMA-IR, glycated hemoglobin (HbA1c), and BMI (in kg/m2), in 1822 decreasing to 833 adults (week 156) with overweight and prediabetes, during the 3-y PREVIEW (PREVention of diabetes through lifestyle intervention and population studies In Europe and around the World) study on weight-loss maintenance. Eating behavior and measurement errors (MEs) of dietary intake were assessed. Thus, observational post hoc analyses were applied.Methods: Associations of changes in EIEst, EIRep, PEst, and PRep with changes in HOMA-IR, HbA1c, and BMI were determined by linear mixed-model analysis in 2 arms [high-protein-low-glycemic-index (GI) diet and moderate-protein-moderate-GI diet] of the PREVIEW study. EIEst was derived from energy requirement: total energy expenditure = basal metabolic rate × physical activity level; PEst from urinary nitrogen, and urea. MEs were calculated as [(EIEst - EIRep)/EIEst] × 100% and [(PRep - PEst)/PEst] × 100%. Eating behavior was determined using the Three Factor Eating Questionnaire, examining cognitive dietary restraint, disinhibition, and hunger.Results: Increases in PEst and PRep and decreases in EIEst and EIRep were associated with decreases in BMI, but not independently with decreases in HOMA-IR. Increases in PEst and PRep were associated with decreases in HbA1c. PRep and EIRep showed larger changes and stronger associations than PEst and EIEst. Mean ± SD MEs of EIRep and PRep were 38% ± 9% and 14% ± 4%, respectively; ME changes in EIRep and En% PRep were positively associated with changes in BMI and cognitive dietary restraint and inversely with disinhibition and hunger.Conclusions: During weight-loss maintenance in adults with prediabetes, increase in protein intake and decrease in energy intake were not associated with decrease in HOMA-IR beyond associations with decrease in BMI. Increases in PEst and PRep were associated with decrease in HbA1c.This trial was registered at clinicaltrials.gov as NCT01777893.

Skeletal muscle is an endocrine organ secreting exercise-induced factors (exerkines), which play a pivotal role in interorgan cross talk. Using mass spectrometry (MS)-based proteomics, we characterized the secretome and identified thymosin β4 (TMSB4X) as the most upregulated secreted protein in the media of contracting C2C12 myotubes. TMSB4X was also acutely increased in the plasma of exercising humans irrespective of the insulin resistance condition or exercise mode. Treatment of mice with TMSB4X did not ameliorate the metabolic disruptions associated with diet induced-obesity, nor did it enhance muscle regeneration in vivo. However, TMSB4X increased osteoblast proliferation and neurite outgrowth, consistent with its WADA classification as a prohibited growth factor. Therefore, we report TMSB4X as a human exerkine with a potential role in cellular cross talk.

Context Exercise blunts the effect of beta2-agonists on peripheral glucose uptake and energy expenditure. Whether such attenuation extends into recovery is unknown. Objective To examine the effect of a beta2-agonist on leg glucose uptake and metabolic rate in recovery from exercise. Methods Using leg arteriovenous balance technique and analyses of thigh muscle biopsies, we investigated the effect of a beta2-agonist (24 mg of oral salbutamol) vs placebo on leg glucose, lactate, and oxygen exchange before and during quadriceps exercise, and 0.5 to 5 hours in recovery from quadriceps exercise, as well as on muscle glycogen resynthesis and activity in recovery. Twelve healthy, lean, young men participated. Results Before exercise, leg glucose uptake was 0.42 ± 0.12 and 0.20 ± 0.02 mmol × min–1 (mean ± SD) for salbutamol and placebo (P = .06), respectively, while leg oxygen consumption was around 2-fold higher (P Conclusion Exercise blunts the effect of beta2-agonist salbutamol on leg glucose uptake, but this attenuation diminishes in recovery. Salbutamol increases leg lactate release in recovery, which may relate to glycolytic trafficking due to excessive myocellular glucose uptake.

Over the last decade, the urgency to find alternative and sustainable protein sources has prompted an exponential increase in the interest in insects as a human food source. Edible insects contribute suitable amounts of energy and protein, fatty acids, and micronutrients to the human diet. Nutritional values of insects can be manipulated to meet specific needs. Edible insects in food-insecure countries can contribute to improving diets and preventing undernutrition. Bioactive compounds in insects may reduce health risks. Food safety risks are low and mainly relate to those of allergenicity. Strategies to overcome barriers to the consumption of insect products include emphasizing their sustainability, increasing their tastiness, and developing the ability to disguise insects in familiar products. A new sector of insects as food and feed is emerging. Major challenges include legislation, lowering prices by automation and cheap substrates, developing insect products that appeal to consumers, and exploring the health benefits. Expected final online publication date for the Annual Review of Nutrition, Volume 41 is September 2021. Please see http://www.annualreviews.org/page/journal/pubdates for revised estimates.

Physical exercise results in a duration and intensity-dependent vascular response in healthy human tendon. In overused (tendinopathy) and damagedtendon, angiogenic pathways are activated and neovascularization is observed.Whereas no direct relationship exists between the amount of neovessels and degree of tendinopathy symptoms, almost all tendinopathic patients have elevated neovascularization and tendon blood flow, as assessed by Doppler ultrasound methodology. The enhanced flow in tendinopathy can be successfully abolished by heavy resistance training. Already in the early time-phase of tendinopathy (

The study investigates sex differences in the prevalence of undernutrition in sub-Saharan Africa. Undernutrition was defined by Z-scores using the CDC-2000 growth charts. Some 128 Demographic and Health Surveys (DHS) were analysed, totalling 700,114 children under-five. The results revealed a higher susceptibility of boys to undernutrition. Male-to-female ratios of prevalence averaged 1.18 for stunting (height-for-age Z-score Z-score Z-score Z-scores

We combined game activity analyses with skeletal muscle phenotypes and comprehensive physiological testing to elucidate factors of importance for physical performance in elite women's football. GPS-data from an experimental game, sprint and endurance testing, and muscle tissue analysis of metabolic enzyme activity, protein expression and fiber type composition were completed for international top-level women players (n = 20; age; 23 ± 4 yrs, height; 166 ± 10 cm, weight; 60 ± 8 kg; VO2max ; 51 ± 6 ml/min/kg). Muscle monocarboxylate transporter 4 (MCT4) protein expression explained 46% of the variance in total game distance, while the ability to maintain high-intensity running (HIR) during the final 15 min of the game correlated to myosin heavy chain 1 (MHCI) and Na+-K+ ATPase β1, FXYD1 (phospholemman) and superoxide dismutase 2 (SOD2) protein expression (range: r = 0.51-0.71; all p < 0.05). Total HIR distance correlated with (MHCIIa) protein expression (r = 0.51; p < 0.05), while muscle Na+/H+ exchanger 1 (NHE1) protein explained 36% of the variance in game sprint distance (p < 0.05). Total game accelerations (actions >4 m/s2) correlated with platelet endothelial cell adhesion molecule (PECAM-1) protein expression (r = 0.51; p < 0.05), while concentric knee flexor strength explained 42-62% of the variance in intense decelerations (>4 m/s2). In conclusion, for elite women players' game endurance performance and resistance to end-game fatigue were affected by monocarboxylate transporter expression and myosin heavy chain profile. HIR was also correlated to ion transporter expression and muscle antioxidative capacity. Finally, the importance of functional strength and measures of muscle vascularization in relation to total game decelerations and accelerations, respectively, illustrates the complex physiological demands in elite women's football.

This study aimed to determine and compare the perception, painfulness, and usability of the minimally invasive Dried Blood Spot (DBS) collections from fingertip vs. upper arm from different athlete populations: males and females representing sports dependent on hand/arm, sports less dependent on hand/arm and para-athletes. To accomplish this, 108 national level athletes from Denmark were recruited (♀ = 49, ♂ = 59, 25 ± 6 years; mean±SD) and 11 Doping Control Officers (DCOs) collected manual fingerprick DBS (HemaSpot HF) and automated upper-arm DBS (Tasso-M20) from each athlete. Athletes and DCOs responded to questionnaires regarding the perception of sample collection procedures. On a 0-10 scale, the athletes reported a low pain score and a very good general experience for both sampling sites but following upper-arm DBS collection the associated pain was rated lower (-0.4 ± 1.6, p < 0.05) and the general experience rated better (+0.6 ± 2.3, p ≤ 0.001) than after the fingerprick DBS collection. The DCOs rated the general experience with the upper-arm DBS collection better (+1.6 ± 1.1, p ≤ 0.01) than the fingerprick DBS collection, partly because problems occurred more frequently during the DBS collection from the fingertip (28%) than from the upper arm (6%). In conclusion, it appears that DBS sampling is affiliated with minimal sensation of pain and is preferred by both DCOs and athletes, independent of gender and discipline, over conventional sample collection methods. Collection of DBS from the upper arm was preferred over fingerprick by both athletes and DCOs.

Current markers of iron deficiency (ID) such as ferritin and hemoglobin have shortcomings, and hepcidin and erythroferrone (ERFE) could be of clinical relevance in relation to early assessment of ID. Here, we evaluate whether exposure to altitude-induced hypoxia (2,320 m) alone, or in combination with recombinant human erythropoietin (rHuEPO) treatment, affects hepcidin and ERFE levels before alterations in routine ID biomarkers and stress erythropoiesis manifest. Two interventions were completed, each comprising a 4-wk baseline, a 4-wk intervention at either sea level or altitude, and a 4-wk follow-up. Participants (n=39) were randomly assigned to 20 IU·kg body wt-1 rHuEPO or placebo injections every second day for 3 wk during the two intervention periods. Venous blood was collected weekly. Altitude increased ERFE (P ≤ 0.001) with no changes in hepcidin or routine iron biomarkers, making ERFE of clinical relevance as an early marker of moderate hypoxia. rHuEPO treatment at sea level induced a similar pattern of changes in ERFE (P < 0.05) and hepcidin levels (P < 0.05), demonstrating the impact of accelerated erythropoiesis and not of other hypoxia-induced mechanisms. Compared to altitude alone, concurrent rHuEPO treatment and altitude exposure induced additive changes in hepcidin (P < 0.05) and ERFE (P ≤ 0.001) parallel with increases in hematocrit (P < 0.001), demonstrating a relevant range of both hepcidin and ERFE. A poor but significant correlation between hepcidin and ERFE was found (R2 = 0.13, P < 0.001). The findings demonstrate that hepcidin and ERFE are more rapid biomarkers of changes in iron demands than routine iron markers. Finally, ERFE and hepcidin may be sensitive markers in an anti-doping context.Clinical trial registration: Clinical trials identifier, NCT04227665

Objectives: To provide perspectives from the HEAT-SHIELD project (www.heat-shield.eu): a multinational, inter-sectoral, and cross-disciplinary initiative, incorporating twenty European research institutions, as well as occupational health and industrial partners, on solutions to combat negative health and productivity effects caused by working on a warmer world. Methods: In this invited review, we focus on the theoretical and methodological advancements developed to combat occupational heat stress during the last five years of operation. Results: We outline how we created climate forecast models to incorporate humidity, wind and solar radiation to the traditional temperature-based climate projections, providing the basis for timely, policy-relevant, industry-specific and individualized information. Further, we summarise the industry-specific guidelines we developed regarding technical and biophysical cooling solutions considering effectiveness, cost, sustainability, and the practical implementation potential in outdoor and indoor settings, in addition to field-testing of selected solutions with time-motion analyses and biophysical evaluations. All recommendations were adjusted following feedback from workshops with employers, employees, safety officers, and adjacent stakeholders such as local or national health policy makers. The cross-scientific approach was also used for providing policy-relevant information based on socioeconomic analyses and identification of vulnerable regions considered to be more relevant for political actions than average continental recommendations and interventions. Discussion: From the HEAT-SHIELD experiences developed within European settings, we discuss how this inter-sectoral approach may be adopted or translated into actionable knowledge across continents where workers and societies are affected by escalating environmental temperatures. The study has received funding from the European Union’s Horizon 2020 research and innovation program under the grant agreement No 668786

While misuse of testosterone esters is widespread in elite and recreational sports, direct detection of intact testosterone esters in doping control samples is hampered by the rapid hydrolysis by esterases present in the blood. With dried blood spot (DBS) as sample matrix, continued degradation of the esters is avoided due to inactivation of the hydrolase enzymes in dried blood. Here we have developed the method further for detection of testosterone esters in DBS with focus on robustness and applicability in doping control. To demonstrate the method's feasibility, DBS samples from men receiving two intramuscular injections of Sustanon® 250 (n = 9) or placebo (n = 10), were collected, transported and stored prior to analysis, to mimic a doping control scenario. The presented nanoLC-HRMS/MS method appeared reliable and suitable for direct detection of four testosterone esters (testosterone decanoate, isocaproate, phenylpropionate and propionate) after extraction from DBS. Sustanon® was detected in all subjects for at least five days, with detection window up to 14 days for three of the esters. Evaluation of analyte stability showed that while storage at room temperature is tolerated well for a few days, testosterone esters are highly stable (> 18 months) in DBS when stored in frozen conditions. Collectively, these findings demonstrate the applicability of DBS sampling in doping control for detection of steroid esters. The fast collection and reduced shipment costs of DBS compared to urine and standard blood samples, respectively, will allow more frequent and/or large-scale testing to increase detection and deterrence.

We investigated the effect of caffeine and acetaminophen on power output during a 6-min performance-test, peripheral fatigue, and muscle protein kinase A (PKA) substrate-phosphorylation. Fourteen men (age(mean±SD): 26±6 years; V̇O2max: 63.9±5.0 mL∙min-1∙kg-1) completed four randomized trials with acetaminophen (1500 mg), caffeine (5 mg∙kg body wt-1), combined caffeine and acetaminophen (caffeine+acetaminophen) or placebo. Mean power output during the 6-min performance-test (placebo mean:312±41 W) was higher with caffeine (+5 W; 95% CI: 1 to 9; P = 0.017) and caffeine + acetaminophen (+6 W; 95% CI: 0 to 12; P = 0.049) than placebo, but not with acetaminophen (+1 W; 95% CI: -4 to 7; P = 0.529). Decline in quadriceps maximal isometric voluntary torque immediately after the performance test was lower (treatment × time; P = 0.035) with acetaminophen (-40 N∙m; 95% CI: -53 to -30; P < 0.001) and caffeine + acetaminophen (-44 N∙m; 95% CI: -58 to -30; P < 0.001) than placebo (-53 N∙m; 95% CI: -71 to -39; P < 0.001) but was similar with caffeine (-54 N∙m; 95% CI: -69 to -38; P < 0.001). Muscle phosphocreatine content decreased more during the performance test (treatment × time; P = 0.036) with caffeine + acetaminophen (-55 mmol∙kg dry wt-1; 95% CI: -65 to -46; P < 0.001) than placebo (-40 mmol∙kg dry wt-1; 95% CI: -52 to -24; P < 0.001). Muscle net lactate accumulation was not different from placebo (+85 mmol∙kg dry wt-1; 95% CI: 60 to 110; P < 0.001) for any treatment (treatment × time; P = 0.066), being +75 mmol∙kg dry wt-1 (95% CI: 51 to 99; P < 0.001) with caffeine, +76 mmol∙kg dry wt-1 (95% CI: 58 to 96; P < 0.001) with acetaminophen, and +103 mmol∙kg dry wt-1 (95% CI: 89 to 115; P < 0.001) with caffeine + acetaminophen. Decline in muscle ATP and glycogen content and increase in PKA substrate phosphorylation was not different between treatments (treatment × time; P > 0.1). Thus, acetaminophen provides no additive performance enhancing effect to caffeine during 6-min maximal cycling. In addition, change in PKA activity is likely not a major mechanism of performance improvement with caffeine.

Background Physical inactivity is recognized as a leading global public health threat. Physical Literacy, a concept describing an individual’s prerequisites to participate in and adhere to physical activities, has been suggested to be a key concept in understanding physical activity in various populations. The aim of this study was to describe the prerequisites for physical activity among inactive adults in terms of their physical literacy and previous experience with sport and exercise and how these are interrelated. Methods Sample: 1033 physical inactive Danes. Measures: BREQ-3, ESES, the Levels of knowledge questionnaire and the physical self-confidence scale. Results Inactive Danish adult’s physical literacy scores are generally low compared to samples in other studies. Inactive adults with no or little previous experience with sport and exercise had lower levels of competences, self-efficacy and autonomous motivation for exercise and sport than the inactive with more experience. Previous sport and exercise experience was positively associated to the physical and affective domain of PL. Conclusion Previous experience with sport and exercise is very important to consider when developing sport and exercise activities for currently inactive adults as individuals with low previous experience have lower competences and autonomous motivation and therefore need lower challenges and other important attention to the motivational climate in order to ensure that the activities are motivating enough to secure continued engagement.

Skin grafting following a burn injury attenuates/abolishes sweat production within grafted areas. It is presently unknown whether the thermoregulatory consequences of skin grafting depend on anatomical location.Purpose: To test the hypothesis that a simulated burn injury on the torso will be no more or less detrimental to core temperature control than on the limbs during uncompensable exercise-heat stress.Methods: Nine non-burned individuals (7 males, 2 females) completed the protocol. On separate occasions, burn injuries of identical surface area (0.45 ± 0.08 m2 or 24.4% ± 4.4% of total body surface area) were simulated on the torso or the arms/legs using an absorbent, vapor-impermeable material that impedes sweat evaporation in those regions. Participants performed 60 min of treadmill walking at 5.3 km·h-1 and a 4.1% ± 0.8% grade, targeting 6 W·kg-1 of metabolic heat production in 40.1°C ± 0.2°C and 19.6% ± 0.6% relative humidity conditions. Rectal temperature, heart rate, and perceptual responses were measured.Results: Rectal temperature increased to a similar extent with simulated injuries on the torso and limbs (condition-by-time interaction: P = 0.86), with a final rectal temperature 0.9 ± 0.3°C above baseline in both conditions. No differences in heart rate, perceived exertion, or thermal sensation were observed between conditions (condition-by-time interactions: P ≥ 0.50).Conclusion: During uncompensable exercise-heat stress, sized-matched simulated burn injuries on the torso or limbs evoke comparable core temperature, heart rate, and perceptual responses, suggesting that the risk of exertional heat illness in such environmental conditions is independent of injury location.

Background: Electroencephalography (EEG) and single-pulse transcranial magnetic stimulation (spTMS) of the primary motor hand area (M1-HAND) have been combined to explore whether the instantaneous expression of pericentral mu-rhythm drives fluctuations in corticomotor excitability, but this line of research has yielded diverging results.Objectives: To re-assess the relationship between the mu-rhythm power expressed in left pericentral cortex and the amplitude of motor potentials (MEP) evoked with spTMS in left M1-HAND.Methods: 15 non-preselected healthy young participants received spTMS to the motor hot spot of left M1-HAND. Regional expression of mu-rhythm was estimated online based on a radial source at motor hotspot and informed the timing of spTMS which was applied either during epochs belonging to the highest or lowest quartile of regionally expressed mu-power. Using MEP amplitude as dependent variable, we computed a linear mixed-effects model, which included mu-power and mu-phase at the time of stimulation and the inter-stimulus interval (ISI) as fixed effects and subject as a random effect. Mu-phase was estimated by post-hoc sorting of trials into four discrete phase bins. We performed a follow-up analysis on the same EEG-triggered MEP data set in which we isolated mu-power at the sensor level using a Laplacian montage centered on the electrode above the M1-HAND.Results: Pericentral mu-power traced as radial source at motor hot spot did not significantly modulate the MEP, but mu-power determined by the surface Laplacian did, showing a positive relation between mu-power and MEP amplitude. In neither case, there was an effect of mu-phase on MEP amplitude.Conclusion: The relationship between cortical oscillatory activity and cortical excitability is complex and minor differences in the methodological choices may critically affect sensitivity.

Background: Vegan diets, where animal- and all their by-products are excluded from the diet, have gained popularity, especially in the last decade. However, the evaluation of this type of diet has not been well addressed in the scientific literature. This study aimed to investigate the adequacy of vegan diets in European populations and of their macro- and micronutrient intakes compared to World Health Organization recommendations.Methods: A systematic search in PubMed, Web of Science, IBSS, Cochrane library and Google Scholar was conducted and 48 studies (12 cohorts and 36 cross-sectional) were included.Results: Regarding macronutrients, vegan diets are lower in protein intake compared with all other diet types. Veganism is also associated with low intake of vitamins B2, Niacin (B3), B12, D, iodine, zinc, calcium, potassium, selenium. Vitamin B12 intake among vegans is significantly lower (0.24-0.49 μg, recommendations are 2.4 μg) and calcium intake in the majority of vegans was below recommendations (750 mg/d). No significant differences in fat intake were observed. Vegan diets are not related to deficiencies in vitamins A, B1, Β6, C, E, iron, phosphorus, magnesium, copper and folate and have a low glycemic load.Conclusions: Following a vegan diet may result in deficiencies in micronutrients (vitamin B12, zinc, calcium and selenium) which should not be disregarded. However, low micro- and macronutrient intakes are not always associated with health impairments. Individuals who consume a vegan diet should be aware of the risk of potential dietary deficiencies.

We investigated whether immature reticulocyte fraction (IRF) and immature reticulocytes to red blood cells ratio (IR/RBC) are sensitive biomarkers for low-dose recombinant human erythropoietin (rhEpo) treatment at sea-level (SL) and moderate altitude (AL) and whether multi (FACS) or single (Sysmex-XN) fluorescence flow cytometry is superior for IRF and IR/RBC determination. Thirty-nine participants completed two interventions, each containing a four-week baseline, a four-week SL or AL (2,230m) exposure and a four-week follow-up. During exposure, rhEpo (20 IU·kg-1) or placebo (PLA) was injected at SL (SLrhEpo n = 25, SLPLA n = 9) and AL (ALrhEpo n = 12, ALPLA n = 27) every second day for three weeks. Venous blood was collected weekly. Sysmex measurements revealed that IRF and IR/RBC was up to ~70% (P < 0.01) and ~190% (P < 0.001) higher in SLrhEpo than SLPLA during treatment and up to ~45% (P < 0.001) and ~55% (P < 0.01) lower post-treatment, respectively. Compared with ALPLA, IRF and IR/RBC was up to ~20% (P < 0.05) and ~45% (P < 0.001) lower post-treatment in SLrhEpo, respectively. In ALrhEpo, IRF and IR/RBC was up to ~40% (P < 0.05) and ~110% (P < 0.001) higher during treatment and up to ~25% (P < 0.05) and ~40% (P < 0.05) lower post-treatment, respectively, compared with ALPLA. Calculated thresholds provided ~90% sensitivity for both biomarkers at SL and 33% (IRF) and 66% (IR/RBC) at AL. Specificity was >99%. Single-fluorescence flow cytometry coefficient of variation was >twofold higher at baseline (P < 0.001), and provided larger or similar changes compared to multi-fluorescence, albeit with smaller precision. In conclusion, IRF and IR/RBC were sensitive and specific biomarkers for low-dose rhEpo misuse at SL and AL.

Purpose It is controversial whether a higher intake of n-3 long-chain polyunsaturated fatty acids (n-3 LC PUFA) through breastfeeding is associated or not to a lower blood pressure (BP) during childhood. We aimed to clarify this point by undertaking a meta-analysis involving the data from seven European birth cohorts. Methods We searched https://www.birthcohort.net for studies that had collected breast milk samples, and had at least one BP measurement in childhood. Principal investigators were contacted, and all agreed to share data. One additional study was identified by contacts with the principal investigators. For each cohort, we analyzed the association of breast milk n-3 LC PUFAs with systolic and diastolic BP with linear mixed effects models or linear regression, and pooled the estimates with a random effects model. We also investigated age-specific and sex-specific associations. Results A total of 2188 participants from 7 cohorts were included. Overall, no associations between breast milk n-3 LC PUFAs and BP were observed. In the pooled analysis, each 0.1 wt% increment in breast milk docosahexaenoic acid (DHA) was associated with a 1.19 (95% CI − 3.31, 0.94) mmHg lower systolic BP. Associations were similar for boys and girls and at different ages. Conclusion In this individual participant meta-analysis, we found no evidence for an association between breast milk n-3 LC PUFAs and BP.

Exercise in humans increases muscle glucose uptake up to 100-fold compared with rest. The magnitude of increase depends on exercise intensity and duration. Although knockout of glucose transporter type 4 (GLUT4) convincingly has shown that GLUT4 is necessary for exercise to increase muscle glucose uptake, studies only show an approximate twofold increase in GLUT4 translocation to the muscle cell membrane when transitioning from rest to exercise. Therefore, there is a big discrepancy between the increase in glucose uptake and GLUT4 translocation. It is suggested that either the methods for measurements of GLUT4 translocation in muscle grossly underestimate the real translocation of GLUT4 or, alternatively, GLUT4 intrinsic activity increases in muscle during exercise, perhaps due to increased muscle temperature and/or mechanical effects during contraction/relaxation cycles.

As individuals seek increasingly individualised nutrition and lifestyle guidance, numerous apps and nutrition programmes have emerged. However, complex individual variations in dietary behaviours, genotypes, gene expression and composition of the microbiome are increasingly recognised. Advances in digital tools and artificial intelligence can help individuals more easily track nutrient intakes and identify nutritional gaps. However, the influence of these nutrients on health outcomes can vary widely among individuals depending upon life stage, genetics and microbial composition. For example, folate may elicit favourable epigenetic effects on brain development during a critical developmental time window of pregnancy. Genes affecting vitamin B12 metabolism may lead to cardiometabolic traits that play an essential role in the context of obesity. Finally, an individual’s gut microbial composition can determine their response to dietary fibre interventions during weight loss. These recent advances in understanding can lead to a more complete and integrated approach to promoting optimal health through personalised nutrition, in clinical practice settings and for individuals in their daily lives. The purpose of this review is to summarise presentations made during the DSM Science and Technology Award Symposium at the 13th European Nutrition Conference, which focused on personalised nutrition and novel technologies for health in the modern world.

Background Malnutrition continues to be a major cause of mortality and morbidity among children in resource limited settings. Children with severe acute malnutrition (SAM) experience severe thymus atrophy, possibly reflecting poor immune function. This immune dysfunction is responsible for the severe infections they experience which lead to mortality. Since their immune dysfunction is not fully understood and there has been a lapse in research in this field, more research is needed. Knowing the correlates of thymus size may help clinicians identify those with more severe atrophy who might have more severe immune impairment. We aimed to describe thymus size and its correlates at admission among children hospitalized with SAM. Methods This cross-sectional study involved children 6-59 months admitted with complicated SAM in Mulago National Referral Hospital. Well-nourished children from same communities were used as a community reference group for thymus size. At admission, thymus size was measured by ultrasound scan. Demographic, clinical and laboratory variables were identified at admission. A linear regression model was used to determine correlates of thymus size among children with SAM. Results Among 388 children with SAM, the mean age was 17±8.5 months and 58% were boys. The mean thymus size was 3.14 (95% CI 2.9; 3.4) cm2 lower than that of the 27 healthy community reference children (1.06 vs 4.2 cm2, p 2 weeks duration of sickness (-0.10; 95% CI -0.19; -0.01). Conclusion The thymus is indeed a barometer for nutrition since all anthropometric measurements and breastfeeding were associated with bigger thymus. The immune benefits of breastfeeding among children with SAM is underscored. Children with longer duration of illness had a smaller thymus gland indicating that infections have a role in the cause or consequence of thymus atrophy.

Background: Observational studies have documented lower risks of coronary heart disease and diabetes among moderate alcohol consumers relative to abstainers, but only a randomized clinical trial can provide conclusive evidence for or against these associations. Aim: The purpose of this study was to describe the rationale and design of the Moderate Alcohol and Cardiovascular Health Trial, aimed to assess the cardiometabolic effects of one alcoholic drink daily over an average of six years among adults 50 years or older. Methods: This multicenter, parallel-arm randomized trial was designed to compare the effects of one standard serving (∼11–15 g) daily of a preferred alcoholic beverage to abstention. The trial aimed to enroll 7800 people at high risk of cardiovascular disease. The primary composite endpoint comprised time to the first occurrence of non-fatal myocardial infarction, non-fatal ischemic stroke, hospitalized angina, coronary/carotid revascularization, or total mortality. The trial was designed to provide >80% power to detect a 15% reduction in the risk of the primary outcome. Secondary outcomes included diabetes. Adverse effects of special interest included injuries, congestive heart failure, alcohol use disorders, and cancer. Results: We describe the design, governance, masking issues, and data handling. In three months of field center activity until termination by the funder, the trial randomized 32 participants, successfully screened another 70, and identified ∼400 additional interested individuals. Conclusions: We describe a feasible design for a long-term randomized trial of moderate alcohol consumption. Such a study will provide the highest level of evidence for the effects of moderate alcohol consumption on cardiovascular disease and diabetes, and will directly inform clinical and public health guidelines. Fil: Spiegelman, Donna. Harvard University. Harvard School of Public Health; Estados Unidos Fil: Lovato, Laura C.. Universidad de Barcelona; España Fil: Khudyakov, Polyna. Harvard University. Harvard School of Public Health; Estados Unidos. Universidad de Barcelona; España Fil: Wilkens, Trine L.. Universidad de Copenhagen; Dinamarca Fil: Adebamowo, Clement A.. University of Maryland; Estados Unidos Fil: Adebamowo, Sally N.. University of Maryland; Estados Unidos Fil: Appel, Lawrence J.. No especifíca; Fil: Beulens, Joline W.J.. No especifíca; Fil: Coughlin, Janelle W.. No especifíca; Fil: Dragsted, Lars Ove. Universidad de Copenhagen; Dinamarca Fil: Edenberg, Howard J. No especifíca; Fil: Eriksen, Jane N.. Universidad de Copenhagen; Dinamarca Fil: Estruch, Ramon. Universidad de Barcelona; España Fil: Grobbee, Diederick E.. No especifíca; Fil: Gulayin, Pablo Elías. No especifíca; Fil: Irazola, Vilma. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Centro de Investigaciones en Epidemiología y Salud Pública. Instituto de Efectividad Clínica y Sanitaria. Centro de Investigaciones en Epidemiología y Salud Pública; Argentina Fil: Krystal, John H.. University of Yale. School of Medicine; Estados Unidos Fil: Lazo, Mariana. No especifíca; Fil: Murray, Margaret M.. University of Yale. School of Medicine; Estados Unidos Fil: Rimm, Eric B.. Harvard University. Harvard School of Public Health; Estados Unidos Fil: Schrieks, Ilse C.. Universidad de Barcelona; España Fil: Williamson, Jeff D.. No especifíca; Fil: Mukamal, Kenneth J.. Harvard Medical School; Estados Unidos

KEY POINTS Patients with renal failure undergoing maintenance haemodialysis are associated with insulin resistance and protein metabolism dysfunction. Novel research suggests that disruption to the transmembrane protein linkage between the cytoskeleton and the extracellular matrix in skeletal muscle may contribute to reduced amino acid metabolism and insulin resistance in haemodialysis. ILK, PINCH1 and pFAKTyr397 were significantly decreased in haemodialysis compared to controls, whereas Rac1 and Akt2 showed no different between groups. Rac1 deletion in the Rac1 knockout model did not alter the expression of integrin-associated proteins. Phenylalanine kinetics were reduced in the haemodialysis group at 30 and 60 min post meal ingestion compared to controls; both groups showed similar levels of insulin sensitivity and β-cell function. Key proteins in the integrin-cytoskeleton linkage are reduced in haemodialysis patients, suggesting for the first time that integrin-associated proteins dysfunction may contribute to reduced phenylalanine flux without affecting insulin resistance in haemodialysis patients. ABSTRACT Muscle atrophy, insulin resistance and reduced muscle phosphoinositide 3-kinase-Akt signalling are common characteristics of patients undergoing maintenance haemodialysis (MHD). Disruption to the transmembrane protein linkage between the cytoskeleton and the extracellular matrix in skeletal muscle may contribute to reduced amino acid metabolism and insulin resistance in MHD patients. Eight MHD patients (age: 56 ± 5 years: body mass index: 32 ± 2 kg m-2 ) and non-diseased controls (age: 50 ± 2 years: body mass index: 31 ± 1 kg m-2 ) received primed continuous l-[ring-2 H5 ]phenylalanine before consuming a mixed meal. Phenylalanine metabolism was determined using two-compartment modelling. Muscle biopsies were collected prior to the meal and at 300 min postprandially. In a separate experiment, skeletal muscle tissue from muscle-specific Rac1 knockout (Rac1 mKO) was harvested to investigate whether Rac1 depletion disrupted the cytoskeleton-integrin linkage, allowing for cross-model examination of proteins of interest. ILK, PINCH1 and pFAKTyr397 were significantly lower in MHD (P

Background & aims: Treatment of children with uncomplicated severe acute malnutrition (SAM) is based on ready-to-use therapeutic foods (RUTF) and aims for quick regain of lost body tissues while providing sufficient micronutrients to restore diminished body stores. Little evidence exists on the success of the treatment to establish normal micronutrient status. We aimed to assess the changes in vitamin A and iron status of children treated for SAM with RUTF, and explore the effect of a reduced RUTF dose.Methods: We collected blood samples from children 6-59 months old with SAM included in a randomised trial at admission to and discharge from treatment and analysed haemoglobin (Hb) and serum concentrations of retinol binding protein (RBP), ferritin (SF), soluble transferrin receptor (sTfR), C-reactive protein (CRP) and α1-acid glycoprotein (AGP). SF, sTfR and RBP were adjusted for inflammation (CRP and AGP) prior to analysis using internal regression coefficients. Vitamin A deficiency (VAD) was defined as RBP < 0.7 μmol/l, anaemia as Hb < 110 g/l, storage iron deficiency (sID) as SF < 12 μg/l, tissue iron deficiency (tID) as sTfR > 8.3 mg/l and iron deficiency anaemia (IDA) as both anaemia and sID. Linear and logistic mixed models were fitted including research team and study site as random effects and adjusting for sex, age and outcome at admission.Results: Children included in the study (n = 801) were on average 13 months of age at admission to treatment and the median treatment duration was 56 days [IQR: 35; 91] in both arms. Vitamin A and iron status markers did not differ between trial arms at admission or at discharge. Only Hb was 1.7 g/l lower (95% CI -0.3, 3.7; p = 0.088) in the reduced dose arm compared to the standard dose, at recovery. Mean concentrations of all biomarkers improved from admission to discharge: Hb increased by 12% or 11.6 g/l (95% CI 10.2, 13.0), RBP increased by 13% or 0.12 μmol/l (95% CI 0.09, 0.15), SF increased by 36% or 4.4 μg/l (95% CI 3.1, 5.7) and sTfR decreased by 16% or 1.5 mg/l (95% CI 1.0, 1.9). However, at discharge, micronutrient deficiencies were still common, as 9% had VAD, 55% had anaemia, 35% had sID, 41% had tID and 21% had IDA.Conclusion: Reduced dose of RUTF did not result in poorer vitamin A and iron status of children. Only haemoglobin seemed slightly lower at recovery among children treated with the reduced dose. While improvement was observed, the vitamin A and iron status remained sub-optimal among children treated successfully for SAM with RUTF. There is a need to reconsider RUTF fortification levels or test other potential strategies in order to fully restore the micronutrient status of children treated for SAM.

Background & Aims: Treatment of children with uncomplicated severe acute malnutrition (SAM) is based on ready-to-use therapeutic foods (RUTF) prescribed based on body weight and administered at home. Treatment performance is typically monitored through weight gain. We previously reported that a reduced dose of RUTF resulted in weight gain velocity similar to standard dose. Here we investigate the change in body composition of children treated for SAM and compare it to community controls, and describe the effect of a reduced RUTF dose on body composition at recovery.Methods: Body composition was measured via bio-electrical impedance analysis at admission and recovery among a sub-group of children with SAM participating in a clinical trial and receiving a reduced or a standard dose of RUTF. Non-malnourished children were measured to represent community controls. Linear mixed regression models were fitted.Results: We obtained body composition data from 452 children at admission, 259 at recovery and 97 community controls. During SAM treatment the average weight increased by 1.20 kg of which 0.55 kg (45%) was fat-free mass (FFM) and 0.67 kg (55%) was fat mass (FM). At recovery, children treated for SAM had 1.27 kg lower weight, 0.38 kg lower FFM, and 0.90 kg lower FM compared to community controls. However, their fat-free mass index (FFMI) was not different from community controls (Δ0.2 kg/m2; 95% CI -0.1, 0.4). No differences were observed in FFM, FM or fat mass index (FMI) between the study arms at recovery. However, FFMI was 0.35 kg/m2 higher at recovery with the reduced compared to standard dose (p = 0.007) due to slightly lower height (Δ0.22 cm; p = 0.25) and higher FFM (Δ0.11 kg; p = 0.078) in the reduced dose group.Conclusions: Almost half of the weight gain during SAM treatment was FFM. Compared to community controls, children recovered from SAM had a lower FM while their height-adjusted FFM was similar. There was no evidence of a differential effect of a reduced RUTF dose on the tissue accretion of treated children when compared to standard treatment.

Background: It has been suggested that low-energy sweeteners (LES) may be associated with an increased risk of metabolic diseases, possibly due to stimulation of glucose-responsive mechanisms.Objective: We conducted a systematic review and meta-analysis of human intervention studies examining the acute effect of LES intake on postprandial glucose (PPG) and postprandial insulin (PPI) responses, in order to comprehensively and objectively quantify these relations.Methods: We systematically searched the Medline, OVID FSTA, and SCOPUS databases until January 2020. Randomized controlled trials comparing acute postprandial effects on PPG and/or PPI after exposure to LES, either alone, with a meal, or with other nutrient-containing preloads to the same intervention without LES were eligible for inclusion. PPG and PPI responses were calculated as mean incremental area under the curve divided by time. Meta-analyses were performed using random effects models with inverse variance weighing.Results: Twenty-six papers (34 PPG trials and 29 PPI trials) were included. There were no reports of statistically significant differences in the effects of LES on PPG and PPI responses compared with control interventions. Pooled effects of LES intake on the mean change difference in PPG and PPI were -0.02 mmol/L (95% CI: -0.09, 0.05) and -2.39 pmol/L (95% CI: -11.83, 7.05), respectively. The results did not appreciably differ by the type or dose of LES consumed, cointervention type, or fasting glucose and insulin levels. Among patients with type 2 diabetes, the mean change difference indicated a smaller PPG response after exposure to LES compared with the control (-0.3 mmol/L; 95% CI: -0.53, -0.07).Conclusions: Ingestion of LES, administered alone or in combination with a nutrient-containing preload, has no acute effects on the mean change in postprandial glycemic or insulinemic responses compared with a control intervention. Apart from a small beneficial effect on PPG (-0.3 mmol/L) in studies enrolling patients with type 2 diabetes, the effects did not differ by type or dose of LES, or fasting glucose or insulin levels. This review and meta-analysis was registered at PROSPERO as CRD42018099608.

[Context and purpose]: Individual participant data-level meta-regression (IPD) analysis is superior to meta-regression based on aggregate data in determining Dietary Reference Values (DRV) for vitamin D. Using data from randomized controlled trials (RCTs) with vitamin D3-fortified foods, we undertook an IPD analysis of the response of winter serum 25-hydroxyvitamin (25(OH)D) to total vitamin D intake among children and adults and derived DRV for vitamin D., [Methods]: IPD analysis using data from 1429 participants (ages 2–89 years) in 11 RCTs with vitamin D-fortified foods identified via a systematic review and predefined eligibility criteria. Outcome measures were vitamin D DRV estimates across a range of serum 25(OH)D thresholds using unadjusted and adjusted models., [Results]: Our IPD-derived estimates of vitamin D intakes required to maintain 97.5% of winter 25(OH)D concentrations ≥ 25 and ≥ 30 nmol/L are 6 and 12 µg/day, respectively (unadjusted model). The intake estimates to maintain 90%, 95% and 97.5% of concentrations ≥ 50 nmol/L are 33.4, 57.5 and 92.3 µg/day, respectively (unadjusted) and 17.0, 28.1 and 43.6 µg/day, respectively (adjusted for mean values for baseline serum 25(OH)D, age and BMI)., [Conclusions]: IPD-derived vitamin D intakes required to maintain 90%, 95% and 97.5% of winter 25(OH)D concentrations ≥ 50 nmol/L are much higher than those derived from standard meta-regression based on aggregate data, due to the inability of the latter to capture between person-variability. Our IPD provides further evidence that using food-based approaches to achieve an intake of 12 µg/day could prevent vitamin D deficiency (i.e., serum 25(OH)D

Introduction: Major risk factors for type 2 diabetes are lifestyle choices such as lack of physical activity (PA) and poor diet. Many individuals either do not take part or struggle to complete interventions supporting lifestyle changes. Demographic and theory-based sociocognitive factors associated with PREVIEW intervention attrition after successful weight loss were examined.Methods: Participants (1,856) who started the weight maintenance phase after completion of low-energy diet were retrospectively divided into three clusters depending on the point they left the trial. Discriminant analysis examined which demographic and theory-based sociocognitive variables were associated with cluster membership.Results: Most of the participants were women and well-educated. Two discriminant functions were calculated (χ2 (24) = 247.0, p ≥ .05, d = 0.78). The demographic variables, such as age and ethnicity, and the social cognitive variable outcome expectancies on the other side were associated with cluster membership. Older age, Caucasian ethnicity, and fewer expected disadvantages of PA were associated with high success.Discussion: The discriminant model gave insight into some factors associated with early attrition. For practitioners planning interventions it underlines the necessity to take extra attention to younger participants and to those being afraid that being physically active causes unpleasant ramifications.

Female sex hormones fluctuate in a predictable manner throughout the menstrual cycle in eumenorrheic women. In studies conducted in both animal and humans, estrogen and progesterone have been found to exert individual metabolic effects during both rest and exercise, suggesting that estrogen may cause an increase in fat oxidation during exercise. However, not all studies find these metabolic changes with the natural physiological variation in the sex hormones. To date, no studies have investigated whether whole body peak fat oxidation rate (PFO) and maximal fat oxidation intensity (FATmax) are affected at different time points [mid-follicular (MF), late-follicular (LF), and mid-luteal (ML)] in the menstrual cycle, where plasma estrogen and progesterone are either at their minimum or maximum. We hypothesized that an increased plasma estrogen concentration together with low progesterone concentration in LF would result in a modest but significant increase in PFO. We found no differences in body weight, body composition, or peak oxygen uptake (V̇o2peak) between any of the menstrual phases in the 19 healthy, young eumenorrheic women included in this study. PFO [MF: 0.379 (0.324–0.433) g/min; LF: 0.375 (0.329–0.421) g/min; ML: 0.382 (0.337–0.442) g/min; mean ± (95% CI)] and resting plasma free fatty acid concentrations [MF: 392 (293–492) µmol/l; LF: 477 (324–631) µmol/l; ML: 396 (285–508) µmol/L] were also similar across the menstrual cycle phases. Contrary to our hypothesis, we conclude that the naturally occurring fluctuations in the sex hormones estrogen and progesterone do not affect the whole body PFO and FATmax in young eumenorrheic women measured during a graded exercise test. NEW & NOTEWORTHY Menstrual cycle phase does not affect the peak fat oxidation rate during a graded exercise test. Natural physiological fluctuations in estrogen do not increase peak fat oxidation rate. FATmax is not influenced by menstrual cycle phase in healthy, young eumenorrheic women.

The present study examined skeletal muscle metabolism and changes in repeated sprint performance during match play for n = 20 competitive elite women outfield players. We obtained musculus vastus lateralis biopsies and blood samples before, after, and following intense periods in each half of a friendly match, along with 5 × 30-meter sprint tests and movement pattern analyses (10-Hz S5 Global Positioning System [GPS]). Muscle glycogen decreased by 39% and 42% after an intense period of the second half and after the match, respectively, compared to baseline (p < 0.05). Post-match, 80% type I fibers and 69% type II fibers were almost empty or completely empty of glycogen. Muscle lactate was higher (p < 0.05) after the intense period of the first half and post-match compared to baseline (14.3 ± 4.6 (±SEM) and 12.9 ± 5.7 vs. 6.4 ± 3.7 mmol/kg d.w.). Muscle phosphocreatine was reduced (p < 0.05) by 16% and 12%, respectively, after an intense period in the first and second half compared to baseline. Blood lactate and glucose increased during the match and peaked at 8.4 ± 2.0 and 7.9 ± 1.2 mmol/L, respectively. Mean 5 × 30 m sprint time declined by 3.2 ± 1.7 and 7.0 ± 2.1% after the first and second half, respectively, and 4.7 ± 1.6% (p < 0.05) after an intense period in the first half compared to baseline. In conclusion, match play in elite female football players resulted in marked glycogen depletion in both fiber types, which may explain fatigue at the end of a match. Repeated sprint ability was impaired after intense periods in the first half and after both halves, which may be associated with the observed muscle metabolite perturbations.

Aim: Gastrointestinal (GI) symptoms are often reported by CF-patients. Despite a proven relation to exocrine pancreatic insufficiency (PI), it remains unclear whether GI symptoms are related to the timing of pancreatic enzyme replacement therapy (PERT). Whereas most international recommendations suggest administration of PERT at the beginning of meals, it has not been studied whether such a proceeding is associated with lower burden of symptoms.Methods: Thirty CF patients aged 0-17 years of age with PI were randomized to four weeks of PERT prior to meals followed by four weeks of PERT after meals or vice versa. Using the CF-specific validated CFAbd-Score, abdominal pain, dysfunctional bowel habits and Quality of Life (QoL) related to GI symptoms were assessed in relation to the timing of PERT. Data was analyzed using a linear mixed model.Results: There was no significant difference regarding abdominal pain, bowel habits or QoL related to GI symptoms when timing of PERT was changed from prior to after meals.Conclusion: No significant difference was found when administration mode of PERT changed from prior to after meals or vice versa. However, after an individual assessment, some patients may profit from changing administration mode of PERT from prior to after meals.

Metformin and exercise both improve glycemic control, but in vitro studies have indicated that an interaction between metformin and exercise occurs in skeletal muscle, suggesting a blunting effect of metformin on exercise training adaptations. Two studies (a double-blind, parallel-group, randomized clinical trial conducted in 29 glucose-intolerant individuals and a double-blind, cross-over trial conducted in 15 healthy lean males) were included in this paper. In both studies, the effect of acute exercise ± metformin treatment on different skeletal muscle variables, previously suggested to be involved in a pharmaco-physiological interaction between metformin and exercise, was assessed. Furthermore, in the parallel-group trial, the effect of 12 weeks of exercise training was assessed. Skeletal muscle biopsies were obtained before and after acute exercise and 12 weeks of exercise training, and mitochondrial respiration, oxidative stress and AMPK activation was determined. Metformin did not significantly affect the effects of acute exercise or exercise training on mitochondrial respiration, oxidative stress or AMPK activation, indicating that the response to acute exercise and exercise training adaptations in skeletal muscle is not affected by metformin treatment. Further studies are needed to investigate whether an interaction between metformin and exercise is present in other tissues, e.g., the gut. Trial registration: ClinicalTrials.gov (NCT03316690 and NCT02951260). Novelty: Metformin does not affect exercise-induced alterations in mitochondrial respiratory capacity in human skeletal muscle. Metformin does not affect exercise-induced alterations in systemic levels of oxidative stress nor emission of reactive oxygen species from human skeletal muscle. Metformin does not affect exercise-induced AMPK activation in human skeletal muscle.

Treatment of obesity with repurposed or novel drugs is an expanding research field. One approach is to target beta2-adrenergic receptors because they regulate the metabolism and phenotype of adipose and skeletal muscle tissue. Several observations support a role of the beta2-adrenergic receptor in obesity. Specific human beta2-adrenergic receptor polymorphisms are associated with body composition and obesity, for which the Gln27Glu polymorphism is associated with obesity, while the Arg16Gly polymorphism is associated with lean mass in men and the development of obesity in specific populations. Individuals with obesity also have lower abundancy of beta2-adrenergic receptors in adipose tissue and are less sensitive to catecholamines. In addition, studies in livestock and rodents demonstrate that selective beta2-agonists induce a so-called "repartitioning effect" characterized by muscle accretion and reduced fat deposition. In humans, beta2-agonists dose-dependently increase resting metabolic rate by 10-50%. And like that observed in other mammals, only a few weeks of treatment with beta2-agonists increases muscle mass and reduces fat mass in young healthy individuals. Beta2-agonists also exert beneficial effects on body composition when used concomitantly with training and work additively to increase muscle strength and mass during periods with resistance training. Thus, the beta2-adrenergic receptor seems like an attractive target in the development of anti-obesity drugs. However, future studies need to verify the long-term efficacy and safety of beta2-agonists in individuals with obesity, particularly in those with comorbidities.

Salmeterol is a long acting beta2-agonist (LABA) used widely for the treatment of airways disease. There is evidence that beta2-agonists, including salmeterol, have the potential for performance enhancing effects when delivered at supratherapeutic doses. For this reason, all beta2-agonists are currently on the Prohibited List issued by the World Anti-Doping Agency (WADA), regardless of dosing route with some exemptions for inhaled salbutamol, formoterol, and salmeterol when used at therapeutic inhaled doses. For 2020, salmeterol use is permitted up to a therapeutic dosing threshold of 200 μg daily, but unlike salbutamol and formoterol, there is an anomaly; currently there is no urine threshold to control for supratherapeutic dosing beyond this dosing threshold. Salmeterol, however, is reportable as an adverse analytical finding (AAF) at levels above 10 ng/mL. Complicating matters is that following inhalation, salmeterol parent drug is present at relatively low levels compared with other beta2-agonists due to rapid metabolism to the metabolite, alpha-hydroxysalmeterol, which is typically present at higher levels than the parent drug. Moreover, peak parent drug levels following permitted therapeutic dosing are below the minimum required performance level (MRPL) of 10 ng/mL for salmeterol (50% of the MRPL that analytical laboratories are required to meet for non-threshold beta2-agonists), hence the presence of salmeterol may be unreported. For consistency, a urine threshold should be introduced for salmeterol as a matter of priority, to balance the needs of athletes who use salmeterol therapeutically up to the agreed dosing threshold, with the need to control supratherapeutic dosing for doping intentions and athlete harm minimization.

Background Although the burden of impaired renal function is rising in sub-Saharan Africa (SSA), little is known about correlates of impaired renal function in the region. We determined factors associated with estimated glomerular filtration rate (eGFR) and impaired renal function in HIV-infected and HIV-uninfected adults. Methods We undertook cross-sectional analysis of data from 1947 adults at enrolment for a cohort study on diabetes and associated complications in HIV patients in Mwanza, north-western Tanzania. A structured questionnaire was used to collect data on sociodemography, smoking, alcohol, physical activity, antiretroviral therapy (ART) and anthropometry. We measured blood pressure, tested blood samples for creatinine, glucose and HIV, and performed Kato Katz for Schistosoma mansoni. Correlates of eGFR (mL/min/1.73 m2) and impaired renal function (eGFR2) were determined using linear regression and logistic regression, respectively. Results 655 (34%) participants were HIV-uninfected, 956 (49%) were ART-naive HIV-infected and 336 (17%) were HIV-infected adults on ART. The mean age was 41 years (SD12) and majority (59%) were females. Overall, the mean eGFR was 113.6 mL/min/1.73 m2 but 111.2 mL/min/1.73 m2 in HIV-uninfected, 109.7 mL/min/1.73 m2 in ART-naive HIV-infected and 129.5 mL/min/1.73 m2 in HIV-infected ART-experienced adults, and respective prevalence of impaired renal function was 7.0, 5.7, 8.1 and 6.3%. Correlates of lower eGFR were increasing age, higher socioeconomic status, unhealthy alcohol drinking, higher body mass index and diabetes mellitus. Anaemia was associated with 1.9 (95% Confidence Interval (CI):1.2, 2.7, p = 0.001) higher odds of impaired renal function compared to no anaemia and this effect was modified by HIV status (p value 0.02 for interaction). Conclusion Impaired renal function is prevalent in this middle-aged study population. Interventions for prevention of impaired renal function are needed in the study population with special focus in HIV-infected adults and those with high socioeconomic status. Interventions targeting modifiable risk factors such as alcohol and weight reduction are warranted.

Hemorrhage is a leading cause of battlefield and civilian trauma deaths. Several pain medications, including fentanyl, are recommended for use in the prehospital (i.e., field setting) for a hemorrhaging solider. However, it is unknown whether fentanyl impairs arterial blood pressure (BP) regulation, which would compromise hemorrhagic tolerance. Thus, the purpose of this study was to test the hypothesis that an analgesic dose of fentanyl impairs hemorrhagic tolerance in conscious humans. Twenty-eight volunteers (13 females) participated in this double-blinded, randomized, placebo-controlled trial. We conducted a pre-syncopal limited progressive lower-body negative pressure test (LBNP; a validated model to simulate hemorrhage) following intravenous administration of fentanyl (75 µg) or placebo (saline). We quantified tolerance as a cumulative stress index (mmHg•min), which was compared between trials using a paired, two-tailed t test. We also compared muscle sympathetic nerve activity (MSNA; microneurography) and beat-to-beat BP (photoplethysmography) during the LBNP test using a mixed effects model (time [LBNP stage] x trial). LBNP tolerance was not different between trials (Fentanyl: 647 ± 386 vs. Placebo: 676 ± 295 mmHg•min, P = 0.61, Cohen's d = 0.08). Increases in MSNA burst frequency (time: P < 0.01, trial: P = 0.29, interaction: P = 0.94) and reductions in mean BP (time: P < 0.01, trial: P = 0.50, interaction: P = 0.16) during LBNP were not different between trials. These data, the first to be obtained in conscious humans, demonstrate that administration of an analgesic dose of fentanyl does not alter MSNA or BP during profound central hypovolemia, nor does it impair tolerance to this simulated hemorrhagic insult.

Background Copy number (CN) variation (CNV) of the salivary amylase gene (AMY1) influences the ability to digest starch and may influence glucose homeostasis, obesity and gut microbiota composition. Hence, the aim was to examine the association of AMY1 CNV with fasting glucose, BMI, and gut microbiota composition considering habitual starch intake and to investigate the effect of AMY1 CNV on the postprandial response after two different starch doses. Methods The Malmö Offspring Study (n = 1764, 18–71 years) was used to assess interaction effects between AMY1 CNV (genotyped by digital droplet polymerase chain reaction) and starch intake (assessed by 4-day food records) on fasting glucose, BMI, and 64 gut bacteria (16S rRNA sequencing). Participants with low (≤ 4 copies, n = 9) and high (≥ 10 copies, n = 10) AMY1 CN were recruited for a crossover meal study to compare postprandial glycemic and insulinemic responses to 40 g and 80 g starch from white wheat bread. Results In the observational study, no overall associations were found between AMY1 CNV and fasting glucose, BMI, or gut microbiota composition. However, interaction effects between AMY1 CNV and habitual starch intake on fasting glucose (P = 0.03) and BMI (P = 0.05) were observed, suggesting inverse associations between AMY1 CNV and fasting glucose and BMI at high starch intake levels and positive association at low starch intake levels. No associations with the gut microbiota were observed. In the meal study, increased postprandial glucose (P = 0.02) and insulin (P = 0.05) were observed in those with high AMY1 CN after consuming 40 g starch. This difference was smaller and nonsignificant after consuming 80 g starch. Conclusions Starch intake modified the observed association between AMY1 CNV and fasting glucose and BMI. Furthermore, depending on the starch dose, a higher postprandial glucose and insulin response was observed in individuals with high AMY1 CN than in those with low AMY1 CN. Trial registration ClinicalTrials.gov, NCT03974126. Registered 4 June 2019—retrospectively registered.

Background Physical activity may be a way to increase and maintain fat-free mass (FFM) in later life, similar to the prevention of fractures by increasing peak bone mass. Objectives A study is presented of the association between FFM and physical activity in relation to age. Methods In a cross-sectional study, FFM was analyzed in relation to physical activity in a large participant group as compiled in the International Atomic Energy Agency Doubly Labeled Water database. The database included 2000 participants, age 3–96 y, with measurements of total energy expenditure (TEE) and resting energy expenditure (REE) to allow calculation of physical activity level (PAL = TEE/REE), and calculation of FFM from isotope dilution. Results PAL was a main determinant of body composition at all ages. Models with age, fat mass (FM), and PAL explained 76% and 85% of the variation in FFM in females and males

Background Approximately 20% of older people are readmitted to the hospital within 30 days of discharge. Even a short hospital stay decreases the ability to cope with the activities of daily living. The aims of this study were to (1) assess the feasibility of recruitment, (2) assess the acceptability of the intervention, and (3) investigate if an individual nutritional intervention could reduce the readmission rate of geriatric patients within 30 days of being discharged to their own homes. Methods The unblinded, randomized, controlled pilot trial includes geriatric patients discharged to their own homes. Forty patients were recruited from a medical ward and randomized to standard treatment (n = 19) or individualized nutritional intervention (n = 21). The intervention was dietary counseling and a nutrition plan before discharge, combined with two home visits performed by an educated nutritionist over a period of 4 weeks. Outcomes were readmission (primary), mortality, protein and energy intake, body weight, activity of daily living, handgrip strength, number of chair stands, and quality of life. Intention-to-treat analysis, per-protocol analysis, and post hoc analysis of readmissions were carried out. Results Recruitment was feasible, and there was high compliance to the intervention. There was no difference in readmission between the intervention group and control group 30 days after discharge (29% vs 11%). The individual nutritional intervention had a positive impact on achieving 75% of energy requirements at 30 days for the intervention group compared to the control group (93% vs 47%, p = 0.01). No other differences were found between the groups. Conclusion The individual nutritional intervention did not prevent readmission among geriatric patients in this trial. Recruitment procedures functioned well, and the intervention was well accepted by the patients. Trial registration ClinicalTrial.gov, NCT03519139. Retrospectively registered on 8 May 2018

Background: Individuals with pre-diabetes are commonly overweight and benefit from dietary and physical activity strategies aimed at decreasing body weight and hyperglycemia. Early insulin resistance can be estimated via the triglyceride glucose index {TyG = Ln [TG (mg/dl) × fasting plasma glucose (FPG) (mg/dl)/2]} and the hypertriglyceridemic-high waist phenotype (TyG-waist), based on TyG x waist circumference (WC) measurements. Both indices may be useful for implementing personalized metabolic management. In this secondary analysis of a randomized controlled trial (RCT), we aimed to determine whether the differences in baseline TyG values and TyG-waist phenotype predicted individual responses to type-2 diabetes (T2D) prevention programs.Methods: The present post-hoc analyses were conducted within the Prevention of Diabetes through Lifestyle intervention and population studies in Europe and around the world (PREVIEW) study completers (n = 899), a multi-center RCT conducted in eight countries (NCT01777893). The study aimed to reduce the incidence of T2D in a population with pre-diabetes during a 3-year randomized intervention with two sequential phases. The first phase was a 2-month weight loss intervention to achieve ≥8% weight loss. The second phase was a 34-month weight loss maintenance intervention with two diets providing different amounts of protein and different glycemic indices, and two physical activity programs with different exercise intensities in a 2 x 2 factorial design. On investigation days, we assessed anthropometrics, glucose/lipid metabolism markers, and diet and exercise questionnaires under standardized procedures.Results: Diabetes-related markers improved during all four lifestyle interventions. Higher baseline TyG index (p < 0.001) was associated with greater reductions in body weight, fasting glucose, and triglyceride (TG), while a high TyG-waist phenotype predicted better TG responses, particularly in those randomized to physical activity (PA) of moderate intensity.Conclusions: Two novel indices of insulin resistance (TyG and TyG-waist) may allow for a more personalized approach to avoiding progression to T2D.Clinical Trial Registration:https://clinicaltrials.gov/ct2/show/NCT01777893 reference, identifier: NCT01777893.

Objective: We aimed to determine the associations of non-alcoholic fatty liver disease (NAFLD) with cardio-metabolic risk factors for diabetes in adult Kenyans.Methods: A cross-sectional study was undertaken among rural and urban Kenyans of different ethnic origin. Ultrasonography scanning (USS) methods were used for the assessment of hepatic fat accumulation for NAFLD assessment and abdominal fat distribution, and simple anthropometry measurements were performed. All participants underwent a 2-h oral glucose tolerance test, and biochemical, haemodynamic and lifestyle data were obtained. Multivariate logistic regression analyses were used to assess sex, age, residency and ethnic differences in the association between NAFLD and various metabolic parameters.Results: In total, 743 individuals (59.1% women) with a mean age of 38.0 (range 18-68) years participated in the study. Overall, 118 individuals (15.9%) had NAFLD, of whom 94.1% had mild steatosis. Age >40 years was significantly associated with having NAFLD compared to p < 0.045 for OR).Conclusion: Finding lower odds for NAFLD in men was unexpected, as was the lack of differences in NAFLD among the ethnic groups, while higher odds for NAFLD with increasing age and in urban vs. rural populations was expected. Especially the sex-specific results warrant further studies in black African populations on biology of body composition for having NAFLD, and whether this translates into insulin resistance and higher risk of diabetes and consequently cardiovascular disease in black African women.

Adequate protein intake is essential for the maintenance of whole-body protein mass. Different methodological approaches are used to substantiate the evidence for the current protein recommendations, and it is continuously debated whether older adults require more protein to counteract the age-dependent loss of muscle mass, sarcopenia. Thus, the purpose of this critical narrative review is to outline and discuss differences in the approaches and methodologies assessing the protein requirements and, hence, resulting in controversies in current protein recommendations for healthy older adults. Through a literature search, this narrative review first summarises the historical development of the Food and Agriculture Organization/World Health Organization/United Nations University setting of protein requirements and recommendations for healthy older adults. Hereafter, we describe the various types of studies (epidemiological studies and protein turnover kinetic measurements) and applied methodological approaches founding the basis and the different recommendations with focus on healthy older adults. Finally, we discuss important factors to be considered in future studies to obtain evidence for international agreement on protein requirements and recommendations for healthy older adults. We conclude by proposing future directions to determine ‘true’ protein requirements and recommendations for healthy older adults.

Growth differentiation factor 15 (GDF15) has recently moved to the forefront of metabolism research. When administered pharmacologically, GDF15 reduces food intake and lowers body weight via the hindbrain-situated receptor GFRAL (glial cell–derived neurotrophic factor family receptor alpha-like). Endogenous GDF15 is a ubiquitous cellular stress signal that can be produced and secreted by a variety of cell types. Circulating levels are elevated in a series of disease states, but also in response to exogenous agents such as metformin, colchicine, AICAR, and cisplatin. Recently, exercise has emerged as a relevant intervention to interrogate GDF15 physiology. Prolonged endurance exercise increases circulating GDF15 to levels otherwise associated with certain pathological states and in response to metformin treatment. The jury is still out on whether GDF15 is a functional “exerkine” mediating organ-to-brain crosstalk or whether it is a coincidental bystander. In this review, we discuss the putative physiological implication of exercise-induced GDF15, focusing on the potential impact on appetite and metabolism.

Background Without high-quality nutritional support, there is a risk that people infected with human immunodeficiency virus (HIV) will replace lost muscle mass with fat mass when initiating antiretroviral therapy (ART). We have shown that lipid-based nutrient supplements (LNS) with whey or soy considerably increases lean mass among Ethiopian people with HIV starting ART. Here, we aim to assess the effects of LNS on insulin function and glucose metabolism. Methods This is a secondary analysis of a randomized trial testing the effect of three-month supplementation with LNS containing whey (LNS/whey) or soy (LNS/soy) among people with HIV. LNS/whey and LNS/soy groups were combined and then were compared against the non-supplemented group. The outcomes were change in fasting plasma-glucose (FPG), and 30-min glucose and 120-min glucose after oral glucose tolerance test. We further assessed effect on glycated hemoglobin (HbA1c), fasting insulin, homeostatic model assessment index for beta-cell function (HOMA-B) and insulin resistance (HOMA-IR). Results Of the 318 patients enrolled, 268 (84.3%) had available FPG and HbA1c and included. After 3 months of ART, HbA1c tended to be 2 mmol/mol higher in the LNS supplemented group, most pronounced among those receiving whey as the protein source. LNS led to higher 30-min glucose (0.5 mmol/L, 95% CI 0.2, 0.8) and 120-min glucose (0.4 mmol/L, 95% CI 0.03, 0.8) and a > 50% increase in fasting insulin, HOMA-B and HOMA-IR compared to the non-supplemented. Conclusion Among Ethiopian people with HIV initiating ART, short-term LNS intake increased glucose and insulin levels, and tended to increase HbA1c, potentially leading to more insulin resistance. Higher intake of carbohydrates with LNS could influence glycemic status. Whether these metabolic changes in early HIV treatment are beneficial or increase long-term risk of metabolic disorders needs to be explored.

Running economy (RE) at a given submaximal running velocity is defined as oxygen consumption per minute per kg body mass. We investigated RE in a group of 12 male elite runners of national class. In addition to RE at 14 and 18 km h−1 we measured the maximal oxygen consumption (VO2max) and anthropometric measures including the moment arm of the Achilles tendon (L Ach), shank and foot volumes, and muscular fascicle lengths. A 3‐D biomechanical movement analysis of treadmill running was also conducted. RE was on average 47.8 and 62.3 ml O2 min−1 kg−1 at 14 and 18 km h−1. Maximal difference between the individual athletes was 21% at 18 km h−1. Mechanical work rate was significantly correlated with VO2 measured in L min−1 at both running velocities. However, RE and relative work rate were not significantly correlated. L Ach was significantly correlated with RE at 18 km h−1 implying that a short moment arm is advantageous regarding RE. Neither foot volume nor shank volume were significantly correlated to RE. Relative muscle fascicle length of m. soleus was significantly correlated with RE at 18 km h−1. Whole body stiffness and leg stiffness were significantly correlated with L Ach indicating that a short moment arm coincided with high stiffness. It is concluded that a short L Ach is correlated with RE. Probably, a short L Ach allows for storage of a larger amount of elastic energy in the tendon and influences the force–velocity relation toward a lower contraction velocity., Running economy was found to be significantly related to Achilles tendon moment arm, foot length ratio, whole body stiffness and leg stiffness, and muscular fascicle length.

Background: This study aimed to investigate the putative role of the Triglyceride-glucose index (TyG index) computed as ln[TG (mg/dL) × glucose (mg/dL)/2] and derived proxies as predictors of adiposity and weight loss changes after a low calorie diet (LCD) intervention.Methods: A total of 744 adult participants from the multicenter DIOGenes intervention study were prescribed a LCD (800 kcal/day) during 8 weeks. Body composition and fat content at baseline and after 8 weeks were estimated by DEXA/BIA. A multivariate analysis approach was used to estimate the difference in ∆Weight1-2 (kg), ∆BMI1-2 (kg/m2) or ∆Fat1-2 (%) between the basal value (point 1) and after 8 weeks following a LCD (point 2), respectively. The TyG index at baseline (TyG1), after following the LCD for 8 weeks (TyG2), or the TyG index differences between both time points (∆TyG1-2) were analyzed as predictors of weight and fat changes.Results: TyG1 was associated with ∆Weight1-2 (kg) and ∆BMI1-2 (kg/m2), with β=0.812 (p = 0.017) and β=0.265 (p = 0.018), respectively. Also, TyG2 values were inversely related to ∆Fat1-2 (%), β=-1.473 (p = 0.015). Moreover, ∆TyG1-2 was associated with ∆Weight1-2 (kg) and ∆Fat1-2 (%), β= 0.689 (p = 0.045) and β=1.764 (p = 0.002), respectively. Furthermore, an association between TyG2 and resistance to fat loss was found (p = 0.015).Conclusion: TyG1 index is a good predictor of weight loss induced by LCD. Moreover, TyG2 was closely related to resistance to fat loss, while ∆TyG1-2 values were positively associated with body fat changes. Therefore, TyG index and derived estimations could be used as markers of individualized responses to energy restriction and a surrogate of body composition outcomes in clinical/epidemiological settings in obesity conditions.

Background Fibulin-1 is an extracellular matrix protein expressed at high levels in the placenta. Elevated circulating fibulin-1 have been observed in women with severe pre-eclampsia, whereas low levels have been found in the fetal membranes, prior to membrane rupture. The aim of the study was primarily to evaluate plasma fibulin-1 during expected normal pregnancy and delivery, and secondarily to explore fibulin-1 levels in women developing pre-eclampsia or preterm premature rupture of fetal membranes (PPROM). Methods From the historical longitudinal cohort originally consisting of 801 healthy Danish women with a singleton pregnancy, 128 women (632 samples) were selected. Of these, 107 women had normal pregnancies, nine experienced PPROM, and 12 pre-eclampsia. All samples were analyzed for fibulin-1, and levels were compared with blood donors. Differences in mean fibulin-1 between groups were estimated using a linear mixed model. Results The mean concentration of fibulin-1 in 120 blood donors was 15.7 µg/mL, (25th-75th-percentiles, 12.3–18.2), with no significant difference in groups stratified by gender or age. Compared to baseline levels in week 12–20, fibulin-1 levels increased significantly from week 29–34 (estimated difference, 5.6 µg/mL; standard error, 1.7; p p p = 0.002) and emergency (-5.6 µg/mL; 2.9; p = 0.05) cesarean section than after vaginal delivery (reference group). Women who developed PPROM had lower fibulin-1 levels throughout their pregnancies (-11.6 µg/mL; 4.2; p = 0.006). We did not observe a correlate between late pre-eclampsia and fibulin-1 (-0.2 µg/mL; 3.0; p = 0.9). Conclusions Fibulin-1 was above non-pregnant levels at week 12 and increased significantly throughout pregnancy. We observed an association between low levels of fibulin-1 and PPROM. Further studies are needed to examine if fibulin-1 could serve as biomarker for the risk of PPROM. However, its role in late preeclampsia is doubtful. Trial registration The study was conducted in accordance with the Declaration of Helsinki. The participants provided written informed consent, including storage for future use. The study was approved on July 18, 2005 by The Danish National Committee on Bioethics (No. KA 05065 and S-20,090,061) and the Danish Data Protection Agency.