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It has been postulated that rare coding variants (RVs; MAF5%, with height having the highest h2RV at 21.9% (95% CI: 19.0-24.8%). The total heritability, including common and rare variants, recovered pedigree-based estimates for 11 traits. RARity can estimate gene-level h2RV, enabling the assessment of gene-level characteristics and revealing 12 novel gene-phenotype relationships. Finally, we demonstrated that in silico pathogenicity prediction (variant-level) and gene-level annotations do not generally enrich for RVs that over-contribute to complex trait variance, and thus, novel methods are needed to predict RV functionality.

Poor adherence is a global health issue, affecting all chronic conditions and all age groups. Medications will only work if they are taken, and ongoing adherence to medication and treatment is difficult in chronic illness. Average adherence rates are approximately 50% in paediatric patients with asthma, and this can lead to poor disease control and an increase in morbidity. Thus, it is prudent to consider and discuss non-adherence, whether it be intentional or unintentional, to avoid unnecessary escalation of treatment. In this review, we discuss the fundamentals of adherence and the importance of goal setting. We discuss the challenges in varying age-groups, and methods that can be incorporated in various settings to optimize adherence. We explore how the advent of e-health (the combination of healthcare and technology) has impacted upon our ability to monitor adherence.

Previous longitudinal studies suggest that left ventricular (LV) structure is unaltered with resistance exercise training (RT) in young men. However, evidence from aerobic exercise training suggests that early changes in functional LV wall mechanics may occur prior to and independently of changes in LV size, although short-term changes in LV mechanics and structural remodelling in response to RT protocols have not been reported. Therefore, the purpose of this study was to examine the effects of RT on LV mechanics in healthy men performing 2 different time-under-tension protocols. Forty recreationally trained men (age: 23 ± 3 years) were randomized into 12 weeks of whole-body higher-repetition RT (20–25 repetitions/set to failure at ∼30%–50% 1 repetition maximum (1RM); n = 13), lower-repetition RT (8–12 repetitions/set to failure at ∼75%–90% 1RM; n = 13), or an active control period (n = 14). Speckle tracking echocardiography was performed at baseline and following the intervention period. Neither RT program altered standard measures of LV volumes (end-diastolic volume, end-systolic volume, or ejection fraction; P > 0.05) or indices of LV mechanics (total LV twist, untwisting rate, twist-to-shortening ratio, untwisting-to-twist ratio, or longitudinal strain; P > 0.05). This is the first longitudinal study to assess both LV size and mechanics after RT in healthy men, suggesting a maintenance of LV size and twist mechanics despite peripheral muscle adaptations to the training programs. These results provide no evidence for adverse LV structural or functional remodelling in response to RT in young men and support the positive role of RT in the maintenance of optimal cardiovascular function, even with strenuous RT.

ObjectiveTo determine the effects of multi-ingredient protein (MIP) supplements on resistance exercise training (RT)-induced gains in muscle mass and strength compared with protein-only (PRO) or placebo supplementation.Data sourcesSystematic search of MEDLINE, Embase, CINAHL and SPORTDiscus.Eligibility criteriaRandomised controlled trials with interventions including RT ≥6 weeks in duration and a MIP supplement.DesignRandom effects meta-analyses were conducted to determine the effect of supplementation on fat-free mass (FFM), fat mass, one-repetition maximum (1RM) upper body and 1RM lower body muscular strength. Subgroup analyses compared the efficacy of MIP supplementation relative to training status and chronological age.ResultsThe most common MIP supplements included protein with creatine (n=17) or vitamin D (n=10). Data from 35 trials with 1387 participants showed significant (pSummary/conclusionsWhen MIP supplements were combined with resistance exercise training, there were greater gains in FFM and strength in healthy adults than in counterparts who were supplemented with non-MIP. MIP supplements were not superior when directly compared with PRO supplements. The magnitude of effect of MIP supplements was greater (in absolute values) in untrained and elderly individuals undertaking RT than it was in trained individuals and in younger people.Trial registration numberCRD42017081970.

Supplemental digital content is available in the text., Ingestion of proteins with high leucine content during resistance training (RT) can augment hypertrophy. Some data suggest that a leucine metabolite, β-hydroxy, β-methylbutyrate (HMB), is substantially more anabolically efficacious than leucine. Purpose We aimed to test whether supplementation with HMB versus leucine, added to whey protein, would result in differential muscle hypertrophy and strength gains in young men performing RT. Methods Twenty-six resistance-trained men (23 ± 2 yr) performed 12 wk of RT with three phases. Phase 1: 8 wk of periodized RT (three training sessions per week). Phase 2: 2 wk overreaching period (five sessions per week). Phase 3: 2 wk taper (three sessions per week). Participants were randomly assigned to twice daily ingestion of: whey protein (25 g) plus HMB (1.5 g) (whey+HMB; n = 13) or whey protein (25 g) plus leucine (1.5 g) (whey+leu; n = 13). Skeletal muscle biopsies were performed before and after RT. Measures of fat- and bone-free mass, vastus lateralis (VL) muscle thickness and muscle cross-sectional area (CSA) (both by ultrasound), muscle fiber CSA, and 1-repetition maximum (1-RM) strength tests were determined. Results We observed increases in fat- and bone-free mass, VL muscle thickness, muscle CSA and fiber type CSA and 1-RM strength with no differences between groups at any phase. We observed no differences between groups or time–group interactions in hormone concentrations at any phase of the RT program. Conclusions β-Hydroxy-β-methylbutyrate added to whey did not result in greater increases in any measure of muscle mass, strength, or hormonal concentration compared to leucine added to whey. Our results show that HMB is no more effective in stimulating RT-induced hypertrophy and strength gains than leucine.

Background Higher-protein (HP) diets are advocated for several reasons, including mitigation of sarcopenia, but their effects on kidney function are unclear. Objective This meta-analysis was conducted to determine the effect of HP intakes on kidney function in healthy adults. Methods We conducted a systematic review and meta-analysis of trials comparing HP (≥1.5 g/kg body weight or ≥20% energy intake or ≥100 g protein/d) with normal- or lower-protein (NLP; ≥5% less energy intake from protein/d compared with HP group) intakes on kidney function. Medline and EMBASE databases were searched. Randomized controlled trials comparing the effects of HP with NLP (>4 d duration) intakes on glomerular filtration rate (GFR) in adults without kidney disease were included. Results A total of 2144 abstracts were reviewed, with 40 articles selected for full-text review; 28 of these were analyzed and included data from 1358 participants. Data were analyzed using random-effects meta-analysis (RevMan 5; The Cochrane Collaboration), meta-regression (STATA; StataCorp), and dose-response analysis (Prism; GraphPad). Analyses were conducted using postintervention (post) GFR and the change in GFR from preintervention to post. The post-only comparison showed a trivial effect for GFR to be higher after HP intakes [standardized mean difference (SMD): 0.19; 95% CI: 0.07, 0.31; P = 0.002]. The change in GFR did not differ between interventions (SMD: 0.11; 95% CI: -0.05, 0.27; P = 0.16). There was a linear relation between protein intake and GFR in the post-only comparison (r = 0.332, P = 0.03), but not between protein intake and the change in GFR (r = 0.184, P = 0.33). The main limitation of the current analysis is the unclear risk of selection bias of the included trials. Conclusions Postintervention GFR comparisons indicate that HP diets result in higher GFRs; however, when changes in GFR were compared, dietary protein had no effect. Our analysis indicates that HP intakes do not adversely influence kidney function on GFR in healthy adults.

Mitochondrial DNA copy number (mtDNA-CN) is an accessible blood-based measurement believed to capture underlying mitochondrial function. The specific biological processes underpinning its regulation, and whether those processes are causative for disease, is an area of active investigation. We developed a novel method for array-based mtDNA-CN estimation suitable for biobank-scale studies, called “AutoMitoC”. We applied AutoMitoC to 395,781 UKBiobank study participants and performed genome and exome-wide association studies, identifying novel common and rare genetic determinants. Overall, genetic analyses identified 73 loci for mtDNA-CN, which implicated several genes involved in rare mtDNA depletion disorders, dNTP metabolism, and the mitochondrial central dogma. Rare variant analysis identified SAMHD1 mutation carriers as having higher mtDNA-CN (beta=0.23 SDs; 95% CI, 0.18-0.29; P=2.6×10−19), a potential therapeutic target for patients with mtDNA depletion disorders, but at increased risk of breast cancer (OR=1.91; 95% CI, 1.52-2.40; P=2.7×10−8). Finally, Mendelian randomization analyses suggest a causal effect of low mtDNA-CN on dementia risk (OR=1.94 per 1 SD decrease in mtDNA-CN; 95% CI, 1.55-2.32; P=7.5×10−4). Altogether, our genetic findings indicate that mtDNA-CN is a complex biomarker reflecting specific mitochondrial processes related to mtDNA regulation, and that these processes are causally related to human diseases.

In the long term, 137Cs is probably the most biologically important agent released in many accidental (or malicious) radiation disasters. It can enter the food chain, and be consumed, or, if present in the environment (e.g. from fallout), can provide external irradiation over prolonged times. In either case, due to the high penetration of the energetic γ rays emitted by 137Cs, the individual will be exposed to a low dose rate, uniform, whole body, irradiation. The VADER (VAriable Dose-rate External 137Cs irradiatoR) allows modeling these exposures, bypassing many of the problems inherent in internal emitter studies. Making use of discarded 137Cs brachytherapy seeds, the VADER can provide varying low dose rate irradiations at dose rates of 0.1 to 1.2 Gy/day. The VADER includes a mouse “hotel”, designed to allow long term simultaneous residency of up to 15 mice. Two source platters containing ~ 250 mCi each of 137Cs brachytherapy seeds are mounted above and below the “hotel” and can be moved under computer control to provide constant low dose rate or a varying dose rate mimicking 137Cs biokinetics in mouse or man. We present the VADER design and characterization of its performance over 18 months of use.

Magnetic resonance imaging (MRI) is the current gold standard for measuring changes in muscle size (cross‐sectional area [CSA] and volume) but can be cost‐prohibitive and resource‐intensive. We evaluated the validity of B‐mode ultrasonography (US) as a low‐cost alternative to MRI for measuring muscle hypertrophy and atrophy in response to resistance training and immobilization, respectively. Fourteen young men performed 10wk of unilateral resistance training (RT) to induce muscle hypertrophy. In the final two weeks of the 10wk, the subjects’ contralateral leg was immobilized (IMB). The cross‐sectional area of the vastus lateralis (VLCSA) was measured at the mid‐thigh before and after each intervention using MRI (VLCSAMRI) and US (VLCSAUS). The relationship and agreement between methods were assessed. Reliability of US measurements ranged from good to excellent in all comparisons (ICC >0.67). VLCSA significantly increased after 10 weeks of RT (VLCSAUS: 7.9 ± 3.8%; VLCSAMRI: 7.8 ± 4.5%) and decreased after 2 weeks of IMB (VLCSAUS: −8.2%±5.8%; VLCSAMRI: −8.7 ± 6.1%). Significant correlations were identified between MRI and US at each time point measured (all r > 0.85) and, importantly, between MRI‐ and US‐derived changes in VLCSA. Bland‐Altman analysis revealed minimal bias in US measurements relative to the MRI (−0.5 ± 3.0%) and all measurements were within the upper and lower limits of agreement. Our data suggest that B‐mode ultrasonography can be a suitable alternative to MRI for measuring changes in muscle size in response to increased and decreased muscle loading in young men., We demonstrate that ultrasound‐derived measurements of vastus lateralis hypertrophy and atrophy induced by resistance training and immobilization are significantly correlated with MRI‐derived measurements. The reliability of our ultrasound technique was also in the range of good‐excellent. Together, these data suggest that B‐mode ultrasonography is a suitable alternative for the assessment of muscle hypertrophy and atrophy under conditions of dynamic loading in young men.

In order for inhaled corticosteroids to be delivered adequately to the airways they require patients to take them regularly using an effective technique. Patients often have a poor inhaler technique, and this has been shown to result in sub-optimal asthma control. It is important for all clinicians prescribing inhaled medication to be experienced in the correct technique, and take time to train children so that they have mastered corrected inhaler technique. Using Teach to Goal or teach back methodology is a simple and effective way to provide this in the clinic setting. More than one training session is typically needed before children can master correct inhaler technique. Adherence to inhaled therapy has been shown to be sub-optimal in pediatric populations, with studies showing an average rate of around 50%. Subjective methods of measuring adherence have been shown to be inaccurate and overestimate rates. The advent of new technology has allowed adherence rates to be measured electronically, and it has been shown that regular feedback of these data can be effective at improving asthma control. New mobile apps and smart technology aim to engage patients and families with their asthma care. Effective use of these apps in collaboration with health care professionals has a vast potential to improve adherence rates and inhaler technique, resulting in improved asthma control.

Testosterone products are prescribed to males for a variety of possible health benefits, but causal effects are unclear. Evidence from randomized trials are difficult to obtain, particularly regarding effects on long-term or rare outcomes. Mendelian randomization analyses were performed to infer phenome-wide effects of free testosterone on 461 outcomes in 161,268 males from the UK Biobank study. Lifelong increased free testosterone had beneficial effects on increased bone mineral density, and decreased body fat; adverse effects on decreased HDL, and increased risks of prostate cancer, androgenic alopecia, spinal stenosis, and hypertension; and context-dependent effects on increased hematocrit and decreased C-reactive protein. No benefit was observed for type 2 diabetes, cardiovascular or cognitive outcomes. Mendelian randomization suggests benefits of long-term increased testosterone should be considered against adverse effects, notably increased prostate cancer and hypertension. Well-powered randomized trials are needed to conclusively address risks and benefits of testosterone treatment on these outcomes., eLife digest Men experience a gradual decline in their testosterone levels as they grow older. However, the effects of testosterone and the consequences of supplementation on the human body have been unclear. Scientists use so-called randomized controlled trials to establish cause-and-effect and to reduce bias. In these experiments, participants are randomly assigned to a either a treatment group (that receives the intervention being tested) or a control group (that either receives an alternative intervention, a dummy or placebo, or no intervention at all). Randomization ensures that both groups are balanced, and any resulting differences can be attributed to the treatment. However, randomized controlled trials are time-consuming and expensive, so trials of testosterone have had relatively small numbers of participants and short follow-up periods. This makes it difficult to draw conclusions about any potential effects of testosterone administration on less common diseases in men. Now, Paré et al. investigated the effects of naturally produced testosterone using Mendelian randomization, which mimics randomized trials by exploiting the fact that parents randomly pass on their unique genetic variants to their children at conception. This random assignment of genetic variants leads to its informal namesake, “nature’s clinical trial”, and provides the ability to study cause-and-effect for any genetically determined factors, such as testosterone levels. Paré et al. studied the long-term effects of testosterone on 22 diseases previously explored in randomized controlled trials, and hundreds of other traits and diseases that have not been investigated in any randomized controlled trials yet. The Mendelian randomization analysis made it possible to examine the effects of lifelong naturally elevated testosterone levels on 469 traits and diseases. Paré et al. found that testosterone increased the density of bone mineral and decreased body fat. However, it also increased the risks of prostate cancer, high blood pressure, baldness and a condition affecting the spine. It also increased the number of red blood cells and decreased a marker of inflammation, which may be beneficial or detrimental depending on the context. This shows that genetic analyses can be powerful methods to prioritize the allocation of limited resources towards investigating the most pressing clinical questions. The results of this study may help inform physicians and patients about the effects of long-term testosterone use. Ultimately, large randomized controlled trials are needed to conclusively address the cause-and-effect on these diseases.

β-hydroxy-β-methylbutyrate (HMB) is a leucine metabolite that is purported to increase fat-free mass (FFM) gain and performance in response to resistance exercise training (RET). The aim of this systematic review and meta-analysis was to determine the efficacy of HMB supplementation in augmenting FFM and strength gains during RET in young adults. Outcomes investigated were: total body mass (TBM), FFM, fat mass (FM), total single repetition maximum (1RM), bench press (BP) 1RM, and lower body (LwB) 1RM. Databases consulted were: Medical Literature Analysis and Retrieval System Online (Medline), Excerpta Medica database (Embase), The Cumulative Index to Nursing and Allied Health Literature (CINAHL), and SportDiscus. Fourteen studies fit the inclusion criteria; however, 11 were analyzed after data extraction and funnel plot analysis exclusion. A total of 302 participants (18–45 y) were included in body mass and composition analysis, and 248 were included in the strength analysis. A significant effect was found on TBM. However, there were no significant effects for FFM, FM, or strength outcomes. We conclude that HMB produces a small effect on TBM gain, but this effect does not translate into significantly greater increases in FFM, strength or decreases in FM during periods of RET. Our findings do not support the use of HMB aiming at improvement of body composition or strength with RET.

In the long term, 137Cs is probably the most biologically important agent released in many accidental (or malicious) radiation disasters. It can enter the food chain, and be consumed, or, if present in the environment (e.g. from fallout), can provide external irradiation over prolonged times. In either case, due to the high penetration of the energetic γ rays emitted by 137Cs, the individual will be exposed to a low dose rate, uniform, whole body, irradiation. The VADER (VAriable Dose-rate External 137Cs irradiatoR) allows modeling these exposures, bypassing many of the problems inherent in internal emitter studies. Making use of discarded 137Cs brachytherapy seeds, the VADER can provide varying low dose rate irradiations at dose rates of 0.1 to 1.2 Gy/day. The VADER includes a mouse “hotel”, designed to allow long term simultaneous residency of up to 15 mice. Two source platters containing ~ 250 mCi each of 137Cs brachytherapy seeds are mounted above and below the “hotel” and can be moved under computer control to provide constant low dose rate or a varying dose rate mimicking 137Cs biokinetics in mouse or man. We present the VADER design and characterization of its performance over 18 months of use.

To permanently attach to surfaces, Caulobacter crescentus produces a strong adhesive, the holdfast. The timing of holdfast synthesis is developmentally regulated by cell cycle cues. When C. crescentus is grown in a complex medium, holdfast synthesis can also be stimulated by surface sensing, in which swarmer cells rapidly synthesize holdfast in direct response to surface contact. In contrast to growth in complex medium, here we show that when cells are grown in a defined medium, surface contact does not trigger holdfast synthesis. Moreover, we show that in a defined medium, flagellum synthesis and regulation of holdfast production are linked. In these conditions, mutants lacking a flagellum attach to surfaces over time more efficiently than either wild-type strains or strains harboring a paralyzed flagellum. Enhanced adhesion in mutants lacking flagellar components is due to premature holdfast synthesis during the cell cycle and is regulated by the holdfast synthesis inhibitor HfiA. hfiA transcription is reduced in flagellar mutants and this reduction is modulated by the diguanylate cyclase developmental regulator PleD. We also show that, in contrast to previous predictions, flagella are not necessarily required for C. crescentus surface sensing in the absence of flow, and that arrest of flagellar rotation does not stimulate holdfast synthesis. Rather, our data support a model in which flagellum assembly feeds back to control holdfast synthesis via HfiA expression in a c-di-GMP dependent manner under defined nutrient conditions.

BACKGROUND: Physical inactivity impairs insulin sensitivity, which is exacerbated with aging. We examined the impact of 2 wk of acute inactivity and recovery on glycemic control, and integrated rates of muscle protein synthesis in older men and women. METHODS: Twenty-two overweight, prediabetic older adults (12 men, 10 women, 69 ± 4 y) undertook 7 d of habitual activity (baseline; BL), step reduction (SR

Carotid artery longitudinal wall motion (CALM) exhibits reduced magnitude in older adults and in individuals with chronic diseases, although longitudinal data are lacking to indicate how changes in CALM might develop over time. Therefore, the aim of this study was to investigate the effect of exercise training in healthy men on CALM using a retrospective design. Carotid ultrasound data were analysed from two previous studies in which men performed 12 wk of moderate-intensity continuous exercise training (n = 9), sprint-interval training (n = 7), higher-repetition resistance exercise training (n = 15) or lower-repetition resistance exercise training (n = 15). The CALM pattern was unaltered after 12 wk of exercise training, regardless of exercise mode, with no differences in systolic or diastolic CALM magnitudes (p > 0.05), similar to carotid intima-media thickness (p > 0.05). Our findings suggest that CALM is resistant to transient changes in lifestyle factors, similar to wall thickness in otherwise healthy populations.

Lower-load (LL), higher-repetition resistance exercise training (RET) can increase muscle mass in a similar degree as higher-load (HL), lower-repetition RET. However, little is known about how LL and HL RET modulate other aspects of the RET phenotype such as satellite cells, myonuclei, and mitochondrial proteins. We aimed to investigate changes in muscle mass, muscle strength, satellite cell activity, myonuclear addition, and mitochondrial protein content after prolonged RET with LL and HL RET.We recruited 21 young men and randomly assigned them to perform 10 wk RET (leg press, leg extension, and leg curl) three times per week with the following conditions: 80FAIL (80% one-repetition maximum [1RM] performed to volitional fatigue), 30WM (30%1RM with volume matched to 80FAIL), and 30FAIL (30%1RM to volitional fatigue). Skeletal muscle biopsies were taken from the vastus lateralis pre- and post-RET intervention.After 10 wk of RET, only 30FAIL and 80FAIL showed an increase in peak torque and type I fiber cross-sectional area (P0.05). Moreover, only 30FAIL resulted in a significant decrease in the myonuclear domain of type II muscle fibers and an increase in mitochondrial proteins related to autophagy, fission, and fusion (all P0.05).We discovered that LL RET was effective at increasing the content of several mitochondrial proteins. Similar to previous research, we found that changes in muscle mass and strength were independent of load when repetitions were performed to volitional fatigue.

When you lift weights you get stronger and your muscles can get bigger, a process we call hypertrophy, and these changes can mean a big advantage in certain sports. We all ‘know’ that we need to consume supplemental protein when we lift weights to get bigger muscles, right? But what’s the real (science-based) answer? A meta-analysis is a way of looking at all of the studies that have been done in a particular area of science. In our study,1 we performed …

Leucine metabolites may reduce training-induced inflammation; however, there is scant evidence for this assertion. We conducted a double-blind randomized controlled pragmatic trial where 40 male participants were allocated into 4 groups: α-hydroxyisocaproic acid group ([α-HICA], n = 10, Fat-free mass [FFM] = 62.0 ± 7.1 kg), β-hydroxy-β-methylbutyrate free acid group ([HMB-FA], n = 11, FFM = 62.7 ± 10.5 kg), calcium β-hydroxy-β-methylbutyrate group ([HMB-Ca], n = 9, FFM = 65.6 ± 10.1 kg) or placebo group ([PLA]; n = 10, FFM = 64.2 ± 5.7 kg). An 8-week whole-body resistance training routine (3 training sessions per week) was employed to induce gains in skeletal-muscle thickness. Skeletal muscle thickness (MT), one repetition maximum (1RM), interleukin-6 (IL-6), high-sensitivity C-reactive protein (hsCRP) and tumour necrosis factor alpha (TNF-α) were assessed at baseline and at the end of weeks 4 and 8. Time-dependent increases were detected from baseline to week 8 for MT (vastus lateralis: p = 0.009; rectus femoris: p = 0.018), 1RM (back squat: α-HICA, 18.5% ± 18.9%; HMB-FA, 23.2% ± 16%; HMB-Ca, 10.5% ± 13.8%; PLA, 19.7% ± 9% and bench press: α-HICA, 13.8% ± 19.1%; HMB-FA, 15.5% ± 9.3%; HMB-Ca, 10% ± 10.4%; PLA, 14.4 ± 11.3%, both p 0.001), IL-6, hsCRP (both p 0.001) and TNF-α (p = 0.045). No differences were found between groups at any time point. No leucine metabolite attenuated inflammation during training. Additionally, backwards elimination regressions showed that no circulating inflammatory marker consistently shared variance with the change in any outcome. Using leucine metabolites to modulate inflammation cannot be recommended from the results obtained herein. Furthermore, increases in inflammatory markers, from training, do not correlate with any outcome variable and are likely the result of training adaptations.

KEY POINTS Performing resistance exercise with heavier loads is often proposed to be necessary for the recruitment of larger motor units and activation of type II muscle fibres, leading to type II fibre hypertrophy. Indirect measures [surface electromyography (EMG)] have been used to support this thesis, although we propose that lighter loads lifted to task failure (i.e. volitional fatigue) result in the similar activation of type II fibres. In the present study, participants performed resistance exercise to task failure with heavier and lighter loads with both a normal and longer repetition duration (i.e. time under tension). Type I and type II muscle fibre glycogen depletion was determined by neither load, nor repetition duration during resistance exercise performed to task failure. Surface EMG amplitude was not related to muscle fibre glycogen depletion or anabolic signalling; however, muscle fibre glycogen depletion and anabolic signalling were related. Performing resistance exercise to task failure, regardless of load lifted or repetition duration, necessitates the activation of type II muscle fibres. ABSTRACT Heavier loads (>60% of maximal strength) are considered to be necessary during resistance exercise (RE) to activate and stimulate hypertrophy of type II fibres. Support for this proposition comes from observation of higher surface electromyography (EMG) amplitudes during RE when lifting heavier vs. lighter loads. We aimed to determine the effect of RE, to task failure, with heavier vs. lighter loads and shorter or longer repetition durations on: EMG-derived variables, muscle fibre activation, and anabolic signalling. Ten recreationally-trained young men performed four unilateral RE conditions randomly on two occasions (two conditions, one per leg per visit). Muscle biopsies were taken from the vastus lateralis before and one hour after RE. Broadly, total time under load, number of repetitions, exercise volume, EMG amplitude (at the beginning and end of each set) and total EMG activity were significantly different between conditions (P

Loading of skeletal muscle leads to remodeling of myofibrillar and extracellular matrix proteins to withstand metabolic stress and unloading results in the opposite. In humans, the heterogenous response to altered loading greatly complicates molecular modeling of the underpinning processes. We utilized a within-person paired Hypertrophy and Atrophy (‘HypAt’) strategy that reduced response heterogeneity by ~40%. We applied a new genome-wide transcriptome analysis methodology to model mRNA, the 3’ or 5’ untranslated regions (UTR, sites of translation regulation) and proteome-constrained networks. We discovered > 4 times more regulated genes compared with similarly sized studies while 1,000 genes were only modified at their UTRs. A core of 141 genes were consistently modulated in proportion to muscle growth, across three independent studies (n=100). This new model revealed, at a pathway level, direct interactions between the proteome features of exercise-trained muscle, and the molecular processes underpinning muscle aging and insulin sensitivity.

Purpose:Self–myofascial release (SMR) is a common exercise and therapeutic modality shown to induce acute improvements in joint range of motion (ROM) and recovery; however, no long-term studies have been conducted. Static stretching (SS) is the most common method used to increase joint ROM and decrease muscle stiffness. It was hypothesized that SMR paired with SS (SMR+SS) compared with SS alone over a 4-wk intervention would yield greater improvement in knee-extension ROM and hamstring stiffness.Methods:19 men (22 ± 3 y) with bilateral reduced hamstring ROM had each of their legs randomly assigned to either an SMR+SS or an SS-only group. The intervention consisted of 4 repetitions of SS each for 45 s or the identical amount of SS preceded by 4 repetitions of SMR each for 60 s and was performed on the respective leg twice daily for 4 wk. Passive ROM, hamstring stiffness, rate of torque development (RTD), and maximum voluntary contraction (MVC) were assessed pre- and postintervention.Results:Passive ROM (P < .001), RTD, and MVC (P < .05) all increased after the intervention. Hamstring stiffness toward end-ROM was reduced postintervention (P = .02). There were no differences between the intervention groups for any variable.Conclusion:The addition of SMR to SS did not enhance the efficacy of SS alone. SS increases joint ROM through a combination of decreased muscle stiffness and increased stretch tolerance.

Summary Loading of skeletal muscle changes the tissue phenotype reflecting altered metabolic and functional demands. In humans, heterogeneous adaptation to loading complicates the identification of the underpinning molecular regulators. A within-person differential loading and analysis strategy reduces heterogeneity for changes in muscle mass by ∼40% and uses a genome-wide transcriptome method that models each mRNA from coding exons and 3′ and 5′ untranslated regions (UTRs). Our strategy detects ∼3–4 times more regulated genes than similarly sized studies, including substantial UTR-selective regulation undetected by other methods. We discover a core of 141 genes correlated to muscle growth, which we validate from newly analyzed independent samples (n = 100). Further validating these identified genes via RNAi in primary muscle cells, we demonstrate that members of the core genes were regulators of protein synthesis. Using proteome-constrained networks and pathway analysis reveals notable relationships with the molecular characteristics of human muscle aging and insulin sensitivity, as well as potential drug therapies., Graphical Abstract, Highlights • Muscle loading and unloading regulate the untranslated regions of mRNA • Regulated genes form functional networks central to muscle plasticity • 141 genes correlate with muscle growth in 3 independent validation cohorts • Several growth-correlated network genes directly regulate myocyte protein synthesis, Stokes et al. identify and validate a core set of genes that are regulated in proportion to the magnitude of muscle protein turnover with loading. Several of these genes correlate with muscle growth only at their 3′ or 5′ untranslated region, and a subset directly influences protein synthesis in vitro.

Resistance training promotes microvasculature expansion; however, it remains unknown how different resistance training programs contribute to angiogenesis. Thus, we recruited experienced resistance-trained participants and determined the effect of 12 wk of either high-repetition/low-load or low-repetition/high-load resistance training performed to volitional fatigue on muscle microvasculature. Twenty men performed either a high-repetition [20–25 repetitions, 30–50% of 1-repetition maximum (1RM); n = 10] or a low-repetition (8–12 repetitions, 75–90% of 1RM; n = 10) resistance training program. Muscle biopsies were taken before and after resistance training, and immunohistochemistry was used to assess fiber type (I and II)-specific microvascular variables. High-repetition/low-load and low-repetition/high-load groups were not different in any variable before resistance training. Both protocols resulted in an increase in capillarization. Specifically, after resistance training, the capillary-to-fiber ratio, capillary contacts, and capillary-to-fiber perimeter exchange index were elevated, and sharing factor was reduced. These data demonstrate that resistance training performed to volitional failure, using either high repetition/low load or low repetition/high load, induced similar microvascular adaptations in recreationally resistance-trained young men.

Purpose of review Skeletal muscle mass with aging, during critical care, and following critical care is a determinant of quality of life and survival. In this review, we discuss the mechanisms that underpin skeletal muscle atrophy and recommendations to offset skeletal muscle atrophy with aging and during, as well as following, critical care. Recent findings Anabolic resistance is responsible, in part, for skeletal muscle atrophy with aging, muscle disuse, and during disease states. Anabolic resistance describes the reduced stimulation of muscle protein synthesis to a given dose of protein/amino acids and contributes to declines in skeletal muscle mass. Physical inactivity induces: Anabolic resistance (that is likely exacerbated with aging), insulin resistance, systemic inflammation, decreased satellite cell content, and decreased capillary density. Critical illness results in rapid skeletal muscle atrophy that is a result of both anabolic resistance and enhanced skeletal muscle breakdown. Summary Insofar as atrophic loss of skeletal muscle mass is concerned, anabolic resistance is a principal determinant of age-induced losses and appears to be a contributor to critical illness-induced skeletal muscle atrophy. Older individuals should perform exercise using both heavy and light loads three times per week, ingest at least 1.2 g of protein/kg/day, evenly distribute their meals into protein boluses of 0.40 g/kg, and consume protein within 2 h of retiring for sleep. During critical care, early, frequent, and multimodal physical therapies in combination with early, enteral, hypocaloric energy (∼10-15 kcal/kg/day), and high-protein (>1.2 g/kg/day) provision is recommended.

Resistance exercise training (RET)-induced increases in voluntary 1RM strength are greater if the RET is performed with higher loads and replication (or close) of the strength test. In contrast, RET-induced muscular hypertrophy is primarily mediated by intensity of effort, which is achieved by performing RET to volitional fatigue and with an internal focus on contracting a muscle throughout the exercise range of motion. In addition, RET-induced muscular hypertrophy is augmented by increasing training volume, but with diminishing returns. Other training variables such as volume-load, inter-set rest, and time under tension have negligible effects on RET-induced changes in muscle size or strength. We conclude that an uncomplicated, evidence-based approach to optimizing RET-induced changes in muscle size and strength follows the FITT principle: frequency, intensity (effort), type, and time.

Robert W Morton,1,2 Heather E Elphick,2 Elaine Edwards,1 William J Daw,1,2 Noreen S West1 1Cystic Fibrosis Unit, Sheffield Children’s Hospital, 2Academic Unit of Child Health, University of Sheffield, Sheffield, UK Background: Children with cystic fibrosis (CF) often have suboptimal adherence rates to nebulized medication. Adherence barriers cited include forgetting to take the nebulizers, due to busy home and social lives. Text message reminders have been shown to be effective at improving adherence rates in other chronic diseases such as asthma and diabetes. Objective: The objective of this study was to assess the feasibility and efficacy of sending text reminders for a prolonged period of time to children with CF. Materials and methods: Children with CF aged 5–16 years taking at least one medication via a nebulizer with an electronic adherence monitor were consented for the study. Text message reminders were sent to participants and/or parents via the hospital’s automated text service, up to twice a day, for 6months. The adherence rates for the 6-month text period were compared to the previous 6months before the study. Rates were calculated for weekdays, weekends, and school holidays. Results: Seventeen participants were recruited to the study, with a mean age of 12 years and a mean forced expiratory volume in 1 second (FEV1) of 81% predicted. Fifteen children ­completed the 6-month text period, and I-neb data were accurately analyzed for 13 participants. The mean adherence rate in the 6 months receiving texts was 80%, compared to 81% in the prior 6 months. Overall adherence rates on weekdays, weekends, and school holidays were equivalent during the 2 time periods. A subgroup of patients with moderate baseline adherence showed increased adherence during the text period, particularly at weekends. Conclusion: It is feasible to send text message reminders to children with CF, and they are amenable to this approach. Although text reminders do not increase rates in patients with existing optimal adherence, they may be of value in patients with more moderate baseline rates. Keywords: cystic fibrosis, adherence, telehealth

The principal radiation modality for the treatment of deep-seated tumors is x-rays of very high energy and penetrating power. Such x-rays are created when high-energy electrons are stopped in a target material such as tungsten. Alternatively, the electrons themselves may be used directly to treat more superficial cancers. The electron linear accelerator (linac) accelerates charged particles in a straight line, in contrast to the circular or racetrack orbits that characterize the cyclotron and synchrotron. The purpose of this primer is to explain the principles of operation and use of the electron linear accelerator and to acquaint the reader with pertinent features and terminology.

By the mid-1950s, a linear accelerator suitable for treating deep-seated tumors was built in the Stanford Microwave Laboratory and installed at Stanford Hospital. It served as a prototype for commercial units that were built later. Since that time, medical linear accelerators gained in popularity as major radiation therapy devices, but few basic training materials on their operation had been produced for use by medical professionals. C.J. Karzmark, a radiological physicist at Stanford University, was involved with medical linacs since their development, and he agreed to collaborate with Robert Morton of the Center for Devices and Radiological Health (formerly the Bureau of Radiological Health), U.S. Food and Drug Administration, in writing the first edition of this primer. Since its first appearance, this book has become a classic. This third edition takes into account the significant advances occurring in radiotherapy linacs since the second edition was published in 1998. Again, the level of treating these advances is simplified so that the audience of radiation therapists as well as physicians, engineers, and physicists can benefit.

Discrepancies regarding the effect of resistance exercise training (RET) on arterial stiffness have led to uncertainty regarding the effect of RET on cardiovascular health. Confounding our understanding in this area are the roles of the following: load (heavier vs lighter), participant cardiovascular health, and arterial stiffness assessment method. We aimed to investigate the effects of a heavier versus a lighter load resistance training protocol on both central and local arterial stiffness in previously trained young men. Participants were randomly assigned to a 12-wk supervised whole-body RET program consisting of three sets of 8-12 repetitions (heavier-load, lower-repetition [LR]; n = 16) or three sets of 20-25 repetitions (lighter-load, higher-repetition [HR]; n = 16) to volitional failure, or a control group who maintained their regular activity habits (n = 14). Central arterial stiffness (carotid-femoral pulse wave velocity), local arterial stiffness (common carotid arterial distensibility), and left ventricular mass were measured before and after 12 wk of RET. There was a reduction in carotid-femoral pulse wave velocity in both LR (6.24 ± 0.56 vs 5.77 ± 0.76 m·s; P < 0.05) and HR (6.42 ± 0.70 vs 5.72 ± 0.60 m·s; P < 0.05) with no changes in carotid distensibility (P = 0.52) or left ventricular mass allometrically scaled to fat-free mass (P = 0.60). There were no changes in any variable in the control group. Using current criterion-standard assessment methods, central arterial stiffness was reduced after resistance training, regardless of the load lifted during RET, with no effect on local carotid artery distensibility or left ventricular mass. Our results support a role of RET in the promotion of positive adaptations in vascular function.