An intron variant of the GLI family zinc finger 3 (GLI3) gene differentiates resistance training-induced muscle fiber hypertrophy in younger men.

We examined the association between genotype and resistance training-induced changes (12 wk) in dual x-ray energy absorptiometry (DXA)-derived lean soft tissue mass (LSTM) as well as muscle fiber cross-sectional area (fCSA; vastus lateralis; n = 109; age = 22 ± 2 y, BMI = 24.7 ± 3.1 kg/m2 ). Over 315 000 genetic polymorphisms were interrogated from muscle using DNA microarrays. First, a targeted investigation was performed where single nucleotide polymorphisms (SNP) identified from a systematic literature review were related to changes in LSTM and fCSA. Next, genome-wide association (GWA) studies were performed to reveal associations between novel SNP targets with pre- to post-training change scores in mean fCSA and LSTM. Our targeted investigation revealed no genotype-by-time interactions for 12 common polymorphisms regarding the change in mean fCSA or change in LSTM. Our first GWA study indicated no SNP were associated with the change in LSTM. However, the second GWA study indicated two SNP exceeded the significance level with the change in mean fCSA (P = 6.9 × 10-7 for rs4675569, 1.7 × 10-6 for rs10263647). While the former target is not annotated (chr2:205936846 (GRCh38.p12)), the latter target (chr7:41971865 (GRCh38.p12)) is an intron variant of the GLI Family Zinc Finger 3 (GLI3) gene. Follow-up analyses indicated fCSA increases were greater in the T/C and C/C GLI3 genotypes than the T/T GLI3 genotype (P < .05). Data from the Auburn cohort also revealed participants with the T/C and C/C genotypes exhibited increases in satellite cell number with training (P < .05), whereas T/T participants did not. Additionally, those with the T/C and C/C genotypes achieved myonuclear addition in response to training (P < .05), whereas the T/T participants did not. In summary, this is the first GWA study to examine how polymorphisms associate with the change in hypertrophy measures following resistance training. Future studies are needed to determine if the GLI3 variant differentiates hypertrophic responses to resistance training given the potential link between this gene and satellite cell physiology.

Do multi-ingredient protein supplements augment resistance training-induced gains in skeletal muscle mass and strength? A systematic review and meta-analysis of 35 trials.

OBJECTIVE: To 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 SOURCES: Systematic search of MEDLINE, Embase, CINAHL and SPORTDiscus. ELIGIBILITY CRITERIA: Randomised controlled trials with interventions including RT ≥6 weeks in duration and a MIP supplement. DESIGN: Random 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. RESULTS: The most common MIP supplements included protein with creatine (n=17) or vitamin D (n=10). Data from 35 trials with 1387 participants showed significant (p<0.05) increases in FFM (0.80 kg (95% CI 0.44 to 1.15)), 1RM lower body (4.22 kg (95% CI 0.79 to 7.64)) and 1RM upper body (2.56 kg (95% CI 0.79 to 4.33)) where a supplement was compared with all non-MIP supplemented conditions (means (95% CI)). Subgroup analyses indicated a greater effect of MIP supplements compared with all non-MIP supplements on FFM in untrained (0.95 kg (95% CI 0.51 to 1.39), p<0.0001) and older participants (0.77 kg (95% CI 0.11 to 1.43), p=0.02); taking MIP supplements was also associated with gains in 1RM upper body (1.56 kg (95% CI 0.80 to 2.33), p=0.01) in older adults. SUMMARY/CONCLUSIONS: When 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 NUMBER: CRD42017081970.

Muscle fibre activation is unaffected by load and repetition duration when resistance exercise is performed to task failure.

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 < 0.05); however, neither glycogen depletion (in both type I and type II fibres), nor phosphorylation of relevant signalling proteins showed any difference between conditions. We conclude that muscle fibre activation and subsequent anabolic signalling are independent of load, repetition duration and surface EMG amplitude when RE is performed to task failure. The results of the present study provide evidence indicating that type I and type II fibres are activated when heavier and lighter loads are lifted to task failure. We propose that our results explain why RE training with higher or lower loads, when loads are lifted to task failure, leads to equivalent muscle hypertrophy and occurs in both type I and type II fibres.

Leucine metabolites do not attenuate training-induced inflammation in young resistance trained men.

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), ß-hydroxy-ß-methylbutyrate free acid group ([HMB-FA], n = 11, FFM = 62.7 ± 10.5 kg), calcium ß-hydroxy-ß-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.

Microvascular adaptations to resistance training are independent of load in resistance-trained young men.

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.

Changes in Kidney Function Do Not Differ between Healthy Adults Consuming Higher- Compared with Lower- or Normal-Protein Diets: A Systematic Review and Meta-Analysis.

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.

Defining anabolic resistance: implications for delivery of clinical care nutrition.

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.

A systematic review, meta-analysis and meta-regression of the effect of protein supplementation on resistance training-induced gains in muscle mass and strength in healthy adults.

OBJECTIVE: We performed a systematic review, meta-analysis and meta-regression to determine if dietary protein supplementation augments resistance exercise training (RET)-induced gains in muscle mass and strength. DATA SOURCES: A systematic search of Medline, Embase, CINAHL and SportDiscus. ELIGIBILITY CRITERIA: Only randomised controlled trials with RET ≥6 weeks in duration and dietary protein supplementation. DESIGN: Random-effects meta-analyses and meta-regressions with four a priori determined covariates. Two-phase break point analysis was used to determine the relationship between total protein intake and changes in fat-free mass (FFM). RESULTS: Data from 49 studies with 1863 participants showed that dietary protein supplementation significantly (all p<0.05) increased changes (means (95% CI)) in: strength-one-repetition-maximum (2.49 kg (0.64, 4.33)), FFM (0.30 kg (0.09, 0.52)) and muscle size-muscle fibre cross-sectional area (CSA; 310 µm2 (51, 570)) and mid-femur CSA (7.2 mm2 (0.20, 14.30)) during periods of prolonged RET. The impact of protein supplementation on gains in FFM was reduced with increasing age (-0.01 kg (-0.02,-0.00), p=0.002) and was more effective in resistance-trained individuals (0.75 kg (0.09, 1.40), p=0.03). Protein supplementation beyond total protein intakes of 1.62 g/kg/day resulted in no further RET-induced gains in FFM. SUMMARY/CONCLUSION: Dietary protein supplementation significantly enhanced changes in muscle strength and size during prolonged RET in healthy adults. Increasing age reduces and training experience increases the efficacy of protein supplementation during RET. With protein supplementation, protein intakes at amounts greater than ~1.6 g/kg/day do not further contribute RET-induced gains in FFM.

STAAR: a randomised controlled trial of electronic adherence monitoring with reminder alarms and feedback to improve clinical outcomes for children with asthma.

BACKGROUND: Suboptimal adherence to inhaled steroids is common in children with asthma and is associated with poor disease control, reduced quality of life and even death. Previous studies using feedback of electronically monitored adherence data have demonstrated improved adherence, but have not demonstrated a significant impact on clinical outcomes. The aim of this study was to determine whether introduction of this approach into routine practice would result in improved clinical outcomes. METHODS: Children with asthma aged 6-16 years were randomised to the active intervention consisting of electronic adherence monitoring with daily reminder alarms together with feedback in the clinic regarding their inhaled corticosteroid (ICS) use or to the usual care arm with adherence monitoring alone. All children had poorly controlled asthma at baseline, taking ICS and long-acting ß-agonists. Subjects were seen in routine clinics every 3 months for 1 year. The primary outcome was the Asthma Control Questionnaire (ACQ) score. Secondary outcomes included adherence and markers of asthma morbidity. RESULTS: 77 of 90 children completed the study (39 interventions, 38 controls). Adherence in the intervention group was 70% vs 49% in the control group (p≤0.001). There was no significant difference in the change in ACQ, but children in the intervention group required significantly fewer courses of oral steroids (p=0.008) and fewer hospital admissions (p≤0.001). CONCLUSIONS: The results indicate that electronic adherence monitoring with feedback is likely to be of significant benefit in the routine management of poorly controlled asthmatic subjects. TRIAL REGISTRATION NUMBER: NCT02451709; pre-result.

A method to estimate the contribution of rare coding variants to complex trait heritability.

It has been postulated that rare coding variants (RVs; MAF < 0.01) contribute to the "missing" heritability of complex traits. We developed a framework, the Rare variant heritability (RARity) estimator, to assess RV heritability (h2RV) without assuming a particular genetic architecture. We applied RARity to 31 complex traits in the UK Biobank (n = 167,348) and showed that gene-level RV aggregation suffers from 79% (95% CI: 68-93%) loss of h2RV. Using unaggregated variants, 27 traits had h2RV > 5%, 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 11, previously unreported, 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, innovative methods are needed to predict RV functionality.

Genome-wide study investigating effector genes and polygenic prediction for kidney function in persons with ancestry from Africa and the Americas.

Chronic kidney disease is a leading cause of death and disability globally and impacts individuals of African ancestry (AFR) or with ancestry in the Americas (AMS) who are under-represented in genome-wide association studies (GWASs) of kidney function. To address this bias, we conducted a large meta-analysis of GWASs of estimated glomerular filtration rate (eGFR) in 145,732 AFR and AMS individuals. We identified 41 loci at genome-wide significance (p < 5 × 10-8), of which two have not been previously reported in any ancestry group. We integrated fine-mapped loci with epigenomic and transcriptomic resources to highlight potential effector genes relevant to kidney physiology and disease, and reveal key regulatory elements and pathways involved in renal function and development. We demonstrate the varying but increased predictive power offered by a multi-ancestry polygenic score for eGFR and highlight the importance of population diversity in GWASs and multi-omics resources to enhance opportunities for clinical translation for all.

Precision medicine for cardiometabolic disease: a framework for clinical translation.

Cardiometabolic disease is a major threat to global health. Precision medicine has great potential to help to reduce the burden of this common and complex disease cluster, and to enhance contemporary evidence-based medicine. Its key pillars are diagnostics; prediction (of the primary disease); prevention (of the primary disease); prognosis (prediction of complications of the primary disease); treatment (of the primary disease or its complications); and monitoring (of risk exposure, treatment response, and disease progression or remission). To contextualise precision medicine in both research and clinical settings, and to encourage the successful translation of discovery science into clinical practice, in this Series paper we outline a model (the EPPOS model) that builds on contemporary evidence-based approaches; includes precision medicine that improves disease-related predictions by stratifying a cohort into subgroups of similar characteristics, or using participants' characteristics to model treatment outcomes directly; includes personalised medicine with the use of a person's data to objectively gauge the efficacy, safety, and tolerability of therapeutics; and subjectively tailors medical decisions to the individual's preferences, circumstances, and capabilities. Precision medicine requires a well functioning system comprised of multiple stakeholders, including health-care recipients, health-care providers, scientists, health economists, funders, innovators of medicines and technologies, regulators, and policy makers. Powerful computing infrastructures supporting appropriate analysis of large-scale, well curated, and accessible health databases that contain high-quality, multidimensional, time-series data will be required; so too will prospective cohort studies in diverse populations designed to generate novel hypotheses, and clinical trials designed to test them. Here, we carefully consider these topics and describe a framework for the integration of precision medicine in cardiometabolic disease.

The case for precision medicine in the prevention, diagnosis, and treatment of cardiometabolic diseases in low-income and middle-income countries.

Cardiometabolic diseases are the leading preventable causes of death in most geographies. The causes, clinical presentations, and pathogenesis of cardiometabolic diseases vary greatly worldwide, as do the resources and strategies needed to prevent and treat them. Therefore, there is no single solution and health care should be optimised, if not to the individual (ie, personalised health care), then at least to population subgroups (ie, precision medicine). This optimisation should involve tailoring health care to individual disease characteristics according to ethnicity, biology, behaviour, environment, and subjective person-level characteristics. The capacity and availability of local resources and infrastructures should also be considered. Evidence needed for equitable precision medicine cannot be generated without adequate data from all target populations, and the idea that research done in high-income countries will transfer adequately to low-income and middle-income countries (LMICs) is problematic, as many migration studies and transethnic comparisons have shown. However, most data for precision medicine research are derived from people of European ancestry living in high-income countries. In this Series paper, we discuss the case for precision medicine for cardiometabolic diseases in LMICs, the barriers and enablers, and key considerations for implementation. We focus on three propositions: first, failure to explore and implement precision medicine for cardiometabolic disease in LMICs will enhance global health disparities. Second, some LMICs might already be placed to implement cardiometabolic precision medicine under appropriate circumstances, owing to progress made in treating infectious diseases. Third, improvements in population health from precision medicine are most probably asymptotic; the greatest gains are more likely to be obtained in countries where health-care systems are less developed. We outline key recommendations for implementation of precision medicine approaches in LMICs.

Role of sociodemographic, clinical, behavioral, and molecular factors in precision prevention of type 2 diabetes: a systematic review.

The variability in the effectiveness of type 2 diabetes (T2D) preventive interventions highlights the potential to identify the factors that determine treatment responses and those that would benefit the most from a given intervention. We conducted a systematic review to synthesize the evidence to support whether sociodemographic, clinical, behavioral, and molecular characteristics modify the efficacy of dietary or lifestyle interventions to prevent T2D. Among the 80 publications that met our criteria for inclusion, the evidence was low to very low to attribute variability in intervention effectiveness to individual characteristics such as age, sex, BMI, race/ethnicity, socioeconomic status, baseline behavioral factors, or genetic predisposition. We found evidence, albeit low certainty, to support conclusions that those with poorer health status, particularly those with prediabetes at baseline, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our synthesis highlights the need for purposefully designed clinical trials to inform whether individual factors influence the success of T2D prevention strategies.

Impact of individual and environmental factors on dietary or lifestyle interventions to prevent type 2 diabetes development: a systematic review.

BACKGROUND: The variability in the effectiveness of type 2 diabetes (T2D) preventive interventions highlights the potential to identify the factors that determine treatment responses and those that would benefit the most from a given intervention. We conducted a systematic review to synthesize the evidence to support whether sociodemographic, clinical, behavioral, and molecular factors modify the efficacy of dietary or lifestyle interventions to prevent T2D. METHODS: We searched MEDLINE, Embase, and Cochrane databases for studies reporting on the effect of a lifestyle, dietary pattern, or dietary supplement interventions on the incidence of T2D and reporting the results stratified by any effect modifier. We extracted relevant statistical findings and qualitatively synthesized the evidence for each modifier based on the direction of findings reported in available studies. We used the Diabetes Canada Clinical Practice Scale to assess the certainty of the evidence for a given effect modifier. RESULTS: The 81 publications that met our criteria for inclusion are from 33 unique trials. The evidence is low to very low to attribute variability in intervention effectiveness to individual characteristics such as age, sex, BMI, race/ethnicity, socioeconomic status, baseline behavioral factors, or genetic predisposition. CONCLUSIONS: We report evidence, albeit low certainty, that those with poorer health status, particularly those with prediabetes at baseline, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our synthesis highlights the need for purposefully designed clinical trials to inform whether individual factors influence the success of T2D prevention strategies.

Clinical trials to prevent development of type 2 diabetes (T2D) that test dietary and lifestyle interventions have resulted in different results for different study participants. We hypothesized that the differing responses could be because of different personal, social and inherited factors. We searched different databases containing details of published research studies investigating this to look at the effect of these factors on prevention of the development of T2D. We found a small amount of evidence suggesting that those with poorer health, particularly those with a higher amount of sugar in their blood, tend to benefit more from T2D prevention strategies compared to healthier counterparts. Our results suggest that further clinical trials that are designed to examine the effect of personal and social factors on interventions for T2D prevention are needed to better determine the impact of these factors on the success of diet and lifestyle interventions for T2D.

Methodological considerations for and validation of the ultrasonographic determination of human skeletal muscle hypertrophy and atrophy.

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.

Aerosol Therapy in Asthma-Why We Are Failing Our Patients and How We Can Do Better.

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.

Effects of lifelong testosterone exposure on health and disease using Mendelian randomization.

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.

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.