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Inclusion body myositis (IBM) is the most commonly acquired skeletal muscle disease of older adults involving both autoimmune attack and muscle degeneration. As exercise training can improve outcomes in IBM, this study assessed whether a combination of testosterone supplementation and exercise training would improve muscle strength, physical function and quality of life in men affected by IBM, more than exercise alone. This pilot study was a single site randomised, double-blind, placebo-controlled, crossover study. Testosterone (exercise and testosterone cream) and placebo (exercise and placebo cream) were each delivered for 12 weeks, with a two-week wash-out between the two periods. The primary outcome measure was improvement in quadriceps isokinetic muscle strength. Secondary outcomes included assessment of isokinetic peak flexion force, walk capacity and patient reported outcomes, and other tests, comparing results between the placebo and testosterone arms. A 12-month Open Label Extension (OLE) was offered using the same outcome measures collected at 6 and 12-months. 14 men completed the trial. There were no significant improvements in quadriceps extension strength or lean body mass, nor any of the secondary outcomes. Improvement in the RAND Short Form 36 patient reported outcome questionnaire 'emotional wellbeing' sub-category was reported during the testosterone arm compared to the placebo arm (mean difference [95% CI]: 6.0 points, [95% CI 1.7,10.3]). The OLE demonstrated relative disease stability over the 12-month period but with a higher number of testosterone-related adverse events. Adding testosterone supplementation to exercise training did not significantly improve muscle strength or physical function over a 12-week intervention period, compared to exercise alone. However, the combination improved emotional well-being over this period, and relative stabilisation of disease was found during the 12-month OLE. A longer duration trial involving a larger group of participants is warranted.

Athletes regularly perform resistance training, yet it is unknown how best to monitor its intensity. This study compared different resistance exercise intensity metrics to determine their sensitivity to manipulating work rate (via altering inter-set rest and load). Following baseline testing for 10- and 3-repetition maximum (RM; squat and bench press), fourteen trained participants completed four volume-matched protocols in a randomised order: 3x10 with 85% 10RM, 60 s rest (3x10.sub.60s ); 3x10 with 85% 10RM, 180 s (3x10.sub.180s ); 8x3 with 85% 3RM, 120 s (8x3.sub.120s ); 8x3 with 85% 3RM, 300 s (8x3.sub.300s). Internal intensity was quantified via rate of oxygen consumption (VO2), heart rate, blood lactate concentration, and rating of perceived exertion (RPE). External intensity was assessed via previously developed \"Training-Intensity\" (TI) and \"Intensity-Index\" (II) metrics, and from exercise work rate (expressed as kgâmin.sup.-1 and joulesâmin.sup.-1). Internal intensity and work-rate metrics were highest for 3x10.sub.60s, followed by 3x10.sub.180s, 8x3.sub.120s and 8x3.sub.300s (p[less than or equal to]0.027). TI and II were higher for 8x3 than 3x10 protocols (p<0.001), but not different within these configurations. Internal intensity measures were more strongly correlated with work rate (r = 0.37-0.96) than TI and II (r = -0.42-0.33) metrics. Work rate corroborated objective internal intensity metrics during resistance exercise, with the highest work rate session (3x10.sub.60s) also eliciting greater RPE scores than other protocols. In contrast, the TI and II did not agree with other intensity measures, likely because they do not consider rest periods. Practitioners can plan for the physiological and perceptual demands of resistance training by estimating work rate.

Maximal strength can be predicted from the load-velocity relationship (LVR), although it is important to understand methodological approaches which ensure the validity and reliability of these strength predictions. The aim of this systematic review was to determine factors which influence the validity of maximal strength predictions from the LVR, and secondarily to highlight the effects of these factors on the reliability of predictions. A search strategy was developed and implemented in PubMed, Scopus, Web of Science and CINAHL databases. Rayyan software was used to screen titles, abstracts, and full texts to determine their inclusion/eligibility. Eligible studies compared direct assessments of one-repetition maximum (1RM) with predictions performed using the LVR and reported prediction validity. Validity was extracted and represented graphically via effect size forest plots. Twenty-five eligible studies were included and comprised of a total of 842 participants, three different 1RM prediction methods, 16 different exercises, and 12 different velocity monitoring devices. Four primary factors appear relevant to the efficacy of predicting 1RM: the number of loads used, the exercise examined, the velocity metric used, and the velocity monitoring device. Additionally, the specific loads, provision of velocity feedback, use of lifting straps and regression model used may require further consideration.

A CRISPR/Cas9 genome editing framework has been developed that allows controlled introduction of mono- and bi-allelic sequence changes, and is used to generate induced human pluripotent stem cells with heterozygous and homozygous dominant mutations in amyloid precursor protein and presenilin 1 that have been associated with early onset Alzheimer’s disease. CRISPR/Cas9 editing for stem cells Marc Tessier-Lavigne and colleagues have developed a CRISPR/Cas9-based genome-editing method that allows selective introduction of mono- and bi-allelic sequence changes with high efficiency and accuracy. The authors demonstrate the application of these methods in the generation of human induced pluripotent stem cells (iPS cells) with heterozygous and homozygous dominant mutations in amyloid precursor protein and presenilin that have been associated with early onset Alzheimer's disease. The bacterial CRISPR/Cas9 system allows sequence-specific gene editing in many organisms and holds promise as a tool to generate models of human diseases, for example, in human pluripotent stem cells 1 , 2 . CRISPR/Cas9 introduces targeted double-stranded breaks (DSBs) with high efficiency, which are typically repaired by non-homologous end-joining (NHEJ) resulting in nonspecific insertions, deletions or other mutations (indels) 2 . DSBs may also be repaired by homology-directed repair (HDR) 1 , 2 using a DNA repair template, such as an introduced single-stranded oligo DNA nucleotide (ssODN), allowing knock-in of specific mutations 3 . Although CRISPR/Cas9 is used extensively to engineer gene knockouts through NHEJ, editing by HDR remains inefficient 3 , 4 , 5 , 6 , 7 , 8 and can be corrupted by additional indels 9 , preventing its widespread use for modelling genetic disorders through introducing disease-associated mutations. Furthermore, targeted mutational knock-in at single alleles to model diseases caused by heterozygous mutations has not been reported. Here we describe a CRISPR/Cas9-based genome-editing framework that allows selective introduction of mono- and bi-allelic sequence changes with high efficiency and accuracy. We show that HDR accuracy is increased dramatically by incorporating silent CRISPR/Cas-blocking mutations along with pathogenic mutations, and establish a method termed ‘CORRECT’ for scarless genome editing. By characterizing and exploiting a stereotyped inverse relationship between a mutation’s incorporation rate and its distance to the DSB, we achieve predictable control of zygosity. Homozygous introduction requires a guide RNA targeting close to the intended mutation, whereas heterozygous introduction can be accomplished by distance-dependent suboptimal mutation incorporation or by use of mixed repair templates. Using this approach, we generated human induced pluripotent stem cells with heterozygous and homozygous dominant early onset Alzheimer’s disease-causing mutations in amyloid precursor protein (APP Swe ) 10 and presenilin 1 (PSEN1 M146V ) 11 and derived cortical neurons, which displayed genotype-dependent disease-associated phenotypes. Our findings enable efficient introduction of specific sequence changes with CRISPR/Cas9, facilitating study of human disease.

[This corrects the article DOI: 10.1371/journal.pone.0283394.].

IntroductionThere is growing evidence for a preventative effect of resistance training on cognitive decline through physiological mechanisms; yet, the effect of resistance training on resting growth factors and homocysteine levels is incompletely understood. This study aimed to investigate the effect of intense resistance training, for 12 weeks, on changes in peripheral growth factors and homocysteine in late middle-aged adults.Methods45 healthy adults were enrolled into the single-site parallel groups’ randomized-controlled trial conducted at the Department of Exercise Science, Strength and Conditioning Laboratory, Murdoch University. Participants were allocated to the following conditions: (1) high-load resistance training (n = 14), or (2) moderate-load resistance training (n = 15) twice per week for 12 weeks; or (3) non-exercising control group (n = 16). Data were collected from September 2016 to December 2017. Fasted blood samples were collected at baseline and within 7 days of trial completion for the analysis of resting serum brain-derived neurotrophic factor (BDNF), insulin-like growth factor 1, vascular endothelial growth factor, and plasma homocysteine levels.ResultsNo differences in baseline to post-intervention change in serum growth factors or plasma homocysteine levels were observed between groups. A medium effect was calculated for BDNF change within the high-load condition alone (+ 12.9%, g = 0.54).ConclusionsHigh-load or moderate-load resistance training twice per week for 12 weeks has no effect on peripheral growth factors or homocysteine in healthy late middle-aged adults.Trial registrationAustralian New Zealand Clinical Trials Registry: ACTRN12616000690459.

High-intensity exercise is a potential therapeutic tool to postpone or prevent the onset of cognitive decline. However, there is a lack of sufficient evidence regarding the longitudinal effects of structured resistance training on cognitive function in healthy adults. The purpose of this study was to investigate the effect of two ecologically valid, intense 12-week resistance training programs on cognitive function in late middle-aged adults. Single-site parallel randomised controlled trial at the Department of Exercise Science strength and conditioning laboratory. Groups allocated by minimisation randomisation. Forty-five healthy adults (age range=41–69 years) were enrolled and randomised into (A) high-load, long rest resistance training (n=14), or (B) moderate-load, short rest resistance training (n=15) twice per week for 12 weeks, or a non-exercising control (n=16). Follow-up within seven days. Data were collected September 2016–December 2017. Cognitive function assessed using the CogState computerised battery. Assessors were blinded to participant group allocation. Secondary outcomes were maximal muscle strength and body composition. Forty-four participants were analysed in 2018. Delayed verbal memory performance was improved (p=0.02) in resistance training groups (g=0.67–0.79) when compared to the control group, with no differences between training groups. Likewise, increases in maximal muscle strength were observed (p<0.01) in resistance training groups when compared to the control group, with no differences between training groups. No differences in body composition were observed. There were no adverse events or side-effects of the intervention. 12 weeks of intense resistance training improves delayed verbal memory irrespective of training design (i.e., high-load vs. moderate-load). This study is registered at www.anzctr.org.au ACTRN12616000690459.

A novel mobile health (mHealth) app \"acT1ve,\" developed using a co-design model, provides real-time support during exercise for young people with type 1 diabetes (T1D). This study aimed to demonstrate the noninferiority of acT1ve compared with \"treatment as usual\" with regard to hypoglycemic events. Thirty-nine participants living with T1D (age: 17.2, SD 3.3 years; HbA1c: 64, SD 6.0 mmol/mol) completed a 12-week single-arm, pre-post noninferiority study with a follow-up qualitative component. During the intervention, continuous glucose monitoring (CGM) and physical activity were monitored while participants used acT1ve to manage exercise. CGM data were used to assess the number of hypoglycemic events (<3.9 mmol/L for ≥15 minutes) in each phase. Using a mixed effects negative binomial regression, the difference in the rates of hypoglycemia between the preapp and app-use phases was analyzed. Participants completed both a semistructured interview and the user Mobile Application Rating Scale (uMARS) questionnaire postintervention. All interviews were audio-recorded for transcription, and a deductive content analysis approach was used to analyze the participant interviews. The uMARS Likert scores for each subscale (engagement, functionality, esthetics, and information) were calculated and reported as medians with IQRs. The rates of hypoglycemia were similar for both the preapp and app-use phases (0.79 and 0.83 hypoglycemia events per day, respectively). The upper bound of the CI of the hypoglycemia rate ratio met the prespecified criteria for noninferiority (rate ratio=1.06; 95% CI 0.91-1.22). The uMARS analysis showed a high rating (≥4 out of 5) of acT1ve by 80% of participants for both functionality and information, 72% for esthetics, and 63% for overall uMARS rating. Content analysis of the interview transcripts identified 3 main themes: \"Provision of information,\" \"Exercising with the App,\" and \"Targeted Population.\" The mHealth app \"acT1ve,\" which was developed in collaboration with young people with T1D, is functional, acceptable, and safe for diabetes management around exercise. The study supports the noninferiority of acT1ve compared with \"treatment as usual\" with regards to hypoglycemic events.

Athletes regularly perform resistance training, yet it is unknown how best to monitor its intensity. This study compared different resistance exercise intensity metrics to determine their sensitivity to manipulating work rate (via altering inter-set rest and load). Following baseline testing for 10- and 3-repetition maximum (RM; squat and bench press), fourteen trained participants completed four volume-matched protocols in a randomised order: 3x10 with 85% 10RM, 60 s rest (3x10.sub.60s ); 3x10 with 85% 10RM, 180 s (3x10.sub.180s ); 8x3 with 85% 3RM, 120 s (8x3.sub.120s ); 8x3 with 85% 3RM, 300 s (8x3.sub.300s). Internal intensity was quantified via rate of oxygen consumption (VO2), heart rate, blood lactate concentration, and rating of perceived exertion (RPE). External intensity was assessed via previously developed \"Training-Intensity\" (TI) and \"Intensity-Index\" (II) metrics, and from exercise work rate (expressed as kgâmin.sup.-1 and joulesâmin.sup.-1). Internal intensity and work-rate metrics were highest for 3x10.sub.60s, followed by 3x10.sub.180s, 8x3.sub.120s and 8x3.sub.300s (p[less than or equal to]0.027). TI and II were higher for 8x3 than 3x10 protocols (p<0.001), but not different within these configurations. Internal intensity measures were more strongly correlated with work rate (r = 0.37-0.96) than TI and II (r = -0.42-0.33) metrics. Work rate corroborated objective internal intensity metrics during resistance exercise, with the highest work rate session (3x10.sub.60s) also eliciting greater RPE scores than other protocols. In contrast, the TI and II did not agree with other intensity measures, likely because they do not consider rest periods. Practitioners can plan for the physiological and perceptual demands of resistance training by estimating work rate.

Inclusion body myositis (IBM) is the most commonly acquired skeletal muscle disease of older adults involving both autoimmune attack and muscle degeneration. As exercise training can improve outcomes in IBM, this study assessed whether a combination of testosterone supplementation and exercise training would improve muscle strength, physical function and quality of life in men affected by IBM, more than exercise alone. This pilot study was a single site randomised, double-blind, placebo-controlled, crossover study. Testosterone (exercise and testosterone cream) and placebo (exercise and placebo cream) were each delivered for 12 weeks, with a two-week wash-out between the two periods. The primary outcome measure was improvement in quadriceps isokinetic muscle strength. Secondary outcomes included assessment of isokinetic peak flexion force, walk capacity and patient reported outcomes, and other tests, comparing results between the placebo and testosterone arms. A 12-month Open Label Extension (OLE) was offered using the same outcome measures collected at 6 and 12-months. 14 men completed the trial. There were no significant improvements in quadriceps extension strength or lean body mass, nor any of the secondary outcomes. Improvement in the RAND Short Form 36 patient reported outcome questionnaire 'emotional wellbeing' sub-category was reported during the testosterone arm compared to the placebo arm (mean difference [95% CI]: 6.0 points, [95% CI 1.7,10.3]). The OLE demonstrated relative disease stability over the 12-month period but with a higher number of testosterone-related adverse events. Adding testosterone supplementation to exercise training did not significantly improve muscle strength or physical function over a 12-week intervention period, compared to exercise alone. However, the combination improved emotional well-being over this period, and relative stabilisation of disease was found during the 12-month OLE. A longer duration trial involving a larger group of participants is warranted.