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BackgroundSelective androgen receptor modulators (SARMs) increase muscle mass via the androgen receptor. This phase 2A trial investigated the effects of a SARM, GSK2881078, in conjunction with exercise, on leg strength in patients with chronic obstructive pulmonary disease (COPD) and impaired physical function.Methods47 postmenopausal women and 50 men with COPD (forced expiratory volume in 1 s 30%-65% predicted; short physical performance battery score: 3-11) were enrolled into a randomised double-blind, placebo control trial. Patients were randomised 1:1 to once daily placebo or oral GSK2881078 (females: 1.0 mg; males: 2.0 mg) for 13 weeks with a concurrent home-exercise programme, involving strength training and physical activity. Primary endpoints were change from baseline in leg strength at 90 days (one-repetition maximum; absolute (kg) and relative (% change)) and multiple safety outcomes. Secondary endpoints included lean body mass, physical function and patient-reported outcomes.ResultsGSK2881078 increased leg strength in men. The difference in adjusted mean change from baseline and adjusted mean percentage change from baseline between treatment and placebo were: for women, 8.0 kg (90% CI -2.5 to 18.4) and 5.2% (90% CI -4.7 to 15.0), respectively; for men, 11.8 kg (90% CI -0.5 to 24.0) and 7.0% (90% CI 0.5 to 13.6), respectively. Lean body mass increased, but no changes in patient-reported outcomes were observed. Reversible reductions in high-density lipoprotein-cholesterol and transient elevations in hepatic transaminases were the main treatment-related safety findings.ConclusionsGSK2881078 was well tolerated and short-term treatment increased leg strength, when expressed as per cent predicted, in men with COPD more than physical training alone.Trial registration numberNCT03359473.

The Gene Ontology Consortium (GOC) provides the most comprehensive resource currently available for computable knowledge regarding the functions of genes and gene products. Here, we report the advances of the consortium over the past two years. The new GO-CAM annotation framework was notably improved, and we formalized the model with a computational schema to check and validate the rapidly increasing repository of 2838 GO-CAMs. In addition, we describe the impacts of several collaborations to refine GO and report a 10% increase in the number of GO annotations, a 25% increase in annotated gene products, and over 9,400 new scientific articles annotated. As the project matures, we continue our efforts to review older annotations in light of newer findings, and, to maintain consistency with other ontologies. As a result, 20 000 annotations derived from experimental data were reviewed, corresponding to 2.5% of experimental GO annotations. The website (http://geneontology.org) was redesigned for quick access to documentation, downloads and tools. To maintain an accurate resource and support traceability and reproducibility, we have made available a historical archive covering the past 15 years of GO data with a consistent format and file structure for both the ontology and annotations.

The aim of this review was to explore the relevant neurobiology and the association between peripheral levels of brain-derived neurotrophic factor (BDNF) and acute and short to long-term exercise regimes, as well as its relation to depression and antidepressant treatment. A 20-year literature search was conducted. The screening process resulted in 100 manuscripts. Antidepressants as well as acute exercise, particularly high-intensity, elevates BDNF in healthy humans and clinical populations, as evidenced from aerobic and resistance-based studies. Although exercise is increasingly recognised in the management of depression, acute and short-term exercise studies have failed to establish a relationship between the severity of depression and changes in peripheral BDNF. The latter rapidly returns to baseline, possibly indicating a quick re-uptake by the brain, aiding its neuroplasticity functions. The timescale of administration needed for the antidepressants to stimulate biochemical changes is longer than similar increases with acute exercise.

Soccer is a team sport that requires players to process a significant amount of information quickly and respond with both speed and accuracy to the ever-changing demands of the game. As such, success in soccer depends not only on physical attributes but also on cognitive abilities such as perception and decision-making. The aim of the current study was to investigate the acute effects of caffeine ingestion on Stroop test performance before and after repeated small-sided games (SSG) in professional soccer players. Twelve professional male soccer players (29 ± 4.1 years; 78.1 ± 7.7 kg body mass) participated in this study. A randomized crossover double-blind placebo-controlled trial was used. Caffeine (5 mg.kg−1) or a placebo was ingested 45 min before a protocol consisting of five 5 min SSG with 1 min rest intervals. A computerized version of the colour Stroop test was completed immediately before and after the exercise protocol. During the Stroop test, words appeared on the computer screen in three different ways: (i) neutral words (neutral condition); (ii) correspondent colour (i.e., “red” painted in red; congruent condition), or; (iii) different colour (i.e., “red” painted in green; incongruent condition). The incongruent condition aimed to cause the interference effect, as the colour and the word did not match. Ratings of perceived exertion (RPE) were assessed after each SSG. RPE increased during the five sets of the SSG protocol (p < 0.001), without differences between the caffeine and placebo trials. The soccer-specific exercise protocol promoted a faster response during the Stroop test (two-way ANOVA main effect for SSG protocol: p < 0.05), with no differences in accuracy (p > 0.05). Caffeine ingestion resulted in slower reaction time during the Stroop test during the congruent and neutral trials but not during the incongruent trial (two-way ANOVA main effect for supplementation: p = 0.009, p = 0.045, and p = 0.071, respectively). Accuracy was lower in the caffeine trial in congruent and incongruent trials (p < 0.05 caffeine vs. placebo both on the pre- and post-SSG protocol). In conclusion, a soccer-specific exercise protocol improved the Stroop test performance in professional soccer players, but acute caffeine ingestion (5 mg.kg−1) was detrimental.

Background: Chronic obstructive pulmonary disease (COPD) and muscle weakness can cause impaired physical function, significantly impacting patients' health-related quality of life (HRQoL). Loss of muscle strength is usually assessed through clinical and performance outcome (PerfO) assessments, which consists of tasks performed in a standardized manner, providing evidence of a patient's functional ability. However, evidence documenting the patient experience of COPD and muscle weakness is limited. Methods: This two-stage qualitative study used semi-structured interviews in patients aged 45–80 years with COPD (post-bronchodilator forced expiratory volume in 1s [FEV1]/forced vital capacity ratio < 0.70, and FEV1% predicted of 30–80%) and muscle weakness. In Stage 1, 30-minute concept elicitation interviews were conducted with participants recruited across three US sites to explore impacts on physical functioning and activities of daily living. In Stage 2, interviews were performed with participants exiting a Phase IIa trial investigating the efficacy of a selective androgen receptor modulator (GSK2881078) on leg strength, whereby PerfOs were used to evaluate strength and physical functioning endpoints. These participants completed either 60-minute in-depth (n = 32) or 15-minute confirmatory (n = 35) interviews exploring trial experience, completion of outcome measures, disease experience and treatment satisfaction. Results: In Stage 1 (n = 20), most participants described their muscles as weak (83.3%). Difficulties with walking (100%) and lifting heavy objects (90%) were reported. In Stage 2, 60-minute interviews, all participants (n = 32) reported a positive trial experience. Most participants reported that the home exercise program was easy to fit into daily life (77.8%), the PROactive daily diary was easy to complete (100%) and wearable sensors were easy to use (65.6%). However, technical issues were reported (71%), and few participants (19.4%) found physical assessments easy to complete. Improvements in muscle strength and functional limitations were reported by most participants. The shorter 15-minute confirmatory interviews (n = 35) supported the in-depth interview results. Conclusion: The qualitative interviews generated in-depth evidence of key concepts relevant to patients with COPD and muscle weakness and support the assessments of patient strength and physical function as outcome measures in this population in future studies. Trial number: GSK Stage 1: 206869; Stage 2: 200182, NCT03359473; Registered December 2, 2017, https://clinicaltrials.gov/ct2/show/NCT03359473. [ABSTRACT FROM AUTHOR]

The effect of caffeine on mitigating exercise-induced muscle damage (EIMD) is still poorly understood, but it was hypothesized that caffeine could contribute to decreasing delayed onset muscle soreness, attenuating temporary loss of strength, and reducing circulating levels of blood markers of muscle damage. However, evidence is not conclusive and beneficial effects of caffeine ingestion on EIMD are not always observed. Factors, such as the type of exercise that induces muscle damage, supplementation protocol, and type of marker analyzed contribute to the differences between the studies. To expand knowledge on the role of caffeine supplementation in EIMD, this systematic review aimed to investigate the effect of caffeine supplementation on different markers of muscle damage. Fourteen studies were included, evaluating the effect of caffeine on indirect muscle damage markers, including blood markers (nine studies), pain perception (six studies), and MVC maximal voluntary contraction force (four studies). It was observed in four studies that repeated administration of caffeine between 24 and 72 h after muscle damage can attenuate the perception of pain in magnitudes ranging from 3.9% to 26%. The use of a single dose of caffeine pre-exercise (five studies) or post-exercise (one study) did not alter the circulating blood levels of creatine kinase (CK). Caffeine supplementation appears to attenuate pain perception, but this does not appear to be related to an attenuation of EIMD, per se. Furthermore, the effect of caffeine supplementation after muscle damage on strength recovery remains inconclusive due to the low number of studies found (four studies) and controversial results for both dynamic and isometric strength tests.

In soccer, physical, tactical, and decision-making processes are highly important facets of successful performance. Caffeine has well established effects for promoting both physical and cognitive performance, but the translation of such benefits specifically for soccer match play is not well established. This study examined the effects of acute caffeine ingestion on tactical performance during small-sided games (SSG) in professional soccer players. Nineteen soccer players (22 ± 4 years) underwent a randomized, counterbalanced, crossover, double-blind placebo-controlled trial. The protocol consisted of 5 bouts of 5-min SSG with 3 players plus a goalkeeper in each team (3 + GK × 3 + GK) with each SSG separated by 1 min rest intervals. Tactical performance was assessed using the system of tactical assessment in soccer (FUT-SAT). Prior to each experimental trial, participants ingested caffeine (5 mg·kg−1) or a placebo 60 min before the protocol. Overall, caffeine ingestion resulted in an increased ball possession time when compared to the placebo. When the offensive and defensive core principles were analyzed, the results were equivocal. Caffeine resulted in positive effects on some tactical decisions during the protocol, but it was deleterious or promoted no observed effect on other of the core tactical principles. Caffeine ingestion resulted in less offensive (during SSG3) and defensive (SSG 2, SSG3, and SSG4) errors. Caffeine ingestion also resulted in higher total offensive success during SSG 1 and SSG2, but it was detrimental during SSG3. Additionally, total defensive success was lower for the caffeine conditions during SSG 2 and SSG5 when compared to the placebo. In conclusion, caffeine influenced aspects of tactical decisions in soccer, resulting in fewer offensive and defensive errors, although it may be deleterious considering other tactical parameters. Future studies may clarify the effects of caffeine ingestion on specific decision-making parameters in soccer.

To eliminate schistosomiasis, appropriate diagnostic tests are required to monitor its prevalence and transmission, especially in the settings with low endemicity resulting from the consecutive mass drug administration. Antibodies that react with either crude soluble schistosome egg antigens or soluble worm antigen preparations have been used to monitor infection in low-prevalence regions. However, these detection methods cannot discriminate current and past infections and are cross-reactive with other parasites because both antigens contain numerous proteins and glycans from schistosomes, and standard preparations need maintenance of the life cycle of the schistosome. To evaluate the potential utility of nine recombinant Schistosoma mansoni proteins as single defined antigens for serological diagnosis, we monitored the kinetics of antibodies to each antigen during S. mansoni infection in mice before and after the treatment with praziquantel. C57BL/6 mice were infected with 50 cercariae. The levels of immunoglobulin G (IgG) raised against five recombinant antigens (RP26, sm31, sm32, GST, and LAP1) significantly increased as early as 2–4 weeks after infection and rapidly declined by 2 weeks after the treatment, whereas those raised against crude S. mansoni egg antigens or other antigens remained elevated long after the treatment. The IgG1 raised against RP26, sm31, and serpin decreased after the treatment with praziquantel, whereas the IgE raised against serpin declined strikingly after the treatment. This study clarifies the dynamics of the serological responses to recombinant S. mansoni proteins during infection and after the treatment with praziquantel and identifies several candidate antigens with potential utility in the monitoring and surveillance of schistosomiasis toward the elimination of schistosomiasis. Author summary Schistosomiasis is the second most important human parasitic disease in tropical and subtropical areas: estimates show that at least 218 million people required treatment in 2015 and remains a major Neglected Tropical Disease impacting the health of the poorest populations. The global strategy for schistosomiasis control is focused on eliminating disease through periodic, large-scale population treatment with praziquantel (PZQ). With the progress towards the control and the elimination of schistosomiasis by mass drug administration (MDA) with PZQ, more sensitive diagnostics that can monitor the dynamics of schistosomiasis transmission are required to instruct MDA programs and assess reinfection. Detecting antibodies react with either crude soluble schistosome egg antigens or soluble worm antigen preparations have been used to monitor infection in low-prevalence settings. However, these detection methods cannot discriminate current and past infections and are cross-reactive with other parasites because it contains numerous proteins and glycans from schistosomes, and standard preparations need maintenance of the life cycle of the schistosome. This study clarified that the dynamics of the serological responses to defined recombinant proteins during S. mansoni infection in mice before and after the treatment with PZQ and identifies several candidate antigens with potential utility in the monitoring and surveillance of schistosomiasis toward the elimination of schistosomiasis.

The Oxford Nanopore MinION DNA sequencing device can produce large amounts of long sequences, typically several kilobases, within a few hours. This long read capacity was exploited to detect antimicrobial resistance genes (ARGs) in a large veterinary teaching hospital environment, and to assess their taxonomic origin, genetic organisation and association with mobilisation markers concurrently. Samples were collected on eight occasions between November 2016 and May 2017 (inclusive) in a longitudinal study. Nanopore sequencing was performed on total DNA extracted from the samples after a minimal enrichment step in broth. Many ARGs present in the veterinary hospital environment could potentially confer resistance to antimicrobials widely used in treating infections of companion animals, including aminoglycosides, extended-spectrum beta-lactams, sulphonamides, macrolides, and tetracyclines. High-risk ARGs, defined here as single or multiple ARGs associated with pathogenic bacterial species or with mobile genetic elements, were shared between the intensive care unit (ICU) patient cages, a dedicated laundry trolley and a floor cleaning mop-bucket. By contrast, a floor surface from an office corridor without animal contact and located outside the veterinary hospital did not contain such high-risk ARGs. Relative abundances of high-risk ARGs and co-localisation of these genes on the same sequence read were higher in the laundry trolley and mop bucket samples, compared to the ICU cages, suggesting that amplification of ARGs is likely to occur in the collection points for hospital waste. These findings have prompted the implementation of targeted intervention measures in the veterinary hospital to mitigate the risks of transferring clinically important ARGs between sites and to improve biosecurity practices in the facility.

Infection with the food-borne liver fluke Opisthorchis viverrini is the principal risk factor (IARC Working Group on the Evaluation of Carcinogenic Risks to Humans, 2012) for cholangiocarcinoma (CCA) in the Lower Mekong River Basin countries including Thailand, Lao PDR, Vietnam and Cambodia. We exploited this link to explore the role of the secreted growth factor termed liver fluke granulin (Ov-GRN-1) in pre-malignant lesions by undertaking programmed CRISPR/Cas9 knockout of the Ov-GRN-1 gene from the liver fluke genome. Deep sequencing of amplicon libraries from genomic DNA of gene-edited parasites revealed Cas9-catalyzed mutations within Ov-GRN-1. Gene editing resulted in rapid depletion of Ov-GRN-1 transcripts and the encoded Ov-GRN-1 protein. Gene-edited parasites colonized the biliary tract of hamsters and developed into adult flukes, but the infection resulted in reduced pathology as evidenced by attenuated biliary hyperplasia and fibrosis. Not only does this report pioneer programmed gene-editing in parasitic flatworms, but also the striking, clinically-relevant pathophysiological phenotype confirms the role for Ov-GRN-1 in virulence morbidity during opisthorchiasis.

Transoesophageal echocardiography (TOE) has, in certain clinical situations, become an almost universal monitor and diagnostic tool. In the perioperative environment, TOE is frequently used to guide anaesthetic management and assist with surgical decision making for, but not limited to, cardiothoracic, major vascular and transplant operations. The use of TOE is not limited to the theatre environment being frequently used in outpatient clinics, emergency departments and intensive care settings. Two case reports, one of oesophageal perforation and another of TOE utilization in a patient having previously undergone an oesophagectomy, introduce the need for care while using TOE and highlight the need for vigilance. The safe use of TOE, the potential complications and the suggested contra-indications are then considered together with suggestions for improving the safety of TOE in adult and paediatric patients.