Genome-wide association analyses of physical activity and sedentary behavior provide insights into underlying mechanisms and roles in disease prevention.

Although physical activity and sedentary behavior are moderately heritable, little is known about the mechanisms that influence these traits. Combining data for up to 703,901 individuals from 51 studies in a multi-ancestry meta-analysis of genome-wide association studies yields 99 loci that associate with self-reported moderate-to-vigorous intensity physical activity during leisure time (MVPA), leisure screen time (LST) and/or sedentary behavior at work. Loci associated with LST are enriched for genes whose expression in skeletal muscle is altered by resistance training. A missense variant in ACTN3 makes the alpha-actinin-3 filaments more flexible, resulting in lower maximal force in isolated type IIA muscle fibers, and possibly protection from exercise-induced muscle damage. Finally, Mendelian randomization analyses show that beneficial effects of lower LST and higher MVPA on several risk factors and diseases are mediated or confounded by body mass index (BMI). Our results provide insights into physical activity mechanisms and its role in disease prevention.

Validation of shear wave elastography as a noninvasive measure of pelvic floor muscle stiffness.

OBJECTIVES: To investigate the validity of shear wave elastography (SWE) as a measure of stiffness of the puborectalis muscle by examining: (1) the relationship between puborectalis muscle stiffness and pelvic floor muscle (PFM) activation at different intensities; and (2) the relationship between puborectalis stiffness and pelvic floor morphometry during contractions at different intensities. METHODS: Fifteen healthy asymptomatic women performed 6-s isometric PFM contractions at different intensities (0, 10%, 20%, 30%, 50%, 75%, and 100% of maximal voluntary contraction) guided by intravaginal electromyography (EMG). Stiffness of the puborectalis muscle was measured using SWE by calculating the average shear modulus in regions of interest that contained puborectalis muscle fibers parallel to the transducer. Pelvic floor morphometry was assessed in the mid-sagittal plane using transperineal B-mode ultrasound imaging. Shear modulus, EMG (root mean square amplitude) and pelvic floor morphometry parameters were normalized to the value recorded during maximal voluntary contraction. To assess the relationship between stiffness and pelvic floor activation/morphometry, coefficient of determination (r2 ) was calculated for each participant and a group average was computed. RESULTS: Shear modulus and EMG were highly correlated (average r2 ; left 0.90 ± 0.08, right 0.87 ± 0.15). Shear modulus also strongly correlated with bladder neck position (x-axis horizontal coordinates relative to the pubic symphysis), anorectal rectal angle and position, levator plate angle, and antero-posterior diameter of the levator hiatus (average r2 : range 0.62-0.78). CONCLUSIONS: These findings support the validity of SWE to assess puborectalis muscle stiffness in females. Stiffness measures were strongly associated with PFM EMG and pelvic floor morphometry and may be used to indirectly assess the level of activation of the puborectalis muscle without the use of more invasive techniques. By overcoming limitations of current assessment tools, this promising noninvasive and real-time technique could enable important breakthrough in the pathophysiology and management of pelvic floor disorders.

A study protocol for a randomised controlled trial of ice to reduce the pain of immunisation: The ICE trial.

BACKGROUND AND OBJECTIVES: Vaccine injections commonly cause iatrogenic pain. Ice may reduce pain. This is a study protocol for a prospective randomised controlled trial aiming to investigate the efficacy of ice packs to decrease vaccine-related pain in adults. METHOD: The intervention group (n = 45) will receive ice packs (0 °C) and the control group (n = 45) receive placebo cold packs (10 °C) on the injection site for 30 seconds prior to vaccination. RESULTS: The primary outcomes will test the hypothesis that applying an ice pack will significantly reduce pain of vaccination when compared with a cold pack. The primary dependent variable will be pain score recorded on a visual analogue scale. Secondary outcomes aim to assess potential adverse reactions. The main analysis of data will follow the intention-to-treat principle. The primary dependent variable will be compared using an independent t-test or a Mann-Whitney U test. Multivariable logistic regression analysis may be used. DISCUSSION: The trial may guide general practitioners in the use of ice packs to reduce injection-related pain in adults.

International comparison of guidelines for management of impetigo: a systematic review.

BACKGROUND: Impetigo is a common superficial skin infection that affects people worldwide and is usually treated with antibiotics; therefore, its management has implications for global antibiotic stewardship. OBJECTIVE: This systematic review and narrative synthesis compares and contrasts international impetigo management guidelines. METHODS: Guidelines for treatment of impetigo that were produced by a national authority; available to primary care physicians; and published since 2008 were included. Following a comprehensive search strategy, data extraction from eligible studies was performed independently in duplicate. Details of antiseptic and antibiotic treatment; methicillin-resistant Staphylococcus aureus treatment; and conservative management and preventative measures were tabulated and analysed descriptively. RESULTS: Fifty-one guidelines were included from 42 different countries. All guidelines recommended systemic antibiotics, 78% of these only for widespread lesions or failure of topical antibiotic treatment. The first-line systemic antibiotic treatment was restricted to narrow-spectrum options in 21 (41%) whilst 7 (14%) recommended only broad-spectrum antibiotics first-line. Thirty-four (67%) guidelines included recommendations for topical antibiotic use. Twenty guidelines (39%) did not mention antiseptic treatment for impetigo. Guidelines did not always provide clear indications for different treatment options. CONCLUSIONS: Despite potentially equal efficacy to systemic antibiotics, only two-thirds of guidelines include topical antibiotic options. Many fail to include recommendations for non-antibiotic treatments such as antiseptics, preventative measures and conservative management, despite potential for antibiotic-sparing. Provision of clear definitions of disease severity and indications for treatment would enhance the ability of clinicians to adhere to recommendations. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42018117770.

Cooling to reduce the pain associated with vaccination: A systematic review.

BACKGROUND: Vaccine injections are the most common cause of iatrogenic pain in childhood and a cause of anxiety in adulthood. Skin cooling techniques, including icepacks and vapocoolants, may provide pain relief during intramuscular injections. OBJECTIVE: To identify the effects of skin cooling techniques on pain associated with immunisation. METHODS: MEDLINE (Ovid), CINAHL, EMCARE, INFORMIT and Scopus were searched for randomised controlled trials (RCTs) investigating the use of skin cooling techniques on pain associated with vaccination. Study and intervention details, outcomes measures and results were extracted and risk of bias assessed using the Cochrane Risk of Bias tool. Due to heterogeneity of studies, a narrative synthesis was performed. RESULTS: Thirteen trials were included, involving 689 paediatric and 829 adult participants. All studies used vapocoolant or ice as one of the interventions. Comparator groups included topical EMLA cream, breastfeeding, distraction techniques and tactile stimulation. Vapocoolant reduced vaccination-related pain in all adult studies and six paediatric studies however the use of ice packs in paediatric patients was not effective. CONCLUSION: The use of cooling techniques reduces pain associated with vaccinations in adults. Paediatric studies show mixed results for vapocoolants and an inability for ice to decrease vaccine-injection pain. Larger RCTs are required to determine the most effective administration techniques and optimise the analgesic effects of skin cooling.

Systematic Review and Synthesis of Mechanism-based Classification Systems for Pain Experienced in the Musculoskeletal System.

OBJECTIVES: Improvements in pain management might be achieved by matching treatment to underlying mechanisms for pain persistence. Many authors argue for a mechanism-based classification of pain, but the field is challenged by the wide variation in the proposed terminology, definitions, and typical characteristics. This study aimed to (1) systematically review mechanism-based classifications of pain experienced in the musculoskeletal system; (2) synthesize and thematically analyze classifications, using the International Association for the Study of Pain categories of nociceptive, neuropathic, and nociplastic as an initial foundation; and (3) identify convergence and divergence between categories, terminology, and descriptions of each mechanism-based pain classification. MATERIALS AND METHODS: Databases were searched for papers that discussed a mechanism-based classification of pain experienced in the musculoskeletal system. Terminology, definitions, underlying neurobiology/pathophysiology, aggravating/easing factors/response to treatment, and pain characteristics were extracted and synthesized on the basis of thematic analysis. RESULTS: From 224 papers, 174 terms referred to pain mechanisms categories. Data synthesis agreed with the broad classification on the basis of ongoing nociceptive input, neuropathic mechanisms, and nociplastic mechanisms (eg, central sensitization). "Mixed," "other," and the disputed categories of "sympathetic" and "psychogenic" pain were also identified. Thematic analysis revealed convergence and divergence of opinion on the definitions, underlying neurobiology, and characteristics. DISCUSSION: Some pain categories were defined consistently, and despite the extensive efforts to develop global consensus on pain definitions, disagreement still exists on how each could be defined, subdivided, and their characteristic features that could aid differentiation. These data form a foundation for reaching consensus on classification.

Design, Delivery, Maintenance, and Outcomes of Peer-to-Peer Online Support Groups for People With Chronic Musculoskeletal Disorders: Systematic Review.

BACKGROUND: Online support groups (OSGs) are one way for people with chronic diseases, their family or friends, and health professionals to communicate, gain information, and provide social support. As the number of peer-to-peer OSGs for chronic musculoskeletal conditions grows, it is important to gain insight into the different designs of groups available, who is accessing them, if and how they may be effective, and what strategies are being used to implement or increase consumer engagement. OBJECTIVE: The objectives of this systematic review of people with musculoskeletal conditions were to (1) describe the design features (functions, usage options, moderation, and expert input) of peer-to-peer OSGs, (2) describe the characteristics of the individuals using peer-to-peer OSGs, (3) synthesize the evidence on outcomes of participation, and (4) identify strategies used in the delivery and maintenance of OSGs. METHODS: A search comprising terms related to the population (people with musculoskeletal disorders) and the intervention (peer-to-peer OSGs) was conducted in 6 databases. Results were filtered from 1990 (internet inception) to February 2019. Studies identified in the search were screened according to predefined eligibility criteria using a 2-step process. Quantitative studies were appraised by 2 reviewers using the Risk Of Bias In Non-Randomized Studies of Interventions tool. Qualitative studies were appraised by 2 different reviewers using the Critical Appraisal Skills Programme checklist. Extracted data were synthesized narratively. RESULTS: We examined 21 studies with low to moderate risk of bias. Of these studies, 13 studies included OSGs hosted on public platforms, 11 studies examined OSGs that were conducted in English, and 6 studies used moderators or peer leaders to facilitate engagement. Studies either reported the number of OSG members (n=1985 across all studies) or the number of posts (range: 223-200,000). The majority of OSG members were females who were not full-time employees and with varied levels of education. There were no randomized controlled trials measuring the efficacy of OSGs. Qualitative and quantitative studies identified empowerment, social support, self-management behavior, and health literacy as primary constructs to measure OSG efficacy. Neutral or marginal improvement was reported in these constructs. Sharing experiences and a greater level of engagement appeared to have an important influence on OSGs efficacy. The extent to which members posted on the website influenced engagement. CONCLUSIONS: Across a diverse range of designs, languages, included features, and delivery platforms, peer-to-peer OSGs for chronic musculoskeletal conditions attract predominantly female participants of all ages and education levels. The level of participation of a member appears to be related to their perceived benefit, health literacy, and empowerment. Future studies are needed to identify which design and maintenance strategies have superior efficacy and whether there are concomitant improvements in health outcomes for people with chronic musculoskeletal conditions resulting from participation in OSGs. TRIAL REGISTRATION: PROSPERO International Prospective Register of Systematic Reviews CRD42018090326; https://www.crd.york.ac.uk/prospero/display_record.php?ID=CRD42018090326.

Do features of randomized controlled trials of pelvic floor muscle training for postprostatectomy urinary incontinence differentiate successful from unsuccessful patient outcomes? A systematic review with a series of meta-analyses.

AIMS: Efficacy of pelvic floor muscle training (PFMT) for postprostatectomy incontinence (PPI) differs between randomized clinical trials (RCT). This might be explained by variation in content/delivery of PFMT (eg, biofeedback, muscles targeted, and time of commencement of training). This review investigated whether outcome of meta-analysis differs based on presence or not of specific RCT features. METHODS: PubMed, CINAHL, EMBASE, Physiotherapy Evidence Database (PEDro), and Cochrane were searched for RCTs that investigated efficacy of PFMT on PPI. PFMT details and outcomes were extracted. Methodological quality and comprehensiveness of PFMT reporting was assessed using the PEDro scale and Consensus on Reporting Template, respectively. Effect size and 95% confidence intervals were calculated for incontinence rate at 3 months. To identify features that influenced efficacy, separate meta-analyses were performed for studies with and without specific features. RESULTS: Twenty-two trials were included, and 15 were used for meta-analysis of 3-month outcomes. Overall, meta-analysis showed reduced incontinence with PFMT (risk ratio [RR] = 0.85; I2 = 55%; P = .005). Meta-analyses showed better outcomes for PFMT than control groups when the study included preoperative PFMT (RR = 0.76; I2 = 30%; P = .006), biofeedback (RR = 0.73; I2 = 58%; P = .006), instruction to contract around the urethra (RR = 0.9; I2 = 43%; P = .009), a control group without PFMT instruction (RR = 0.85; I2 = 69%; P = .05), inclusion of all men irrespective of continence status (RR = 0.84; I2 = 30%; P = .003) and continence defined as no leakage (RR = 0.85; I2 = 48%; P = .05). CONCLUSIONS: Preoperative PFMT, biofeedback, urethral instructions, no PFMT instruction for controls, inclusion of all men, and continence defined as no leakage are features associated with successful patient outcomes. Future studies should consider these features in design of interventions and pooling data for meta-analysis.

KCND3 potassium channel gene variant confers susceptibility to electrocardiographic early repolarization pattern.

BACKGROUNDThe presence of an early repolarization pattern (ERP) on the surface ECG is associated with risk of ventricular fibrillation and sudden cardiac death. Family studies have shown that ERP is a highly heritable trait, but molecular genetic determinants are unknown.METHODSTo identify genetic susceptibility loci for ERP, we performed a GWAS and meta-analysis in 2,181 cases and 23,641 controls of European ancestry.RESULTSWe identified a genome-wide significant (P < 5 × 10-8) locus in the potassium voltage-gated channel subfamily D member 3 (KCND3) gene that was successfully replicated in additional 1,124 cases and 12,510 controls. A subsequent joint meta-analysis of the discovery and replication cohorts identified rs1545300 as the lead SNP at the KCND3 locus (OR 0.82 per minor T allele, P = 7.7 × 10-12) but did not reveal additional loci. Colocalization analyses indicate causal effects of KCND3 gene expression levels on ERP in both cardiac left ventricle and tibial artery.CONCLUSIONSIn this study, we identified for the first time to our knowledge a genome-wide significant association of a genetic variant with ERP. Our findings of a locus in the KCND3 gene provide insights not only into the genetic determinants but also into the pathophysiological mechanism of ERP, discovering a promising candidate for functional studies.FUNDINGThis project was funded by the German Center for Cardiovascular Research (DZHK Shared Expertise SE081 - STATS). For detailed funding information per study, see the Supplemental Acknowledgments.

MyBackPain-evaluation of an innovative consumer-focused website for low back pain: study protocol for a randomised controlled trial.

INTRODUCTION: Despite the prevalence of low back pain (LBP) worldwide, many people with the condition do not receive evidence-based care or achieve the best possible outcomes. There is a gap in the dissemination of evidence-based information across the globe. The advent of the internet has changed the way people obtain health information. As such, trustworthy, tailored and validated LBP resources may help bridge the gap. This study aims to measure the effectiveness of a new website (MyBackPain) in improving spinal health literacy, treatment preferences and clinical outcomes for people with LBP, in comparison with other online resources. METHODS AND ANALYSIS: This online, pragmatic, randomised controlled trial will comprise 440 people with non-specific LBP of any duration. In addition to access to publicly available online information (control group), the intervention group will be given access to the MyBackPain.org.au website. Participants and research staff, including the biostatistician, will be blinded to treatment allocation. Data will be collected at baseline, 1, 3 (primary end-point), 6 and 12 months via online surveys and questionnaires. The primary outcome is spinal health literacy. Secondary outcomes include quality of treatment preferences (stated and observed) and LBP clinical outcomes (pain, disability and quality of life). Analyses will be by intention-to-treat and include outcome data on all randomised participants. Descriptive statistics will be presented for demographic and clinical characteristics. ETHICS AND DISSEMINATION: This trial has been prospectively registered with the Australian New Zealand Clinical Trials Registry and has ethical approval from the University of Queensland Human Research Ethics Committee (2017000995). Trial outcomes will be shared via national and international conference presentations and peer-reviewed journal publications. TRIAL REGISTRATION NUMBER: ACTRN12617001292369; Pre-results.

Efficacy of a personalised pelvic floor muscle training programme on urinary incontinence after radical prostatectomy (MaTchUP): protocol for a randomised controlled trial.

INTRODUCTION: Prostate cancer is the most common cancer in men. Prostatectomy is the most common treatment. Morbidity from prostatectomy is high-80% of men experience urinary incontinence which negatively impacts the quality of life. Postsurgical pelvic floor muscle training is commonly prescribed but recent systematic reviews found no evidence of efficacy. We propose a new treatment that commences preoperatively and targets functional training of specific pelvic floor muscles that contribute to urinary continence. Assessment and biofeedback using transperineal ultrasound imaging assists in training. This will be compared against conventional training (maximal pelvic floor muscle contraction assessed by digital rectal examination) and no training. Embedded physiological studies will allow the investigation of moderation and mediation of the treatment effect on the outcomes. METHODS AND ANALYSIS: This randomised clinical trial will include 363 men scheduled to undergo radical prostatectomy for prostate cancer. Participants will be randomised into urethral training, conventional training and no training groups. Clinical data will be collected at baseline (1-2 weeks presurgery) and postsurgery after catheter removal, weekly to 3 months (primary endpoint) and monthly to 12 months. Outcomes include 24-hour pad weight test (primary), incontinence, quality of life and cost-effectiveness data. Neuromuscular control measures of pelvic floor muscles will be measured at baseline, postsurgery, 6 weeks, 3 and 12 months. Study assessors and statisticians will be blinded to the group allocation. ETHICS AND DISSEMINATION: This study is registered with the Australian New Zealand Clinical Trials Registry and has ethical approval from the university and host hospital ethics committees. Trial outcomes will be shared via national/international conference presentations and peer-reviewed journal publications. TRIAL REGISTRATION NUMBER: ACTRN12617000788370; Pre-results.

Task-specific differences in respiration-related activation of deep and superficial pelvic floor muscles.

The female pelvic floor muscles (PFM) are arranged in distinct superficial and deep layers that function to support the pelvic/abdominal organs and maintain continence, but with some potential differences in function. Although general recordings of PFM activity show amplitude modulation in conjunction with fluctuation in intra-abdominal pressure such as that associated with respiration, it is unclear whether the activities of the two PFM layers modulate in a similar manner. This study aimed to investigate the activation of the deep and superficial PFM during a range of respiratory tasks in different postures. Twelve women without pelvic floor dysfunction participated. A custom-built surface electromyography (EMG) electrode was used to record the activation of the superficial and deep PFM during quiet breathing, breathing with increased dead space, coughing, and maximal and submaximal inspiratory and expiratory efforts. As breathing demand increased, the deep PFM layer EMG had greater coherence with respiratory airflow at the frequency of respiration than the superficial PFM (P = 0.038). During cough, the superficial PFM activated earlier than the deep PFM in the sitting position (P = 0.043). In contrast, during maximal and submaximal inspiratory and expiratory efforts, the superficial PFM EMG was greater than that for the deep PFM (P = 0.011). These data show that both layers of PFM are activated during both inspiration and expiration, but with a bias to greater activation in expiratory tasks/phases. Activation of the deep and superficial PFM layers differed in most of the respiratory tasks, but there was no consistent bias to one muscle layer. NEW & NOTEWORTHY Although pelvic floor muscles are generally considered as a single entity, deep and superficial layers have different anatomies and biomechanics. Here we show task-specific differences in recruitment between layers during respiratory tasks in women. The deep layer was more tightly modulated with respiration than the superficial layer, but activation of the superficial layer was greater during maximal/submaximal occluded respiratory efforts and earlier during cough. These data highlight tightly coordinated recruitment of discrete pelvic floor muscles for respiration.

Activity of Deep and Superficial Pelvic Floor Muscles in Women in Response to Different Verbal Instructions: A Preliminary Investigation Using a Novel Electromyography Electrode.

INTRODUCTION: Verbal instructions are used clinically to encourage activation of the pelvic floor muscles (PFM). Whether separate layers of PFM activate differently in response to instructions remains unknown. AIM: To test the hypotheses that (i) instructions that aimed to bias activity of a specific muscle layer would increase activation of the targeted layer to a greater extent than the other layer, (ii) activity of individual PFM layers would differ between instructions, and (iii) PFM activity would be symmetrical for all instructions. METHOD: PFM electromyography (EMG) was recorded using custom-designed surface electrodes in 12 women without PFM dysfunction. The electrode included 4 pairs of recording surfaces orientated to measure EMG from deep and superficial PFM on each side. 3 submaximal contractions were performed for 5 seconds in response to 7 verbal instructions. Root-mean-squared EMG amplitude was calculated for 1 second during the period when participants most closely matched the target activation level. A repeated-measures anova was used to test whether PFM EMG differed between instructions and between regions. The EMG increase of individual muscles relative to that of the reference muscle [deep/right PFM] was compared to no change with t-tests for single samples. MAIN OUTCOME MEASURE: PFM EMG amplitude. RESULTS: Superficial PFM EMG was greater than deep PFM for all instructions (P = .039). 2 instructions induced the greatest amplitude of EMG for the superficial PFM: "squeeze the muscles around the vaginal opening as if to purse lips of your mouth" and "draw the clitoris in a posterior direction" (P = .036). Asymmetry was found in the deeper PFM in 3 instructions designed to bias the superficial PFM. STRENGTH & LIMITATIONS: This preliminary study recorded activation of deep and superficial PFM layers in females with a custom-designed novel electrode. Some cross-talk of recording between muscle layers is possible but unlikely to impact the major findings. CONCLUSION: Verbal instructions used to teach PFM contractions can influence their pattern of activity. This study provides preliminary evidence that, in a selection of verbal instructions, the superficial PFM activates more than the deep PFM, and that the deep PFM can have asymmetrical activation. Aljuraifani R, Stafford RE, Hall LM, et al. Activity of Deep and Superficial Pelvic Floor Muscles in Women in Response to Different Verbal Instructions: A Preliminary Investigation Using a Novel Electromyography Electrode J Sex Med 2019;16:673-679.

Genome-wide association meta-analysis of 30,000 samples identifies seven novel loci for quantitative ECG traits.

Genome-wide association studies (GWAS) of quantitative electrocardiographic (ECG) traits in large consortia have identified more than 130 loci associated with QT interval, QRS duration, PR interval, and heart rate (RR interval). In the current study, we meta-analyzed genome-wide association results from 30,000 mostly Dutch samples on four ECG traits: PR interval, QRS duration, QT interval, and RR interval. SNP genotype data was imputed using the Genome of the Netherlands reference panel encompassing 19 million SNPs, including millions of rare SNPs (minor allele frequency < 5%). In addition to many known loci, we identified seven novel locus-trait associations: KCND3, NR3C1, and PLN for PR interval, KCNE1, SGIP1, and NFKB1 for QT interval, and ATP2A2 for QRS duration, of which six were successfully replicated. At these seven loci, we performed conditional analyses and annotated significant SNPs (in exons and regulatory regions), demonstrating involvement of cardiac-related pathways and regulation of nearby genes.

Exome-chip meta-analysis identifies novel loci associated with cardiac conduction, including ADAMTS6.

BACKGROUND: Genome-wide association studies conducted on QRS duration, an electrocardiographic measurement associated with heart failure and sudden cardiac death, have led to novel biological insights into cardiac function. However, the variants identified fall predominantly in non-coding regions and their underlying mechanisms remain unclear. RESULTS: Here, we identify putative functional coding variation associated with changes in the QRS interval duration by combining Illumina HumanExome BeadChip genotype data from 77,898 participants of European ancestry and 7695 of African descent in our discovery cohort, followed by replication in 111,874 individuals of European ancestry from the UK Biobank and deCODE cohorts. We identify ten novel loci, seven within coding regions, including ADAMTS6, significantly associated with QRS duration in gene-based analyses. ADAMTS6 encodes a secreted metalloprotease of currently unknown function. In vitro validation analysis shows that the QRS-associated variants lead to impaired ADAMTS6 secretion and loss-of function analysis in mice demonstrates a previously unappreciated role for ADAMTS6 in connexin 43 gap junction expression, which is essential for myocardial conduction. CONCLUSIONS: Our approach identifies novel coding and non-coding variants underlying ventricular depolarization and provides a possible mechanism for the ADAMTS6-associated conduction changes.

Location-specific responses to nociceptive input support the purposeful nature of motor adaptation to pain.

Movement is changed in pain, but the mechanisms remain unclear. Key questions are unresolved such as whether activation can be inhomogeneously distributed within a muscle in a manner that is specific to the location of noxious input. This study addressed this question using high-density electromyography (EMG) to study regional redistribution of muscle activation within the vasti muscles and changes in knee extension force direction in response to noxious stimulation applied to muscular and nonmuscular tissues around the knee. Fourteen participants performed a low-force knee extension contraction at baseline, during, and after pain induced in 4 locations (infrapatellar fat pad, vastus lateralis, distal vastus medialis, or proximal vastus medialis). The knee extension force direction was estimated from a 3-dimensional load cell positioned just above the ankle. Regional muscle activation was estimated from amplitude of high-density surface EMG signals from vastus medialis and lateralis. Pain-induced spatial variations of activation were identified as the position of the 5 channels that showed the largest decrease (or smallest increase) in amplitude from baseline to pain or after pain. Knee extension force was produced more medially during pain after infrapatellar pad injection only (P = 0.01). Preferential reduction of activation of the distal region of vastus medialis was observed when distal vastus medialis (P < 0.001) or vastus lateralis (P < 0.05) was injected. Both adaptations persisted after pain resolution. These results support the hypothesis that specific adaptation depends on the location of a noxious stimulus and imply that recovery of pain is not necessarily concomitant with return of the EMG to prepain patterns.

ExomeChip-Wide Analysis of 95 626 Individuals Identifies 10 Novel Loci Associated With QT and JT Intervals.

BACKGROUND: QT interval, measured through a standard ECG, captures the time it takes for the cardiac ventricles to depolarize and repolarize. JT interval is the component of the QT interval that reflects ventricular repolarization alone. Prolonged QT interval has been linked to higher risk of sudden cardiac arrest. METHODS AND RESULTS: We performed an ExomeChip-wide analysis for both QT and JT intervals, including 209 449 variants, both common and rare, in 17 341 genes from the Illumina Infinium HumanExome BeadChip. We identified 10 loci that modulate QT and JT interval duration that have not been previously reported in the literature using single-variant statistical models in a meta-analysis of 95 626 individuals from 23 cohorts (comprised 83 884 European ancestry individuals, 9610 blacks, 1382 Hispanics, and 750 Asians). This brings the total number of ventricular repolarization associated loci to 45. In addition, our approach of using coding variants has highlighted the role of 17 specific genes for involvement in ventricular repolarization, 7 of which are in novel loci. CONCLUSIONS: Our analyses show a role for myocyte internal structure and interconnections in modulating QT interval duration, adding to previous known roles of potassium, sodium, and calcium ion regulation, as well as autonomic control. We anticipate that these discoveries will open new paths to the goal of making novel remedies for the prevention of lethal ventricular arrhythmias and sudden cardiac arrest.

Design of programs to train pelvic floor muscles in men with urinary dysfunction: Systematic review.

AIMS: Pelvic floor muscle training (PFMT) is a first line conservative treatment for men with urinary dysfunction, but reports of its efficacy are variable. This study aimed to systematically review the content of PFMT programs used for urinary dysfunction in men. METHODS: Electronic databases (PubMed, CINAHL, EMBASE, Cochrane, PEDro) were searched for studies that used PFMT in the treatment of adult men with urinary dysfunction. Details of PFMT treatment sessions and home exercise protocols were extracted. Criteria specific to PFMT were developed, based on the Consensus on Exercise Reporting Template, and applied to all studies to measure the comprehensiveness of the PFMT description in the manuscript. RESULTS: Results from the 108 included studies indicate substantial heterogeneity in both the content of PFMT and the quality of reporting of the components of the exercise regimes. There was notable disparity in the muscles targeted by the interventions (and few focused on urethral control despite the use in management of urinary conditions) and the intensity of the programs (eg, 18-240 contractions per day). Most studies were missing key details of description of the PFMT programs (eg, the position in which the pelvic floor muscle [PFM] contraction was taught and how it was assessed, methods used to ensure exercise adherence). CONCLUSIONS: Variation in content of PFMT programs is likely to contribute to variation in the reported efficacy for management of urinary dysfunction in men, and unclear description of the details of the evaluated programs makes it difficult to identify the effective/ineffective components. PROSPERO registration number CRD42017071038.

Discovery of novel heart rate-associated loci using the Exome Chip.

Resting heart rate is a heritable trait, and an increase in heart rate is associated with increased mortality risk. Genome-wide association study analyses have found loci associated with resting heart rate, at the time of our study these loci explained 0.9% of the variation. This study aims to discover new genetic loci associated with heart rate from Exome Chip meta-analyses.Heart rate was measured from either elecrtrocardiograms or pulse recordings. We meta-analysed heart rate association results from 104 452 European-ancestry individuals from 30 cohorts, genotyped using the Exome Chip. Twenty-four variants were selected for follow-up in an independent dataset (UK Biobank, N = 134 251). Conditional and gene-based testing was undertaken, and variants were investigated with bioinformatics methods.We discovered five novel heart rate loci, and one new independent low-frequency non-synonymous variant in an established heart rate locus (KIAA1755). Lead variants in four of the novel loci are non-synonymous variants in the genes C10orf71, DALDR3, TESK2 and SEC31B. The variant at SEC31B is significantly associated with SEC31B expression in heart and tibial nerve tissue. Further candidate genes were detected from long-range regulatory chromatin interactions in heart tissue (SCD, SLF2 and MAPK8). We observed significant enrichment in DNase I hypersensitive sites in fetal heart and lung. Moreover, enrichment was seen for the first time in human neuronal progenitor cells (derived from embryonic stem cells) and fetal muscle samples by including our novel variants.Our findings advance the knowledge of the genetic architecture of heart rate, and indicate new candidate genes for follow-up functional studies.

Genome-wide association study identifies 74 loci associated with educational attainment.

Educational attainment is strongly influenced by social and other environmental factors, but genetic factors are estimated to account for at least 20% of the variation across individuals. Here we report the results of a genome-wide association study (GWAS) for educational attainment that extends our earlier discovery sample of 101,069 individuals to 293,723 individuals, and a replication study in an independent sample of 111,349 individuals from the UK Biobank. We identify 74 genome-wide significant loci associated with the number of years of schooling completed. Single-nucleotide polymorphisms associated with educational attainment are disproportionately found in genomic regions regulating gene expression in the fetal brain. Candidate genes are preferentially expressed in neural tissue, especially during the prenatal period, and enriched for biological pathways involved in neural development. Our findings demonstrate that, even for a behavioural phenotype that is mostly environmentally determined, a well-powered GWAS identifies replicable associated genetic variants that suggest biologically relevant pathways. Because educational attainment is measured in large numbers of individuals, it will continue to be useful as a proxy phenotype in efforts to characterize the genetic influences of related phenotypes, including cognition and neuropsychiatric diseases.