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Arrhythmogenic cardiomyopathy (ACM) is an inherited arrhythmia syndrome characterized by severe structural and electrical cardiac phenotypes, including myocardial fibrofatty replacement and sudden cardiac death. Clinical management of ACM is largely palliative, owing to an absence of therapies that target its underlying pathophysiology, which stems partially from our limited insight into the condition. Following identification of deceased ACM probands possessing ANK2 rare variants and evidence of ankyrin-B loss of function on cardiac tissue analysis, an ANK2 mouse model was found to develop dramatic structural abnormalities reflective of human ACM, including biventricular dilation, reduced ejection fraction, cardiac fibrosis, and premature death. Desmosomal structure and function appeared preserved in diseased human and murine specimens in the presence of markedly abnormal beta-catenin expression and patterning, leading to identification of a previously unknown interaction between ankyrin-B and beta-catenin. A pharmacological activator of the WNT/beta-catenin pathway, SB-216763, successfully prevented and partially reversed the murine ACM phenotypes. Our findings introduce what we believe to be a new pathway for ACM, a role of ankyrin-B in cardiac structure and signaling, a molecular link between ankyrin-B and beta-catenin, and evidence for targeted activation of the WNT/beta-catenin pathway as a potential treatment for this disease. Funding Agencies|Marianne Barrie Philanthropic Fund; Canadian Institutes of Health Research [RN332805]; Netherlands CardioVascular Research Initiative: the Dutch Heart Foundation; Dutch Federation of University Medical Centers; Netherlands Organisation for Health Research and Development; Royal Netherlands Academy of Sciences [CVON-PREDICT 2012-10]; Netherlands Cardiovascular Research Initiative - Dutch Heart Foundation [CVON2012-10 PREDICT CVON2018-30 PREDICT2, CVON2015-12 eDETECT]; Netherlands Organization for Scientific Research (NWO) [040.11.586]; Fondation Leducq [16 CVD 02]; Dr. Francis P. Chiramonte Private Foundation; Leyla Erkan Family Fund for ARVD Research; Robin Shah ARVD Fund at Johns Hopkins; Bogle Foundation; Healing Hearts Foundation; Campanella Family; Patrick J. Harrison Family; Peter French Memorial Foundation; Wilmerding Endowments; NIH [HL135754, HL134824, HL139348, HL135096, HL114383, HL114893, HL137331, HL137325, 2UM1HG006542, UL1 TR 001079]; Ohio State Frick Center; JB Project

Background Hospitalisation during the last weeks of life when there is no medical need or desire to be there is distressing and expensive. This study sought palliative care initiatives which may avoid or shorten hospital stay at the end of life and analysed their success in terms reducing bed days. Methods Part 1 included a search of literature in PubMed and Google Scholar between 2013 and 2018, an examination of governmental and organisational publications plus discussions with external and co-author experts regarding other sources. This initial sweep sought to identify and categorise relevant palliative care initiatives. In Part 2, we looked for publications providing data on hospital admissions and bed days for each category. Results A total of 1252 abstracts were reviewed, resulting in ten broad classes being identified. Further screening revealed 50 relevant publications describing a range of multi-component initiatives. Studies were generally small and retrospective. Most researchers claim their service delivered benefits. In descending frequency, benefits identified were support in the community, integrated care, out-of-hours telephone advice, care home education and telemedicine. Nurses and hospices were central to many initiatives. Barriers and factors underpinning success were rarely addressed. Conclusions A wide range of initiatives have been introduced to improve end-of-life experiences. Formal evidence supporting their effectiveness in reducing inappropriate/non-beneficial hospital bed days was generally limited or absent. Trial registration N/A

Background: The aim of this study was to investigate the effect of whey protein supplementation on myofibrillar protein synthesis (myoPS) and muscle recovery over a 7-d period of intensified resistance training (RT). Methods: In a double-blind randomised parallel group design, 16 resistance-trained men aged 18 to 35 years completed a 7-d RT protocol, consisting of three lower-body RT sessions on non-consecutive days. Participants consumed a controlled diet (146 kJ&middot, kg&minus, 1&middot, d&minus, 1, 1.7 g&middot, 1 protein) with either a whey protein supplement or an isonitrogenous control (0.33 g&middot, 1 protein). To measure myoPS, 400 ml of deuterium oxide (D2O) (70 atom %) was ingested the day prior to starting the study and m. vastus lateralis biopsies were taken before and after RT-intervention. Myofibrillar fractional synthetic rate (myoFSR) was calculated via deuterium labelling of myofibrillar-bound alanine, measured by gas chromatography-pyrolysis-isotope ratio mass spectrometry (GC-Pyr-IRMS). Muscle recovery parameters (i.e., countermovement jump height, isometric-squat force, muscle soreness and serum creatine kinase) were assessed daily. Results: MyoFSR PRE was 1.6 (0.2) %∙d&minus, 1 (mean (SD)). Whey protein supplementation had no effect on myoFSR (p = 0.771) or any recovery parameter (p = 0.390&ndash, 0.989). Conclusions: Over an intense 7-d RT protocol, 0.33 g&middot, 1 of supplemental whey protein does not enhance day-to-day measures of myoPS or postexercise recovery in resistance-trained men.

Identification of genetic biomarkers associated with autism spectrum disorders (ASDs) could improve recurrence prediction for families with a child with ASD. Here, we describe clinical microarray findings for 253 longitudinally phenotyped ASD families from the Baby Siblings Research Consortium (BSRC), encompassing 288 infant siblings. By age 3, 103 siblings (35.8%) were diagnosed with ASD and 54 (18.8%) were developing atypically. Thirteen siblings have copy number variants (CNVs) involving ASD-relevant genes: 6 with ASD, 5 atypically developing, and 2 typically developing. Within these families, an ASD-related CNV in a sibling has a positive predictive value (PPV) for ASD or atypical development of 0.83; the Simons Simplex Collection of ASD families shows similar PPVs. Polygenic risk analyses suggest that common genetic variants may also contribute to ASD. CNV findings would have been pre-symptomatically predictive of ASD or atypical development in 11 (7%) of the 157 BSRC siblings who were eventually diagnosed clinically., Siblings of those with autism spectrum disorder (ASD) have increased likelihood of ASD or related subclinical traits. Here, studying 253 ASD families, D’Abate et al. test the predictive value of genomic copy number variation involving ASD-associated loci, with confirmation in a second cohort.

peer-reviewed The effects of nutrition on exercise metabolism and performance remain an important topic among sports scientists, clinical, and athletic populations. Recently, fasted exercise has garnered interest as a beneficial stimulus which induces superior metabolic adaptations to fed exercise in key peripheral tissues. Conversely, pre‐exercise feeding augments exercise performance compared with fasting conditions. Given these seemingly divergent effects on performance and metabolism, an appraisal of the literature is warranted. This review determined the effects of fasting vs pre‐exercise feeding on continuous aerobic and anaerobic or intermittent exercise performance, and post‐exercise metabolic adaptations. A search was performed using the MEDLINE and PubMed search engines. The literature search identified 46 studies meeting the relevant inclusion criteria. The Delphi list was used to assess study quality. A meta‐analysis and meta‐regression were performed where appropriate. Findings indicated that pre‐exercise feeding enhanced prolonged (P = .012), but not shorter duration aerobic exercise performance (P = .687). Fasted exercise increased post‐exercise circulating FFAs (P = .023) compared to fed exercise. It is evidenced that pre‐exercise feeding blunted signaling in skeletal muscle and adipose tissue implicated in regulating components of metabolism, including mitochondrial adaptation and substrate utilization. This review's findings support the hypothesis that the fasted and fed conditions can divergently influence exercise metabolism and performance. Pre‐exercise feeding bolsters prolonged aerobic performance, while seminal evidence highlights potential beneficial metabolic adaptations that fasted exercise may induce in peripheral tissues. However, further research is required to fully elucidate the acute and chronic physiological adaptations to fasted vs fed exercise.

Longitudinal change in body composition for elite-level inter-county hurlers was reported over a single season and four consecutive seasons. Body composition measured by dual-energy x-ray absorptiometry (DXA) of 66 senior, male, outfield players was obtained. Four successive measurements were taken: off-season (OFF1), pre-season (PRE), mid-season (MID) and the off-season of the following season (OFF2). A subsample of 11 hurlers were measured at all time points over 4 consecutive seasons. DXA-derived estimates of fat and lean mass were normalised to stature for analysis (kg∙m‒2); data are (mean [lower: upper, 95% confidence interval]). A concurrent increase of lean mass (0.31 [0.19: 0.43] kg∙m‒2) and loss of fat mass occurred (−0.38 [−0.50: −0.26] kg∙m‒2) OFF1 to PRE. Lean mass accrual was maintained PRE to OFF2 while the initial loss of fat mass was restored MID to OFF2 (0.52 [0.40: 0.64] kg ∙ m‒2), with the trunk acting as the primary region of change. Over the four seasons, a net increase of lea...

peer-reviewed To investigate sex differences in the temporal recovery of neuromuscular function following resistance training (RT), eleven men and eight women 18–35 years completed a single RT bout (barbell back-squats, 80 % 1RM, 5 sets × 5 reps, 25 % duty cycle, then 1 set × max reps). Measures of muscle function (isometric, concentric, eccentric knee extensor strength, and countermovement jump (CMJ) height), serum creatine kinase activity (CK) and lower-body muscle pain were assessed before RT (0 h), +4 h, +24 h, +48 h, and +72 h post-RT. Data are mean % change from PRE (SD) and effect size (ω2, d). Men and women had similar RT-experience (men, 2.1 (0.8) years vs. women 2.4 (1.0) years, P = 0.746, and d = 0.3) and 1RM strength per kg lean mass (men, 1.9 (0.2) kg⋅kg-1 vs. women, 1.8 (0.3) kg⋅kg-1, P = 0.303, and d = 0.3). A 36 (12)% increase in lower-body muscle pain was reported following RT (P < 0.05, d > 0.9). There was an absence of any overt change in CK [+24 h, 74 (41) IU⋅L-1; pooled mean (SD)]. Decrements in knee extensor strength and CMJ height were observed +4 to +72 h for both men and women (P < 0.05, ω2 = 0.19–0.69). Sex differences were apparent for CMJ height (+24 h men, -10 (6)% vs. women, -20 (11)%, P < 0.001, and d = 1.8) and isokinetic concentric strength (+24 h men, -10 (13)% vs. women -25 (14)%, P = 0.006, and d = 1.8), with a more pronounced loss and prolonged recovery in women compared to men (e.g., CMJ + 72 h men, -3 (6)% vs. women, -13 (12)%, P = 0.051, and d = 1.1). We conclude that the different temporal recovery patterns between men and women are not explicable by differences in muscle strength, RT performance, experience, muscle damage or fatigability.

peer-reviewed Twenty‐three resistance trained men 18‐35 years (23 [3] years, 1.8 [0.1] m, 81 [10] kg body mass, 2.3 [1.1] years resistance training experience; mean [SD]) performed repeated maximal voluntary isometric squats (ISQ) and countermovement jumps (CMJ) pre‐ and +30 minutes post a unilateral microbiopsy of m. vastus lateralis. ISQ and CMJ were simultaneously measured by two force plates sampling ipsilateral (biopsied) and contralateral (non‐biopsied) limb force. Bilateral limb force (ipsilateral + contralateral) and imbalance (ipsilateral/bilateral) data are reported as % change from pre‐biopsy (mean [95% CI]). A post‐biopsy reduction in bilateral ISQ peak force (−17 [−23, −11] %; P < 0.001), ISQ rate of force development (RFD; −28 [−41, −15] %, P = 0.002) and CMJ peak take‐off force (−7 [−13, −1]%, P = 0.019) occurred. Imbalance was observed for ISQ peak force (3.2 [2.1, 4.3] %, P < 0.001), RFD (2.8 [1.6, 4.0] %, P < 0.001) and CMJ landing (3.3 [1.0, 5.6] %, P = 0.009), resultant of a force transfer from the ipsilateral (biopsied) to the contralateral (non‐biopsied) limb. These data suggest that in young, resistance trained men a modulatory influence on maximal voluntary static and dynamic lower‐body contractile function is evoked acutely (+30 minutes) following a microbiopsy of m. vastus lateralis.

Gaelic Football and Hurling are two sporting codes within the Gaelic Athletic Association. The purpose of this study was to report the body composition phenotype of inter-county Gaelic athletic association players, comparing groups by code and field position. 190 senior, male, outfield inter-county players (144 hurlers and 46 Gaelic footballers) were recruited. Stature and body mass was measured, estimates of three components of body composition, i.e., lean mass, fat mass and bone mineral content was obtained by dual energy X-ray absorptiometry (DXA), and normative data for Gaelic athletic association athletes by code and position was compared. Other than in the midfield, there was limited difference in body composition between codes or playing position. Stature-corrected indices nullified any existing group differences between midfielders for both codes. Further comparisons with a non-athletic control group (n = 431) showed no difference for body mass index (BMI); however, the athletic group has a lower fat mass index, with a greater lean mass in accounting for the matched BMI between groups. In addition to providing previously unknown normative data for the Gaelic athletic association athlete, a proportional and independent tissue evaluation of body composition is given.

Recent genome-wide association studies have identified multiple loci robustly associated with plasma lipids, which also contribute to extreme lipid phenotypes. However, these common genetic variants explain

Recent genome-wide association studies (GWASs) have provided a vast amount of new information relevant to the myriad of biological pathways related to atherosclerosis and its progression. Although atherosclerosis is a complex process, both GWASs and candidate gene studies add support to the hypothesis that proinflammatory pathways, involving both innate and adaptive immunity, play a causal role in coronary artery disease (CAD) and its clinical manifestations. Recent GWASs have identified several inflammation-related loci associated with CAD risk. These include CXCL2, encoding an atheroprotective chemokine, and a region near HLA-C in the major histocompatibility locus on chromosome 6p21. The ABO locus, also linked to CAD risk by the GWAS approach, is related to multiple phenotypes, including plasma interleukin-6 (IL-6) levels. Finally, relevant to inflammation, the 9p21 CAD risk locus appears to play a role in interferon-gamma signalling. Candidate gene studies also support a causative role of inflammation pathways in atherosclerosis. Of note, a common loss of function coding variant in the IL-6 receptor gene (IL6R) is associated with a reduction in CAD risk.

Atrial fibrillation is a highly prevalent arrhythmia and a major risk factor for stroke, heart failure and death. We conducted a genome-wide association study (GWAS) in individuals of European ancestry, including 6,707 with and 52,426 without atrial fibrillation. Six new atrial fibrillation susceptibility loci were identified and replicated in an additional sample of individuals of European ancestry, including 5,381 subjects with and 10,030 subjects without atrial fibrillation (P < 5 × 10(-8)). Four of the loci identified in Europeans were further replicated in silico in a GWAS of Japanese individuals, including 843 individuals with and 3,350 individuals without atrial fibrillation. The identified loci implicate candidate genes that encode transcription factors related to cardiopulmonary development, cardiac-expressed ion channels and cell signaling molecules.

We analyze whole-genome sequencing data from 141,431 Chinese women generated for non-invasive prenatal testing (NIPT). We use these data to characterize the population genetic structure and to investigate genetic associations with maternal and infectious traits. We show that the present day distribution of alleles is a function of both ancient migration and very recent population movements. We reveal novel phenotype-genotype associations, including several replicated associations with height and BMI, an association between maternal age and EMB, and between twin pregnancy and NRG1. Finally, we identify a unique pattern of circulating viral DNA in plasma with high prevalence of hepatitis B and other clinically relevant maternal infections. A GWAS for viral infections identifies an exceptionally strong association between integrated herpesvirus 6 and MOV10L1, which affects piwi-interacting RNA (piRNA) processing and PIWI protein function. These findings demonstrate the great value and potential of accumulating NIPT data for worldwide medical and genetic analyses.

Background— Genome-wide association studies (GWAS) have identified single-nucleotide polymorphisms (SNPs) at multiple loci that are significantly associated with coronary artery disease (CAD) risk. In this study, we sought to determine and compare the predictive capabilities of 9p21.3 alone and a panel of SNPs identified and replicated through GWAS for CAD. Methods and Results— We used the Ottawa Heart Genomics Study (OHGS) (3323 cases, 2319 control subjects) and the Wellcome Trust Case Control Consortium (WTCCC) (1926 cases, 2938 control subjects) data sets. We compared the ability of allele counting, logistic regression, and support vector machines. Two sets of SNPs, 9p21.3 alone and a set of 12 SNPs identified by GWAS and through a model-fitting procedure, were considered. Performance was assessed by measuring area under the curve (AUC) for OHGS using 10-fold cross-validation and WTCCC as a replication set. AUC for logistic regression using OHGS increased significantly from 0.555 to 0.608 ( P =3.59×10 −14 ) for 9p21.3 versus the 12 SNPs, respectively. This difference remained when traditional risk factors were considered in a subgroup of OHGS (1388 cases, 2038 control subjects), with AUC increasing from 0.804 to 0.809 ( P =0.037). The added predictive value over and above the traditional risk factors was not significant for 9p21.3 (AUC 0.801 versus 0.804, P =0.097) but was for the 12 SNPs (AUC 0.801 versus 0.809, P =0.0073). Performance was similar between OHGS and WTCCC. Logistic regression outperformed both support vector machines and allele counting. Conclusions— Using the collective of 12 SNPs confers significantly greater predictive capabilities for CAD than 9p21.3, whether traditional risks are or are not considered. More accurate models probably will evolve as additional CAD-associated SNPs are identified.

Background: Serum protein profiling patterns can reflect the pathological state of a patient and therefore may be useful for clinical diagnostics. Here, we present results from a pilot study of proteomic expression patterns in hemodialysis patients designed to evaluate the range of serum proteomic alterations in this population. Methods: Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) was used to analyze serum obtained from patients on periodic hemodialysis treatment and healthy controls. Serum samples from patients and controls were first fractionated into six eluants on a strong anion exchange column, followed by application to four array chemistries representing cation exchange, anion exchange, metal affinity and hydrophobic surfaces. A total of 144 SELDI-TOF-MS spectra were obtained from each serum sample. Results: The overall profiles of the patient and control samples were consistent and reproducible. However, 30 well-defined protein differences were observed; 15 proteins were elevated and 15 were decreased in patients compared to controls. Serum from 1 patient exhibited novel protein peaks suggesting possible additional changes due to a secondary disease process. Conclusion: SELDI-TOF-MS demonstrated consistent serum protein profile differences between patients and controls. Similarity in protein profiles among dialysis patients suggests that patient physiological responses to end-stage renal disease and/or dialysis therapy have a major effect on serum protein profiles.

Common intronic SNPs in the human fat mass and obesity associated (FTO) gene are strongly associated with body mass index (BMI). In mouse models, inactivation of the Fto gene results in a lean phenotype, whereas overexpression of Fto leads to increased food intake and obesity. The latter finding suggests that copy number variants at the FTO locus might be associated with extremes of adiposity. To address this question, we searched for rare, private or de novo copy number variation in a cohort of 985 obese and 869 lean subjects of European ancestry drawn from the extremes of the BMI distribution, genotyped on Affymetrix 6.0 arrays. A ∼680 kb duplication, confirmed by real-time PCR and G-to-FISH analyses, was observed between ∼rs11859825 and rs9932411 in a 68-year-old male with severe obesity. The duplicated region on chromosome 16 spans the entire genome-wide association studies risk locus for obesity, and further encompasses RBL2, AKTIP, RPGRIP1L and all but the last exon of the FTO gene. Affected family members exhibit a unique obesity phenotype, characterized by increased fat distribution in the shoulders and neck with a significantly increased neck circumference. This phenotype was accompanied by increased peripheral blood expression of RBL2 with no alteration in expression of FTO or other genes in the region. No other duplications or deletions in this region were identified in the cohort of obese and lean individuals or in a further survey of 4778 individuals, suggesting that large rare copy number variants surrounding the FTO gene are not a frequent cause of obesity.

Contains fulltext : 97601.pdf (Publisher’s version ) (Closed access) Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 x 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 x 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 x 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression. 9 p.

Aims Atrial fibrillation (AF), the most common sustained cardiac arrhythmia, is an important cause of morbidity and mortality. A genetic mutation in the NPPA gene, which encodes the atrial natriuretic peptide, has been identified as the putative causative factor in a family with an autosomal dominant pattern of inheritance for AF. Two common single nucleotide polymorphisms (SNPs) in NPPA , rs5063 and rs5065, result in amino acid changes of the primary peptide and have been previously implicated in conditions associated with AF, including stroke and hypertension. Recently, the rs5063 SNP has been reported to confer an increased risk of AF development in a Chinese population. We sought to examine the associations of both rs5063 and rs5065 with AF in two separate North American cohorts of European ancestry. Methods and results Patients with early-onset AF, along with healthy controls, were recruited at the University of Ottawa Heart Institute (UOHI) and the Massachusetts General Hospital (MGH). Study participants were genotyped for rs5063 and rs5065 using a combination of restriction fragment length polymorphism analysis and DNA microarrays. The study genotyped a total of 620 AF cases and 2446 healthy controls. The UOHI arm of the study identified an odds ratio (OR) of 0.72 [95% confidence interval (CI): 0.42–1.24] for rs5063, whereas an OR of 1.33 (95% CI: 0.80–2.21) was observed in the MGH arm. The combined OR approximated unity (OR 0.99; 95% CI: 0.54–1.80). Analysis of rs5065 revealed an OR of 1.12 (95% CI: 0.84–1.48) in UOHI, 1.08 (95% CI 0.80–1.45) in MGH, and 1.10 (95% CI 0.90–1.35) when combined. Conclusion Common non-synonymous genetic variants within NPPA in these two large North American cohorts of European ancestry are not associated with the development of AF.

Introduction Atrioventricular (AV) block is infrequently associated with QT prolongation and torsades de pointes (TdP). It was hypothesized that patients with AV block-mediated QT-related arrhythmia may have latent congenital long QT syndrome or a vulnerable genetic polymorphism. Methods Eleven patients with complete AV block and TdP were prospectively identified. Patients underwent assessment, resting electrocardiography and telemetry at baseline, during AV block and pre-TdP. Genetic testing of KCNH2 , KCNQ1 , KCNE1 , KCNE2 and SCN5A was performed. Thirty-three patients with AV block without TdP were included for comparison. Results Genetic variants were identified in 36% of patients with AV block and TdP. Patients with AV block who developed TdP had significantly longer mean (± SD) corrected QT intervals (440±93ms versus 376±40ms, P=0.048) and T peak to T end (T p -T e ) intervals (147±25ms versus 94±25ms, P=0.0001) than patients with AV block alone. In patients with a genetic variant, there was a significant increase in T p -T e intervals at baseline, in AV block and pre-TdP compared with those who were genotype negative. A personal or family history of syncope or sudden death was more likely observed in patients with a genetic variant. Conclusions TdP in the setting of AV block may be a marker of an underlying genetic predisposition to reduced repolarization reserve. The T p -T e interval at baseline, in AV block and pre-TdP may predict a genetic mutation or polymorphism compromising repolarization reserve. Patients with TdP in the setting of AV block represent a phenotypic manifestation of latent congenital long QT syndrome.