Dynamic Conduction and Repolarisation Changes in Early Arrhythmogenic Right Ventricular Cardiomyopathy versus Benign Outflow Tract Ectopy Demonstrated by High Density Mapping and Paced Surface ECG Analysis

Aims: The concealed phase of arrhythmogenic right ventricular cardiomyopathy (ARVC) may initially manifest electrophysiologically. No studies have examined dynamic conduction/repolarization kinetics to distinguish benign right ventricular outflow tract ectopy (RVOT ectopy) from ARVC's early phase. We investigated dynamic endocardial electrophysiological changes that differentiate early ARVC disease expression from RVOT ectopy. Methods: 22 ARVC (12 definite based upon family history and mutation carrier status, 10 probable) patients without right ventricular structural anomalies underwent high-density non-contact mapping of the right ventricle. These were compared to data from 14 RVOT ectopy and 12 patients with supraventricular tachycardias and normal hearts. Endocardial & surface ECG conduction and repolarization parameters were assessed during a standard S1-S2 restitution protocol. Results: Definite ARVC without RV structural disease could not be clearly distinguished from RVOT ectopy during sinus rhythm or during steady state pacing. Delay in Activation Times at coupling intervals just above the ventricular effective refractory period (VERP) increased in definite ARVC (43±20 ms) more than RVOT ectopy patients (36±14 ms, p = 0.03) or Normals (25±16 ms, p = 0.008) and a progressive separation of the repolarisation time curves between groups existed. Repolarization time increases in the RVOT were also greatest in ARVC (definite ARVC: 18±20 ms; RVOT ectopy: 5±14, Normal: 1±18, p<0.05). Surface ECG correlates of these intracardiac measurements demonstrated an increase of greater than 48 ms in stimulus to surface ECG J-point pre-ERP versus steady state, with an 88% specificity and 68% sensitivity in distinguishing definite ARVC from the other groups. This technique could not distinguish patients with genetic predisposition to ARVC only (probable ARVC) from controls. Conclusions: Significant changes in dynamic conduction and repolarization are apparent in early ARVC before detectable RV structural abnormalities, and were present to a lesser degree in probable ARVC patients. Investigation of dynamic electrophysiological parameters may be useful to identify concealed ARVC in patients without disease pedigrees by using endocardial electrogram or paced ECG parameters

The impact of the COVID-19 pandemic on an international rehabilitation study in MS: the CogEx experience

Pandemic restrictions have led to changes in therapy plans and disrupted rehabilitation services for people with multiple sclerosis. CogEx is an international, multicentre MS dual-intervention (cognitive rehabilitation, aerobic exercise) randomized, controlled rehabilitation trial confined to people with progressive disease. The primary outcome is cognition (processing speed).There are 11 treatment sites in six countries with participants required to make 27 site visits over 12 weeks. Collectively, the large, in-person demands of the trial, and the varying international policies for the containment of COVID-19, might disproportionately impact the administration of CogEx. During the first lockdown, all centres closed on average for 82.9 (SD = 24.3) days. One site was required to lockdown on two further occasions. One site remained closed for 16 months. Ten staff (19.2%) were required to quarantine and eight staff (15.4%) tested positive for COVID. 10 of 264 (3.8%) participants acquired COVID-19. All survived. The mean duration of enrollment delay has been [236.7 (SD = 214.5) days]. Restarting participants whose interventions were interrupted by the pandemic meant recalculating the intervention prescriptions for these individuals. While the impact of the pandemic on CogEx has been considerable, all study sites are again open. Participants and staff have shown considerable flexibility and resilience in keeping a complex, international endeavour running. The future in general remains uncertain in the midst of a pandemic, but there is cautious optimism the study will be completed with sufficient sample size to robustly evaluate our hypothesis and provide meaningful results to the MS community on the impact of these interventions on people with progressive MS. Trial registration: The trial was registered on September 20th 2018 at www.clinicaltrials.gov having identifier NCT03679468. Registration was performed before recruitment was initiated

The relationship between processing speed and verbal and non-verbal new learning and memory in progressive multiple sclerosis

Objective: Processing speed (PS) deficits are the most common cognitive deficits in multiple sclerosis (MS), followed by learning and memory deficits, and are often an early cognitive problem. It has been argued that impaired PS is a primary consequence of MS, which in turn decreases learning. The current analysis examined the association between PS and learning in a large cohort of individuals with progressive MS. Methods: Baseline data from a randomized clinical trial on rehabilitation taking place at 11 centers across North America and Europe were analyzed. Participants included 275 individuals with clinically definite progressive MS (primary, secondary) consented into the trial. Results: Symbol Digit Modalities Test (SDMT) significantly correlated with California Verbal Learning Test-II (CVLT-II) (r = 0.21, p = 0.0003) and Brief Visuospatial Memory Test–Revised (BVMT-R) (r = 0.516, p < 0.0001). Receiver operating characteristic (ROC) analysis of the SDMT z score to distinguish between impaired and non-impaired CVLT-II performance demonstrated an area under the curve (AUC) of 0.61 (95% confidence interval (CI): 0.55–0.68) and a threshold of −1.62. ROC analysis between SDMT and BVMT-R resulted in an AUC of 0.77 (95% CI: 0.71–0.83) and threshold of −1.75 for the SDMT z score to predict impaired BVMT-R. Conclusion: Results indicate little ability beyond chance to predict CVLT-II from SDMT (61%), albeit statistically significant. In contrast, there was a 77% chance that the model could distinguish between impaired and non-impaired BVMT-R. Several potential explanations are discussed

The Role of Industry, Geography and Firm Heterogeneity in Credit Risk Diversification

In theory the potential for credit risk diversification for banks could be substantial. Portfolio diversification is driven broadly by two characteristics: the degree to which systematic risk factors are correlated with each other and the degree of dependence individual firms have to the different types of risk factors. We propose a model for exploring these dimensions of credit risk diversification: across industry sectors and across different countries or regions. We find that full firm-level parameter heterogeneity matters a great deal for capturing differences in simulated credit loss distributions. Imposing homogeneity results in overly skewed and fat-tailed loss distributions. These differences become more pronounced in the presence of systematic risk factor shocks: increased parameter heterogeneity greatly reduces shock sensitivity. Allowing for regional parameter heterogeneity seems to better approximate the loss distributions generated by the fully heterogeneous model than allowing just for industry heterogeneity. The regional model also exhibits less shock sensitivity

LGMD2I in a North American population

<p>Abstract</p> <p>Background</p> <p>There is a marked variation in clinical phenotypes that have been associated with mutations in <it>FKRP</it>, ranging from severe congenital muscular dystrophies to limb-girdle muscular dystrophy type 2I (LGMD2I).</p> <p>Methods</p> <p>We screened the <it>FKRP </it>gene in two cohorts totaling 87 patients with the LGMD phenotype.</p> <p>Results</p> <p>The c.826C>A, p.L276I mutation was present in six patients and a compound heterozygote mutation in a seventh patient. Six patients had a mild LGMD2I phenotype, which resembles that of Becker muscular dystrophy. The other patient had onset before the age of 3 years, and thus may follow a more severe course.</p> <p>Conclusion</p> <p>These findings suggest that LGMD2I may be common in certain North American populations. This diagnosis should be considered early in the evaluation of LGMD.</p

Novel mutations in human and mouse SCN4A implicate AMPK in myotonia and periodic paralysis

Mutations in the skeletal muscle channel (SCN4A), encoding the Nav1.4 voltage-gated sodium channel, are causative of a variety of muscle channelopathies, including non-dystrophic myotonias and periodic paralysis. The effects of many of these mutations on channel function have been characterized both in vitro and in vivo. However, little is known about the consequences of SCN4A mutations downstream from their impact on the electrophysiology of the Nav1.4 channel. Here we report the discovery of a novel SCN4A mutation (c.1762A>G; p.I588V) in a patient with myotonia and periodic paralysis, located within the S1 segment of the second domain of the Nav1.4 channel. Using N-ethyl-N-nitrosourea mutagenesis, we generated and characterized a mouse model (named draggen), carrying the equivalent point mutation (c.1744A>G; p.I582V) to that found in the patient with periodic paralysis and myotonia. Draggen mice have myotonia and suffer from intermittent hind-limb immobility attacks. In-depth characterization of draggen mice uncovered novel systemic metabolic abnormalities in Scn4a mouse models and provided novel insights into disease mechanisms. We discovered metabolic alterations leading to lean mice, as well as abnormal AMP-activated protein kinase activation, which were associated with the immobility attacks and may provide a novel potential therapeutic target

Safety and efficacy of arimoclomol for inclusion body myositis: a multicentre, randomised, double-blind, placebo-controlled trial

BACKGROUND: Inclusion body myositis is the most common progressive muscle wasting disease in people older than 50 years, with no effective drug treatment. Arimoclomol is an oral co-inducer of the cellular heat shock response that was safe and well-tolerated in a pilot study of inclusion body myositis, reduced key pathological markers of inclusion body myositis in two in-vitro models representing degenerative and inflammatory components of this disease, and improved disease pathology and muscle function in mutant valosin-containing protein mice. In the current study, we aimed to assess the safety, tolerability, and efficacy of arimoclomol in people with inclusion body myositis. METHODS: This multicentre, randomised, double-blind, placebo-controlled study enrolled adults in specialist neuromuscular centres in the USA (11 centres) and UK (one centre). Eligible participants had a diagnosis of inclusion body myositis fulfilling the European Neuromuscular Centre research diagnostic criteria 2011. Participants were randomised (1:1) to receive either oral arimoclomol 400 mg or matching placebo three times daily (1200 mg/day) for 20 months. The randomisation sequence was computer generated centrally using a permuted block algorithm with randomisation numbers masked to participants and trial staff, including those assessing outcomes. The primary endpoint was the change from baseline to month 20 in the Inclusion Body Myositis Functional Rating Scale (IBMFRS) total score, assessed in all randomly assigned participants, except for those who were randomised in error and did not receive any study medication, and those who did not meet inclusion criteria. Safety analyses included all randomly assigned participants who received at least one dose of study medication. This trial is registered with ClinicalTrials.gov, number NCT02753530, and is completed. FINDINGS: Between Aug 16, 2017 and May 22, 2019, 152 participants with inclusion body myositis were randomly assigned to arimoclomol (n=74) or placebo (n=78). One participant was randomised in error (to arimoclomol) but not treated, and another (assigned to placebo) did not meet inclusion criteria. 150 participants (114 [76%] male and 36 [24%] female) were included in the efficacy analyses, 73 in the arimoclomol group and 77 in the placebo group. 126 completed the trial on treatment (56 [77%] and 70 [90%], respectively) and the most common reason for treatment discontinuation was adverse events. At month 20, mean IBMFRS change from baseline was not statistically significantly different between arimoclomol and placebo (-3·26, 95% CI -4·15 to -2·36 in the arimoclomol group vs -2·26, -3·11 to -1·41 in the placebo group; mean difference -0·99 [95% CI -2·23 to 0·24]; p=0·12). Adverse events leading to discontinuation occurred in 13 (18%) of 73 participants in the arimoclomol group and four (5%) of 78 participants in the placebo group. Serious adverse events occurred in 11 (15%) participants in the arimoclomol group and 18 (23%) in the placebo group. Elevated transaminases three times or more of the upper limit of normal occurred in five (7%) participants in the arimoclomol group and one (1%) in the placebo group. Tubulointerstitial nephritis was observed in one (1%) participant in the arimoclomol group and none in the placebo group. INTERPRETATION: Arimoclomol did not improve efficacy outcomes, relative to placebo, but had an acceptable safety profile in individuals with inclusion body myositis. This is one of the largest trials done in people with inclusion body myositis, providing data on disease progression that might be used for subsequent clinical trial design. FUNDING: US Food and Drug Administration Office of Orphan Products Development and Orphazyme

Zoonotic Viruses Associated with Illegally Imported Wildlife Products

The global trade in wildlife has historically contributed to the emergence and spread of infectious diseases. The United States is the world's largest importer of wildlife and wildlife products, yet minimal pathogen surveillance has precluded assessment of the health risks posed by this practice. This report details the findings of a pilot project to establish surveillance methodology for zoonotic agents in confiscated wildlife products. Initial findings from samples collected at several international airports identified parts originating from nonhuman primate (NHP) and rodent species, including baboon, chimpanzee, mangabey, guenon, green monkey, cane rat and rat. Pathogen screening identified retroviruses (simian foamy virus) and/or herpesviruses (cytomegalovirus and lymphocryptovirus) in the NHP samples. These results are the first demonstration that illegal bushmeat importation into the United States could act as a conduit for pathogen spread, and suggest that implementation of disease surveillance of the wildlife trade will help facilitate prevention of disease emergence