Global Seroprevalence of Pre-existing Immunity Against AAV5 and Other AAV Serotypes in People with Hemophilia A.

Adeno-associated virus (AAV)-mediated gene therapy may provide durable protection from bleeding events and reduce treatment burden for people with hemophilia A (HA). However, pre-existing immunity against AAV may limit transduction efficiency and hence treatment success. Global data on the prevalence of AAV serotypes are limited. In this global, prospective, noninterventional study, we determined the prevalence of pre-existing immunity against AAV2, AAV5, AAV6, AAV8, and AAVrh10 among people ≥12 years of age with HA and residual FVIII levels ≤2 IU/dL. Antibodies against each serotype were detected using validated, electrochemiluminescent-based enzyme-linked immunosorbent assays. To evaluate changes in antibody titers over time, 20% of participants were retested at 3 and 6 months. In total, 546 participants with HA were enrolled at 19 sites in 9 countries. Mean (standard deviation) age at enrollment was 36.0 (14.87) years, including 12.5% younger than 18 years, and 20.0% 50 years of age and older. On day 1, global seroprevalence was 58.5% for AAV2, 34.8% for AAV5, 48.7% for AAV6, 45.6% for AAV8, and 46.0% for AAVrh10. Considerable geographic variability was observed in the prevalence of pre-existing antibodies against each serotype, but AAV5 consistently had the lowest seroprevalence across the countries studied. AAV5 seropositivity rates were 51.8% in South Africa (n = 56), 46.2% in Russia (n = 91), 40% in Italy (n = 20), 37.2% in France (n = 86), 26.8% in the United States (n = 71), 26.9% in Brazil (n = 26), 28.1% in Germany (n = 89), 29.8% in Japan (n = 84), and 5.9% in the United Kingdom (n = 17). For all serotypes, seropositivity tended to increase with age. Serostatus and antibody titer were generally stable over the 6-month sampling period. As clinical trials of AAV-mediated gene therapies progress, data on the natural prevalence of antibodies against various AAV serotypes may become increasingly important.

Using the Hendrich II Inpatient Fall Risk Screen to Predict Outpatient Falls After Emergency Department Visits.

OBJECTIVES: To evaluate the utility of routinely collected Hendrich II fall scores in predicting returns to the emergency department (ED) for falls within 6 months. DESIGN: Retrospective electronic record review. SETTING: Academic medical center ED. PARTICIPANTS: Individuals aged 65 and older seen in the ED from January 1, 2013, through September 30, 2015. MEASUREMENTS: We evaluated the utility of routinely collected Hendrich II fall risk scores in predicting ED visits for a fall within 6 months of an all-cause index ED visit. RESULTS: For in-network patient visits resulting in discharge with a completed Hendrich II score (N = 4,366), the return rate for a fall within 6 months was 8.3%. When applying the score alone to predict revisit for falls among the study population the resultant receiver operating characteristic (ROC) plot had an area under the curve (AUC) of 0.64. In a univariate model, the odds of returning to the ED for a fall in 6 months were 1.23 times as high for every 1-point increase in Hendrich II score (odds ratio (OR)=1.23 (95% confidence interval (CI)=1.19-1.28). When included in a model with other potential confounders or predictors of falls, the Hendrich II score is a significant predictor of a return ED visit for fall (adjusted OR=1.15, 95% CI=1.10-1.20, AUC=0.75). CONCLUSION: Routinely collected Hendrich II scores were correlated with outpatient falls, but it is likely that they would have little utility as a stand-alone fall risk screen. When combined with easily extractable covariates, the screen performs much better. These results highlight the potential for secondary use of electronic health record data for risk stratification of individuals in the ED. Using data already routinely collected, individuals at high risk of falls after discharge could be identified for referral without requiring additional screening resources.

Pilot Study to Determine Accuracy of Posterior Approach Ultrasound for Shoulder Dislocation by Novice Sonographers.

INTRODUCTION: The goal of this study was to investigate the efficacy of diagnosing shoulder dislocation using a single-view, posterior approach point-of-care ultrasound (POCUS) performed by undergraduate research students, and to establish the range of measured distance that discriminates dislocated shoulder from normal. METHODS: We enrolled a prospective, convenience sample of adult patients presenting to the emergency department with acute shoulder pain following injury. Patients underwent ultrasonographic evaluation of possible shoulder dislocation comprising a single transverse view of the posterior shoulder and assessment of the relative positioning of the glenoid fossa and the humeral head. The sonographic measurement of the distance between these two anatomic structures was termed the Glenohumeral Separation Distance (GhSD). A positive GhSD represented a posterior position of the glenoid rim relative to the humeral head and a negative GhSD value represented an anterior position of the glenoid rim relative to the humeral head. We compared ultrasound (US) findings to conventional radiography to determine the optimum GhSD cutoff for the diagnosis of shoulder dislocation. Sensitivity, specificity, positive predictive value, and negative predictive value of the derived US method were calculated. RESULTS: A total of 84 patients were enrolled and 19 (22.6%) demonstrated shoulder dislocation on conventional radiography, all of which were anterior. All confirmed dislocations had a negative measurement of the GhSD, while all patients with normal anatomic position had GhSD>0. This value represents an optimum GhSD cutoff of 0 for the diagnosis of (anterior) shoulder dislocation. This method demonstrated a sensitivity of 100% (95% CI [82.4-100]), specificity of 100% (95% CI [94.5-100]), positive predictive value of 100% (95% CI [82.4-100]), and negative predictive value of 100% (95% CI [94.5-100]). CONCLUSION: Our study suggests that a single, posterior-approach POCUS can diagnose anterior shoulder dislocation, and that this method can be employed by novice ultrasonographers, such as non-medical trainees, after a brief educational session. Further validation studies are necessary to confirm these findings.

Involvement of myosin Vb in glutamate receptor trafficking.

Myosin V motors mediate cargo transport; however, the identity of neuronal molecules transported by these proteins remains unknown. Here we show that myosin Vb is expressed in several neuronal populations and associates with the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate-type glutamate receptor subunit GluR1. In developing hippocampal neurons, expression of the tail domain of myosin Vb, but not myosin Va, enhanced GluR1 accumulation in the soma and reduced its surface expression. These changes were accompanied by reduced GluR1 clustering and diminished frequency of excitatory but not inhibitory synaptic currents. Similar effects were observed upon expression of full-length myosin Vb lacking a C-terminal region required for binding to the small GTPase Rab11. In contrast, mutant myosin Vb did not change the localization of several other neurotransmitter receptors, including the glutamate receptor subunit NR1. These results reveal a novel mechanism for the transport of a specific glutamate receptor subunit in neurons mediated by a member of the myosin V family.