Minority youth and social transformation in Australia: Identities, belonging and cultural capital

© 2014 by the authors; licensee Cogitatio (Lisbon, Portugal). Increasingly minority youth, especially from Muslim backgrounds, have been seen in Australian public policy and the media as potentially disruptive and transgressive. In some European societies similar young people have been portrayed as living in parallel and disconnected social spaces, self-segregated from interaction with the wider community. Yet Australian ethnic minority youth do not fulfil either of these stereotypes. Rather, despite their often regular experiences of racism or discrimination, they continue to assert a strong identification with and belonging to Australian society, albeit the society that marginalizes and denigrates their cultural capital. In particular it is the neighbourhood and the locality that provides the bridge between their home cultures and the broader world, contributing to a range of positive aspirations and fluid identities

Rare variant analyses validate known ALS genes in a multi-ethnic population and identifies ANTXR2 as a candidate in PLS

BackgroundAmyotrophic lateral sclerosis (ALS) is a neurodegenerative disease affecting over 300,000 people worldwide. It is characterized by the progressive decline of the nervous system that leads to the weakening of muscles which impacts physical function. Approximately, 15% of individuals diagnosed with ALS have a known genetic variant that contributes to their disease. As therapies that slow or prevent symptoms continue to develop, such as antisense oligonucleotides, it is important to discover novel genes that could be targets for treatment. Additionally, as cohorts continue to grow, performing analyses in ALS subtypes, such as primary lateral sclerosis (PLS), becomes possible due to an increase in power. These analyses could highlight novel pathways in disease manifestation.MethodsBuilding on our previous discoveries using rare variant association analyses, we conducted rare variant burden testing on a substantially larger multi-ethnic cohort of 6,970 ALS patients, 166 PLS patients, and 22,524 controls. We used intolerant domain percentiles based on sub-region Residual Variation Intolerance Score (subRVIS) that have been described previously in conjunction with gene based collapsing approaches to conduct burden testing to identify genes that associate with ALS and PLS.ResultsA gene based collapsing model showed significant associations with SOD1, TARDBP, and TBK1 (OR = 19.18, p = 3.67 × 10–39; OR = 4.73, p = 2 × 10–10; OR = 2.3, p = 7.49 × 10–9, respectively). These genes have been previously associated with ALS. Additionally, a significant novel control enriched gene, ALKBH3 (p = 4.88 × 10–7), was protective for ALS in this model. An intolerant domain-based collapsing model showed a significant improvement in identifying regions in TARDBP that associated with ALS (OR = 10.08, p = 3.62 × 10–16). Our PLS protein truncating variant collapsing analysis demonstrated significant case enrichment in ANTXR2 (p = 8.38 × 10–6).ConclusionsIn a large multi-ethnic cohort of 6,970 ALS patients, collapsing analyses validated known ALS genes and identified a novel potentially protective gene, ALKBH3. A first-ever analysis in 166 patients with PLS found a candidate association with loss-of-function mutations in ANTXR2

Neuropathy symptom and change: Inotersen treatment of hereditary transthyretin amyloidosis

Introduction: Hereditary transthyretin-mediated amyloidosis (hATTR) manifests as multisystem dysfunction, including progressive polyneuropathy. Inotersen, an antisense oligonucleotide, improved the course of neuropathic impairment in patients with hATTR in the pivotal NEURO-TTR study (NCT01737398). To determine inotersen's impact on symptoms and patients' neuropathy experience, we performed a post hoc analysis of the Neuropathy Symptoms and Change (NSC) score. Methods: Stage 1 or 2 hATTR patients were randomized to receive weekly subcutaneous inotersen or placebo for 65 weeks. NSC score was assessed at baseline and 35 and 66 weeks. Results: At 66 weeks, inotersen-treated patients had symptom stabilization as compared with worsening in patients receiving placebo, based on total NSC score. There were also improvements in the subdomains of muscle weakness, sensory, pain, and autonomic symptoms, and for various individual items. Discussion: Inotersen treatment stabilized neuropathy symptoms, including autonomic symptoms, in patients with hATTR according to NSC score. Thus, the NSC may be an effective measure to assess neuropathy progression and patients' neuropathy experience in clinical practice.info:eu-repo/semantics/publishedVersio

Investigating Late-Onset Pompe Prevalence in Neuromuscular Medicine Academic Practices: The IPaNeMA Study.

Background and objectivesWe investigated the prevalence of late-onset Pompe disease (LOPD) in patients presenting to 13 academic, tertiary neuromuscular practices in the United States and Canada.MethodsAll successive patients presenting with proximal muscle weakness or isolated hyperCKemia and/or neck muscle weakness to these 13 centers were invited to participate in the study. Whole blood was tested for acid alpha-glucosidase (GAA) assay through the fluorometric method, and all cases with enzyme levels of ≤10 pmoL/punch/h were reflexed to molecular testing for mutations in the GAA gene. Clinical and demographic information was abstracted from their clinical visit and, along with study data, entered into a purpose-built REDCap database, and analyzed at the University of California, Irvine.ResultsGAA enzyme assay results were available on 906 of the 921 participants who consented for the study. LOPD was confirmed in 9 participants (1% prevalence). Another 9 (1%) were determined to have pseudodeficiency of GAA, whereas 19 (1.9%) were found to be heterozygous for a pathogenic GAA mutation (carriers). Of the definite LOPD participants, 8 (89%) were Caucasian and were heterozygous for the common leaky (IVS1) splice site mutation in the GAA gene (c -32-13T>G), with a second mutation that was previously confirmed to be pathogenic.DiscussionThe prevalence of LOPD in undiagnosed patients meeting the criteria of proximal muscle weakness, high creatine kinase, and/or neck weakness in academic, tertiary neuromuscular practices in the United States and Canada is estimated to be 1%, with an equal prevalence rate of pseudodeficiency alleles.Trial registration informationClinical trial registration number: NCT02838368

Setting minimum standards for training in EUS and ERCP: Results from a prospective multicenter study evaluating learning curves and competence among advanced endoscopy trainees (AETS).

Background: Despite the dramatic increase in advanced endoscopy training programs (AETPs), there is no fixed mandatory curriculum and minimal standards as to what constitutes a “high quality” AETP has not been defined. Understanding the mean number of procedures required to achieve competence in all aspects of EUS and ERCP would help structure AETPs. Aims: To define the mean number of procedures required by an “average” AET to achieve competence in technical and cognitive EUS and ERCP tasks. Methods: ASGE recognized AETPs were invited and AETs were graded on every 5th EUS and ERCP exam after completion of 25 hands-on EUS and ERCP exams using the validated EUS and ERCP Skills Assessment Tool (TEESAT). Grading for each skill was done using a 4-point scoring system. A comprehensive data collection and reporting system was used to create learning curves (LCs) using cumulative sum (CUSUM) analysis for overall and technical and cognitive components of EUS and ERCP and shared with AETs and trainers quarterly. Acceptable and unacceptable failures rates were set a priori. In order to generate aggregate CUSUM LCs across AETs, we used generalized linear mixed effects models with a random intercept for each AET and an AR1 covariance structure. This allowed us to use data from all AETs to estimate the average learning experience for trainees with 95% CIs. We then fit a spline to the modeled estimates with knots at 40 and 80 evaluations to smooth the results and estimate the mean number of procedures needed to achieve competence. Results: Of the 62 AETPs invited, 37 AETs from 32 AETPs participated in this study; 24 AETs were included in the final analysis. Prior to AETP, 52% reported hands-on EUS (median 20 cases) and 68% hands-on ERCP (median 50 cases) experience prior to AETP. At the end of training, median number of EUS and ERCPs performed/AET was 400 (range 200-750) and 361 (250-650), respectively. Overall, 2616 exams were graded (EUS: 1277, ERCP-biliary 1143, pancreatic 196). Majority of graded EUS exams were performed for pancreatobiliary indications (69.9%) and ERCP exams for ASGE biliary grade of difficulty 1 (72.1%). Table 1 highlights the substantial variability in EUS and ERCP learning curves. The majority of trainees achieved overall technical (EUS: 91.7%; ERCP: 73.9%) and cognitive (EUS: 91.7%, ERCP: 95.7%) competence at the end of training. Table 1 and Figure highlight the number of procedures required by an average AET to achieve competence in all aspects of EUS and ERCP. Conclusions: The results of this study confirm the substantial variability in achieving competence in EUS and ERCP. The thresholds provided for an average AET to achieve competence in EUS (w225 cases) and ERCP (w250) may be used by ASGE and AETPs in establishing the minimal standards for case volume exposure for AETs during their training

A prospective multicenter study evaluating EUS and ERCP competence during advanced endoscopy training and subsequent independent practice: The rapid assessment of trainee endoscopy skills (rates2) study.

Background: We have shown that AETs achieve EUS and ERCP competence at varying rates, validating the shift from defining competence based on an absolute number of procedures to well-defined metrics. However, there are no data to confirm that advanced endoscopy trainees (AETs) who achieve competence during training subsequently perform high quality EUS and ERCP in their 1st year of independent practice. Aims: To report the outcomes of AETs during their 1st year of independent practice using ASGE established quality indicator (QI) thresholds To measure the relationship between achieving competence benchmarks during training and reported outcomes during independent practice. Methods: ASGE recognized advanced endoscopy training programs (AETPs) were invited to participate. In Phase I, AETs were graded on every 5th EUS and ERCP exam after completion of 25 hands-on EUS and ERCPs using the validated EUS and ERCP Skills Assessment Tool (TEESAT). Grading for each skill was done using a 4-point scoring system. A comprehensive data collection and reporting system was used to create learning curves using cumulative sum (CUSUM) analysis. Learning curves were created using CUSUM for overall and technical and cognitive components of EUS and ERCP and shared with AETs and trainers quarterly. Acceptable and unacceptable (Table presented) failures rates were set a priori and AETs with \u3c20 evaluations were excluded. During Phase II, AETs provided QI performance data on all EUS and ERCP procedures during the 1st year of independent practice. Results: Of the 62 programs invited, 37 AETs from 32 AETPs participated in this study and 24 AETs were included in the final analysis (Phase I). At the end of training, median number of EUS and ERCPs performed/ AET was 400 (range 200-750) and 361 (250-650), respectively. Overall, 2616 exams were graded (EUS: 1277, ERCP-biliary 1143, pancreatic 196). Majority of graded EUS exams were performed for pancreatobiliary indications (70%) and ERCPs for ASGE biliary grade of difficulty 1 (72.1%). Majority of trainees achieved overall technical (EUS: 91.6%; ERCP: 73.9%) and cognitive (EUS: 91.6%, ERCP: 95.6%) competence at conclusion of training (Table 1). 22 of 24 AETs participated in (Phase II) and median EUS and ERCP procedures completed in independent practice/AET were 136 (IQR 102-204) and 116 (48-169), respectively. Table 2 highlights QI performance in EUS and ERCP during Phase II. Majority of AETs crossed the QI threshold for obtaining adequate samples (overall rate: 94.4%), diagnostic yield of malignancy (83.8%), and cannulation rates overall (94.9%) and native papilla cases (93.1%). Conclusions: Majority of AETs achieved EUS and ERCP competence by the end of training. Moreover, these AETs achieved QI thresholds for routine EUS and ERCP during their 1st year of independent practice, affirming the effectiveness of AETPs