Search

Adam B Smith,1 Neil Fawkes,2 Helen Kotze,3 Victoria Hodgkinson,4 Cathal Coyle5 1Health Outcomes, Medical Affairs & Evidence Generation, Reckitt Benckiser, Hull, UK; 2Medical Excellence, Medical Affairs & Evidence Generation, Reckitt Benckiser, Hull, UK; 3Global Medical Affairs, Medical Affairs & Evidence Generation, Reckitt Benckiser, Hull, UK; 4Clinical Operations, Medical Affairs & Evidence Generation, Reckitt Benckiser, Hull, UK; 5Global Medical Affairs, Medical Affairs & Evidence Generation, Reckitt Benckiser, Slough, UKCorrespondence: Adam B SmithReckitt Benckiser, Dansom Lane, Hull HU8 7DS, UKTel +44 1482 583528Fax +44 1482 582172Email adam.smith@rb.comBackground: Gastroesophageal reflux disease (GORD) is a common condition affecting 30% of infants aged 0– 23 months. The Infant Gastroesophageal Questionnaire Revised version (I-GERQ-R) is an observer-reported outcome measures (ObsRO) developed to evaluate the impact of GORD on young infants. However, evidence regarding the clinically important difference (CID) for the I-GERQ-R is limited. The aim of this study was to determine a CID for the I-GERQ-R.Methods: A literature review was undertaken (PsycInfo, Embase, MedLine and EconLit databases) for longitudinal studies involving the I-GERQ-R. Articles were not limited by language or publication date. A random effects model was applied to calculate an overall CID, along with I2 and Q statistics. Publication bias was also assessed.Results: The search identified 42 articles; 11 were selected for full-text review and 7 articles were identified for full data extraction. The studies included a total of 661 infants (range: 30 to 313); 424 infants had been diagnosed with GORD (64%). The age range of the infants across the studies was from birth to 7 months. The overall CID was − 6.54 (95% confidence interval: − 4.35 to − 8.74), Q = 17.96, p=0.08 and I2=22.04.Conclusion: This study derived a CID for the I-GERQ-R and indicated a threshold around 6 could signify a clinically important difference for this instrument. The lower limit of the 95% confidence interval suggested a threshold of 3 to 4 could represent a minimally important difference. These results may help inform clinical decisions in evaluating meaningful change in symptom severity in children affected by GORD.Keywords: I-GERQ-R, gastro-esophageal reflux disease, minimally important difference, clinically important difference

The incidence of amyotrophic lateral sclerosis in Ohio 2016-2018: the Ohio population-based ALS Registry. Environmental and occupational risk factors of amyotrophic lateral sclerosis: a population-based case-control study. Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy. [Extracted from the article]

The Canadian Neuromuscular Disease Registry (CNDR) is a pan-neuromuscular disease registry that prospectively collects spinal muscular atrophy (SMA)-specific data in 32 clinics across Canada. The CNDR captures a comprehensive SMA dataset to evaluate long-term real-world experience with available and emerging therapies. The objective of this study is to describe real-world data from the CNDR-SMA patient population. The CNDR has 417 SMA patients registered, 207 adult patients (170 with clinical data) and 198 pediatric patients (181 with clinical data). This represents a large percentage of expected Canadians with SMA. Of those with complete data, Median age is 37 (18-80) for adults, and 9 (1-17) for pediatric patients. 243 (66%) patients have SNM2 copy number reported, 69 (28%) have 2 copies, 134 (55%) have 3 copies, 38 (16%) have 4 copies, and 119 are unknown/not reported. 93 (26%) patients are ambulatory. There are three disease modifying therapies (DMTs) approved for the treatment of SMA: risdiplam, nusinersen, and onasemnogene abeparvovec that all showed efficacy in clinical trials. Real-world effectiveness must be assessed across a broader range of patients presenting with variable comorbidities and disease severity. The CNDR collects DMT-specific real-world data to contextualize the effects of DMTs and to further access to treatment options in Canada. DMT's are differentially accessible across Canada, based on reimbursement recommendations of provincial payers. DMT use has been reported in 222 CNDR SMA patients: 184 on nusinersen, 41 on risdiplam, 36 on zolgensma (152 pediatric, and 71 adult), and 75 with no DMT use. In conclusion, the CNDR captures a comprehensive SMA dataset that prospectively evaluates real-world data, supporting post-marketing surveillance of novel therapies in Canada. Analysis is ongoing and available longitudinal follow-up data will be presented with descriptive statistics for both naive and DMT patients. [ABSTRACT FROM AUTHOR]

Risdiplam (EVRYSDI®) is a disease-modifying therapy approved for the treatment of spinal muscular atrophy (SMA). The efficacy of risdiplam has been demonstrated in clinical trials that included adult patients, but the real-world effectiveness of risdiplam in adults has not yet been extensively investigated. Natural history studies have shown a slow, progressive decline in motor function in adult patients with SMA. It remains unclear how treatment with risdiplam may influence this trajectory in a real-world clinical setting. As such, this study aims to describe adult patients with SMA treated with risdiplam in terms of their demographic and clinical characteristics, treatment patterns and motor function outcomes, and explore, if possible, the comparison of these outcomes with untreated patients. This non-interventional, retrospective cohort study will use data from six registries (clinician and patient reported) from within the TREAT-NMD network (Australia, Belgium, Canada, Czech Republic & Slovakia, Germany & Austria, and the UK & Ireland) to identify adult patients with SMA treated with risdiplam and where feasible, compare with an untreated patient population. Appropriate adjustment methods will be explored to account for potential confounders where possible, and appropriate statistical models will be used to perform comparisons with untreated patients. As of the submission of this abstract, the analysis is ongoing. Available data will be presented with descriptive statistics. In sum, this study will add to the growing real-world evidence for risdiplam in adults. This study will help to contextualise the effect of risdiplam in this patient population and that of untreated patients. [ABSTRACT FROM AUTHOR]

Introduction/aims: Glucocorticoids (GC) are first-line therapy for many neuromuscular diseases. There is a lack of guidelines regarding the prevention and management of GC complications in the context of neuromuscular disease, introducing the potential for practice variation, that may compromise quality of care. Our aim was to evaluate the practice patterns among Canadian adult neuromuscular neurologists on the screening, management, and treatment of GC-related complications and to identify variances in practice., Methods: A web-based anonymous questionnaire was disseminated to 99 Canadian adult neuromuscular neurologists. Questions addressed patterns of screening, prevention, monitoring, and treatment of GC-induced adverse events, including infection prophylaxis, vaccination, bone health, hyperglycemia, and other complications., Results: Seventy-one percent completed the survey. Of those, 52% perform screening blood work prior to initiating GC, 56% screen for infections, and 18% for osteoporosis. The majority monitor glycemic control and blood pressure (>85%). Thirty-two (46%) reported that they do not primarily monitor GC complications, but rather provide recommendations to the primary care physician. Pneumocystis jiroveci pneumonia prophylaxis was never used by 29%, and 29% recommend vaccinations prior to GC initiation. Calcium supplementation was recommended by 80% to prevent osteoporosis. Only 36% were aware of any existing guidelines for preventing GC complications, and 91% endorsed a need for neurology-specific guidelines., Discussion: There is substantial variability in the management of GC adverse effects among neuromuscular neurologists, often not corresponding to limited published literature. Our results support the need for improved education and neurology-specific guidelines to help standardize practice and improve and prevent complications., (© 2024 Wiley Periodicals LLC.)

Background: Spinal muscular atrophy (SMA) is a progressive genetic disorder characterized by muscle weakness ultimately leading to pulmonary impairments that can be fatal. The recent approval of nusinersen, a disease-modifying therapy, substantially changed the prognosis for patients, particularly in children. However, real-world evidence about its long-term effectiveness in adults remains limited. This study aimed to document longitudinal data on motor function, pulmonary function and patient-reported outcome measures of Canadian adults with SMA type 2 and 3 treated with nusinersen., Methods: Outcomes from 17 patients were collected at the Institut de réadaptation en déficience physique de Québec during routine clinical visits over 36 months post nusinersen treatment, using the Hammersmith Functional Motor Scale Expanded for SMA (HFMSE), Revised Upper Limb Module (RULM), 6-Minute Walk Test (6MWT), Children's Hospital of Philadelphia Adult Test of Neuromuscular Disorders (CHOP-ATEND), SMA functional rating scale (SMAFRS), pulmonary function testing and subjective changes reported by patients., Results: After 36 months, 9 patients showed motor function improvement. Changes beyond the minimal clinically important difference were seen for four patients on the HFMSE, four patients on the RULM and five patients on the 6MWT. Pulmonary function remained stable for most subjects. Subjective positive changes were reported in 88% of patients and five patients showed improvement in the SMAFRS., Conclusion: This real-world study demonstrates the positive effects of nusinersen in adults with SMA types 2 and 3. Although stabilizing the patient's condition is considered therapeutic success, this study shows an improvement in motor function and subjective gains in several patients.

Objectives: Spinal muscular atrophy (SMA) is a leading genetic cause of infant death and represents a significant burden of care. An improved understanding of the epidemiology of SMA in Canada may help inform strategies to improve the standard of care for individuals living with SMA., Methods: We employed a multisource approach to estimate the minimal incidence and prevalence of 5q SMA and to gain greater insight into recent clinical practices and treatment trends for the Canadian SMA population. Data sources included the Canadian Paediatric Surveillance Program (CPSP), Canadian Neuromuscular Disease Registry (CNDR), and molecular genetics laboratories in Canada., Results: The estimated annual minimum incidence of 5q SMA was 4.38, 3.44, and 7.99 cases per 100,000 live births in 2020 and 2021, based on CPSP, CNDR, and molecular genetics laboratories data, respectively, representing approximately 1 in 21,472 births (range 12,516-29,070) in Canada. SMA prevalence was estimated to be 0.85 per 100,000 persons aged 0-79 years. Delay in diagnosis exists across all SMA subtypes. Most common presenting symptoms were delayed milestones, hypotonia, and muscle weakness. Nusinersen was the most common disease-modifying treatment received. Most patients utilized multidisciplinary clinics for management of SMA., Conclusion: This study provides data on the annual minimum incidence of pediatric 5q SMA in Canada. Recent therapeutic advances and newborn screening have the potential to drastically alter the natural history of SMA. Findings underline the importance of ongoing surveillance of the epidemiology and long-term health outcomes of SMA in the Canadian population.

Introduction/aims: Consensus criteria to formalize the diagnosis of amyotrophic lateral sclerosis (ALS) and refine clinical trial populations have evolved. The recently proposed Gold Coast consensus criteria are intended to simplify use and increase sensitivity. We aimed to evaluate the potential impact of these criteria on clinical trial eligibility., Methods: We performed a single-center, retrospective study of people diagnosed with ALS between 2016 and 2021 to determine the numbers of those meeting Gold Coast, revised El Escorial (rEEC) criteria, and Awaji criteria. We identified the proportion of those who would have been eligible for participation in three major ALS clinical trials if Gold Coast were used in place of rEEC definite/probable criteria. (rEEC D/P)., Results: Two hundred six people with ALS were included in our study. 48.5% met Gold Coast criteria but not rEEC D/P. Using the Gold Coast criteria would result in higher rates of clinical trial eligibility after other inclusion criteria were met: 95.2% vs 42.5% (P < .001) in a phase III study of riluzole; 100% vs 31.0% (P = .002) in a phase III study of edaravone; and 95.6% vs 45.3% (P < .001) in an ongoing phase III study of sodium phenylbutyrate and taurursodiol. The sensitivity of the Gold Coast criteria (96.1%; 95% confidence interval [CI], 92.2%-98.2%) was significantly higher than that of rEEC D/P (47.6%; 95% CI, 40.6%-54.6%; for difference, χ 2  = 117.6; P < .001)., Discussion: Until robust biomarkers are available to diagnose ALS, consensus diagnostic criteria remain necessary. Gold Coast criteria would expand research and clinical trial eligibility and improve external validity of clinical trial results., (© 2022 Wiley Periodicals LLC.)

Background: Spinal Muscular Atrophy (SMA) is a rare disease that affects 1 in 11 000 live births. Recent developments in SMA treatments have included new disease-modifying therapies that require high quality data to inform decisions around initiation and continuation of therapy. In Canada, there are no nationally agreed upon outcome measures (OM) used in adult SMA. Standardization of OM is essential to obtain high quality data that is comparable among neuromuscular clinics., Objective: To develop a recommended toolkit and timing of OM for assessment of adults with SMA., Methods: A modified delphi method consisting of 2 virtual voting rounds followed by a virtual conference was utilized with a panel of expert clinicians treating adult SMA across Canada., Results: A consensus-derived toolkit of 8 OM was developed across three domains of function, with an additional 3 optional measures. Optimal assessment frequency is 12 months for most patients regardless of therapeutic access, while patients in their first year of receiving disease-modifying therapy should be assessed more frequently., Conclusions: The implementation of the consensus-derived OM toolkit will improve monitoring and assessment of adult SMA patients, and enrich the quality of real-world evidence. Regular updates to the toolkit must be considered as new evidence becomes available.

Objective: To investigate the intragastric acid neutralization activity of a combined alginate-antacid formulation., Significance: Published studies have investigated the reflux-suppressing alginate component of Gaviscon Double Action (Gaviscon DA; RB, UK) but intragastric acid neutralization activity of the antacid component has not been evaluated in vivo., Methods: Intragastric pH monitoring, using a custom-made 10-electrode catheter, was evaluated in a two-part exploratory study in healthy subjects; Part I (n = 6) tested suitability of the catheter using antacid tablets (Rennie; Bayer, Germany); Part II (n = 12) evaluated gastric acid neutralization activity of Gaviscon DA liquid (20 ml) versus placebo in fasted subjects using a randomized, open-label, crossover design. The primary endpoint was the percentage of time that intragastric pH ≥4 was measured during 30 min post-treatment. A confirmatory study of identical design was subsequently conducted (n = 20)., Results: Monitoring pH using the multielectrode catheter was a viable approach, directly detecting changes in intragastric pH following a single dose of antacid tablets. In the exploratory study, the percentage of time that pH ≥4 during 30 minutes post-treatment was 46.8% with Gaviscon DA liquid versus 4.7% with placebo (p = 0.0004). These findings were supported by the confirmatory study, where pH ≥4 was recorded 50.8% of the time with Gaviscon DA versus 3.5% with placebo (p = 0.0051). In this study, Gaviscon DA was safe and well tolerated., Conclusions: These studies demonstrate the effective acid neutralizing capacity of Gaviscon DA versus placebo in healthy, fasted subjects. This adds to the evidence base for the combination of alginates and antacids.

Background: The alginate-antacid Gaviscon Double Action (Gaviscon DA) has a combined acid-neutralizing and reflux-suppressing action. Response to treatment in a symptomatic gastro-oesophageal reflux disease (GERD) population has not yet been tested in a large-scale clinical study., Aim: The aim of this study was to assess the efficacy and safety of Gaviscon DA compared with matched placebo tablets in the reduction of upper gastrointestinal symptoms in patients with GERD., Participants and Methods: In this multicentre, randomized, double-blind, placebo-controlled study, adults with GERD symptoms (N=424) received Gaviscon DA or placebo tablets for 7 days. The primary endpoint was a clinically important reduction of at least 1.5 points in the Reflux Disease Questionnaire (RDQ) GERD dimension (combined heartburn/regurgitation) between baseline and the end of the treatment. Secondary endpoints included the change in RDQ score from baseline for individual RDQ dimensions and Overall Treatment Evaluation., Results: A significantly greater proportion of patients treated with Gaviscon DA met the primary endpoint compared with placebo (47.8 vs. 33.2%, respectively, P=0.0031; odds ratio: 1.85, 95% confidence interval: 1.23-2.78). A significant treatment effect was also observed for heartburn, regurgitation and dyspepsia individually. Patients in the Gaviscon DA group rated their overall treatment response greater than patients in the placebo group [mean Overall Treatment Evaluation (SD): 3.2 (3.08) vs. 2.2 (3.34); P<0.001]. No notable differences in the incidence of adverse events were observed between treatments., Conclusion: The alginate-antacid combination, Gaviscon DA, is an effective and well-tolerated treatment to reduce reflux symptoms and associated dyspepsia in symptomatic GERD patients.

This study describes the functional interaction between the Cav3.1 and Cav3.2 T-type calcium channels and cytoskeletal spectrin (α/β) and ankyrin B proteins. The interactions were identified utilizing a proteomic approach to identify proteins that interact with a conserved negatively charged cytosolic region present in the carboxy-terminus of T-type calcium channels. Deletion of this stretch of amino acids decreased binding of Cav3.1 and Cav3.2 calcium channels to spectrin (α/β) and ankyrin B and notably also reduced T-type whole cell current densities in expression systems. Furthermore, fluorescence recovery after photobleaching analysis of mutant channels lacking the proximal C-terminus region revealed reduced recovery of both Cav3.1 and Cav3.2 mutant channels in hippocampal neurons. Knockdown of spectrin α and ankyrin B decreased the density of endogenous Cav3.2 in hippocampal neurons. These findings reveal spectrin (α/β) / ankyrin B cytoskeletal and signaling proteins as key regulators of T-type calcium channels expressed in the nervous system.

Introduction: Patient registries serve an important role in rare disease research, particularly for the recruitment and planning of clinical trials. The Canadian Neuromuscular Disease Registry was established with the primary objective of improving the future for neuromuscular (NM) patients through the enablement and support of research into potential treatments., Methods: In this report, we discuss design and utilization of the Canadian Neuromuscular Disease Registry with special reference to the paediatric cohort currently enrolled in the registry., Results: As of July 25, 2017, there are 658 paediatric participants enrolled in the registry, 249 are dystrophinopathies (229 are Duchenne muscular dystrophy), 57 are myotonic dystrophy participants, 98 spinal muscular atrophy participants and 65 are limb girdle muscular dystrophy. A total of 175 patients have another NM diagnosis. The registry has facilitated 20 clinical trial inquiries, 5 mail-out survey studies and 5 other studies in the paediatric population., Discussion: The strengths of the registry are discussed. The registry has proven to be an invaluable tool to NM disease research and has increased Canada's visibility as a competitive location for the conduct of clinical trials for NM therapies.

This technical report presents quality control (QC) assays that can be performed in order to qualify clinical biospecimens that have been biobanked for use in research. Some QC assays are specific to a disease area. Some QC assays are specific to a particular downstream analytical platform. When such a qualification is not possible, QC assays are presented that can be performed to stratify clinical biospecimens according to their biomolecular quality.

T-type calcium channels are essential contributors to the transmission of nociceptive signals in the primary afferent pain pathway. Here, we show that T-type calcium channels are ubiquitinated by WWP1, a plasma-membrane-associated ubiquitin ligase that binds to the intracellular domain III-IV linker region of the Cav3.2 T-type channel and modifies specific lysine residues in this region. A proteomic screen identified the deubiquitinating enzyme USP5 as a Cav3.2 III-IV linker interacting partner. Knockdown of USP5 via shRNA increases Cav3.2 ubiquitination, decreases Cav3.2 protein levels, and reduces Cav3.2 whole-cell currents. In vivo knockdown of USP5 or uncoupling USP5 from native Cav3.2 channels via intrathecal delivery of Tat peptides mediates analgesia in both inflammatory and neuropathic mouse models of mechanical hypersensitivity. Altogether, our experiments reveal a cell signaling pathway that regulates T-type channel activity and their role in nociceptive signaling., (Copyright © 2014 Elsevier Inc. All rights reserved.)

The essential requirement for copper in early development is dramatically illustrated by Menkes disease, a fatal neurodegenerative disorder of early childhood caused by loss-of-function mutations in the gene encoding the copper transporting ATPase ATP7A. In this study, we generated mice with enterocyte-specific knockout of the murine ATP7A gene (Atp7a) to test its importance in dietary copper acquisition. Although mice lacking Atp7a protein within intestinal enterocytes appeared normal at birth, they exhibited profound growth impairment and neurological deterioration as a consequence of copper deficiency, resulting in excessive mortality prior to weaning. Copper supplementation of lactating females or parenteral copper injection of the affected offspring markedly attenuated this rapid demise. Enterocyte-specific deletion of Atp7a in rescued pregnant females did not restrict embryogenesis; however, copper accumulation in the late-term fetus was severely reduced, resulting in early postnatal mortality. Taken together, these data demonstrate unique and specific requirements for enterocyte Atp7a in neonatal and maternofetal copper acquisition that are dependent on dietary copper availability, thus providing new insights into the mechanisms of gene-nutrient interaction essential for early human development.

The trace element copper is indispensable for all aerobic life forms. Its ability to cycle between two oxidation states, Cu(1+) and Cu(2+), has been harnessed by a wide array of metalloenzymes that catalyze electron transfer reactions. The metabolic needs for copper are sustained by a complex series of transporters and carrier proteins that regulate its intracellular accumulation and distribution in both pathogenic microbes and their animal hosts. However, copper is also potentially toxic due in part to its ability to generate reactive oxygen species. Recent studies suggest that the macrophage phagosome accumulates copper during bacterial infection, which may constitute an important mechanism of killing. Bacterial countermeasures include the up-regulation of copper export and detoxification genes during infection, which studies suggest are important determinants of virulence. In this minireview, we summarize recent developments that suggest an emerging role for copper as an unexpected component in determining the outcome of host-pathogen interactions.

Copper (Cu) is an essential micronutrient. Its ability to exist in 2 oxidation states (Cu(1+) and Cu(2+)) allows it to function as an enzymatic cofactor in hydrolytic, electron transfer, and oxygen utilization reactions. Cu transporters CTR1, ATP7A, and ATP7B play key roles in ensuring that adequate Cu is available for Cu-requiring processes and the prevention of excess Cu accumulation within cells. Two diseases of Cu metabolism, Menkes disease and Wilson disease, which are caused by mutations in ATP7A and ATP7B, respectively, exemplify the critical importance of regulating Cu balance in humans. Herein, we review recent studies of the biochemical and cell biological characteristics of CTR1, ATP7A, and ATP7B, as well as emerging roles for Cu in new areas of physiology.