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X-linked myotubular myopathy (XL-MTM) is a rare life-threatening congenital myopathy caused by mutations in the MTM1 gene that encodes myotubularin, a ubiquitous enzyme required for normal development and function of skeletal muscle. The incidence of XLMTM in newborn males is 1:50,000. Recent evidence has revealed a previously unrecognized cholestatic tendency in patients with XL-MTM. EXCEL is a 48-week, prospective, observational, multicenter study to evaluate hepatobiliary health in patients with XLMTM. Approximately 50 male participants <18 years of age (up to half <5 years of age) with genetically confirmed XLMTM will be enrolled at 15–25 specialist sites in Canada, UK, and USA. The primary objective is to assess hepatobiliary health by estimating the incidence and prevalence of cholestatic complications in participants with XL-MTM. Secondary objectives are to evaluate the: (1) association between genetic variants of MTM1 and cholestasis; (2) association between environmental modifiers and cholestasis; and (3) healthcare utilization related to hepatobiliary and cholestatic complications. Participant assessments will be performed at the investigator's discretion based on standard of care at the site. A recommended schedule of assessments includes liver function tests (including serum bile acids), blood clotting parameters, creatinine, triglycerides and total cholesterol, and vitamin panel. Further clinical evaluation including liver ultrasound and Fibroscan will be used where appropriate. To reduce patient and caregiver burden, home healthcare services will collect laboratory tests when possible. Remote data collection may be used for healthcare resource utilization and patient medical history. Findings are expected to improve our understanding of cholestatic tendencies in participants with XL-MTM and provide critical information to improve the current management and treatment of XL-MTM, as well as future clinical trial designs. *Co-first authors. [ABSTRACT FROM AUTHOR]

BACKGROUND: The Epidemiology and Natural History of Asthma: Outcomes and Treatment Regimens study is among the largest to assess persistent airflow limitation and the first to evaluate a wide range of potential risk factors in high-risk patients with severe or difficult-to-treat asthma. A better understanding is needed regarding factors associated with persistent airway obstruction; this study was performed to determine demographic and clinical characteristics associated with persistent airflow limitation. METHODS: Data from adult patients (>or= 18 years old) with severe or difficult-to-treat asthma were evaluated. Patients with COPD, obesity with a restrictive respiratory pattern, or a >or= 30 pack-year history of smoking were excluded. Patients with persistent airflow limitation (postbronchodilator FEV1/FVC ratio

Objective: To examine the descriptive epidemiologic features of incident thyroid cancers diagnosed among Los Angeles County residents between 1972 and 1995.Methods: The Los Angeles County/University of Southern California Cancer Surveillance Program (CSP) collected data on 8820 newly diagnosed thyroid cancer of cases occurring in Los Angeles County. Average annual age-adjusted incidence rates were calculated to study the epidemiology of each of the major histologic types of thyroid carcinoma.Results: For all races combined, the age-adjusted incidence rates were 2.5 per 100,000 males and 6.0 per 100,000 females. Differences in incidence by ethnicity were particularly striking, with Filipinos demonstrating the highest incidence rates (4.44 per 100,000 males, 11.3 per 100,000 females). Over the 23-year period, thyroid cancer incidence rates increased 1.5% per year for males and 1% per year for females. By histology, papillary carcinoma rates increased over time and follicular carcinoma rates decreased. Non-Spanish surnamed white men employed in certain white-collar occupations and radiologic technicians were at greater risk of thyroid cancer.Conclusions: Additional research on the epidemiologic risk factors for thyroid cancer, particularly for gender and ethnicity, is needed to explain the marked elevated incidence rates among females and the Filipino population in Los Angeles County. [ABSTRACT FROM AUTHOR]

Centronuclear myopathies (CNMs) are a group of rare inherited congenital myopathies for which there is currently no cure. The most common form is X-linked myotubular myopathy (XL-MTM) with an estimated incidence of 1 in 50,000 male births and a typically severe clinical phenotype. The international Myotubular and Centronuclear Myopathy Patient Registry collects demographic, genetic and clinical data for affected individuals (living and deceased) and female carriers of XL-MTM. In the past few years two clinical trials have taken place, ASPIRO & Unite-CNM, both of which were halted prematurely because of liver-related serious adverse events, ranging from reversible liver function abnormalities to fatal cholestatic liver failure. These events have led to an increasing awareness of liver-related pathology, including pre-existing liver dysfunction in XL-MTM and CNM which may predispose patients to treatment-related adverse events, as highlighted in a recent publication on the ASPIRO gene therapy trial for XL-MTM. Driven by two patient organisations (MTM-CNM Family Connection and Myotubular Trust UK), a group of international experts was assembled to create the 'Liver Collaborative' to better understand liver challenges experienced in the community from both a natural history perspective and in the context of emerging clinical trials. Working with the MTM & CNM Patient Registry, a liver health questionnaire was developed and implemented into the registry platform in April 2023, with 168 questionnaires completed. The Collaborative is responsive to emerging new research which is advancing the understanding of potential liver dysfunction in XLMTM and CNM. The liver health questionnaire will be updated to capture additional data on nutritional diet and patient liver testing results. Findings from the current and expanded questionnaire will be presented. The registry has been a key instrument for the longitudinal collection of this data. [ABSTRACT FROM AUTHOR]

Background: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital disease, which is not well-defined. To our knowledge, no studies characterizing the XLMTM disease burden have been conducted in Brazil. We identified and described patients with suspected XLMTM using administrative claims data from the Brazilian public healthcare system., Methods: Data from 2015 to 2019 were extracted from the DATASUS database. As no XLMTM-specific ICD-10 code was available, a stepwise algorithm was applied to identify patients with suspected XLMTM by selecting male patients with a congenital myopathies code (G71.2), aged < 18 years at index date (first claim of G71.2), with an associated diagnostic procedure (muscle biopsy/genetic test) and without spinal muscular atrophy or Duchenne muscular dystrophy. We attempted to identify patients with suspected severe XLMTM based on use of both respiratory and feeding support, which are nearly universal in the care of XLMTM patients. Analyses were performed for the overall cohort and stratified by age at index date < 5 years old and ≥ 5 years old., Results: Of 173 patients with suspected XLMTM identified, 39% were < 5 years old at index date. Nearly all (N = 166) patients (96%) were diagnosed by muscle biopsy (91% of patients < 5 years old and 99% of patients ≥ 5 years old), six (3.5%) were diagnosed by clinical evaluation (8% of patients < 5 years old and 1% of patients ≥ 5 years old), and one was diagnosed by a genetic test. Most patients lived in Brasilia (n = 55), São Paulo (n = 33) and Minas Gerais (n = 27). More than 85% of patients < 5 years old and approximately 75% of patients ≥ 5 years old had physiotherapy at the index date. In both age groups, nearly 50% of patients required hospitalization at some point and 25% required mobility support. Respiratory and feeding support were required for 3% and 12% of patients, respectively, suggesting that between 5 and 21 patients may have had severe XLMTM., Conclusion: In this real-world study, genetic testing for XLMTM appears to be underutilized in Brazil and may contribute to underdiagnosis of the disease. Access to diagnosis and care is limited outside of specific regions with specialized clinics and hospitals. Substantial use of healthcare resources included hospitalization, physiotherapy, mobility support, and, to a lesser extent, feeding support and respiratory support., (© 2024. The Author(s).)

Background: X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy with multisystem involvement, often requiring invasive ventilator support, gastrostomy tube feeding, and wheelchair use. Understanding healthcare resource utilization in patients with XLMTM is important for development of targeted therapies but data are limited., Methods: We analyzed individual medical codes as governed by Healthcare Common Procedure Coding System, Current Procedural Terminology, and International Classification of Diseases, 10th Revision (ICD-10) for a defined cohort of XLMTM patients within a US medical claims database. Using third-party tokenization software, we defined a cohort of XLMTM patient tokens from a de-identified dataset in a research registry of diagnostically confirmed XLMTM patients and de-identified data from a genetic testing company. After approval of an ICD-10 diagnosis code for XLMTM (G71.220) in October 2020, we identified additional patients., Results: A total of 192 males with a diagnosis of XLMTM were included: 80 patient tokens and 112 patients with the new ICD-10 code. From 2016 to 2020, the annual number of patients with claims increased from 120 to 154 and the average number of claims per patient per year increased from 93 to 134. Of 146 patients coded with hospitalization claims, 80 patients (55%) were first hospitalized between 0 and 4 years of age. Across all patients, 31% were hospitalized 1-2 times, 32% 3-9 times, and 14% ≥ 10 times. Patients received care from multiple specialty practices: pulmonology (53%), pediatrics (47%), neurology (34%), and critical care medicine (31%). The most common conditions and procedures related to XLMTM were respiratory events (82%), ventilation management (82%), feeding difficulties (81%), feeding support (72%), gastrostomy (69%), and tracheostomy (64%). Nearly all patients with respiratory events had chronic respiratory claims (96%). The most frequent diagnostic codes were those investigating hepatobiliary abnormalities., Conclusions: This innovative medical claims analysis shows substantial healthcare resource use in XLMTM patients that increased over the last 5 years. Most patients required respiratory and feeding support and experienced multiple hospitalizations throughout childhood and beyond for those that survived. This pattern delineation will inform outcome assessments with the emergence of novel therapies and supportive care measures., (© 2023. The Author(s).)

Background: Dupilumab, a fully human monoclonal antibody, blocks the shared receptor component for interleukin-4 and interleukin-13, key and central drivers of type 2 inflammation. In clinical studies, dupilumab reduced the risk of severe asthma exacerbations, and improved forced expiratory volume in 1 s and quality of life in patients with uncontrolled moderate-to-severe asthma., Objectives: The objectives of RAPID (NCT04287621) are to characterize patients with asthma initiating dupilumab in routine clinical practice and to collect information on long-term effectiveness and safety in these patients., Methods: RAPID is a global, prospective, observational registry that will enroll approximately 1000 patients (aged ≥ 12 years) with asthma from 150 sites globally. Dupilumab treatment will be initiated in routine clinical practice according to country-specific prescribing information, per physician discretion as part of routine care. Patients will be followed prospectively for up to 3 years, with postbaseline assessments at months 1 and 3, and every 3 months thereafter., Planned Outcomes: Baseline data collected will include patient demographics, disease characteristics, and medication history. Patient adherence and persistence will be recorded alongside health-care resource utilization, and effectiveness of dupilumab will be assessed (clinician assessment) as per standard of care. Quality of life, asthma control, type 2 inflammatory comorbidities, work productivity, and physical activity limitation will be assessed. Incidence and severity of adverse events will be recorded., Conclusion: RAPID is the first global registry to characterize patients beginning dupilumab treatment for asthma in clinical practice and will expand on prior clinical studies by providing real-world data., Clinical Trial Registration: ClinicalTrials.gov identifier NCT04287621., (© 2023. The Author(s).)

Background: Effectiveness of asthma treatment, including biologics, may be different in patients with higher body mass index (BMI)., Objective: To evaluate response to omalizumab (dosed by serum immunoglobulin E level and weight) by BMI category., Methods: Pooled data from 2 randomized, double-blind, placebo-controlled studies of adults with moderate-to-severe allergic asthma were analyzed by BMI category (<25 kg/m 2 [normal or underweight], n = 397; 25 to <30 kg/m 2 [overweight], n = 330; ≥ 30 kg/m 2 [obese], n = 268). Placebo-adjusted exacerbation rate reductions were evaluated by Poisson regression modeling. Changes from baseline in forced expiratory volume in 1 second, beclomethasone dipropionate (BDP) dose, Total Asthma Symptom Score, and Asthma Quality of Life Questionnaire were evaluated by analysis of covariance., Results: Greater placebo-adjusted exacerbation rate reductions (95% confidence interval) were observed with increasing BMI (normal or underweight, -37.4% [-69.0% to 26.8%]; overweight, -52.7% [-78.4% to 3.7%]; obese, -71.9% [-86.9% to -39.5%]). There were no differences in forced expiratory volume in 1 second improvement between BMI categories at week 16 (normal or underweight, 76.2 [5.3-147.1] mL; overweight, 98.1 [13.9-182.4] mL; obese, 69.1 [-18.9 to 157.2] mL). No differences in BDP dose reduction (µg) were noted between BMI categories (normal or underweight, 23.0 [15.7-30.3]; overweight, 22.5 [13.5-31.5]; obese, 16.6 [5.8-27.3]). Fewer patients in the higher BMI categories eliminated BDP use. There were trends for smaller improvements with higher BMI in Total Asthma Symptom Score (normal/underweight, -0.52 [-0.82 to -0.22]; overweight, -0.50 [-0.80 to -0.20]; obese, -0.39 [-0.77 to 0.00]) and Asthma Quality of Life Questionnaire (normal or underweight, 0.34 [0.16-0.52]; overweight, 0.34 [0.13-0.55]; obese, 0.15 [-0.08 to 0.39])., Conclusion: Omalizumab provides benefit to patients with moderate-to-severe allergic asthma, regardless of BMI., Trial Registration: Studies 008/009 were conducted before clinical trial registration was required, and therefore clinical trial registration numbers are not available., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Although asthma is typically characterized by bronchodilator responsiveness (BDR), fixed airflow obstruction (FAO) occurs in ∼50% of patients with severe asthma., Objective: Do FAO/BDR associate with efficacy of omalizumab, a monoclonal antibody that targets IgE?, Methods: In EXTRA, patients aged 12-75 years with inadequately controlled severe allergic asthma despite high-dose inhaled corticosteroids plus long-acting β 2 -agonists were randomized to omalizumab (n = 427) or placebo (n = 423) for 48 weeks of treatment. In this post hoc analysis, high/low BDR were defined as ≥12%/<12% increases in baseline forced expiratory volume in 1 second (FEV 1 ) after bronchodilator administration, respectively. FAO presence (+)/absence (-) were defined as baseline postbronchodilator FEV 1 /forced vital capacity <70%/≥70%, respectively. Poisson regression/analysis of covariance models were used to estimate exacerbation relative rate reductions (RRRs)/least-squares mean changes in FEV 1 , respectively., Results: In patients with high BDR, omalizumab reduced exacerbations more than placebo over the 48-week treatment period regardless of FAO status (RRR [95% confidence interval (CI)]: FAO+, 59.8% [17.7-80.4%]; FAO-, 44.3% [16.6-62.8%]). Omalizumab improved FEV 1 compared with placebo in the FAO-, high BDR subgroup (FEV 1 change from baseline [95% CI] for omalizumab vs placebo, 0.065 L [-0.071 to 0.201 L] to 0.236 L [0.112-0.359 L]) across 48 weeks. This was not observed in patients with low BDR, irrespective of FAO., Conclusion: Omalizumab was more efficacious than placebo at reducing exacerbations in patients with high, but not low, BDR, regardless of the presence of FAO. Lung function improvement primarily occurred in FAO-, high BDR patients, suggesting that asthma with low BDR may represent a difficult-to-treat phenotype., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)