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Background X-linked myotubular myopathy (XLMTM) is a rare, life-threatening congenital myopathy with multisystem involvement, which often includes the need for invasive ventilator support, gastrostomy tube feeding, and wheelchair use in approximately 80% of patients. The direct and indirect financial impact of extensive supportive care, as reported by caregivers of individuals with XLMTM, and the health-related quality of life (HRQoL) of caregivers has not been previously described. Here, we use a survey co-designed by patient advocates to provide objective information on the physical and financial challenges of caregiving for individuals with XLMTM. Methods A real-world web-based survey was conducted in the United States between November 19, 2019, and January 23, 2020. The survey was developed in association with patient advocacy leaders from the XLMTM community, who were also caregivers of individuals with XLMTM. The survey included the EuroQol 5-dimension 5-level HRQoL instrument and visual analog scale, and a cost (direct and indirect medical costs) and healthcare resource questionnaire. The survey was shared among the XLMTM community by patient advocacy organizations. Caregivers who completed the survey and met the eligibility criteria were included. Descriptive statistics were conducted using Microsoft Excel. Results Twenty-two caregiver respondents agreed to participate. All respondents completed the cost and health resource survey. Productivity loss varied between participants over the prior 12 months. Durable medical equipment expenses comprised most of the direct medical out-of-pocket costs. Non-medical expenditures (e.g. home and vehicle modifications) were higher than direct medical out-of-pocket costs. Twelve of the 22 respondents completed the HRQoL survey. The HRQoL domains most impacted were usual activities, anxiety/depression, and pain/discomfort. Conclusions Findings from this real-world survey of caregivers for individuals with XLMTM describe the caregiver experience, as well as the multifaceted impact of the disease on caregiver productivity loss, out-of-pocket expenses, and HRQoL. XLMTM comes with financial constraints and substantial impacts on caregivers’ physical and mental health. Understanding these gaps is crucial to support the caregivers who provide care for this medically fragile population.

Individuals with spinal muscular atrophy (SMA) type 3 are able to walk but they have weakness, gait impairments and fatigue. Our primary study objective was to examine longitudinal changes in the six-minute walk test (6MWT) and to evaluate whether age and SMA type 3 subtype are associated with decline in ambulatory function. Data from three prospective natural history studies were used. Seventy-three participants who performed the 6MWT more than once, at least 6 months apart, were included; follow-up ranged from 0.5-9 years. Only data from patients who completed the 6MWT were included. The mean age of the participants was 13.5 years (range 2.6-49.1), with 52 having disease onset before age 3 years (type 3A). At baseline, type 3A participants walked a shorter distance on average (257.1 m) than type 3B participants (390.2 m) (difference = 133.1 m, 95% confidence interval [CI] 71.8-194.3, p < 0.001). Distance walked was weakly associated with age (r = 0.25, p = 0.04). Linear mixed effects models were used to estimate the mean annual rate of change. The overall mean rate of change was -7.8 m/year (95% CI -13.6 --2.0, p = 0.009) and this did not differ by subtype (type 3A: -8.5 m/year, type 3B: -6.6 m/year, p = 0.78), but it did differ by age group (< 6: 9.8 m/year; 6-10: -7.9 m/year; 11-19: -20.8 m/year; ≥ 20: -9.7 m/year; p = 0.005). Our results showed an overall decline on the 6MWT over time, but different trajectories were observed depending on age. Young ambulant SMA patients gain function but in adolescence, patients lose function. Future clinical trials in ambulant SMA patients should consider in their design the different trajectories of ambulatory function over time, based on age.

Background The financial burden of cancer treatment can increase the risk of housing insecurity for patients undergoing treatment and survivors. Objective To evaluate the burden of housing and utility insecurity among cancer survivors compared to individuals without a cancer history, examine outcome differences by housing tenure (renters vs. homeowners) and treatment status (active vs. posttreatment), and identify predictors of housing insecurity. Methods We analyzed data from 14 states that completed the Social Determinants and Cancer Survivorship modules of the 2022 and 2023 Behavioral Risk Factor Surveillance System (BRFSS), yielding 5499 respondents with a previous cancer diagnosis (excluding skin cancers) and 61,883 respondents without a cancer diagnosis. We estimated prevalences and fit logistic regressions. Key Results Cancer history was associated with greater odds of housing (AOR 1.43, 95% CI: 1.18–1.74) and utility (AOR 1.36, 95% CI: 1.09–1.69) insecurity, but this varied by treatment timing and housing tenure. Patients currently undergoing treatment were more likely to report housing and utility insecurity (AOR 1.96, 95% CI: 1.28–3.01 and AOR 1.67, 95% CI: 1.06–2.61, respectively) than individuals without a history of cancer. Such insecurity was elevated even after treatment for renters, but not for homeowners. In absolute terms, 34.7% of renters with a cancer history reported housing insecurity, compared to 7.1% of their homeowner counterparts. Conclusions Cancer diagnosis and treatment can contribute to housing and utility insecurity during and after treatment. Addressing this through targeted interventions within both healthcare systems and social policy may mitigate hardship and improve well‐being. Using the latest BRFSS data, our study found that nearly 2 in 5 renters and more than 1 in 9 homeowners currently undergoing cancer treatment cannot pay their housing or utility bills. We also identified subgroups of cancer survivors at elevated risk of housing insecurity and threats of utility shut‐offs, highlighting the urgent need for multilevel interventions that support this vulnerable group of patients and survivors.

Recent translational research developments in Spinal Muscular Atrophy (SMA), outcome measure design and demands from regulatory authorities require that clinical outcome assessments are 'fit for purpose'. An international collaboration (SMA REACH UK, Italian SMA Network and PNCRN USA) undertook an iterative process to address discontinuity in the recorded performance of the Hammersmith Functional Motor Scale Expanded and developed a revised functional scale using Rasch analysis, traditional psychometric techniques and the application of clinical sensibility via expert panels. Specifically, we intended to develop a psychometrically and clinically robust functional clinician rated outcome measure to assess physical abilities in weak SMA type 2 through to strong ambulant SMA type 3 patients. The final scale, the Revised Hammersmith Scale (RHS) for SMA, consisting of 36 items and two timed tests, was piloted in 138 patients with type 2 and 3 SMA in an observational cross-sectional multi-centre study across the three national networks. Rasch analysis demonstrated very good fit of all 36 items to the construct of motor performance, good reliability with a high Person Separation Index PSI 0.98, logical and hierarchical scoring in 27/36 items and excellent targeting with minimal ceiling. The RHS differentiated between clinically different groups: SMA type, World Health Organisation (WHO) categories, ambulatory status, and SMA type combined with ambulatory status (all p < 0.001). Construct and concurrent validity was also confirmed with a strong significant positive correlation with the WHO motor milestones rs = 0.860, p < 0.001. We conclude that the RHS is a psychometrically sound and versatile clinical outcome assessment to test the broad range of physical abilities of patients with type 2 and 3 SMA. Further longitudinal testing of the scale with regards change in scores over 6 and 12 months are required prior to its adoption in clinical trials.

Myotonic dystrophy (DM), the most common adult-onset muscular dystrophy, affects not only motor function and muscle integrity but also leads to debilitating cardiopulmonary, gastrointestinal, and multisystem complications. Central nervous system (CNS) involvement is increasingly recognized, manifesting as impairments in working memory, executive function, sleep regulation, and mood and behavior. These interrelated, multisystemic features contribute to multifaceted symptoms that significantly reduce quality of life for patients and their families. To identify potential biomarkers of CNS disease activity in DM1, we performed the first exploratory cerebrospinal fluid (CSF) proteomic profiling study. CSF samples from patients with DM1 (  = 11) and healthy controls (  = 5) were analyzed using Olink monoclonal antibody panels, quantifying 1,072 proteins. LASSO (Least Absolute Shrinkage and Selection Operator) regression identified proteins discriminating between DM1 and controls. Pathway enrichment analysis was performed using the Reactome database to assess biological significance. Six candidate biomarker proteins were differentially expressed between between DM1 patients and controls: CKAP4, SCARF1, NCAM1, CD59, PTH1R, and CA4. LASSO analysis further identified 15 proteins discriminating DM1 and controls, implicating pathways related to neuronal health, neuroinflammation, cognitive impairment, skeletal abnormalities, motor control, neuromuscular junction integrity, and cytoskeletal regulation. Dysregulated pathways included IGF transport, MAPK signaling, NCAM signaling, and broader signal transduction cascades pathways also implicated in other neurodevelopmental, neurodegenerative, and neuromuscular disorders. This first exploratory CSF proteomic analysis in DM1 identified dysregulated protein networks that may underlie CNS dysfunction in this multisystemic disease. These findings provide novel insights into DM1 pathophysiology and support the potential of CSF proteomic signatures as candidate diagnostic tools, indicators of disease activity, and measures of therapeutic response, pending validation in larger, independent cohorts.

Background Spinal muscular atrophy causes progressive motor neuron degeneration that impedes an infant's ability to maintain full oral nutrition and manage secretions. Development of pharmaceuticals that halt neuromuscular degeneration have enabled survival and improvement in motor function, with infants who receive treatment before symptoms exhibiting better outcomes than those who receive treatment after symptom onset. Little is known about the impact of treatment timing on swallowing. We retrospectively evaluated swallowing biomechanics and function among infants who received a disease modifying treatment and a swallow study as part of routine clinical care at 13 international children's hospitals. Swallow studies were prospectively analyzed for measures of biomechanics using BabyVFSSImP© and Swallowtail, with chart reviews used to evaluate measures of function including oral intake status and secretion management. Data was reported with descriptive statistics, with differences in swallowing outcomes compared between infants who received pre-symptomatic and symptomatic treatment using non-parametric t-tests. Results 69 infants meeting eligibility criteria were included. The majority received treatment after symptom onset (N = 52, 75%) and had two copies of survival motor neuron 2 (SMN2) (pre-symptomatic N = 17, 100%; symptomatic N = 48, 92%). Median age of infants at the time of their last videofluoroscopic swallow study was 7.92 months (IQR 4.83). While profound impairments in swallowing biomechanics were rare among infants who received pre-symptomatic treatment, they were common among infants treated after symptom onset, with significantly worse (higher) scores in four BabyVFSSImP© domains (ts > 3.25, ps ≤ 0.01, δ > 0.42): Palatal-Pharyngeal Approximation, Airway Invasion/Laryngeal Closure, Aspiration, and Pharyngeal Transport and Clearance. Although all pre-symptomatic treated infants were managing secretions without suctioning and nearly all were consuming full age-appropriate nutrition (N = 15, 88%), similar to biomechanics, select pre-symptomatic treated infants did exhibit profound functional impairments. Conclusions Infants who receive pre-symptomatic treatment for spinal muscular atrophy typically have good swallowing outcomes, without profound impairments in biomechanics, reliance on suctioning for secretion management, and reliance on alternative nutrition care. Pharyngeal biomechanical deficits are substantially more common among those infants that receive treatment after symptom onset, and likely are associated with subclinical neural degradation at the time treatment is administered.

Background: Invasive dental treatment in patients exposed to antiresorptive and antiangiogenic drugs can cause medication-related osteonecrosis of the jaw (MRONJ). Currently, the exact pathogenesis of this disease is unclear. Methods: In March 2022, Medline (Ovid), Embase (Ovid), Scopus, and Web of Science were screened to identify eligible in vitro studies investigating the effects of antiresorptive and antiangiogenic compounds on orally derived cells. Results: Fifty-nine articles met the inclusion criteria. Bisphosphonates were used in 57 studies, denosumab in two, and sunitinib and bevacizumab in one. Zoledronate was the most commonly used nitrogen-containing bisphosphonate. The only non-nitrogen-containing bisphosphonate studied was clodronate. The most frequently tested tissues were gingival fibroblasts, oral keratinocytes, and alveolar osteoblasts. These drugs caused a decrease in cell proliferation, viability, and migration. Conclusions: Antiresorptive and antiangiogenic drugs displayed cytotoxic effects in a dose and time-dependent manner. Additional research is required to further elucidate the pathways of MRONJ.

Duchenne muscular dystrophy (DMD) is characterized by muscle degeneration and progressive weakness. There is considerable inter-patient variability in disease onset and progression, which can confound the results of clinical trials. Here we show that a common null polymorphism (R577X) in ACTN3 results in significantly reduced muscle strength and a longer 10 m walk test time in young, ambulant patients with DMD; both of which are primary outcome measures in clinical trials. We have developed a double knockout mouse model, which also shows reduced muscle strength, but is protected from stretch-induced eccentric damage with age. This suggests that α-actinin-3 deficiency reduces muscle performance at baseline, but ameliorates the progression of dystrophic pathology. Mechanistically, we show that α-actinin-3 deficiency triggers an increase in oxidative muscle metabolism through activation of calcineurin, which likely confers the protective effect. Our studies suggest that ACTN3 R577X genotype is a modifier of clinical phenotype in DMD patients. Duchenne muscular dystrophy is a disease caused by a single gene, characterized by progressive muscle weakness, but is variable between patients partly due to interactions of other genes. Here, the authors show that a common ACTN3 polymorphism can modify the clinical phenotype.

Background The 32-item Motor Function Measure (MFM32) is a clinician-reported outcome measure used to assess the functional abilities of individuals with neuromuscular diseases, including those with spinal muscular atrophy (SMA). This two-part study explored the relationship between the functional abilities assessed in the MFM32 and activities of daily living (ADLs) from the perspective of individuals with Type 2 and Type 3 (non-ambulant and ambulant) SMA and their caregivers through qualitative interviews and a quantitative online survey. Methods In-depth, semi-structured, qualitative interviews were conducted with individuals with SMA and caregivers from the US. Subsequently, a quantitative online survey was completed by individuals with SMA or their caregivers from France, Germany, Italy, Poland, Spain, Canada, the United States (US) and the UK. In both parts of the study, participants were asked to describe the ADLs considered to be related to the functional abilities assessed in the MFM32. Results from the qualitative interviews informed the content of the quantitative online survey. Results Qualitative interviews were conducted with 15 adult participants, and 217 participants completed the quantitative online survey. From the qualitative interviews, all of the functional abilities assessed in the patient-friendly MFM32 were deemed as related to one or more ADL. The specific ADLs that participants considered related to the patient-friendly MFM32 items could be grouped into 10 key ADL domains: dressing, mobility/transferring, self-care, self-feeding, reaching, picking up and holding objects, physical activity, writing and technology use, social contact/engagement, toileting and performing work/school activities. These results were confirmed by the quantitative online survey whereby the ADLs reported to be related to each patient-friendly MFM32 item were consistent and could be grouped into the same 10 ADL domains. Conclusion This study provides in-depth evidence from the patient/caregiver perspective supporting the relevance of the patient-friendly MFM32 items to the ADLs of individuals with Type 2 and Type 3 SMA.

Objective We report longitudinal data from 144 type III SMA pediatric and adult patients treated with nusinersen as part of an international effort. Methods Patients were assessed using Hammersmith Functional Motor Scale Expanded (HFMSE), Revised Upper Limb Module (RULM), and 6‐Minute Walk Test (6MWT) with a mean follow‐up of 1.83 years after nusinersen treatment. Results Over 75% of the 144 patients had a 12‐month follow‐up. There was an increase in the mean scores from baseline to 12 months on both HFMSE (1.18 points, p = 0.004) and RULM scores (0.58 points, p = 0.014) but not on the 6MWT (mean difference = 6.65 m, p = 0.33). When the 12‐month HFMSE changes in the treated cohort were compared to an external cohort of untreated patients, in all untreated patients older than 7 years, the mean changes were always negative, while always positive in the treated ones. To reduce a selection bias, we also used a multivariable analysis. On the HFMSE scale, age, gender, baseline value, and functional status contributed significantly to the changes, while the number of SMN2 copies did not contribute. The effect of these variables was less obvious on the RULM and 6MWT. Interpretation Our results expand the available data on the effect of Nusinersen on type III patients, so far mostly limited to data from adult type III patients.