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A high-saturated-fat diet (HFD) during pregnancy and lactation leads to metabolic disorders in offspring concomitant with increased adiposity and a proinflammatory phenotype in later life. During the fetal period, the impact of maternal diet on skeletal muscle development is poorly described, despite this tissue exerting a major influence on life-long metabolic health. This study investigated the effect of a maternal HFD on skeletal muscle anabolic, catabolic, and inflammatory signaling in adult rat offspring. Furthermore, the actions of maternal-supplemented conjugated linoleic acid (CLA) on these measures of muscle phenotype were investigated. A purified control diet (CD; 10% kcal fat), a CD supplemented with CLA (CLA; 10% kcal fat, 1% total fat as CLA), a high-fat (HFD; 45% kcal fat from lard), or a HFD supplemented with CLA (HFCLA; 45% kcal fat from lard, 1% total fat as CLA) was fed ad libitum to female Sprague-Dawley rats for 10 days before mating and throughout gestation and lactation. Male offspring received a standard chow diet from weaning, and the gastrocnemius was collected for analysis at day 150. Offspring from HF and HFCLA mothers displayed lower muscular protein content accompanied by elevated monocyte chemotactic protein-1, IL-6, and IL-1β concentrations. Phosphorylation of NF-κBp65 (Ser536) and expression of the catabolic E3 ligase muscle ring finger 1 (MuRF1) were increased in HF offspring, an effect reversed by maternal CLA supplementation. The present study demonstrates the importance of early life interventions to ameliorate the negative effects of poor maternal diet on offspring skeletal muscle development. [ABSTRACT FROM AUTHOR]

BackgroundElectronic patient questionnaires are becoming ubiquitous in health care. To address care gaps that contribute to poor asthma management, we developed the Electronic Asthma Management System, which includes a previsit electronic patient questionnaire linked to a computerized clinical decision support system. ObjectiveThis study aims to identify the determinants (barriers and enablers) of patient uptake and completion of a previsit mobile health questionnaire. MethodsWe conducted semistructured interviews with adult patients with asthma in Toronto, Canada. After demonstrating the questionnaire, participants completed the questionnaire using their smartphones and were then interviewed regarding perceived barriers and enablers to using and completing the questionnaire. Interview questions were based on the Theoretical Domains Framework to identify the determinants of health-related behavior. We generated themes that addressed the enablers and barriers to the uptake and completion of the questionnaire. ResultsIn total, 12 participants were interviewed for saturation. Key enablers were as follows: the questionnaire was easy to complete without additional knowledge or skills and was perceived as a priority and responsibility for patients, use could lead to more efficient and personalized care, completion on one’s own time would be convenient, and uptake and completion could be optimized through patient reminders. Concerns about data security, the usefulness of questionnaire data, the stress of completing it accurately and on time, competing priorities, and preferences to complete the questionnaire on other devices were the main barriers. ConclusionsThe barriers and enablers identified by patients should be addressed by developing implementation strategies to enhance e-questionnaire use and completion by patients. As the use of e-questionnaires grows, our findings will contribute to implementation efforts across settings and diseases.

Patients with complex neuromuscular diseases require multidisciplinary care which results in multiple outpatient hospital appointments. The lack of coordination may result in unnecessary unplanned admissions and delay in timely care provision. The multiple hospital appointments add to the burden of care for patients and their caregivers and may have an impact on QoL and participation in ADLs. One-stop shop model of care has been implemented in other centres and proven to be a successful model for neuromuscular patients. We aim to establish a Neuromuscular Complex Care Day Unit for multidisciplinary management of neuromuscular patients from North East and Cumbria in England where Standards of Care appointments will be scheduled over a 1-2 day admission. We applied quality improvement methodology to demonstrate the necessity and impact of this service improvement proposal. Driver diagrams helped plan and structure the initiative, identifying change ideas that will be implemented using PDSA cycles. To measure the effects of this proposal we defined 1) Outcome measures: completion of care pathway and patient experience; 2) Process measures: identification of complex patients; 3) Balance measures: rate of fail to attend and unplanned admissions. A survey (PDSA cycle 1) circulated nationally to patients with neuromuscular diseases and their caregivers: 107 patients and care givers took part in the survey. Patients on average attend 4.7 specialist appointments a year. 19% of patients have had an unplanned hospital admission in the last 12 months. 45.8% of patients report that their physiotherapy needs are not met in the community. On average 37.4 % of patients travel 30-60 minutes to attend their clinic appointment. 69.8% of patients and 48.1 % of parent/care givers prefer to have their neuromuscular care appointments scheduled over one day. 80% of patients would be keen to attend such a unit, should this be available to them. Overall, the survey showed patients are supportive of such a model of care and allowed us to better shape this initiative to meet their needs. We are carrying out stakeholder engagement meetings (PDSA cycle 2) to gather feedback. We are also collecting data retrospectively on patients' attendance to appointments with other MDTs involved. Based on these results we will establish criteria for patients entering the pathway and refine the proposed model of care for the business case. [ABSTRACT FROM AUTHOR]

As we know, Pompe disease is a rare genetic myopathy with two main clinical phenotypes: Infantile Onset Pompe Disease (IOPD) and Late Onset Pompe Disease (LOPD). Epidemiological studies showed a disease prevalence about 1:40.000 but reliable data in Spain is lacking. Here we analyzed the data of the 130 patients in the Spanish Pompe, included between 2019 and 2024. We collected information about demographics, family history, clinical features, ancillary tests, functional outcomes and response to treatments from each individual clinical report. We analyzed the data of 130 patients 118 patients were classified as LOPD while 12 had an IOPD phenotype. 70 patients were males (53,85%). Mean age of our population was of 29.75 years old (SD 42,75). 44 had family history of Pompe, being most commonplace of birth and parent's origin Andalusia, 100 patients were symptomatic. The most frequent symptom reported was lower limb and axial weakness in 60.7%. Forty patients required ventilation support (34 patients) The most common mutation reported was IVS1-13T>G (c.‐13‐32T>G) in 85 patients. 89 were treated with Enzyme Replace Therapy. According to our data the Pompe prevalence is 3/1.000.000 in our country. The Spanish Pompe Registry give us valuable information about the demographics and clinical features of our population of patients with this rare disease, yielding a lower prevalence. [ABSTRACT FROM AUTHOR]

The UK SMA Patient Registry collects patient-reported outcome measures (PROMs) from individuals living with spinal muscular atrophy (SMA) in the UK and Ireland. In 2022, PROMs collection was introduced in the registry to supplement clinical and genetic data held therein. PROMs capture the perspectives of adults and caregivers of young people living with SMA about the impact of their condition and treatment, their quality of life and activities of daily living. Importance of the patient voice is increasingly recognised and valued. Currently, SMA therapies Nusinersen and Risdiplam are available in the UK via managed access agreements (MAAs). The collection of clinical and patient-reported data will inform review of treatment impact by UK regulatory authorities. In collaboration with clinical networks Adult SMA REACH and SMA REACH UK, the registry aims to collect PROMs data of 100 Nusinersen and 100 Risdiplam patients. PROMs will be aligned with Adult SMA REACH and SMA REACH clinical data, anonymised, analysed and submitted to regulatory authorities for consideration as part of the treatment MAAs. Registration in the UK SMA Patient Registry is patient-initiated through a secure online portal. Patients are invited to complete questionnaires about their condition and PROMs: EQ-5D; Patient Global Impression of Change; SMA Independence Scale (SMAIS-ULM); and a free-text box. Enabled through patient consent and data sharing agreements, patient-level PROMs data is shared with each patient's SMA REACH clinic and with the SMA REACH coordination teams. In clinic, the data informs patient care. At project coordination level, PROMs are aligned with clinical data collected by SMA REACH. At the time of abstract submission, the registry has 642 participants: 443 adults (16+years); 199 paediatric (<16years). PROMs have been completed by 205 adults and by the caregivers of 80 paediatric patients. The fraction of PROMs able to be aligned with Adult SMA REACH and SMA REACH clinical data is growing and will be presented. The UK SMA Patient Registry represents a well-defined cohort of individuals with SMA and is a valuable tool for the collection of SMA real-world data reported by treated and treatment-naïve patients. Expansion of the registry to collect PROMs supports UK SMA data collection and supplements Adult SMA REACH and SMA REACH clinical data, assisting in therapy evaluation by regulatory authorities. [ABSTRACT FROM AUTHOR]

Sarcoglycanopathies, severe forms of autosomal recessive LGMDs, include four subtypes: LGMDR3, LGMDR4, LGMDR5, and LGMDR6. A retrospective audit at a single centre gathered motor function, respiratory, cardiac and genetic data for sarcoglycanopathy individuals diagnosed by the Highly Specialised Service for Rare Neuromuscular Disorders in Newcastle upon Tyne, UK, from 1987 to 2024. Forty-three individuals from 30 unrelated families were diagnosed with sarcoglycanopathy, 12 with LGMDR3, 11 with LGMDR4, 14 with LGMDR5, and 2 with LGMDR6. The main pathogenic variants were SCGA c.229C>T;p.(Arg77Cys), SCGB c.341C>T;p.(Ser114Phe) and SGCG c.787G>A;p.(Glu263Lys). Mean onset ages were 8.7, 7.8, 6.4, and 8.3 years for LGMDR3, LGMDR4, LGMDR5, and LGMDR6, respectively. Thirty-nine had pediatric onset (0-16), and four had young adult onset (16-40). Individuals with <3-year disease duration showed preserved motor function. Five out of six with LGMDR6 had <3 years of disease duration. The mean disease duration for loss of ambulation (LoA) occurred at ages 8.2, 12.3, and 9.5 years for LGMDR3, LGMDR4, and LGMDR5, respectively. Six out of nine non-ambulant LGMDR5 cases showed loss of ability to lift arms before LoA. This was less common in LGMDR3 and LGMDR4 cases (1/10). Four young adult-onset individuals, none with LGMDR5, remained ambulatory for an average of 21.5 years post-onset. No correlation existed between early disease onset age and time to LoA (p=0.74). The mean disease duration for losing the ability to rise from the floor and climb stairs were 6.5 and 7.6, respectively, with a strong correlation (p<0.01). Five individuals developed cardiomyopathy, with an average disease duration of 25.4 years. Forced vital capacity (FVC) was <80% in 18/43 individuals, while 11/18 developed severe restrictive pulmonary disease (FVC<50%), with an average disease duration of 19.7 years. This sarcoglycanopathy cohort may display subtype-specific patterns but lacked a correlation between disease onset age and LoA. [ABSTRACT FROM AUTHOR]

Recent therapeutic developments have led to the approval of three Spinal Muscular Atrophy (SMA) treatments by the European Medicines Agency. This approval highlighted the urgent need to collect data to gain a better understanding in the impact of new drugs on natural history of the disease in the UK. Currently, in the UK, only gene therapy (Zolgensma) is approved, with Nusinersen and Risdiplam having conditional approval only available for patients via Managed Access Agreement. The Adult SMA Reach Real-World Data Collection Study, conducted across 19 sites in the UK, collects patients' clinical data and functional outcome measures generated during routine clinical assessments. For treated patients clinical data is collected every 6 months and for non-treated patients every 12 months. The project aims to provide an overview of the disease progression for treated and non-treated patients. The collection of data contributes towards the final approval of the two drug treatments, but also to academic research with broader objectives. Adult SMA project has collected data from 417 patients so far. The project analyses data from 373 patients consented to academic research, comprising 1433 visits, on 17th April 2024. The cohort used for the analyses comprises different SMA types: Type 1 (n=4), 2 (n=168), 3 (n=189) and 4 (n=1). Currently the UK Adult population exhibits delay in treatment initiation for SMA type 2 and 3 patients from symptom onset and diagnosis. SMA Type 2 patients have an average delay of 26 years at treatment initiation from diagnosis. Similarly, for SMA Type 3 patients that is 24 years delay in treatment initiation from diagnosis. The mean age at time of treatment initiation for the whole adult population is 34.8 years in the UK. 39.1% of adult SMA patients (n=146) have experienced ventilatory support during the study period, with 21 patients subsequently discontinuing this intervention. 141 patients were treated only non-invasively, 4 patients were treated non-invasively and invasively at any point, and 1 patient had been treated only invasively. As expected, symptom onset age exhibits a correlation with SMA type, with Type 3 patients demonstrating later onset. The distribution by functional type at baseline is non-sitters 37% (n=105), sitters 43% (n=123) and walkers 19%(n=55). The present analysis comprised 254 Risdiplam, 101 Nusinersen and 18 non-treated patients. These findings, and further comprehensive analysis of the UK Adult SMA dataset, provide valuable insights into SMA real-world data, disease progression and treatment-driven disease progression. The collected data contributes to optimising patient care and advancing SMA research. [ABSTRACT FROM AUTHOR]

Background and Purpose: The Rasch-Built Pompe-Specific Activity (R-PAct) scale is a patient-reported outcome measure specifically designed to quantify the effects of Pompe disease on daily life activities, developed for use in Dutch- and English-speaking countries. This study aimed to validate the R-PAct for use in other countries., Methods: Four other language versions (German, French, Italian, and Spanish) of the R-PAct were created and distributed among Pompe patients (≥16 years old) in Germany, France, Spain, Italy, and Switzerland and pooled with data of newly diagnosed patients from Australia, Belgium, Canada, the Netherlands, New Zealand, the USA, and the UK and the original validation cohort (n = 186). The psychometric properties of the scale were assessed by exploratory factor analysis and Rasch analysis., Results: Data for 520 patients were eligible for analysis. Exploratory factor analysis suggested that the items separated into two domains: Activities of Daily Living and Mobility. Both domains independently displayed adequate Rasch model measurement properties, following the removal of one item ("Are you able to practice a sport?") from the Mobility domain, and can be added together to form a "higher order" factor as well. Differential item functioning (DIF)-by-language assessment indicated DIF for several items; however, the impact of accounting for DIF was negligible. We recalibrated the nomogram (raw score interval-level transformation) for the updated 17-item R-PAct scale. The minimal detectable change value was 13.85 for the overall R-PAct., Conclusions: After removing one item, the modified-R-PAct scale is a valid disease-specific patient-reported outcome measure for patients with Pompe disease across multiple countries., (© 2024 The Author(s). European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

T follicular regulatory (T fr ) cells can counteract the B cell helper activity of T follicular helper (T fh ) cells and hinder the production of antibodies against self-antigens or allergens. A mechanistic understanding of the cytokines initiating the differentiation of human regulatory T (T reg ) cells into T fr cells is still missing. Herein, we report that low doses of the pro-T fh cytokine interleukin-12 (IL-12) drive the induction of a T fr cell program on activated human T reg cells while also preserving their regulatory function. Mechanistically, we found that IL-12 led to STAT4 (signal transducer and activator of transcription 4) phosphorylation and binding to IL-12-driven follicular signature genes. Patients with inborn errors of immunity in the IL12RB1 gene presented with a strong decrease in circulating T fr cells and produced higher levels of anti-actin autoantibodies in vivo. Overall, this study unveils IL-12 as an inducer of T fr cell differentiation in vivo and provides an approach for the in vitro generation of human T fr -like cells.

Background: Computerized clinical decision support systems (CDSSs) can improve care by bridging knowledge to practice gaps. However, the real-world uptake of such systems in health care settings has been suboptimal. We sought to: (1) use the Theoretical Domains Framework (TDF) to identify determinants (barriers/enablers) of uptake of the Electronic Asthma Management System (eAMS) CDSS; (2) match identified TDF belief statements to elements in the Guideline Implementation with Decision Support (GUIDES) Checklist; and (3) explore the relationship between the TDF and GUIDES frameworks and the usefulness of this sequential approach for identifying opportunities to improve CDSS uptake., Methods: In Phase 1, we conducted semistructured interviews with primary care physicians in Toronto, Canada regarding the uptake of the eAMS CDSS. Using content analysis, two coders independently analyzed interview transcripts guided by the TDF to generate themes representing barriers and enablers to CDSS uptake. In Phase 2, the same reviewers independently mapped each belief statement to a GUIDES domain and factor. We calculated the proportion of TDF belief statements that linked to each GUIDES domain and the proportion of TDF domains that linked to GUIDES factors (and vice-versa) and domains., Results: We interviewed 10 participants before data saturation. In Phase 1, we identified 53 belief statements covering 12 TDF domains; 18 (34.0%) were barriers, and 35 (66.0%) were enablers. In Phase 2, 41 statements (77.4%) linked to at least one GUIDES factor, while 12 (22.6%) did not link to any specific factor. The GUIDES Context Domain was linked to the largest number of belief statements (19/53; 35.8%). Each TDF domain linked to one or more GUIDES factor, with 6 TDF domains linking to more than 1 factor and 8 TDF domains linking to more than 1 GUIDES domain., Conclusions: The TDF provides unique insights into barriers and enablers to CDSS uptake, which can then be mapped to GUIDES domains and factors to identify required changes to CDSS context, content, and system. This can be followed by conventional mapping of TDF domains to behaviour change techniques to optimize CDSS implementation. This novel step-wise approach combines two established frameworks to optimize CDSS interventions, and requires prospective validation., (© 2023. BioMed Central Ltd., part of Springer Nature.)