Upper Limb Changes in DMD Patients Amenable to Skipping Exons 44, 45, 51 and 53: A 24-Month Study

Introduction: The Performance of Upper Limb version 2.0 (PUL 2.0) is increasingly used in Duchenne Muscular Dystrophy (DMD) to study longitudinal functional changes of motor upper limb function in ambulant and non-ambulant patients. The aim of this study was to evaluate changes in upper limb functions in patients carrying mutations amenable to skipping exons 44, 45, 51 and 53. Methods: All DMD patients were assessed using the PUL 2.0 for at least 2 years, focusing on 24-month paired visits in those with mutations eligible for skipping exons 44, 45, 51 and 53. Results: 285 paired assessments were available. The mean total PUL 2.0 12-month change was -0.67 (2.80), -1.15 (3.98), -1.46 (3.37) and -1.95 (4.04) in patients carrying mutations amenable to skipping exon 44, 45, 51 and 53, respectively. The mean total PUL 2.0 24-month change was -1.47 (3.73), -2.78 (5.86), -2.95 (4.56) and -4.53 (6.13) in patients amenable to skipping exon 44, 45, 51 and 53, respectively. The difference in PUL 2.0 mean changes among the type of exon skip class for the total score was not significant at 12 months but was significant at 24 months for the total score (p 0.05). Conclusions: Our results expand the information on upper limb function changes detected by the PUL 2.0 in a relatively large group of DMD patients with distinct exon-skipping classes. This information can be of help when designing clinical trials or in the interpretation of the real world data including non-ambulant patients

Testing the cognitive-behavioural maintenance models across DSM-5 bulimic-type eating disorder diagnostic groups: A multi-centre study

The original cognitive-behavioural (CB) model of bulimia nervosa, which provided the basis for the widely used CB therapy, proposed that specific dysfunctional cognitions and behaviours maintain the disorder. However, amongst treatment completers, only 40–50 % have a full and lasting response. The enhanced CB model (CB-E), upon which the enhanced version of the CB treatment was based, extended the original approach by including four additional maintenance factors. This study evaluated and compared both CB models in a large clinical treatment seeking sample (N = 679), applying both DSM-IV and DSM-5 criteria for bulimic-type eating disorders. Application of the DSM-5 criteria reduced the number of cases of DSM-IV bulimic-type eating disorders not otherwise specified to 29.6 %. Structural equation modelling analysis indicated that (a) although both models provided a good fit to the data, the CB-E model accounted for a greater proportion of variance in eating-disordered behaviours than the original one, (b) interpersonal problems, clinical perfectionism and low self-esteem were indirectly associated with dietary restraint through over-evaluation of shape and weight, (c) interpersonal problems and mood intolerance were directly linked to binge eating, whereas restraint only indirectly affected binge eating through mood intolerance, suggesting that factors other than restraint may play a more critical role in the maintenance of binge eating. In terms of strength of the associations, differences across DSM-5 bulimic-type eating disorder diagnostic groups were not observed. The results are discussed with reference to theory and research, including neurobiological findings and recent hypotheses

Prevalence of Spinal Muscular Atrophy in the Era of Disease-Modifying Therapies: An Italian Nationwide Survey

Objective: Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in the SMN1 gene. The aim of this study was to assess the prevalence of SMA and treatment prescription in Italy. Methods: An online survey was distributed to 36 centers identified by the Italian government as referral centers for SMA. Data on the number of patients with SMA subdivided according to age, type, SMN2 copy number, and treatment were collected. Results: One thousand two hundred fifty-five patients with SMA are currently followed in the Italian centers with an estimated prevalence of 2.12/100,000. Of the 1,255, 284 were type I, 470 type II, 467 type III, and 15 type IV with estimated prevalence of 0.48, 0.79, 0.79 and 0.02/100,000, respectively. Three patients with SMA 0 and 16 presymptomatic patients were also included. Approximately 85% were receiving one of the available treatments. The percentage of treated patients decreased with decreasing severity (SMA I: 95.77%, SMA II: 85.11%, SMA III: 79.01%). Discussion: The results provide for the first time an estimate of the prevalence of SMA at the national level and the current distribution of patients treated with the available therapeutical options. These data provide a baseline to assess future changes in relation to the evolving therapeutical scenario

An epigenetic score for BMI based on DNA methylation correlates with poor physical health and major disease in the Lothian Birth Cohort

Background: The relationship between obesity and adverse health is well established, but little is known about the contribution of DNA methylation to obesity-related health outcomes. This study tests associations between an epigenetic score for\ua0body mass index (BMI) and health-related, cognitive, psychosocial and lifestyle outcomes in the Lothian Birth Cohort 1936. This study also tests whether these associations are independent of phenotypic BMI. Method: Analyses were conducted using data from the Lothian Birth Cohort 1936 (n = 892). Weights for the epigenetic BMI score were derived using penalised regression on methylation data from unrelated Generation Scotland participants (n = 2562). Associations were tested for replication in an independent sample: the Lothian Birth Cohort 1921 (n = 433). Results: A higher\ua0epigenetic BMI score was associated with higher BMI (R = 0.1), greater body weight (R = 0.06), greater time taken to walk 6 m, poorer lung function and poorer general physical health (all R = 0.02), greater levels of triglycerides (R = 0.09), greater %total HbA1c (R = 0.06), lower levels of high-density lipoprotein cholesterol (HDL;\ua0R = 0.08),\ua0higher HDL ratio (HDL/total cholesterol; R = 0.03), lower health-related quality of life, physical inactivity, and greater social deprivation (all\ua0R = 0.02). The epigenetic BMI score (per SD) was also associated with type 2 diabetes (OR 2.17, 95% CI 1.67, 2.84), cardiovascular disease (OR 1.45, 95% CI 1.24, 1.71) and high blood pressure (OR 1.30, 95% CI 1.13, 1.49; all p < 0.00026 after Bonferroni correction). Associations were replicated for BMI (R = 0.06), body weight (R = 0.04), health-related quality of life (R = 0.02), HbA1c (R = 0.07) and triglycerides (R = 0.07; all p < 0.0045 after Bonferroni correction). Conclusions: We observed and replicated associations between an epigenetic score for BMI and variables related to poor physical health and metabolic syndrome. Regression models with both epigenetic and phenotypic BMI scores as predictors accounted for a greater proportion of variance in\ua0all outcome variables than either predictor alone, demonstrating independent and additive effects of epigenetic and phenotypic BMI scores

The SIB Swiss Institute of Bioinformatics' resources: focus on curated databases

The SIB Swiss Institute of Bioinformatics (www.isb-sib.ch) provides world-class bioinformatics databases, software tools, services and training to the international life science community in academia and industry. These solutions allow life scientists to turn the exponentially growing amount of data into knowledge. Here, we provide an overview of SIB's resources and competence areas, with a strong focus on curated databases and SIB's most popular and widely used resources. In particular, SIB's Bioinformatics resource portal ExPASy features over 150 resources, including UniProtKB/Swiss-Prot, ENZYME, PROSITE, neXtProt, STRING, UniCarbKB, SugarBindDB, SwissRegulon, EPD, arrayMap, Bgee, SWISS-MODEL Repository, OMA, OrthoDB and other databases, which are briefly described in this article

Effects of Anacetrapib in Patients with Atherosclerotic Vascular Disease

BACKGROUND: Patients with atherosclerotic vascular disease remain at high risk for cardiovascular events despite effective statin-based treatment of low-density lipoprotein (LDL) cholesterol levels. The inhibition of cholesteryl ester transfer protein (CETP) by anacetrapib reduces LDL cholesterol levels and increases high-density lipoprotein (HDL) cholesterol levels. However, trials of other CETP inhibitors have shown neutral or adverse effects on cardiovascular outcomes. METHODS: We conducted a randomized, double-blind, placebo-controlled trial involving 30,449 adults with atherosclerotic vascular disease who were receiving intensive atorvastatin therapy and who had a mean LDL cholesterol level of 61 mg per deciliter (1.58 mmol per liter), a mean non-HDL cholesterol level of 92 mg per deciliter (2.38 mmol per liter), and a mean HDL cholesterol level of 40 mg per deciliter (1.03 mmol per liter). The patients were assigned to receive either 100 mg of anacetrapib once daily (15,225 patients) or matching placebo (15,224 patients). The primary outcome was the first major coronary event, a composite of coronary death, myocardial infarction, or coronary revascularization. RESULTS: During the median follow-up period of 4.1 years, the primary outcome occurred in significantly fewer patients in the anacetrapib group than in the placebo group (1640 of 15,225 patients [10.8%] vs. 1803 of 15,224 patients [11.8%]; rate ratio, 0.91; 95% confidence interval, 0.85 to 0.97; P=0.004). The relative difference in risk was similar across multiple prespecified subgroups. At the trial midpoint, the mean level of HDL cholesterol was higher by 43 mg per deciliter (1.12 mmol per liter) in the anacetrapib group than in the placebo group (a relative difference of 104%), and the mean level of non-HDL cholesterol was lower by 17 mg per deciliter (0.44 mmol per liter), a relative difference of -18%. There were no significant between-group differences in the risk of death, cancer, or other serious adverse events. CONCLUSIONS: Among patients with atherosclerotic vascular disease who were receiving intensive statin therapy, the use of anacetrapib resulted in a lower incidence of major coronary events than the use of placebo. (Funded by Merck and others; Current Controlled Trials number, ISRCTN48678192 ; ClinicalTrials.gov number, NCT01252953 ; and EudraCT number, 2010-023467-18 .)

Expanding the PURA syndrome phenotype: A child with the recurrent PURA p.(Phe233del) pathogenic variant showing similarities with cutis laxa

Background: PURA syndrome is rare autosomal dominant condition characterized by moderate to severe neurodevelopmental delay with absence of speech in nearly all patients and lack of independent ambulation in many. Early-onset problems include excessive hiccups, hypotonia, hypersomnolence, hypothermia, feeding difficulties, recurrent apneas, epileptic seizures, and abnormal nonepileptic movements. Other less common manifestations comprise congenital heart defects, urogenital malformations, and various skeletal, ophthalmological, gastrointestinal, and endocrine anomalies. Up to now, 78 individuals with PURA syndrome and 64 different pathogenic variants have been reported, but no clear-cut genotype-phenotype correlations have emerged so far. Herein, we report the clinical and molecular characterization of a 3-year-old girl with severe hypotonia, global developmental delay, and soft, loose skin, who came to our attention with a suspicion of cutis laxa (CL), which denotes another condition with variable neurodevelopmental problems. Methods: Amplicon-based whole exome sequencing was performed, and an in-house pipeline was used to conduct filtering and prioritization of variants. New prediction algorithms for indels were used to validate the pathogenicity of the PURA variant, and results were confirmed with the Sanger method. Finally, we collected clinical and mutational data of all PURA syndrome patients reported yet and compared the clinical features with those of our patient. Results: Clinical evaluation and biochemical investigations excluded CL and prompted to perform whole exome sequencing, which confirmed the absence of pathogenic variants in all CL-related genes and revealed the known PURA c.697_699del, p.(Phe233del) variant, identified hitherto in seven additional children with PURA syndrome. Conclusions: Our data expand the phenotypic spectrum of PURA syndrome by showing that it can be regarded as a differential diagnosis for cutis laxa in early infancy. Our patient and literature review emphasize that a wide clinical variability exists not only between individuals with different PURA variants, but also among patients with the same causal mutation

Caractérisation numérique et expérimentale du champ magnétique B.F. généré par des systèmes électrotechniques en vue de la modélisation des courants induits dans le corps humain

Ce travail est consacré au développement de modèles et outils numériques permettant la simulation dans la gamme des fréquences 50Hz-100KHz des phénomènes induits dans le corps humain. Deux problématiques sont abordées : déterminer la répartition du champ rayonné par un système de puissance (champ de fuite) ; calculer les courants induits qui en résultent dans le corps humain. Champ rayonné par un système connu : les méthodes de calcul "classiques" ne sont pas adaptées à cette problématique, car trop couteuses. Nous présentons donc un modèle 3D ne prenant en compte que les aspects essentiels du système. Champ rayoné par un système inconnu : nous avons développé des modèles de source équivalente, basés sur la notion de multipole. Les paramètres de ces modèles sont identifiés à partir de quelque mesure loclae de champ B. Enfin, nous avons développé une formulation spéciale aux éléments finis, pour calculer la densité de courant induit dans le corps humain par ces champs de fuite.This work is devoted to the developpement of models and numerical tools, to simulate the induced phenomena inside the human body, within the frequency range 50Hz-100KHz. Two main problems have to be solved : find the spatial distribution of a magnetic field generated by a power system (stray fields) ; compute the currents, which are induced by these stray fields inside the human body. Field radiated by a known system : classical numerical methods are not well adapted to this problem (they are too expansive) : we present a 3D model, which takes into account only the "essentials" of the system. Field radiated by an unknown system : we have developed several models of equivalent source, basing upon the concept of multipole. The parameters of these models are fitted from some local measurements of the flux density. Finally, we have developed a special formulation using finite elements, in order to compute the induced current density inside the human body.LYON-Ecole Centrale (690812301) / SudocSudocFranceF

Data_Sheet_1_The impact of three SMN2 gene copies on clinical characteristics and effect of disease-modifying treatment in patients with spinal muscular atrophy: a systematic literature review.docx

ObjectiveTo review the clinical characteristics and effect of treatment in patients with spinal muscular atrophy (SMA) and three copies of the SMN2 gene.MethodsWe conducted a literature search in October 2022 to identify English-language clinical research on SMA that included SMN2 copy number according to PRISMA guidelines.ResultsOur search identified 44 studies examining the impact of three SMN2 copies on clinical characteristics (21 on phenotype, 13 on natural history, and 15 on functional status and other signs/symptoms). In children with type I SMA or presymptomatic infants with an SMN1 deletion, three SMN2 copies was associated with later symptom onset, slower decline in motor function and longer survival compared with two SMN2 copies. In patients with SMA type II or III, three SMN2 copies is associated with earlier symptom onset, loss of ambulation, and ventilator dependence compared with four SMN2 copies. Eleven studies examined treatment effects with nusinersen (nine studies), onasemnogene abeparvovec (one study), and a range of treatments (one study) in patients with three SMN2 copies. In presymptomatic infants, early treatment delayed the onset of symptoms and maintained motor function in those with three SMN2 copies. The impact of copy number on treatment response in symptomatic patients is still unclear.ConclusionSMN2 copy number is strongly correlated with SMA phenotype in patients with SMN1 deletion, while no correlation was found in patients with an SMN1 mutation. Patients with three SMN2 copies show a highly variable clinical phenotype. Early initiation of treatment is highly effective in presymptomatic patients with three SMN2 copies.</p