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Spinal muscular atrophy is a rare, autosomal recessive, neuromuscular disease caused by biallelic loss of the survival motor neuron 1 (SMN1) gene, resulting in motor neuron dysfunction. In this STR1VE-EU study, we aimed to evaluate the safety and efficacy of onasemnogene abeparvovec gene replacement therapy in infants with spinal muscular atrophy type 1, using broader eligibility criteria than those used in STR1VE-US. STR1VE-EU was a multicentre, single-arm, single-dose, open-label phase 3 trial done at nine sites (hospitals and universities) in Italy (n=4), the UK (n=2), Belgium (n=2), and France (n=1). We enrolled patients younger than 6 months (180 days) with spinal muscular atrophy type 1 and the common biallelic pathogenic SMN1 exon 7–8 deletion or point mutations, and one or two copies of SMN2. Patients received a one-time intravenous infusion of onasemnogene abeparvovec (1·1 × 1014 vector genomes [vg]/kg). The outpatient follow-up consisted of assessments once per week starting at day 7 post-infusion for 4 weeks and then once per month until the end of the study (at age 18 months or early termination). The primary outcome was independent sitting for at least 10 s, as defined by the WHO Multicentre Growth Reference Study, at any visit up to the 18 months of age study visit, measured in the intention-to-treat population. Efficacy was compared with the Pediatric Neuromuscular Clinical Research (PNCR) natural history cohort. This trial is registered with ClinicalTrials.gov, NCT03461289 (completed). From Aug 16, 2018, to Sept 11, 2020, 41 patients with spinal muscular atrophy were assessed for eligibility. The median age at onasemnogene abeparvovec dosing was 4·1 months (IQR 3·0–5·2). 32 (97%) of 33 patients completed the study and were included in the ITT population (one patient was excluded despite completing the study because of dosing at 181 days). 14 (44%, 97·5% CI 26–100) of 32 patients achieved the primary endpoint of functional independent sitting for at least 10 s at any visit up to the 18 months of age study visit (vs 0 of 23 untreated patients in the PNCR cohort; p<0·0001). 31 (97%, 95% CI 91–100) of 32 patients in the ITT population survived free from permanent ventilatory support at 14 months compared with six (26%, 8–44) of 23 patients in the PNCR natural history cohort (p<0·0001). 32 (97%) of 33 patients had at least one adverse event and six (18%) had adverse events that were considered serious and related to onasemnogene abeparvovec. The most common adverse events were pyrexia (22 [67%] of 33), upper respiratory infection (11 [33%]), and increased alanine aminotransferase (nine [27%]). One death, unrelated to the study drug, occurred from hypoxic-ischaemic brain damage because of a respiratory tract infection during the study. STR1VE-EU showed efficacy of onasemnogene abeparvovec in infants with symptomatic spinal muscular atrophy type 1. No new safety signals were identified, but further studies are needed to show long-term safety. The benefit–risk profile of onasemnogene abeparvovec seems favourable for this patient population, including those with severe disease at baseline. Novartis Gene Therapies.

Background Myosin heavy chain 7 ( MYH7 )-related myopathies are emerging as an important group of muscle diseases of childhood and adulthood, with variable clinical and histopathological expression depending on the type and location of the mutation. Mutations in the head and neck domains are a well-established cause of hypertrophic cardiomyopathy whereas mutation in the distal regions have been associated with a range of skeletal myopathies with or without cardiac involvement, including Laing distal myopathy and Myosin storage myopathy. Recently the spectrum of clinical phenotypes associated with mutations in MYH7 has increased, blurring this scheme and adding further phenotypes to the list. A broader disease spectrum could lead to misdiagnosis of different congenital myopathies, neurogenic atrophy and other neuromuscular conditions. Results As a result of a multicenter Italian study we collected clinical, histopathological and imaging data from a population of 21 cases from 15 families, carrying reported or novel mutations in MYH7 . Patients displayed a variable phenotype including atypical pictures, as dropped head and bent spine, which cannot be classified in previously described groups. Half of the patients showed congenital or early infantile weakness with predominant distal weakness. Conversely, patients with later onset present prevalent proximal weakness. Seven patients were also affected by cardiomyopathy mostly in the form of non-compacted left ventricle. Muscle biopsy was consistent with minicores myopathy in numerous cases. Muscle MRI was meaningful in delineating a shared pattern of selective involvement of tibialis anterior muscles, with relative sparing of quadriceps. Conclusion This work adds to the genotype-phenotype correlation of MYH7 -relatedmyopathies confirming the complexity of the disorder.

Introduction This study aims to report on serial magnetic resonance imaging (MRI) studies and clinical features in a cohort of children with chronic inflammatory demyelinating polyneuropathy (CIDP). Methods Clinical, neuroradiological, and statistical investigations performed on nine children with CIDP were retrospectively reviewed. Pathological nerve root enhancement was categorized according to severity, extension, and morphology. A MRI score was thus obtained, and correlations with the clinical picture and disease course were explored. Results Intrathecal nerve root enhancement (NRE) of varying degrees was seen in a high percentage of patients. There was no significant correlation between the total MRI score at the first MRI study and either severity or course of the disease. However, we found a significant difference ( p  = 0.002) in NRE of patients with improving CIDP with respect to those with stable or progressing disease at the time of follow-up MRI. Conclusion Contrast-enhanced MRI plays a pivotal role in children with CIDP, both for the initial diagnosis as well as a biomarker of clinical evolution, and should be performed in all children with suspected CIDP both at initial presentation and during follow-up. Further multicenter studies on larger cohorts are awaited to determine the ideal timing for follow-up MRI.

Background and ImportanceCosmetic products often contain multiple ingredients, some of which may cause undesirable effects such as hypersensitivity. For this reason, cosmetovigilance is crucial and healthcare professionals are required to report serious adverse reactions linked to the use of cosmetic products. Once reported, the manufacturer may provide the ingredients in a form that is not suitable for direct skin application. The pharmacy department plays a key role in preparing patch tests to allow diagnosis.Aim and ObjectivesTo describe the work procedure for patch tests preparation in the pharmacy department to meet the demand for epicutaneous patches.Material and MethodsThe dermatology department reached out to the pharmacy department concerning an unusual case of allergic contact dermatitis in a 71-year-old woman following the use of a cosmetic cream. The manufacturer was notified of the adverse reaction and provided 28 purified ingredients. A literature review (manufacturers datasheets, PubChem, European Pharmacopoeia) was conducted to select the appropriate vehicle (petrolatum or glycerin) for each ingredient based on their solubility (octanol-water partition coefficient) and desired concentration.ResultsThe 28 patch tests were prepared in a non-sterile compounding area, with one ingredient (perfume) prepared in a Class IIB biosafety cabinet due to its irritant nature. The required concentrations (0.1% to 30%) were formulated in 5 mL polypropylene syringes. Of the 28 ingredients, 23 were dissolved in liquid petrolatum, and five in water. Due to the lack of stability studies, a 72-hour shelf life at 2–8°C was assigned to the preparations. Organoleptic properties and spreadability were assessed for galenic validation. The 28 preparations were applied to the patient’s back, and patch test results were evaluated at 48 and 72 hours. At both time points, allergic reactions (erythema, oedema) were observed with 1% p-hydroxyacetophenone (SymSave H), a preservative commonly used in cosmetic products, and 0.1% Bakuchiol, used for its anti-ageing properties. These findings were promptly communicated to the manufacturer’s cosmetovigilance department.Conclusion and RelevanceThis case has led to the establishment of a work procedure for patch test preparation in a tertiary care hospital and shows the importance of cosmetovigilance and documentation of allergic reactions, offering valuable insights for future allergic reactions caused by this or other cosmetic products.References and/or AcknowledgementsConflict of InterestNo conflict of interest

Background and ImportanceDupilumab (D) and tralokinumab (T) are biological agents approved to treat moderate to severe atopic dermatitis (AD). Clinical outcomes of switching strategy between them have not been thoroughly studied in real-world settings.Aim and ObjectivesTo evaluate the reasons and clinical outcomes of switching between D and T.Material and MethodsA retrospective study was conducted at a tertiary hospital from 01/2020–07/2024. We included all AD patients who initiated treatment with D or T and switched to the other agent. We collected the following data from medical records: age, sex, reasons for switching and adverse effects (AEs).ResultsA total of 301 patients initiated a biologic treatment for AD during the study period: dupilumab (n=234), tralokinumab (n=40) and both agents (n=27). Of these 27 patients who received both drugs, the following transitions were observed: D->T (n=15), T->D (n=7), D->T->D (n=4) and T->D->T (n=1). Consequently, there were 20 transitions D->T and 12, T->D (32 cases).The mean age was 48 (±17) years and 51% were male. In the D->T group, 15 switches (75%) were due to AEs and 5 to ineffectiveness. In the T->D group, eight switches (67%) were due to ineffectiveness and four to AEs.Most AE were conjunctivitis and facial erythema. Among patients who switched their treatment for conjunctivitis in the D->T group, 3/9 cases also experienced it with T (in two this led to treatment discontinuation). Similarly, in the T->D group, 1/3 cases also developed it with D but could continue the therapy with close ophthalmologic follow-up.Among the 20 D->T cases, at time of study analysis, nine cases (45%) continued with T whereas five had discontinued for ineffectiveness, three for AE and three were lost to follow-up. On the other hand, among the 12 T->D cases, eight cases (67%) continued with D, whereas two cases had discontinued for AE and two were lost to follow-up.Conclusion and RelevanceIn our study, the main reason for D->T switching in AD patients was conjunctivitis, whereas for T->D was ineffectiveness. Furthermore, our results suggest that some patients may benefit from a switching strategy between biological agents for AD.References and/or AcknowledgementsConflict of InterestNo conflict of interest

Background and ImportanceDrug related problems (DRPs) are one of the main causes requiring assistance to the Emergency Department (ED) in frailty people. Many of these patients live in nursing homes (NH). Identifying the differential characteristics of patients and DRPs that cause consultation in this subgroup, can help to improve the pharmaceutical care programs implemented in our environment in NH.Aim and ObjectivesTo identify drugs that are associated with DRPs that causes consultation of ED in patients coming from NH and compare the drugs involved, and the characteristics and comorbidities of these patients with non-NH patients.Material and MethodsRetrospective, descriptive observational study was conducted between February 21-May 2022 in the ED of a university hospital. We included adult patients who attended ED for DRPs.The following variables were collected and compared between NH patients and no NH patients: age, sex, chronic pathologies at admission, number of drugs prescribed in the electronic prescription, drug involved in the DRPs and diagnosis related to the DRPs.Qualitative variables have been compared between the NH patients vs no NH patients using the Chi-Square test and quantitative variables using the independent data t-test.Results1029 patients were included. 98 of them (9.53%) were referred from NH nh patients were older (84,6 (8.9) years old vs 77,1 (15.7) P<0.001*), mostly women [64 (65.3%) vs 511 (54.8%) P=0,046*], with a higher percentage of cognitive impairment [59 (60.2%) vs 189 (20.0%) P<0.001*], severe functional dependence [68 (69.3) vs 216 (23.2) P<0.001*] and severe polypharmacy (>=10 home medications) [53 (54.0%) vs 276 (29.6%) P<0.001] than the rest of the patients who consulted the ED for DRPs. DRPs related to the ATC group C (cardiovascular system) were more prevalent in NH patients [21 (21.4% ) vs 310 (33.2%) P=0.017*] as well as diagnostics gastrointestinal motility disorders [23 (23.4%) vs 129 (13.8%) P=0.011*] and confusional syndromes [5 (5.1% ) vs 17 (1.8) P=0.031*]Conclusion and RelevanceNH patients that consult ED for DRPs were older, mostly women with a high degree of socio-functional, cognitive dependence and extreme polypharmacy than no NH patients. DRP related with C ATC group and diagnosis of confusional syndrome and gastrointestinal motility disorders are also more prevalent.References and/or AcknowledgementsConflict of InterestNo conflict of interest.

Background and ImportanceIt is a common practice to discharge patients from the emergency department (ED) with low-molecular-weight-heparin (LMWH). But there is limited knowledge of the risk factors associated with drug related problems secondary to heparin treatment in patients discharged from ED.Aim and ObjectivesTo assess drug related problems secondary to heparin treatment in patients discharged from ED including bleeding and thromboembolic episodes.Material and MethodsRetrospective observational study. Adults patients discharged from ED with LMWH were included (February to April 2022). Study variables included comorbidities of the patient, number of drugs at discharge, drugs that may be related to bleeding episodes, length of treatment, and 30-day ED revisits. The association between 30 days ED revisits, comorbidities and patient treatment was evaluated using Ji-square or Fisher’s test.ResultsOver the duration of the study 90 patients were included (mean age=73.1 years (SD 16.2); females 32 (49.2%). Reason for anticoagulation with LMWH included atrial fibrillation (32;35.6%), prophylaxis (7;7.8%) and thromboembolism (51;56.67%). Duration of treatment with heparin was less than 7 days (17;18.9%), 7 to 30 days (37;41.2%) and more than 30 days (36;40%). Of the 90 patients, 3 came back due to haemorrhage and 2 due to thromboembolism.A greater tendency to return to the ED once discharged at 30 days was observed in patients over 80 years old (10.5% vs 1.9%; p=0.158) and in patients >10 drugs (10% vs 2%; p=0.167).Conclusion and RelevanceAbout a 5% of patients who were discharged with heparin from ED returned after 30 days due problems as bleeding or thromboembolism, more frequently in patients over 80 years old and polypharmacy.References and/or AcknowledgementsConflict of InterestNo conflict of interest

It recently was reported that Duchenne muscular dystrophy (DMD) patients and mdx mice have elevated levels of caveolin-3 expression in their skeletal muscle. However, it remains unknown whether increased caveolin-3 levels in DMD patients contribute to the pathogenesis of DMD. Here, using a genetic approach, we test this hypothesis directly by overexpressing wild-type caveolin-3 as a transgene in mice. Analysis of skeletal muscle tissue from caveolin-3- overexpressing transgenic mice reveals: (i) a dramatic increase in the number of sarcolemmal muscle cell caveolae; (ii) a preponderance of hypertrophic, necrotic, and immature/regenerating skeletal muscle fibers with characteristic central nuclei; and (iii) down-regulation of dystrophin and β -dystroglycan protein expression. In addition, these mice show elevated serum creatine kinase levels, consistent with the myo-necrosis observed morphologically. The Duchenne-like phenotype of caveolin-3 transgenic mice will provide an important mouse model for understanding the pathogenesis of DMD in humans.

Eclogitic lenses of metabasaltic composition-some units as much as 4 km in length and more than 200 m in thickness-are surrounded by and interlayered with deformed, completely serpentinized Beigua peridotite of the Voltri Massif. Relict primary textures indicate that most of the mafic layers were originally gabbros, but some units may represent finer-grained diabasic dikes; a few apparently were converted to rodingites prior to the high-pressure metamorphism. The mafic rocks have been subjected to a complex recrystallization history which involved both an earlier stage (A) and a later stage (B) production of the eclogitic assemblage garnet + omphacite + rutile, separated in time by a period of severe cataclasis. Subsequent recrystallization led to the formation of (C) garnet + glaucophane rocks, then (D) barrositic amphibole-bearing assemblages, and finally, through a stage of prasinitization (E), to the typical greenschist assemblage of albite + chlorite + epidote + actinolite + sphene. Some outcrops preserve evidence of the entire paragenetic sequence; green -schistic assemblages characteristically occur along the contact of the metagabbros with serpentinite, and more eclogitic assemblages are preserved in the interior portions of the mafic lenses. Of 95 specimens studied in detail, XRF bulk rock analyses have been obtained for 83. Combined with petro-graphic data, it is clear that most of the mafic units are especially titanium- and iron-rich compared to common terrestrial rocks of metabasaltic composition. The greenschists and barroisitic amphibo-lites exhibit much greater chemical diversity than do the parental eclogites. This means that either a more heterogeneous leucogabbro protolith was present in addition to the ferrogabbroic layers, and that this more magnesian rock type was selectively converted to the more hydrous, prasinitic assemblages, or that intense metasomatism has affected the later stage, lower grade assemblages. The 37 analyzed eclogitic rocks are relatively homogeneous in terms of their major element chemistry (e.g.,$K_{2}O$ranges between 0.01 and 0.19 wt%), and they compare favorably with some ferro-grabbroic oceanic tholeiites. The parental gabbros were much too iron-rich to have been generated in situ from the enclosing Beigua ultramafic body. Accordingly, it is hypothesized that, at the onset of rifting of the lithosphere, mafic magma-derived elsewhere and already at an advanced stage of differentiation-was injected as a series of layers into relatively primitive mantle material. Relics of an early high-pressure, blue-schist-type recrystallization are preserved in the spatially associated \"calcescisti,\" including rocks of the Sestri-Voltaggio zone and the Savona-type continental basement, hence this entire terrane may have been involved in an early Alpine( ?) subduction event. In contrast, the tectonically higher, deformed, plagioclase-bearing Erro-Tobbio lherzolites and derived serpentinites of the northern Voltri Massif contain only feebly metamorphosed gabbros lacking a high-pressure paragenesis. Apparently this latter unit was brought into juxtaposition with the underlying blueschist + eclogite-bearing terrane after the inferred subduction event.

Electroencephalogram oscillations during general anesthesia may change as a function of cognitive and physical health. This study aimed to characterize associations between anesthesia-induced oscillations and postoperative outcomes in cardiac surgery patients over 60 years. This was a prespecified secondary data analysis from the Minimizing Intensive Care Unit Dysfunction with Dexmedetomidine-induced Sleep (MINDDS) study. Participants were admitted from home for elective cardiac surgery with cardiopulmonary bypass. The primary outcome was postoperative delirium obtained using the Confusion Assessment Method. Secondary outcomes were non-home discharge and 30-day readmission. The exposure of interest was alpha power measured during the maintenance phase of isoflurane-general anesthesia. Confounding cognitive and physical health variables were collected. Of 394 participants in the MINDDS study, 302 had analyzable electroencephalograms. The incidence of postoperative delirium was 11.1 %. Odds of postoperative delirium decreased by 14 % for every decibel increase in alpha power (OR 0.86, 95 % CI: 0.78 to 0.95; P = 0.004). This finding was not significant in adjusted analysis (ORadj 0.92, 95 % CI: 0.81 to 1.03; P = 0.154). Non-home discharge setting findings were not associated with alpha power. The odds of 30-day readmission decreased by 20 % for every decibel increase in alpha power (ORadj 0.80, 95 % CI: 0.71 to 0.91; P < 0.001). Findings were conserved in exploratory and sensitivity analyses. In this study anesthesia-induced oscillations were associated with postoperative outcomes; however, these were not independently associated with delirium or discharge disposition after considering preoperative cognitive and physical health. These oscillations were robustly associated with 30-day readmission however, which may help anesthesiologists identify high-risk patients, offering benefits beyond the operating room. Clinical trial registration: Registration Number: NCT02856594 •Secondary analysis of 394 participants in the MINDDS Study.•Intraoperative alpha power varied with measures of preoperative cognitive and physical health.•Intraoperative alpha power also predicted postoperative delirium, 30-day readmission, but not non-home discharge.•On adjusted analysis, intraoperative alpha power robustly predicted non-home discharge.•Intraoperative EEG oscillations change as a function of cognitive and physical health and predict perioperative outcomes.