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En determinadas circunstancias socioeconómicas, es necesario diseñar metodologías de aprendizaje a partir del análisis del perfil de ingreso de los estudiantes. En el caso de la asignatura de introducción al diseño arquitectónico (Taller de Fundación) de la Universidad San Sebastián, este estudio permite diseñar un curso centrado en abordar el aprendizaje a partir de una serie de actividades de dificultad progresiva. Partiendo de conceptos muy sencillos, desarrollados en ejercicios cortos, guiados y muy restrictivos tanto en términos de material, como de variables de manipulación y formato, se puede aumentar progresivamente la complejidad del problema hasta finalizar el año con un ejercicio arquitectónico básico de programa reducido y exploración material mínima, en el que se haga énfasis en la articulación espacial y la manipulación material. De este modo, se hace posible nivelar las competencias de diseño de los estudiantes de cara a su avance en cursos superiores.

Protein drugs that neutralize vascular endothelial growth factor (VEGF), such as aflibercept or ranibizumab, rescue vision in patients with retinal vascular diseases. Nonetheless, optimal visual outcomes require intraocular injections as frequently as every month. Here we report a method to extend the intravitreal half-life of protein drugs as an alternative to either encapsulation or chemical modifications with polymers. We combine a 97-amino-acid peptide of human origin that binds hyaluronan, a major macromolecular component of the eye’s vitreous, with therapeutic antibodies and proteins. When administered to rabbit and monkey eyes, the half-life of the modified proteins is increased ∼3–4-fold relative to unmodified proteins. We further show that prototype long-acting anti-VEGF drugs (LAVAs) that include this peptide attenuate VEGF-induced retinal changes in animal models of neovascular retinal disease ∼3–4-fold longer than unmodified drugs. This approach has the potential to reduce the dosing frequency associated with retinal disease treatments. Retinal vascular disease treatments involve frequent pharmacological intraocular administrations. Here the authors present a method to increase the half-life of injected drugs by fusing these to a hyaluronan-binding peptide, which might lead to less frequent retinal disease treatments.

In familial amyotrophic lateral sclerosis (ALS) cases, the presence of an abnormal C9ORF72 repeat expansion (C9RE) is the most frequent genetic cause identified. Various clinical phenotypes have been described in relation to the presence of C9RE, including psychiatric disorders or Huntington-like symptoms. In a subset of sporadic ALS, C9RE has also been described. In the present study, all index cases with ALS and C9RE identified in our center and their clinical profile, as well as neurological and psychiatric characteristics of identified family members, were described. Clinical characteristics of ALS patients were compared to 999 patients with sporadic ALS (SALS) from our database. From the 70 index cases with ALS identified, a total of 200 individuals were studied, 118 with ALS, 32 with fronto-temporal lobe degeneration (FTD), 37 with ALS/FTD, and 13 with psychiatric disorders. A familial history was present in 57 of the index cases (81%). In ALS and ALS/FTD cases with C9RE, the age of onset (AoO) was earlier than that in SALS cases, < 0.0001 and = 0.008, respectively. Sporadic cases with C9REALS ( = 13) had an earlier AoO compared to familial C9REALS ones, < 0.0001. Within families, there was an earlier AoO in index cases and their siblings compared to their parental generation ( < 0.01). There was also a significant intrafamilial correlation for bulbar onset of ALS. The parental generation had significant female predominance compared to index cases and their siblings (sex ratio 0.47 vs. 1.4, = 0.004), and this predominance was also present when considering parent-child pairs. In the group with psychiatric disorders, suicide was prominent ( = 9) and mean age was 54 years. Although our sample size is rather limited, the earlier AoO in index cases and their siblings compared to the parental generation may suggest an anticipation. Reasons for predominance of female transmission are unclear, but the hypothesis that gender influences transmission of the genetic trait or C9RE size variation may be taken into account. Intrafamilial correlation suggests that genetic aspects underlie the occurrence of bulbar onset in ALS patients. Studies on larger samples are warranted to confirm those results.

Fasudil is a small molecule inhibitor of Rho-associated kinase (ROCK) and is approved for the treatment of subarachnoid haemorrhage. In preclinical studies, fasudil has been shown to attenuate neurodegeneration, modulate neuroinflammation, and foster axonal regeneration. We aimed to investigate the safety, tolerability, and efficacy of fasudil in patients with amyotrophic lateral sclerosis. ROCK-ALS was a phase 2, randomised, double-blind, placebo-controlled trial conducted at 19 amyotrophic lateral sclerosis centres in Germany, France, and Switzerland. Individuals (aged 18–80 years) with at least probable amyotrophic lateral sclerosis (as per the revised El Escorial criteria), a disease duration of 6–24 months, and a slow vital capacity greater than 65% of predicted normal were eligible for inclusion. Patients were randomly assigned (1:1:1) to receive 30 mg (15 mg twice daily) or 60 mg (30 mg twice daily) fasudil or matched placebo intravenously for 20 days over a 4-week period. Follow-up assessments were performed at 45, 90, and 180 days after treatment initiation. The co-primary endpoints were safety until day 180 (defined as the proportion without drug-related serious adverse events) and tolerability during the treatment period (defined as the proportion who did not discontinue treatment due to suspected drug-related adverse events). The primary analyses were carried out in the intention-to-treat population, which included all participants who entered the treatment phase. This trial is registered at ClinicalTrials.gov (NCT03792490) and Eudra-CT (2017-003676-31) and is now completed. Between Feb 20, 2019, and April 20, 2022, 120 participants were enrolled and randomised; two individuals assigned fasudil 30 mg withdrew consent before the baseline visit. Thus, the intention-to-treat population comprised 35 in the fasudil 30 mg group, 39 in the fasudil 60 mg group, and 44 in the placebo group. The estimated proportion without a drug-related serious adverse event was 1·00 (95% CI 0·91 to 1·00) with placebo, 1·00 (0·89 to 1·00) with fasudil 30 mg, and 1·00 (0·90 to 1·00) with fasudil 60 mg; the difference in proportions was 0·00 (95% CI –0·11 to 0·10; p>0·99) for fasudil 30 mg versus placebo and 0·00 (–0·10 to 0·10; p>0·99) for fasudil 60 mg versus placebo. Treatment tolerability (the estimated proportion who did not discontinue) was 0·93 (95% CI 0·81 to 0·99) with placebo, 1·00 (0·90 to 1·00) with fasudil 30 mg, and 0·90 (0·76 to 0·97) with fasudil 60 mg; the difference in proportions was 0·07 (95% CI –0·05 to 0·20; p=0·25) for fasudil 30 mg versus placebo, and –0·03 (–0·18 to 0·10; p=0·70) for fasudil 60 mg versus placebo. Eight deaths occurred: two in the placebo group, four in the fasudil 30 mg group, and two in the fasudil 60 mg group. The most common serious adverse events were respiratory failure (seven events), gastrostomy (five events), pneumonia (four events), and dysphagia (four events). No serious adverse events or deaths were attributed to study treatment. Adverse events, which were mainly related to disease progression, occurred in 139 participants in the placebo group, 108 in the fasudil 30 mg group, and 105 in the fasudil 60 mg group. Fasudil was well tolerated and safe in people with amyotrophic lateral sclerosis. The effect of fasudil on efficacy outcomes should be explored in larger clinical trials with a longer treatment duration, oral administration, and potentially higher dose of the trial drug. Framework of the E-Rare Joint Transnational Call 2016 “Clinical research for new therapeutic uses of already existing molecules (repurposing) in rare diseases”.

Background Little is known about the influence of Riluzole on serum neurofilament light chain (sNfL) levels, a biomarker of prognosis in amyotrophic lateral sclerosis (ALS), and variations with time of sNfL concentrations are controversial. Methods Sera from ALS patients (n = 141) and controls (n = 33) were collected at inclusion (sNfL1) and second visit (sNfL2, mean delay 10.4 ± 8.7 months). sNfL levels, determined by single‐molecule array, were compared between ALS and controls at both time points. sNfL concentration changes were compared between patients with Riluzole (w/Ril) at inclusion in the study and those who were treated by Riluzole following inclusion (w/o Ril). The factors influencing sNfL concentrations and changes were studied using linear regression and multivariate analysis. Results sNfL levels were higher in ALS patients than in controls at the two time points (p < 0.00001). In ALS patients, sNfL concentrations were higher in females for both sNfL1 (p = 0.014) and sNfL2 (p < 0.001). In the whole ALS group, sNfL levels were higher at sNfL2 than at sNfL1 (p < 0.001). sNfL1 and sNfL2 concentrations were similar between the two ALS subgroups (w/ and w/o Ril). ALS functional rating scale‐revised rate of decline and gender were the two main factors significantly influencing both sNfL1 and sNfL2 levels (p < 0.01). However, only gender was shown to significantly influence sNfL changes with time (p = 0.003). Conclusions In this study, sNfL levels increased with time in ALS patients and there was no difference between subjects already treated by Riluzole and those treated after sNfL1. Further studies with larger population samples and different sampling intervals are warranted to better determine the real potential of sNfL measurement as a tool to monitor treatment response in ALS. NfL levels increased with time in ALS patients. Patients already under Riluzole and those without treatment had similar NfL concentrations at inclusion. After 1 year of treatment, the increase in NfL levels was of the same magnitude in both groups.

Superoxide dismutase (SOD1) gene variants may cause amyotrophic lateral sclerosis, some of which are associated with a distinct phenotype. Most studies assess limited variants or sample sizes. In this international, retrospective observational study, we compare phenotypic and demographic characteristics between people with SOD1 -ALS and people with ALS and no recorded SOD1 variant. We investigate which variants are associated with age at symptom onset and time from onset to death or censoring using Cox proportional-hazards regression. The SOD1 -ALS dataset reports age of onset for 1122 and disease duration for 883 people; the comparator population includes 10,214 and 9010 people respectively. Eight variants are associated with younger age of onset and distinct survival trajectories; a further eight associated with younger onset only and one with distinct survival only. Here we show that onset and survival are decoupled in SOD1 -ALS. Future research should characterise rarer variants and molecular mechanisms causing the observed variability. Analysis of age of onset and disease duration in a large, international cohort of people with SOD1 -ALS shows that there is a distinct phenotype and that onset and progression are decoupled.

ObjectiveTo assess spatial aggregates of amyotrophic lateral sclerosis (ALS) incident cases, using a solid geo-epidemiological statistical method, in France.MethodsThis population-based study (2003–2011) investigated 47.1 million person-years of follow-up (PYFU). Case ascertainment of incident ALS cases was based on multiple sources (ALS referral centers, hospital centres and health insurance data). Neurologists confirmed all ALS diagnoses. Exhaustiveness was estimated through capture-recapture. Aggregates were investigated in four steps: (a) geographical modelling (standardized incidence ratio (SIR) calculation), (b) analysis of the spatial distribution of incidence (Phothoff-Winttinghill’s test, Global Moran’s Index, Kulldorf’s spatial scan statistic, Local Moran’s Index), (c) classification of the level of certainty of spatial aggregates (i.e. definite cluster; probable over-incidence area; possible over-incidence area) and (d) evaluation of the robustness of the results.ResultsThe standardized incidence of ALS was 2.46/100,000 PYFU (95% CI 2.31–2.63, European population as reference) based on 1199 incident cases. We identified 13 areas of spatial aggregates: one cluster (stable in robustness analysis), five probable over-incidence areas (2 stable in robustness analysis) and seven possible over-incidence areas (including 4 stable areas in robustness analysis). A cluster was identified in the Rhône-Alpes region: 100 observed vs 54.07 expected cases for 2,411,514 PYFU, SIR: 1.85 (95% CI 1.50–2.25).ConclusionWe report here one of the largest investigations of incidence and spatial aggregation of ALS ever performed in a western country. Using a solid methodology framework for case ascertainment and cluster analysis, we identified 13 areas that warrant further investigation.

Background Facioscapulohumeral muscular dystrophy (FSHD) is characterized by a typical pattern of muscle involvement, yet it encompasses a wide spectrum of phenotypes, including less common features that remain incompletely defined in the literature. While previous studies have highlighted this clinical variability, no consensus has been reached on how to classify uncommon manifestations, nor have specific predictors been identified. This study aims to describe these uncommon features and explore potential predictors, utilizing data from the French FSHD registry. To this end, we analysed data from 306 FSHD1 patients across nine French neuromuscular referral centres. Descriptive statistics, univariate analyses, and multiple logistic regression models were employed to examine uncommon characteristics and their predictors. Results Uncommon features were observed in 19.6% of cases. The most common was a discrepancy between disease severity and D4Z4 repeat unit (RU) count (41.7%), followed by predominant impairment at proximal lower limb or distal upper limb muscles (21.7%). Three unanticipated features emerged: isolated or predominant axial impairment, anosmia and atopic dermatitis. Univariate analysis revealed that uncommon features were associated with higher RU count (6.5 ± 2.1 vs. 5.8 ± 1.8 in typical patients) and older age of onset (32.0 ± 18.8 years vs. 25.0 ± 15.4 years). Such features were more prevalent in the borderline 8–10 RU range, an association confirmed by multivariate analysis (OR = 2.43, 95% CI 1.21 to 4.87). Later age of onset consistently emerged as a factor across multiple multivariate models. Conclusions This study documents uncommon FSHD features, revealing their association with the 8–10 RU range and later age of onset. These findings further support a complex interplay among genetic and epigenetic modifiers and ageing in shaping the clinical phenotype of FSHD, especially in patients carrying borderline D4Z4 arrays. Differential phenotypes, particularly in relation to RU range and age of onset, points to the importance of harmonized, comprehensive clinical and genetic assessments. Recognizing uncommon features may improve diagnostic accuracy and guide individualized management strategies, highlighting the need for tailored approaches to patient care.