Confronting ALS: understanding multicellular contribution to neurodegeneration : computational analysis and hiPSCs in vitro modelling as a multidisciplinary approach

Amyotrophic Lateral Sclerosis (ALS) is a fatal neurodegenerative disorder characterised by a progressive loss of motor function. Despite the strives into growing knowledge on ALS, fundamental obstacles remain into understanding disease causation and nominating drug targets for a cure. With this work, we widen our understanding of ALS through the analysis of single-nuclei RNA-sequencing dataset of patients’ and control motorcortices. We show intrinsically higher expression of ALS-related genes in Extratelencephalic Neurons accompanied by selective vulnerability of subsets of cortical motor neurons. These changes are found with alterations in oligodendrocytes and microglia that widen our knowledge of cell-to-cell interactions in ALS. We use hiPSC-derived in vitro systems to model the molecular changes identified. Secondly, we offer a wide view on models of human brain cells in a dish to encompass protocols useful for modelling complex cell-to-cell interactions in ALS. Moreover, we describe a human in vitro system for the study of motor neuron that is highly reproducible, scalable and high-throughput. This new method allows the assessment of multiple cell lines in the same dish and could provide insights into heterogeneity in human populations and mechanisms disrupted in disease. We then use these models to further dissect molecular mechanisms disrupted in ALS. We undertake a discussion onto the future of the field and hopefully the opening to a more holistic approach to the understanding of ALS, where multidisciplinary techniques and the use of different models might expand our perspectives on the disease.LUMC / Geneeskund

Management and Outcomes of Tibial Eminence Fractures in the Pediatric Population: A Systematic Review

Background: Tibial eminence fractures (TEF) of Meyers-McKeever type II-III-IV usually require surgical management. No consensus in the literature has been achieved regarding the best treatment option. The aims of the present systematic review were (1) to analyze the current literature and describe the outcomes of surgical treatment for TEF; and (2) to compare the outcomes of different surgical options using arthroscopic reduction and internal fixation (ARIF) with sutures or screws and open reduction and internal fixation (ORIF). Methods: A search was carried out with Pubmed, Medline, and Cochrane. Key terms were used "tibial" AND "eminence" or "spine" or "intercondylar" AND "paediatric" or "children" AND "fracture" or "avulsion" AND "treatment". Twelve articles met the inclusion criteria. Demographic data, clinical outcomes, and complication rates were evaluated for each study. Means/standard deviation and sum/percentage were used for continuous and categorical variables, respectively. Chi-square or t-student tests were applied. A p-value < 0.05 was considered statistically significant. Results: ORIF showed superior clinical outcomes (Tegner (p < 0.05) and Lysholm (p < 0.001) scores) relative to ARIF and a lower incidence of arthrofibrosis (p < 0.05) and implant removal (p < 0.01). The Tegner, IKDC, and Lysholm scores showed statistically significant superior results following arthroscopic sutures compared to arthroscopic screws (p < 0.001). The incidence of arthrofibrosis was higher after arthroscopic sutures (p < 0.05), the implant removal was higher after screw fixation (p < 0.001) Conclusions: Better clinical results with low complication rates were achieved with ORIF surgery rather than ARIF; arthroscopic suture fixation resulted in higher clinical results compared to arthroscopic screw fixation and reduced the incidence of postoperative complications

A Project to Promote English Learning in Primary School: “An English Island®” E-learning Platform

The present study was aimed to investigate English learning as second language, in school, in first, second and third graders of twelve classes randomly assigned to a control or an experimental group. Children in the latter are exposed during English school teaching to the method “An English Island®” and to its platform activities. The method “An English Island®” offers a variety of strategies for teaching English in primary school, an innovative digital tool that promotes teaching/learning English language’s communicative approach, lead students to become familiar with the language in a sort of continuous, inclusive workout, in which everyone participates and talks. English skills as well as cognitive abilities are tested in both groups at the beginning and at the end of the school year with the aim to compare control and experimental classes in both a longitudinal and a cross-sectional design

Direct observation of the turbulent emf and transport of magnetic field in a liquid sodium experiment

International audienceFor the first time, we have directly measured the transport of a vector magnetic field by isotropic turbulence in a high Reynolds number liquid metal flow. In analogy with direct measurements of the turbulent Reynolds stress (turbulent viscosity) that governs momentum transport, we have measured the turbulent electromotive force (emf) by simultaneously measuring three components of velocity and magnetic fields, and computed the correlations that lead to mean-field current generation. Furthermore, we show that this turbulent emf tends to oppose and cancel out the local current, acting to increase the effective resistivity of the medium, i.e., it acts as an enhanced magnetic diffusivity. This has important implications for turbulent transport in astrophysical objects, particularly in dynamos and accretion disks

Utilizing digital technologies to promote well-being in university students: the ‘DigiWell’ research protocol

The COVID-19 pandemic has significantly impacted the well-being of university students, particularly those in healthcare and medical programs. Psychological interventions rooted in positive psychology have proven effective in enhancing mental health, with online and digital delivery methods proving to be equally viable. This study aims to enhance mental health among Italian university students through digital interventions, including virtual reality, utilizing a stepped care approach. Specific objectives include implementing online positive interventions for students experiencing mild distress (DigiWell_Step 1), evaluating a Virtual-Reality intervention for moderate distress (DigiWell_Step 2), and identifying students experiencing high distress or optimal well-being. Cluster analyses and linear models will assess intervention outcomes. It is anticipated that students undergoing these steps will experience significant improvements in well-being and distress reduction, with sustained benefits at a three-month follow-up. This research contributes to understanding the efficacy of mental health interventions for university students, leveraging digital technologies to enhance accessibility and user engagement. The integration of digital technologies enhances the cost-effectiveness and engagement of interventions delivered through a stepped care approach tailored to the targeted population

From SGAP-Model to SGAP-Score: A Simplified Predictive Tool for Post-Surgical Recurrence of Pheochromocytoma

A reliable prediction of the recurrence risk of pheochromocytoma after radical surgery would be a key element for the tailoring/personalization of post-surgical follow-up. Recently, our group developed a multivariable continuous model that quantifies this risk based on genetic, histopathological, and clinical data. The aim of the present study was to simplify this tool to a discrete score for easier clinical use. Data from our previous study were retrieved, which encompassed 177 radically operated pheochromocytoma patients; supervised regression and machine-learning techniques were used for score development. After Cox regression, the variables independently associated with recurrence were tumor size, positive genetic testing, age, and PASS. In order to derive a simpler scoring system, continuous variables were dichotomized, using > 50 mm for tumor size, ≤ 35 years for age, and ≥ 3 for PASS as cut-points. A novel prognostic score was created on an 8-point scale by assigning 1 point for tumor size > 50 mm, 3 points for positive genetic testing, 1 point for age ≤ 35 years, and 3 points for PASS ≥ 3; its predictive performance, as assessed using Somers’ D, was equal to 0.577 and was significantly higher than the performance of any of the four dichotomized predictors alone. In conclusion, this simple scoring system may be of value as an easy-to-use tool to stratify recurrence risk and tailor post-surgical follow-up in radically operated pheochromocytoma patients

The risk stratification of adverse neonatal outcomes in women with gestational diabetes (STRONG) study

Aims: To assess the risk of adverse neonatal outcomes in women with gestational diabetes (GDM) by identifying subgroups of women at higher risk to recognize the characteristics most associated with an excess of risk. Methods: Observational, retrospective, multicenter study involving consecutive women with GDM. To identify distinct and homogeneous subgroups of women at a higher risk, the RECursive Partitioning and AMalgamation (RECPAM) method was used. Overall, 2736 pregnancies complicated by GDM were analyzed. The main outcome measure was the occurrence of adverse neonatal outcomes in pregnancies complicated by GDM. Results: Among study participants (median age 36.8 years, pre-gestational BMI 24.8 kg/m2), six miscarriages, one neonatal death, but no maternal death was recorded. The occurrence of the cumulative adverse outcome (OR 2.48, 95% CI 1.59–3.87), large for gestational age (OR 3.99, 95% CI 2.40–6.63), fetal malformation (OR 2.66, 95% CI 1.00–7.18), and respiratory distress (OR 4.33, 95% CI 1.33–14.12) was associated with previous macrosomia. Large for gestational age was also associated with obesity (OR 1.46, 95% CI 1.00–2.15). Small for gestational age was associated with first trimester glucose levels (OR 1.96, 95% CI 1.04–3.69). Neonatal hypoglycemia was associated with overweight (OR 1.52, 95% CI 1.02–2.27) and obesity (OR 1.62, 95% CI 1.04–2.51). The RECPAM analysis identified high-risk subgroups mainly characterized by high pre-pregnancy BMI (OR 1.68, 95% CI 1.21–2.33 for obese; OR 1.38 95% CI 1.03–1.87 for overweight). Conclusions: A deep investigation on the factors associated with adverse neonatal outcomes requires a risk stratification. In particular, great attention must be paid to the prevention and treatment of obesity

Loss of mouse Stmn2 function causes motor neuropathy

Amyotrophic lateral sclerosis (ALS) is characterized by motor neuron degeneration accompanied by aberrant accumulation and loss of function of the RNA-binding protein TDP43. Thus far, it remains unresolved to what extent TDP43 loss of function directly contributes to motor system dysfunction. Here, we employed gene editing to find whether the mouse ortholog of the TDP43-regulated gene STMN2 has an important function in maintaining the motor system. Both mosaic founders and homozygous loss-of-function Stmn2 mice exhibited neuromuscular junction denervation and fragmentation, resulting in muscle atrophy and impaired motor behavior, accompanied by an imbalance in neuronal microtubule dynamics in the spinal cord. The introduction of human STMN2 through BAC transgenesis was sufficient to rescue the motor phenotypes observed in Stmn2 mutant mice. Collectively, our results demonstrate that disrupting the ortholog of a single TDP43-regulated RNA is sufficient to cause substantial motor dysfunction, indicating that disruption of TDP43 function is likely a contributor to ALS