Understanding why EmpaTeach did not reduce teachers' use of violence in Nyarugusu Refugee Camp: A quantitative process evaluation of a school-based violence prevention intervention.

EmpaTeach was the first intervention to address teacher violence to be tested in a humanitarian setting and the first to focus on reducing impulsive use of violence, but a cluster randomised trial found no evidence that the intervention was effective in reducing physical and emotional violence from teachers. We aimed to understand why. We conducted a quantitative process evaluation to describe the intervention implementation process (what was implemented and how); examine teachers' adoption of positive teaching practices (was the content of the intervention taken up by participants), and test mechanisms of impact underlying the program theory (how the intervention was supposed to produce change). Despite participation in the intervention activities and adoption of intervention-recommended strategies (classroom management and positive disciplinary methods), we show that teachers who used more positive discipline did not appear to use less violence; and teachers in intervention schools did not experience gains in intermediate outcomes such as empathy, growth mindset, self-efficacy or social support. Our findings suggest that the intervention did not work due to the failure of some key hypothesised mechanisms, rather than because of implementation challenges

Effects of digital chatbot on gender attitudes and exposure to intimate partner violence among young women in South Africa

Background South Africa has among the highest rates of intimate partner violence (IPV) globally, with young women at heightened risk due to inequitable gender roles, limited relationship skills, and inadequate social support. Despite an urgent need for violence prevention in low- and middle-income settings, most efficacious approaches are time-intensive and costly to deliver. Digital, interactive chatbots may help young women navigate safer relationships and develop healthier gender beliefs and skills Methods Young women (18–24 years old) across South Africa were recruited via Facebook for participation in an individually randomised controlled trial (n = 19,643) during the period of June 2021-September 2021. Users were randomly allocated, using a pipeline algorithm, to one of four trial arms: Pure Control (PC) had no user engagement outside of study measures; Attention Treatment (T0) provided didactic information about sexual health through a text-based chatbot; Gamified Treatment (T1) was a behaviourally-informed gamified text-based chatbot; Narrative Treatment (T2) was a behaviourally-informed drama delivered through pre-recorded voice notes. All chatbots were delivered in WhatsApp, through which users were invited to complete brief “quizzes” comprising adapted versions of validated scales. Primary outcomes were short-form adaptations of scales for gender attitudes (Gender Relations Scale) and past-month IPV (WHO Multi-country Study Instrument). Secondary outcomes were identification of unhealthy relationship behaviours (Intimate Partner Violence Attitudes Scale) and brief screener for depressive symptoms (Patient Health Questionnaire). A direct chat link to a trained counsellor was a safety measure (accessed by 4.5% of the sample). We estimated treatment effects using ordinary least squares and heteroskedasticity robust standard errors Findings The trial retained 11,630 (59.2%) to the primary endpoint of gender attitudes. Compared to control, all treatments led to moderate and significant changes in attitudes towards greater gender equity (Cohen’s D = 0.10, 0.29, 0.20 for T0, T1, and T2, respectively). The gamified chatbot (T1) had modest but significant effects on IPV: 56% of young women reported past-month IPV, compared to 62% among those without treatment (marginal effects = -0.07, 95%CI = -0.09to-0.05). The narrative treatment (T2) had no effect on IPV exposure. T1 increased identification of unhealthy relationship behaviours at a moderate and significant level (Cohen’s D = 0.25). Neither T1 nor T2 had a measurable effect on depressive symptoms as measured by the brief screener. Interpretation: A behaviourally-informed, gamified chatbot increased gender equitable attitudes and was protective for IPV exposure among young women in South Africa. These effects, while modest in magnitude, could represent a meaningful impact given potential to scale the low-cost intervention

Elastodontic Therapy of Hyperdivergent Class II Patients Using AMCOP® Devices: A Retrospective Study

Background: The management of a hyperdivergent growth pattern is one of the most challenging in orthodontics and different treatments are advocated. The present study analyses the effectiveness of elastodontic therapy with AMCOP® devices in treating children with hyperdivergent class II malocclusion and the effect on the upper airway patency. Methods: The study group included 21 patients (10 males and 11 females, mean age 8.22 ± 1.17 years) with a hyperdivergent growth and a class II malocclusion treated with AMCOP® devices. Cephalometric analysis was performed before treatment (T0) and after treatment (T1). Results: After treatment, the cephalometric analysis revealed a correction of the class II malocclusion and a modification of the growth pattern with a divergence reduction. The improvement of the upper airway space was also observed. Conclusion: The elastodontic therapy effectively corrected hyperdivergent class II malocclusion in growing patients over a short period

Clinico-Genetic, Imaging and Molecular Delineation of COQ8A-Ataxia: A Multicenter Study of 59 Patients.

OBJECTIVE: To foster trial-readiness of coenzyme Q8A (COQ8A)-ataxia, we map the clinicogenetic, molecular, and neuroimaging spectrum of COQ8A-ataxia in a large worldwide cohort, and provide first progression data, including treatment response to coenzyme Q10 (CoQ10). METHODS: Cross-modal analysis of a multicenter cohort of 59 COQ8A patients, including genotype-phenotype correlations, 3D-protein modeling, in vitro mutation analyses, magnetic resonance imaging (MRI) markers, disease progression, and CoQ10 response data. RESULTS: Fifty-nine patients (39 novel) with 44 pathogenic COQ8A variants (18 novel) were identified. Missense variants demonstrated a pleiotropic range of detrimental effects upon protein modeling and in vitro analysis of purified variants. COQ8A-ataxia presented as variable multisystemic, early-onset cerebellar ataxia, with complicating features ranging from epilepsy (32%) and cognitive impairment (49%) to exercise intolerance (25%) and hyperkinetic movement disorders (41%), including dystonia and myoclonus as presenting symptoms. Multisystemic involvement was more prevalent in missense than biallelic loss-of-function variants (82-93% vs 53%; p = 0.029). Cerebellar atrophy was universal on MRI (100%), with cerebral atrophy or dentate and pontine T2 hyperintensities observed in 28%. Cross-sectional (n = 34) and longitudinal (n = 7) assessments consistently indicated mild-to-moderate progression of ataxia (SARA: 0.45/year). CoQ10 treatment led to improvement by clinical report in 14 of 30 patients, and by quantitative longitudinal assessments in 8 of 11 patients (SARA: -0.81/year). Explorative sample size calculations indicate that ≥48 patients per arm may suffice to demonstrate efficacy for interventions that reduce progression by 50%. INTERPRETATION: This study provides a deeper understanding of the disease, and paves the way toward large-scale natural history studies and treatment trials in COQ8A-ataxia. ANN NEUROL 2020;88:251-263

The EmpaTeach intervention for reducing physical violence from teachers to students in Nyarugusu Refugee Camp: A cluster-randomised controlled trial.

BACKGROUND: School-based violence prevention interventions offer enormous potential to reduce children's experience of violence perpetrated by teachers, but few have been rigorously evaluated globally and, to the best of our knowledge, none in humanitarian settings. We tested whether the EmpaTeach intervention could reduce physical violence from teachers to students in Nyarugusu Refugee Camp, Tanzania. METHODS AND FINDINGS: We conducted a 2-arm cluster-randomised controlled trial with parallel assignment. A complete sample of all 27 primary and secondary schools in Nyarugusu Refugee Camp were approached and agreed to participate in the study. Eligible students and teachers participated in cross-sectional baseline, midline, and endline surveys in November/December 2018, May/June 2019, and January/February 2020, respectively. Fourteen schools were randomly assigned to receive a violence prevention intervention targeted at teachers implemented in January-March 2019; 13 formed a wait-list control group. The EmpaTeach intervention used empathy-building exercises and group work to equip teachers with self-regulation, alternative discipline techniques, and classroom management strategies. Allocation was not concealed due to the nature of the intervention. The primary outcome was students' self-reported experience of physical violence from teachers, assessed at midline using a modified version of the ISPCAN Child Abuse Screening Tool-Child Institutional. Secondary outcomes included student reports of emotional violence, depressive symptoms, and school attendance. Analyses were by intention to treat, using generalised estimating equations adjusted for stratification factors. No schools left the study. In total, 1,493 of the 1,866 (80%) randomly sampled students approached for participation took part in the baseline survey; at baseline 54.1% of students reported past-week physical violence from school staff. In total, 1,619 of 1,978 students (81.9%) took part in the midline survey, and 1,617 of 2,032 students (79.6%) participated at endline. Prevalence of past-week violence at midline was not statistically different in intervention (408 of 839 students, 48.6%) and control schools (412 of 777 students, 53.0%; risk ratio = 0.91, 95% CI 0.80 to 1.02, p = 0.106). No effect was detected on secondary outcomes. A camp-wide educational policy change during intervention implementation resulted in 14.7% of teachers in the intervention arm receiving a compressed version of the intervention, but exploratory analyses showed no difference in our primary outcome by school-level adherence to the intervention. Main study limitations included the small number of schools in the camp, which limited statistical power to detect small differences between intervention and control groups. We also did not assess the test-retest reliability of our outcome measures, and interviewers were unmasked to intervention allocation. CONCLUSIONS: There was no evidence that the EmpaTeach intervention effectively reduced physical violence from teachers towards primary or secondary school students in Nyarugusu Refugee Camp. Further research is needed to develop and test interventions to prevent teacher violence in humanitarian settings. TRIAL REGISTRATION: clinicaltrials.gov (NCT03745573)

ATP driven structural changes of the bacterial Mre11:Rad50 catalytic head complex

DNA double-strand breaks (DSBs) threaten genome stability in all kingdoms of life and are linked to cancerogenic chromosome aberrations in humans. The Mre11:Rad50 (MR) complex is an evolutionarily conserved complex of two Rad50 ATPases and a dimer of the Mre11 nuclease that senses and processes DSBs and tethers DNA for repair. ATP binding and hydrolysis by Rad50 is functionally coupled to DNA-binding and tethering, but also regulates Mre11's nuclease in processing DNA ends. To understand how ATP controls the interaction between Mre11 and Rad50, we determined the crystal structure of Thermotoga maritima (Tm) MR trapped in an ATP/ADP state. ATP binding to Rad50 induces a large structural change from an open form with accessible Mre11 nuclease sites into a closed form. Remarkably, the NBD dimer binds in the Mre11 DNA-binding cleft blocking Mre11's dsDNA-binding sites. An accompanying large swivel of the Rad50 coiled coil domains appears to prepare the coiled coils for DNA tethering. DNA-binding studies show that within the complex, Rad50 likely forms a dsDNA-binding site in response to ATP, while the Mre11 nuclease module retains a ssDNA-binding site. Our results suggest a possible mechanism for ATP-dependent DNA tethering and DSB processing by MR

Levodopa-refractory hyperprolactinemia and pituitary findings in inherited disorders of biogenic amine metabolism

Elevated serum prolactin concentrations occur in inherited disorders of biogenic amine metabolism because dopamine deficiency leads to insufficient inhibition of prolactin secretion. This work from the International Working Group on Neurotransmitter Related Disorders (iNTD) presents the results of the first standardized study on levodopa-refractory hyperprolactinemia (LRHP; >1000 mU/L) and pituitary magnetic resonance imaging (MRI) abnormalities in patients with inherited disorders of biogenic amine metabolism. Twenty-six individuals had LRHP or abnormal pituitary findings on MRI. Tetrahydrobiopterin deficiencies were the most common diagnoses (n = 22). The median age at diagnosis of LRHP was 16 years (range: 2.5-30, 1st-3rd quartiles: 12.25-17 years). Twelve individuals (nine females) had symptoms attributed to hyperprolactinemia: menstruation-related abnormalities (n = 7), pubertal delay or arrest (n = 5), galactorrhea (n = 3), and decreased sexual functions (n = 2). MRI of the pituitary gland was obtained in 21 individuals; six had heterogeneity/hyperplasia of the gland, five had adenoma, and 10 had normal findings. Eleven individuals were treated with the dopamine agonist cabergoline, ameliorating the hyperprolactinemia-related symptoms in all those assessed. Routine monitoring of these symptoms together with prolactin concentrations, especially after the first decade of life, should be taken into consideration during follow-up evaluations. The potential of slow-release levodopa formulations and low-dose dopamine agonists as part of first-line therapy in the prevention and treatment of hyperprolactinemia should be investigated further in animal studies and human trials. This work adds hyperprolactinemia-related findings to the current knowledge of the phenotypic spectrum of inherited disorders of biogenic amine metabolism

Report from Working Group 3: Beyond the standard model physics at the HL-LHC and HE-LHC

This is the third out of five chapters of the final report [1] of the Workshop on Physics at HL-LHC, and perspectives on HE-LHC [2]. It is devoted to the study of the potential, in the search for Beyond the Standard Model (BSM) physics, of the High Luminosity (HL) phase of the LHC, defined as $3$ ab$^{-1}$ of data taken at a centre-of-mass energy of 14 TeV, and of a possible future upgrade, the High Energy (HE) LHC, defined as $15$ ab$^{-1}$ of data at a centre-of-mass energy of 27 TeV. We consider a large variety of new physics models, both in a simplified model fashion and in a more model-dependent one. A long list of contributions from the theory and experimental (ATLAS, CMS, LHCb) communities have been collected and merged together to give a complete, wide, and consistent view of future prospects for BSM physics at the considered colliders. On top of the usual standard candles, such as supersymmetric simplified models and resonances, considered for the evaluation of future collider potentials, this report contains results on dark matter and dark sectors, long lived particles, leptoquarks, sterile neutrinos, axion-like particles, heavy scalars, vector-like quarks, and more. Particular attention is placed, especially in the study of the HL-LHC prospects, to the detector upgrades, the assessment of the future systematic uncertainties, and new experimental techniques. The general conclusion is that the HL-LHC, on top of allowing to extend the present LHC mass and coupling reach by $20-50\%$ on most new physics scenarios, will also be able to constrain, and potentially discover, new physics that is presently unconstrained. Moreover, compared to the HL-LHC, the reach in most observables will, generally more than double at the HE-LHC, which may represent a good candidate future facility for a final test of TeV-scale new physics

Common and rare variant association analyses in amyotrophic lateral sclerosis identify 15 risk loci with distinct genetic architectures and neuron-specific biology

A cross-ancestry genome-wide association meta-analysis of amyotrophic lateral sclerosis (ALS) including 29,612 patients with ALS and 122,656 controls identifies 15 risk loci with distinct genetic architectures and neuron-specific biology. Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease with a lifetime risk of one in 350 people and an unmet need for disease-modifying therapies. We conducted a cross-ancestry genome-wide association study (GWAS) including 29,612 patients with ALS and 122,656 controls, which identified 15 risk loci. When combined with 8,953 individuals with whole-genome sequencing (6,538 patients, 2,415 controls) and a large cortex-derived expression quantitative trait locus (eQTL) dataset (MetaBrain), analyses revealed locus-specific genetic architectures in which we prioritized genes either through rare variants, short tandem repeats or regulatory effects. ALS-associated risk loci were shared with multiple traits within the neurodegenerative spectrum but with distinct enrichment patterns across brain regions and cell types. Of the environmental and lifestyle risk factors obtained from the literature, Mendelian randomization analyses indicated a causal role for high cholesterol levels. The combination of all ALS-associated signals reveals a role for perturbations in vesicle-mediated transport and autophagy and provides evidence for cell-autonomous disease initiation in glutamatergic neurons