The MACE architecture represents the state of the art in the field of machine learning force fields for a variety of in-domain, extrapolation, and low-data regime tasks. In this paper, we further evaluate MACE by fitting models for published benchmark datasets. We show that MACE generally outperforms alternatives for a wide range of systems, from amorphous carbon, universal materials modeling, and general small molecule organic chemistry to large molecules and liquid water. We demonstrate the capabilities of the model on tasks ranging from constrained geometry optimization to molecular dynamics simulations and find excellent performance across all tested domains. We show that MACE is very data efficient and can reproduce experimental molecular vibrational spectra when trained on as few as 50 randomly selected reference configurations. We further demonstrate that the strictly local atom-centered model is sufficient for such tasks even in the case of large molecules and weakly interacting molecular assemblies.

Concussions significantly impact sleep quality among adolescents. Despite increasing recognition of these effects, the complex relationship between adolescent concussions and sleep disturbances is still not fully understood and presents mixed findings. Here, we conducted a systematic review and meta-analysis to assess how concussions affect sleep-related symptoms in adolescents. We included papers presenting Pittsburgh Sleep Quality Index (PSQI) differences following concussion in high school and collegiate patients, with sleep measures recorded following concussion. Animal studies, research on participants with conditions other than concussion, non-English articles and papers failing to present PSQI data were excluded. We searched MEDLINE^®, Embase^®, CINAHL, Web of Science™, PsycINFO^®, Google Scholar, and Cochrane Central Register of Controlled Trials databases until 23 August 2024. In addition, we performed hand-searching of relevant reference lists and conference proceedings to identify further studies. Risk of bias was assessed using the Newcastle–Ottawa scale. In total, we considered 4477 studies, with nine meeting the inclusion criteria. Our analysis involved 796 participants, 340 of whom had experienced a concussion. Analysis was carried out using the meta and metafor packages in R (version 4.0.0). We showed a deterioration in sleep quality post-concussion, as evidenced by increased PSQI (standardised mean difference 0.84; 95% CI 0.53–1.16; p < 0.0001). Subgroup and quality assessments confirmed the consistency of these findings. Since poor sleep quality impacts daytime activities, we analysed the relationship between concussion and daytime dysfunction. We showed that concussion is associated with a significant worsening of the daytime dysfunction score by 0.55 (95% CI 0.24–0.70; p = 0.006). We conclude that concussions impair both sleep quality and daytime functioning in adolescents. Our research underscores the need for systematic inclusion of sleep quality assessments in post-concussion protocols and calls for targeted interventions to manage sleep disturbances post-concussion to mitigate their broader impacts on daily functioning.

Primary mitochondrial diseases (PMD) arise from variants in the mitochondrial or nuclear genomes. Phenotype-based recognition of specific PMD genotypes remains difficult, prolonging the diagnostic odyssey. We expanded the MitoPhen database to characterize phenotypic variation across PMD more systematically. Individual-level data on mitochondrial DNA disorders, nuclear-encoded mitochondrial diseases, and single large-scale mitochondrial DNA deletions were manually curated with Human Phenotype Ontology (HPO) terms to produce MitoPhen v2. Principal-component analysis summarized system-level abnormalities; HPO-level enrichment and mean phenotype-similarity scores were then used to distinguish common PMD genotypes. MitoPhen v2 adds 3940 individuals to the original release, now encompassing 1597 publications, 10,626 individuals, and 117 genotypes. Among 7586 affected cases, 72,861 HPO terms were recorded. Principal-component analysis revealed 6 phenotype dimensions capturing most system-level variance. At the HPO level, we observed genotype-specific enrichments and identified 111 gene-phenotype links absent from the current HPO database. Using MT-TL1, single large-scale mitochondrial DNA deletions, and POLG as exemplars, phenotype-similarity scores reliably separated individuals with these genotypes from those without. MitoPhen v2 enabled systematic, genotype-aware analysis of heterogeneous PMD phenotypes and highlighted the diagnostic value of structured, individual-level data. Phenotype-similarity metrics from such data sets can refine variant interpretation in large rare-disease cohorts and provide a transferable framework for other phenotypically complex genetic disorders.

Leber’s hereditary optic neuropathy (LHON) is a debilitating mitochondrial disease characterised by bilateral painless vision loss. Despite being the most prevalent mitochondrial disorder, the precise pathophysiological mechanisms underlying the penetrance of LHON remain poorly understood. Nuclear modifier genes have been long suspected to affect phenotype-severity, however, specific cellular pathways implicated in the disease penetrance have been only suggested recently. In recent years, autosomal recessive variants in nuclear genes involved in complex I function and metabolic pathways were recognised to cause a typical LHON phenotype. This was proposed as a new autosomal recessive disease mechanism for LHON (arLHON). The association between nuclear variants and the LHON phenotype makes the nuclear pathways disrupted in arLHON the strongest candidates to act as modifiers of mitochondrial LHON (mLHON). In this study we systematically investigated a large cohort of 23 symptomatic and 28 asymptomatic individuals carrying one of the three primary mitochondrial LHON variants. We identified several heterozygous pathogenic nuclear variants amongst the affected individuals that were consistently linked to metabolic and complex I related pathways, mirroring those disrupted in arLHON. Our findings are consistent with the presence of a second hit in specific biological pathways impairing ATP production. We propose that in addition to the primary mitochondrial variants, disruption in these nuclear-encoded pathways drives the clinical manifestation of LHON. Genes involved in the same pathways also emerge as exciting candidates for future association with arLHON. The present study deepens our understanding of LHON’s pathophysiology and provides a new framework for identifying novel disease-modifying targets.

Is EEG surveillance routinely indicated in seizure-free patients newly diagnosed with TSC to improve seizure outcomes?