Malformations of cortical development (MCD) are neurological conditions displaying focal disruption of cortical architecture and cellular organization arising during embryogenesis, largely from somatic mosaic mutations, and causing intractable epilepsy. Identifying the genetic causes of MCD has been a challenge, as mutations remain at low allelic fractions in brain tissue resected to treat condition-related epilepsy. Here, we report a genetic landscape from 283 brain resections, identifying 69 mutated genes through intensive profiling of somatic mutations, combining whole-exome and targeted-amplicon sequencing with functional validation including in utero electroporation of mice and single-nucleus RNA sequencing. Genotype-phenotype correlation analysis elucidated specific MCD gene sets associating distinct pathophysiological and clinical phenotypes. The unique single-cell level spatiotemporal expression patterns of mutated genes in control and patient brains implicate critical roles in excitatory neurogenic pools during brain development, and in promoting neuronal hyperexcitability after birth.

Background: Epidemiological evidence on the social determinants of health inequity is well-advanced, but considerably less attention has been given to evaluating the impact of public policies addressing those social determinants. Methodological challenges to produce evidence on policy outcomes present a significant barrier to mobilising policy actions for health equities. This review aims to examine methodological approaches to policy evaluation of health equity outcomes and identify promising approaches for future research. Methods: We conducted a systematic narrative review of literature critically evaluating policy impact on health equity, synthesizing information on the methodological approaches used. We searched and screened records from five electronic databases, using pre-defined protocols resulting in a total of 50 studies included for review. We coded the studies according to (1) type of policy analysed; (2) research design; (3) analytical techniques; (4) health outcomes; and (5) equity dimensions evaluated. Results: We found a growing number of a wide range of policies being evaluated for health equity outcomes using a variety of research designs. The majority of studies employed an observational research design, most of which were cross-sectional, however, other approaches included experimental designs, simulation modelling, and meta-analysis. Regression techniques dominated the analytical approaches, although a number of novel techniques were used which may offer advantages over traditional regression analysis for the study of distributional impacts of policy. Few studies made intra-national or cross-national comparisons or collected primary data. Despite longstanding challenges of attribution in policy outcome evaluation, the majority of the studies attributed change in physical or mental health outcomes to the policy being evaluated. Conclusion: Our review provides an overview of methodological approaches to health equity policy outcome evaluation, demonstrating what is most commonplace and opportunities from novel approaches. We found the number of studies evaluating the impacts of public policies on health equity are on the rise, but this area of policy evaluation still requires more attention given growing inequities.

No abstract

No abstract