Underrepresented and Underserved Populations in Neurological Research.

Underserved and underrepresented populations have historically been excluded from neurological research. This lack of representation has implications for translation of research findings into clinical practice given the impact of social determinants of health on neurological disease risk, progression, and outcomes. Lack of inclusion in research is driven by individual-, investigator-, and study-level barriers as well as larger systemic injustices (e.g., structural racism, discriminatory practices). Although strategies to increase inclusion of underserved and underrepresented populations have been put forth, numerous questions remain about the most effective methodology. In this article, we highlight inclusivity patterns and gaps among the most common neurological conditions and propose best practices informed by our own experiences in engagement of local community organizations and collaboration efforts to increase underserved and underrepresented population participation in neurological research.

Aberrant centrosome biogenesis disrupts nephron and collecting duct progenitor growth and fate resulting in fibrocystic kidney disease.

Mutations that disrupt centrosome biogenesis or function cause congenital kidney developmental defects and fibrocystic pathologies. Yet how centrosome dysfunction results in the kidney disease phenotypes remains unknown. Here, we examined the consequences of conditional knockout of the ciliopathy gene Cep120, essential for centrosome duplication, in the nephron and collecting duct progenitor niches of the mouse embryonic kidney. Cep120 loss led to reduced abundance of both cap mesenchyme and ureteric bud populations, due to a combination of delayed mitosis, increased apoptosis and premature differentiation of progenitor cells. These defects resulted in dysplastic kidneys at birth, which rapidly formed cysts, displayed increased interstitial fibrosis and decline in kidney function. RNA sequencing of embryonic and postnatal kidneys from Cep120-null mice identified changes in the pathways essential for development, fibrosis and cystogenesis. Our study defines the cellular and developmental defects caused by centrosome dysfunction during kidney morphogenesis and identifies new therapeutic targets for patients with renal centrosomopathies.

Aberrant centrosome biogenesis disrupts nephron progenitor cell renewal and fate resulting in fibrocystic kidney disease.

Mutations that disrupt centrosome structure or function cause congenital kidney developmental defects and fibrocystic pathologies. Yet, it remains unclear how mutations in proteins essential for centrosome biogenesis impact embryonic kidney development. Here, we examined the consequences of conditional deletion of a ciliopathy gene, Cep120 , in the two nephron progenitor niches of the embryonic kidney. Cep120 loss led to reduced abundance of both metanephric mesenchyme and ureteric bud progenitor populations. This was due to a combination of delayed mitosis, increased apoptosis, and premature differentiation of progenitor cells. These defects resulted in dysplastic kidneys at birth, which rapidly formed cysts, displayed increased interstitial fibrosis, and decline in filtration function. RNA sequencing of embryonic and postnatal kidneys from Cep120-null mice identified changes in pathways essential for branching morphogenesis, cystogenesis and fibrosis. Our study defines the cellular and developmental defects caused by centrosome dysfunction during kidney development, and identifies new therapeutic targets for renal centrosomopathies. Highlights: Defective centrosome biogenesis in nephron progenitors causes:Reduced abundance of metanephric mesenchyme and premature differentiation into tubular structuresAbnormal branching morphogenesis leading to reduced nephron endowment and smaller kidneysChanges in cell-autonomous and paracrine signaling that drive cystogenesis and fibrosisUnique cellular and developmental defects when compared to Pkd1 knockout models.

Transcriptome analysis provides genome annotation and expression profiles in the central nervous system of Lymnaea stagnalis at different ages.

BACKGROUND: The pond snail, Lymnaea stagnalis (L. stagnalis), has served as a valuable model organism for neurobiology studies due to its simple and easily accessible central nervous system (CNS). L. stagnalis has been widely used to study neuronal networks and recently gained popularity for study of aging and neurodegenerative diseases. However, previous transcriptome studies of L. stagnalis CNS have been exclusively carried out on adult L. stagnalis only. As part of our ongoing effort studying L. stagnalis neuronal growth and connectivity at various developmental stages, we provide the first age-specific transcriptome analysis and gene annotation of young (3 months), adult (6 months), and old (18 months) L. stagnalis CNS. RESULTS: Using the above three age cohorts, our study generated 55-69 millions of 150 bp paired-end RNA sequencing reads using the Illumina NovaSeq 6000 platform. Of these reads, ~ 74% were successfully mapped to the reference genome of L. stagnalis. Our reference-based transcriptome assembly predicted 42,478 gene loci, of which 37,661 genes encode coding sequences (CDS) of at least 100 codons. In addition, we provide gene annotations using Blast2GO and functional annotations using Pfam for ~ 95% of these sequences, contributing to the largest number of annotated genes in L. stagnalis CNS so far. Moreover, among 242 previously cloned L. stagnalis genes, we were able to match ~ 87% of them in our transcriptome assembly, indicating a high percentage of gene coverage. The expressional differences for innexins, FMRFamide, and molluscan insulin peptide genes were validated by real-time qPCR. Lastly, our transcriptomic analyses revealed distinct, age-specific gene clusters, differentially expressed genes, and enriched pathways in young, adult, and old CNS. More specifically, our data show significant changes in expression of critical genes involved in transcription factors, metabolisms (e.g. cytochrome P450), extracellular matrix constituent, and signaling receptor and transduction (e.g. receptors for acetylcholine, N-Methyl-D-aspartic acid, and serotonin), as well as stress- and disease-related genes in young compared to either adult or old snails. CONCLUSIONS: Together, these datasets are the largest and most updated L. stagnalis CNS transcriptomes, which will serve as a resource for future molecular studies and functional annotation of transcripts and genes in L. stagnalis.

Cost-Effectiveness analysis of the surgical management of fractures in Malawi: An economic evaluation of a high and low-income country surgical collaboration.

INTRODUCTION: Cost-effectiveness is an essential tool for identifying high-value interventions in resource-limited settings. This study aims to evaluate the cost-effectiveness of the surgical management of fractures by surgical residents at Kamuzu Central Hospital (KCH). Currently, the 5-year surgical training program is supported by the Malawi Ministry of Health, and two universities in the United States and Norway. METHODS: We performed a modeled cost-effectiveness analysis (CEA) from a public health sector perspective. Cost data were collected from the current residency program and effectiveness data estimated from clinical data derived from operative interventions for fractures between 2013 and 2017 at KCH. Three patient groups were used as the base case; (1) patients of all ages, (2) patients age ≥18 years, and (3) patients who were <18 years. A Monte Carlo simulation of 10,000 trials was conducted for the probabilistic sensitivity analysis. RESULTS: The estimated average lifetime cost of training and compensating residency-trained surgeons over a 35-year career was $448,600 (SD $31,167). The incremental cost-effectiveness ratio (ICER) for providing surgical care to patients of all ages was $215 (SD $3,666) per disability-adjusted life-year (DALY), which is below the willingness-to pay-threshold (WTP) of $1,170 per DALY and highly cost-effective at a WTP threshold of $390. Each surgeon is estimated to avert approximately 5,570 DALYs during their career when performing operations to treat fractures. CONCLUSION: The KCH surgical training program is highly cost-effective at reducing disability at an incremental cost of $215 per averted DALY. This CEA demonstrates that the current surgical training program is cost-effective in reducing morbidity among individuals with fractures.