Citations

Primary enlargement of the cerebrospinal fluid (CSF)–filled brain ventricles, known as congenital cerebral ventriculomegaly (CCV), is a hallmark of congenital hydrocephalus. CCV is also enigmatically but frequently associated with autism and other neurodevelopmental disorders. To gain insight into the developmental genetic regulation of the human CSF-ventricular system, we conducted an integrated, multiomic study of about 2700 trio-based exomes from patients with primary CCV. We found that about 25% of cases were associated with rare, damaging de novo variants in mutation-intolerant genes, many of which are linked to other dominant Mendelian disorders. Thirty-five exome-wide significant CCV genes and dozens of other high-confidence CCV genes converged on pathways involved in ATP-dependent Brahma-related gene 1/Brahma-associated factor chromatin remodeling, histone H3 lysine 4 methylation, and phosphoinositide 3-kinase signaling. Knockout of selected CCV genes in mouse models supported that de novo variants in CCV genes caused ventriculomegaly by impairing both CSF dynamics and cortical cytoarchitecture through dysregulation of neuroprogenitor cell growth and maturation in the ventricular and subventricular zones. These findings indicated that genetic and epigenetic programs coordinate the “hand-in-glove” development of the CSF-ventricular system with that of the cerebral cortex and establish a genetic connection between CCV and neurodevelopmental disorders, potentially explaining why some patients with hydrocephalus continue to exhibit CCV and neurodevelopmental disorders despite CSF shunting. We suggest that combined brain imaging and whole-exome sequencing could enable early detection of, and intervention for, autism and other neurodevelopmental disorders.

Black race and Hispanic ethnicity are associated with higher mortality in severe combined immunodeficiency (SCID) following hematopoietic cell transplantation (HCT), though mechanisms remain unclear. We evaluated 796 children with SCID who received nonsibling HCT between 1982 and 2020 using data from the Primary Immune Deficiency Treatment Consortium. Overall survival for Black (aHR 2.47, 95%CI 1.64, 3.71) and Asian/Pacific Islander patients (aHR 1.82, 95%CI 1.00, 3.30) was significantly lower compared with non-Hispanic White patients, while Hispanic patients had lower event-free survival (aHR 1.83, 95%CI 1.27, 2.63) compared with non-Hispanic White patients. Even after adjusting for age and infection, Black patients with SCID had more than twofold hazard of death compared with non-Hispanic White patients. NBS was associated with earlier diagnosis, reduced infection at HCT, and elimination of survival disparities between Black and non-Hispanic White patients. These findings suggest that universal, system-level interventions such as NBS can mitigate disparities in outcomes for children with SCID.

ABSTRACT Collection of hematopoietic progenitor cells and mononuclear cells by leukocytapheresis is a critical step of procuring cellular starting materials for future therapeutic use. Leukocytapheresis requires use of anticoagulant to prevent blood clotting in the extracorporeal circuit during collection. A commonly used anticoagulant is Acid Citrate Dextrose Solution A (ACD‐A). ACD‐A primarily prevents blood clotting by reversibly chelating free ionized calcium, which is essential for the clotting cascade. Electrolytes frequently affected by ACD‐A include calcium, magnesium, potassium, phosphate, and bicarbonate. Risks for development of electrolyte derangements include procedure‐related parameters as well as patient comorbidities. Symptoms range from mild paresthesias to life‐threatening cardiac arrhythmias. Recognition of related signs and symptoms is important for prompt intervention with procedure modification and electrolyte replacement to optimize patient safety. This paper will provide an enhanced understanding of the underlying pathophysiology and assist in timely identification and management of electrolyte abnormalities associated with cellular therapy collections.

Abstract Background Helicobacter pylori is a major global pathogen with recognized potential for waterborne transmission. Intermittent water supply affects over one billion worldwide and may promote H. pylori contamination of municipal sources. Whether water supply discontinuity contributes to population-level H. pylori burden has not been examined globally. Materials and Methods We conducted a cross-sectional ecological analysis of 79 countries with matched utility-level water infrastructure data and country-level H. pylori prevalence estimates from a published global meta-analysis. The primary exposure was continuity of water supply (hours/day). Secondary exposures included non-revenue water percentage (NRW %), pipe breaks per utility, and operating cost coverage ratio. Unadjusted and adjusted linear regression models with heteroscedasticity-consistent standard errors were estimated, controlling for basic sanitation coverage and log-transformed population density. A sensitivity analysis used a population-based measure of water availability on demand. Results Greater water supply continuity was independently associated with lower H. pylori prevalence in both unadjusted (β = −0.987, 95% CI −1.669 to −0.305, p = 0.005) and adjusted models (β = −1.125, 95% CI −1.876 to −0.375, p = 0.004). Higher NRW % and lower operating cost coverage were each associated with higher H. pylori prevalence after adjustment. Pipe breaks were not significant in regression models though the Spearman correlation was in the expected direction. Sensitivity analysis produced consistent findings. Conclusion IWS and broader water infrastructure deterioration are associated with higher H. pylori prevalence at the country level. These findings implicate water supply continuity as a potentially relevant environmental determinant of H. pylori transmission and suggest a role for water system investment within long-term gastric cancer prevention strategies.

Purpose: Nasopharyngoscopy is an imaging method used to visualize the velopharyngeal mechanism. To quantify the movement of the mechanism during speech, an international working group recommended standardized rating guidelines. While these guidelines are widely cited in research, the extent to which cleft teams apply them in a clinical setting is unclear. Method: This cross-sectional study examined clinical nasopharyngoscopy reports from 11 cleft teams in North America. Descriptive statistics were used to summarize the proportion of reports that included ratings for the extent of velar movement, left and right lateral pharyngeal wall movement, gap size, and a surgical recommendation. Fisher's exact and chi-square tests were used to assess differences in reporting by cleft team and whether the inclusion of quantitative ratings was associated with a surgical recommendation being included. Results: A total of 188 nasopharyngoscopy reports were included. The extent of velar movement was reported in 68% ( n = 127) of reports, the left and right lateral pharyngeal wall movement was reported in 38% ( n = 71), and the size of the gap was reported in 70% ( n = 132). Only 34% ( n = 63) of reports included all three quantitative ratings. Inclusion of all three quantitative ratings varied significantly ( p < .001) across teams. Teams either never included all the ratings ( n = 4/11) or inconsistently included all ratings ( n = 7/11). Conclusions: Findings suggest that what is documented clinically in nasopharyngoscopy reports varies both within and across teams. To achieve more consistent reporting within individual teams, providers may consider implementing standardized clinical templates. To achieve consistency across teams, these findings suggest a need for renewed efforts at developing consensus on the nasopharyngoscopy elements important to clinicians.

Objectives: The electroconvulsive therapy for the acute management of severe agitation in dementia (ECT-AD) trial is a multisite study evaluating the effectiveness of ECT for severe agitation in individuals with advanced dementia. Given that participants lack decisional capacity because of advanced cognitive impairment, the trial required a structured and ethically sound approach to obtaining informed consent and assent across jurisdictions with differing legal requirements, including Massachusetts, New York, Georgia, Minnesota, and Michigan. This paper describes the approach used in the study. Methods: We describe the consent framework developed for the ECT-AD trial, including procedures for identifying legally authorized representatives, complying with state-specific laws for ECT consent, obtaining surrogate consent for research participation, and assessing patient assent and dissent using a standardized tool. Conclusions: The approach used in this study may serve as a practical model for future research involving individuals without decision-making capacity and legally complex interventions such as ECT.