The BabySeq Project: A clinical trial of genome sequencing in a diverse cohort of infants.

Efforts to implement and evaluate genome sequencing (GS) as a screening tool for newborns and infants are expanding worldwide. The first iteration of the BabySeq Project (2015-2019), a randomized controlled trial of newborn sequencing, produced novel evidence on medical, behavioral, and economic outcomes. The second iteration of BabySeq, which began participant recruitment in January 2023, examines GS outcomes in a larger, more diverse cohort of more than 500 infants up to one year of age recruited from pediatric clinics at several sites across the United States. The trial aims for families who self-identify as Black/African American or Hispanic/Latino to make up more than 50% of final enrollment, and key aspects of the trial design were co-developed with a community advisory board. All enrolled families receive genetic counseling and a family history report. Half of enrolled infants are randomized to receive GS with comprehensive interpretation of pathogenic and likely pathogenic variants in more than 4,300 genes associated with childhood-onset and actionable adult-onset conditions, as well as larger-scale chromosomal copy number variants classified as pathogenic or likely pathogenic. GS result reports include variants associated with disease (Mendelian disease risks) and carrier status of autosomal-recessive and X-linked disorders. Investigators evaluate the utility and impacts of implementing a GS screening program in a diverse cohort of infants using medical record review and longitudinal parent surveys. In this perspective, we describe the rationale for the second iteration of the BabySeq Project, the outcomes being assessed, and the key decisions collaboratively made by the study team and community advisory board.

Hodgkin lymphoma presenting as multiple cavitary pulmonary nodules with associated mediastinal adenopathy and neck mass.

Hodgkin lymphoma involving the lung may present in a variety of radiographic and clinical patterns including solid or necrotizing lesions, with or without associated mediastinal adenopathy. Cavitary pulmonary lesions are exceedingly rare, occurring in less than 1% of cases, and are typically solitary. We report a case of an 18-year-old male presenting with multiple cavitating pulmonary nodules and a palpable mass in the neck. Imaging revealed associated mediastinal and cervical adenopathy. Biopsy of the neck mass and lung nodule initially revealed necrosis and granulomata, suggesting infection. Treatment for a presumed infectious etiology was without resolution. Subsequent open lung biopsy revealed marked granulomatous inflammation with diagnostic Reed-Sternberg cells. Hodgkin lymphoma should always be considered in the differential diagnosis of cavitary pulmonary lesions, especially those refractory to treatment.

Disruption of tight junctions during traversal of the respiratory epithelium by Burkholderia cenocepacia.

Burkholderia cenocepacia is an opportunistic bacterial species capable of causing life-threatening respiratory tract infection in persons with cystic fibrosis (CF). Unlike most other pathogens in CF, which typically remain confined to the endobronchial spaces, B. cenocepacia can traverse airway epithelium to cause bacteremia and sepsis. The mechanisms by which this occurs, however, are unknown. We examined the transmigration of B. cenocepacia through polarized respiratory epithelium. Representatives of three "epidemic" lineages common among CF patients in North America were able to traverse polarized 16HBE14o- cells in vitro. Transmigration of bacteria was associated with significant perturbations in epithelial permeability, as measured by a loss of transepithelial electrical resistance and increased flux of bovine serum albumin across the cell layer. Terminal deoxynucleotidyltransferase-mediated dUTP-biotin nick end labeling and trypan blue exclusion assays, as well as lactate dehydrogenase levels, did not indicate excessive cytotoxicity or cell death in infected cell layers. Rather, confocal fluorescence microscopy demonstrated the loss of occludin from tight junctions. In contrast, zonula occludens 1 was well preserved along intercellular borders. Western blot analysis showed a shift in the major occludin isoforms from high- to low-phosphorylation states during infection. These observations suggest that B. cenocepacia traverses polarized respiratory epithelium by the dephosphorylation and dissociation of occludin from the tight-junction complex.