A 14-Year-Old Girl with Shortness of Breath and Chest Pain.

A 14-Year-Old Girl with Dyspnea and Chest PainA 14-year-old girl presented for evaluation of shortness of breath and chest pain after recent travel to the Caribbean. How do you approach the evaluation, and what is the diagnosis?

Modeling injury and repair in kidney organoids reveals that homologous recombination governs tubular intrinsic repair.

Kidneys have the capacity for intrinsic repair, preserving kidney architecture with return to a basal state after tubular injury. When injury is overwhelming or repetitive, however, that capacity is exceeded and incomplete repair results in fibrotic tissue replacing normal kidney parenchyma. Loss of nephrons correlates with reduced kidney function, which defines chronic kidney disease (CKD) and confers substantial morbidity and mortality to the worldwide population. Despite the identification of pathways involved in intrinsic repair, limited treatments for CKD exist, partly because of the limited throughput and predictivity of animal studies. Here, we showed that kidney organoids can model the transition from intrinsic to incomplete repair. Single-nuclear RNA sequencing of kidney organoids after cisplatin exposure identified 159 differentially expressed genes and 29 signal pathways in tubular cells undergoing intrinsic repair. Homology-directed repair (HDR) genes including Fanconi anemia complementation group D2 (FANCD2) and RAD51 recombinase (RAD51) were transiently up-regulated during intrinsic repair but were down-regulated in incomplete repair. Single cellular transcriptomics in mouse models of obstructive and hemodynamic kidney injury and human kidney samples of immune-mediated injury validated HDR gene up-regulation during tubular repair. Kidney biopsy samples with tubular injury and varying degrees of fibrosis confirmed loss of FANCD2 during incomplete repair. Last, we performed targeted drug screening that identified the DNA ligase IV inhibitor, SCR7, as a therapeutic candidate that rescued FANCD2/RAD51-mediated repair to prevent the progression of CKD in the cisplatin-induced organoid injury model. Our findings demonstrate the translational utility of kidney organoids to identify pathologic pathways and potential therapies.

Family Functioning as a Protective Factor for Sexual Risk Behaviors Among Gender Minority Adolescents.

Gender minority (GM) youth are more likely to engage in sexual behaviors that increase risk of exposure to sexually transmitted infections, including HIV. However, family functioning may be protective against sexual risk taking. We characterized longitudinal associations between family functioning (family communication and family satisfaction) and sexual risk behaviors across two years in a community sample of 30 GM adolescents, ages 13-17 years. Participants were purposively recruited from community-based venues, through social media, and peer referrals throughout the New England area and completed surveys every 6 months, with measures of family functioning, sexual risk behaviors, risk factors (depressive and anxious symptoms, perceived stress related to parents), and protective factors (social support, gender-related pride, and community connectedness). Results indicated that higher levels of family communication, improved family satisfaction, and increased social support were protective for sexual risk taking, in general, and specifically for condom use for anal/vaginal sex. In contrast, increased depressive symptoms were associated with lower likelihood of anal/vaginal condom use. Associations between family functioning and sexual risk taking were not attenuated by adding risk and protective factors to the model; thus, these factors did not explain the observed associations between family functioning and sexual risk taking. These findings suggest improved family functioning, greater social support, and lower depressive symptoms are associated with reduced sexual risk taking among gender minority youth, thus making these factors an important target for future prevention efforts.