Characterizing Patients with Recurrent Urinary Tract Infections in Vesicoureteral Reflux: A Pilot Study of the Urinary Proteome

Recurrent urinary tract infections (UTIs) pose a significant burden on the health care system. Underlying mechanisms predisposing children to UTIs and associated changes in the urinary proteome are not well understood. We aimed to investigate the urinary proteome of a subset of children who have vesicoureteral reflux (VUR) and recurrent UTIs because of their risk of developing infection-related renal damage. Improving diagnostic modalities to identify UTI risk factors would significantly alter the clinical management of children with VUR. We profiled the urinary proteomes of 22 VUR patients with low grade VUR (1-3 out of 5), a history of recurrent UTIs, and renal scarring, comparing them to those obtained from 22 age-matched controls. Urinary proteins were analyzed by mass spectrometry followed by protein quantitation based on spectral counting. Of the 2,551 proteins identified across both cohorts, 964 were robustly quantified, as defined by meeting criteria with spectral count (SC) \u3e /=2 in at least 7 patients in either VUR or control cohort based on optimization of signal-to-noise ratio. Eighty proteins had differential expression between the two cohorts, with 44 proteins significantly upregulated and 36 downregulated (q \u3c 0.075, |FC| \u3e 1.2). Urinary proteins involved in inflammation, acute phase response (APR), modulation of extracellular matrix (ECM), and carbohydrate metabolism were overrepresented among the study cohort

Phenotypic spectrum and transcriptomic profile associated with germline variants in TRAF7

PURPOSE: Somatic variants in tumor necrosis factor receptor-associated factor 7 (TRAF7) cause meningioma, while germline variants have recently been identified in seven patients with developmental delay and cardiac, facial, and digital anomalies. We aimed to define the clinical and mutational spectrum associated with TRAF7 germline variants in a large series of patients, and to determine the molecular effects of the variants through transcriptomic analysis of patient fibroblasts. METHODS: We performed exome, targeted capture, and Sanger sequencing of patients with undiagnosed developmental disorders, in multiple independent diagnostic or research centers. Phenotypic and mutational comparisons were facilitated through data exchange platforms. Whole-transcriptome sequencing was performed on RNA from patient- and control-derived fibroblasts. RESULTS: We identified heterozygous missense variants in TRAF7 as the cause of a developmental delay-malformation syndrome in 45 patients. Major features include a recognizable facial gestalt (characterized in particular by blepharophimosis), short neck, pectus carinatum, digital deviations, and patent ductus arteriosus. Almost all variants occur in the WD40 repeats and most are recurrent. Several differentially expressed genes were identified in patient fibroblasts. CONCLUSION: We provide the first large-scale analysis of the clinical and mutational spectrum associated with the TRAF7 developmental syndrome, and we shed light on its molecular etiology through transcriptome studies

A multilevel mHealth intervention boosts adherence to hydroxyurea in individuals with sickle cell disease

Hydroxyurea reduces sickle cell disease (SCD) complications, but medication adherence is low. We tested 2 mobile health (mHealth) interventions targeting determinants of low adherence among patients (InCharge Health) and low prescribing among providers (HU Toolbox) in a multi-center, non-randomized trial of individuals with SCD ages 15-45. We compared the percentage of days covered (PDC), labs, healthcare utilization, and self-reported pain over 24 weeks of intervention and 12 weeks post-study with a 24-week preintervention interval. We enrolled 293 patients (51% male; median age 27.5 years, 86.8% HbSS/HbSβ0-thalassemia). The mean change in PDC among 235 evaluable subjects increased (39.7% to 56.0%; P < 0.001) and sustained (39.7% to 51.4%, P < 0.001). Mean HbF increased (10.95% to 12.78%; P = 0.03). Self-reported pain frequency reduced (3.54 to 3.35 events/year; P = 0.041). InCharge Health was used ≥1 day by 199 of 235 participants (84.7% implementation; median usage: 17% study days; IQR: 4.8-45.8%). For individuals with ≥1 baseline admission for pain, admissions per 24 weeks declined from baseline through 24 weeks (1.97 to 1.48 events/patient, P = 0.0045) and weeks 25-36 (1.25 events/patient, P = 0.0015). PDC increased with app use (P < 0.001), with the greatest effect in those with private insurance (P = 0.0078), older subjects (P = 0.033), and those with lower pain interference (P = 0.0012). Of the 89 providers (49 hematologists, 36 advanced care providers, 4 unreported), only 11.2% used HU Toolbox ≥1/month on average. This use did not affect change in PDC. Tailoring mHealth solutions to address barriers to hydroxyurea adherence can potentially improve adherence and provide clinical benefits. A definitive randomized study is warranted. This trial was registered at www.clinicaltrials.gov as #NCT04080167