Clinical exome sequencing of 1000 families with complex immune phenotypes: Toward comprehensive genomic evaluations.

BACKGROUND: Prospective genetic evaluation of patients at this referral research hospital presents clinical research challenges. OBJECTIVES: This study sought not only a single-gene explanation for participants' immune-related presentations, but viewed each participant holistically, with the potential to have multiple genetic contributions to their immune phenotype and other heritable comorbidities relevant to their presentation and health. METHODS: This study developed a program integrating exome sequencing, chromosomal microarray, phenotyping, results return with genetic counseling, and reanalysis in 1505 individuals from 1000 families with suspected or known inborn errors of immunity. RESULTS: Probands were 50.8% female, 71.5% were ≥18 years, and had diverse immune presentations. Overall, 327 of 1000 probands (32.7%) received 361 molecular diagnoses. These included 17 probands with diagnostic copy number variants, 32 probands with secondary findings, and 31 probands with multiple molecular diagnoses. Reanalysis added 22 molecular diagnoses, predominantly due to new disease-gene associations (9 of 22, 40.9%). One-quarter of the molecular diagnoses (92 of 361) did not involve immune-associated genes. Molecular diagnosis was correlated with younger age, male sex, and a higher number of organ systems involved. This program also facilitated the discovery of new gene-disease associations such as SASH3-related immunodeficiency. A review of treatment options and ClinGen actionability curations suggest that at least 251 of 361 of these molecular diagnoses (69.5%) could translate into ≥1 management option. CONCLUSIONS: This program contributes to our understanding of the diagnostic and clinical utility whole exome analysis on a large scale.

Hospital Chaplains: Through the Eyes of Parents of Hospitalized Children.

BACKGROUND: Chaplain services are available in 68% of hospitals, but hospital chaplains are not yet incorporated into routine patient care. OBJECTIVES: To describe how families of hospitalized children view and utilize hospital chaplains. DESIGN: Telephone survey with 40 questions: Likert, yes/no, and short-answer responses. SUBJECTS: Parents visited by a hospital chaplain during their child's hospitalization in a tertiary care center. MEASUREMENTS: Descriptive statistics were used to characterize the sample. Nonparametrics were used to compare religious versus nonreligious parents. Regression was used to identify independent predictors of a chaplain visit positively influencing satisfaction with hospital care. RESULTS: Seventy-four parents were interviewed; most were 25-50 years old, and 75% felt their child was very sick. Children ranged from newborn to adolescence. Forty-two percent of parents requested a chaplain visit; of the 58% with an unsolicited visit, 11% would have preferred giving prior approval. Parents felt that chaplains provided religious and secular services, including family support and comfort, help with decision making, medical terminology, and advocacy. Chaplains helped most parents maintain hope and reduce stress. Seventy-five percent of parents viewed chaplains as a member of the healthcare team; 38% reported that chaplains helped medical personnel understand their preferences for care and communication. Most parents (66%) felt that hospital chaplaincy increased their satisfaction with hospital care. CONCLUSION: Families play a fundamental role in the recovery of hospitalized children. Parents view hospital chaplains as members of the healthcare team and report that they play an important role in the well-being of the family during childhood hospitalization. Chaplains positively influence satisfaction with hospital care.

Rapid antimicrobial susceptibility test for identification of new therapeutics and drug combinations against multidrug-resistant bacteria.

Current antimicrobial susceptibility testing has limited screening capability for identifying empirical antibiotic combinations to treat severe bacterial infections with multidrug-resistant (MDR) organisms. We developed a new antimicrobial susceptibility assay using automated ultra-high-throughput screen technology in combination with a simple bacterial growth assay. A rapid screening of 5170 approved drugs and other compounds identified 25 compounds with activities against MDR Klebsiella pneumoniae. To further improve the efficacy and reduce the effective drug concentrations, we applied a targeted drug combination approach that integrates drugs' clinical antimicrobial susceptibility breakpoints, achievable plasma concentrations, clinical toxicities and mechanisms of action to identify optimal drug combinations. Three sets of three-drug combinations were identified with broad-spectrum activities against 10 MDR clinical isolates including K. pneumoniae, Acinetobacter baumannii, Pseudomonas aeruginosa, Citrobacter freundii, Enterobacter cloacae and Escherichia coli. Colistin-auranofin-ceftazidime and colistin-auranofin-rifabutin suppressed >80% growth of all 10 MDR strains; while rifabutin-colistin-imipenem inhibited >75% of these strains except two Acinetobacter baumannii isolates. The results demonstrate this new assay has potential as a real-time method to identify new drugs and effective drug combinations to combat severe clinical infections with MDR organisms.