Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry.

Importance: Black patients with dilated cardiomyopathy (DCM) have increased familial risk and worse outcomes than White patients, but most DCM genetic data are from White patients. Objective: To compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM. Design: Cross-sectional study enrolling patients with DCM who self-identified as non-Hispanic Black, Hispanic, or non-Hispanic White from June 7, 2016, to March 15, 2020, at 25 US advanced heart failure programs. Variants in 36 DCM genes were adjudicated as pathogenic, likely pathogenic, or of uncertain significance. Exposure: Presence of DCM. Main Outcomes and Measures: Variants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic). Results: A total of 505, 667, and 26 patients with DCM of predominantly African, European, or Native American genomic ancestry, respectively, were included. Compared with patients of European ancestry, a lower percentage of patients of African ancestry had clinically actionable variants (8.2% [95% CI, 5.2%-11.1%] vs 25.5% [95% CI, 21.3%-29.6%]), reflecting the lower odds of a clinically actionable variant for those with any pathogenic variant/likely pathogenic variant/variant of uncertain significance (odds ratio, 0.25 [95% CI, 0.17-0.37]). On average, patients of African ancestry had fewer clinically actionable variants in TTN (difference, -0.09 [95% CI, -0.14 to -0.05]) and other genes with predicted loss of function as a disease-causing mechanism (difference, -0.06 [95% CI, -0.11 to -0.02]). However, the number of pathogenic variants/likely pathogenic variants/variants of uncertain significance was more comparable between ancestry groups (difference, -0.07 [95% CI, -0.22 to 0.09]) due to a larger number of non-TTN non-predicted loss of function variants of uncertain significance, mostly missense, in patients of African ancestry (difference, 0.15 [95% CI, 0.00-0.30]). Published clinical case-based evidence supporting pathogenicity was less available for variants found only in patients of African ancestry (P < .001). Conclusion and Relevance: Patients of African ancestry with DCM were less likely to have clinically actionable variants in DCM genes than those of European ancestry due to differences in genetic architecture and a lack of representation of African ancestry in clinical data sets.

Use of therapeutic drug monitoring to characterize cefepime-related neurotoxicity.

STUDY OBJECTIVES: Data evaluating cefepime thresholds associated with neurotoxicity remain limited. The objectives of this study were to evaluate the incidence of cefepime-related neurotoxicity (CRN) in patients with plasma cefepime concentrations, assess the relationship between cefepime exposure and CRN, investigate clinical factors associated with CRN, and describe electroencephalogram (EEG) abnormalities in CRN. DESIGN: This was a retrospective study of adult inpatients admitted between 2016 and 2018 who received cefepime therapeutic drug monitoring (TDM). Potential CRN cases were identified utilizing a standard definition. The primary outcomes of the study were to determine the incidence of CRN and evaluate the relationship between cefepime trough concentrations, the average daily AUC, and neurotoxicity. Bayesian posteriors were generated for each patient using a cefepime pharmacokinetic (PK) model, and the mean daily area under the concentration-time curve (AUC) was calculated. Multiple regression was performed to assess the association between CRN, cefepime PK, and clinical predictors of neurotoxicity. MAIN RESULTS: Four hundred eighty-one patients with 503 hospital encounters received cefepime TDM and were included in the analysis. The incidence of CRN was 4.4% (22/503). Patients with CRN had a higher incidence of renal dysfunction, hypertension, and diabetes mellitus compared to patients without CRN (non-NT). The mean cefepime trough concentration was significantly greater in the CRN patients than in the non-NT group (61.8 ± 33.7 vs. 30 ± 27.7 mg/L, respectively, p = 0.0002). Cefepime trough concentration and renal dysfunction were independently associated with increased risk of CRN in the adjusted multiple regression model. Moderate generalized slowing of the background rhythm was the most common EEG pattern associated with CRN. Delaying cefepime TDM greater than 72 h after the initiation of cefepime was associated with a 3-fold increased risk of CRN. CONCLUSION: Cefepime should be used cautiously in hospitalized patients with renal dysfunction due to the risk of neurotoxicity. Dose optimization utilizing TDM early in cefepime treatment may minimize adverse effects and improve patient safety.

Impact of confinement housing on study end-points in the calf model of cryptosporidiosis.

BACKGROUND: Diarrhea is the second leading cause of death in children < 5 years globally and the parasite genus Cryptosporidium is a leading cause of that diarrhea. The global disease burden attributable to cryptosporidiosis is substantial and the only approved chemotherapeutic, nitazoxanide, has poor efficacy in HIV positive children. Chemotherapeutic development is dependent on the calf model of cryptosporidiosis, which is the best approximation of human disease. However, the model is not consistently applied across research studies. Data collection commonly occurs using two different methods: Complete Fecal Collection (CFC), which requires use of confinement housing, and Interval Collection (IC), which permits use of box stalls. CFC mimics human challenge model methodology but it is unknown if confinement housing impacts study end-points and if data gathered via this method is suitable for generalization to human populations. METHODS: Using a modified crossover study design we compared CFC and IC and evaluated the impact of housing on study end-points. At birth, calves were randomly assigned to confinement (n = 14) or box stall housing (n = 9), or were challenged with 5 x 107 C. parvum oocysts, and followed for 10 days. Study end-points included fecal oocyst shedding, severity of diarrhea, degree of dehydration, and plasma cortisol. FINDINGS: Calves in confinement had no significant differences in mean log oocysts enumerated per gram of fecal dry matter between CFC and IC samples (P = 0.6), nor were there diurnal variations in oocyst shedding (P = 0.1). Confinement housed calves shed significantly more oocysts (P = 0.05), had higher plasma cortisol (P = 0.001), and required more supportive care (P = 0.0009) than calves in box stalls. CONCLUSION: Housing method confounds study end-points in the calf model of cryptosporidiosis. Due to increased stress data collected from calves in confinement housing may not accurately estimate the efficacy of chemotherapeutics targeting C. parvum.