Low-frequency inherited complement receptor variants are associated with purpura fulminans.

ABSTRACT: Extreme disease phenotypes can provide key insights into the pathophysiology of common conditions, but studying such cases is challenging due to their rarity and the limited statistical power of existing methods. Herein, we used a novel approach to pathway-based mutational burden testing, the rare variant trend test (RVTT), to investigate genetic risk factors for an extreme form of sepsis-induced coagulopathy, infectious purpura fulminans (PF). In addition to prospective patient sample collection, we electronically screened over 10.4 million medical records from 4 large hospital systems and identified historical cases of PF for which archived specimens were available to perform germline whole-exome sequencing. We found a significantly increased burden of low-frequency, putatively function-altering variants in the complement system in patients with PF compared with unselected patients with sepsis (P = .01). A multivariable logistic regression analysis found that the number of complement system variants per patient was independently associated with PF after controlling for age, sex, and disease acuity (P = .01). Functional characterization of PF-associated variants in the immunomodulatory complement receptors CR3 and CR4 revealed that they result in partial or complete loss of anti-inflammatory CR3 function and/or gain of proinflammatory CR4 function. Taken together, these findings suggest that inherited defects in CR3 and CR4 predispose to the maladaptive hyperinflammation that characterizes severe sepsis with coagulopathy.

Knowledge, attitudes, and practices of registered dietitians and nutritionists regarding enteral and parenteral nutrition support in Ghana: a needs assessment study.

Background: There is a paucity of data on enteral and parenteral (EN and PN) nutrition support (NS) provided by nutrition and dietetic practitioners in adult acute care settings in Ghana. Furthermore, gray literature suggests that Ghanaian clinical nutrition professionals (CNPs) are seldom involved in advanced nutrition care teams. Objectives: To assess the knowledge, attitudes, and practices of Ghanaian CNPs regarding EN and PN. Methods: An online cross-sectional survey was administered to Ghanaian CNPs ahead of a professional development workshop on EN and PN Support. Participants were asked questions about initiation and timing of NS, and knowledge on availability of commercial formula. A 5-point Likert scale was used to assess self-efficacy in using EN and PN. To assess practical knowledge on EN and PN, participants were asked to identify whether EN or PN was indicated for seven short case scenarios. Open-ended questions were used to assess reasons for participant self-ratings. Results: A total of 76 dietitians, nutritionists, students, and interns completed the survey. For EN, self-efficacy scores were lowest for the calculation of enteral goal rate, and goal volume (mean 3.20 ± 1.27), and writing of EN prescriptions (mean 3.07 ± 1.29). Self-efficacy scores for the formulation of alternative formulas in lieu of commercial formula were the highest (3.63 ± 1.36). For PN, self-efficacy scores for all domains were lower than 3, with the lowest scores observed for writing PN prescriptions (2.19 ± 1.14) and determining micronutrient additives (2.12 ± 1.04). We identified limited training and lack of practical exposure to NS, limited ability to effectively monitor tube feeds, and prohibitive cost and limited availability of EN and PN formula among the barriers impacting self-efficacy scores. Conclusion: Given the vital role that CNPs play in the delivery of EN and PN, it is important to develop professional training programs especially focused on PN to bridge knowledge and practice gaps.

Lack of association between the C3435T polymorphism in the human multidrug resistance (MDR1) gene and response to antiepileptic drug treatment.

PURPOSE: P-glycoprotein (P-gp) has been implicated in the causation of refractory epilepsy. The expression and efflux efficiency of P-gp is influenced by a polymorphism (C3435T) in the encoding gene (MDR1). Recent evidence suggests that the homozygous C-variant, which is associated with higher expression and increased activity of P-gp, is more common in patients with pharmacoresistant epilepsy. We have investigated the prevalence of this polymorphism in a series of patients attending a specialist epilepsy clinic. METHODS: DNA samples were obtained from 400 patients, irrespective of seizure type or drug treatment. Genotype of the C3435T polymorphism was determined by traditional polymerase chain reaction (PCR) followed by restriction digest. Classification of response to treatment was determined in a blinded fashion by an independent physician. Results were expressed as genotype and allele frequencies per response group and compared by logistic regression analysis. RESULTS: In total, 170 patients were classified as responders, with > or =12 months seizure freedom on current treatment. The remaining 230 patients were classified as nonresponders. Comparison of responders and nonresponders revealed no significant difference in allele frequency (C vs. T; odds ratio, 1.03; 95% CI, 0.78-1.37; p = 0.83) or genotype frequency (CC vs TT; odds ratio, 1.07; 95% CI, 0.60-1.91; p = 0.81). Subanalyses of individual seizure types were similarly unremarkable. CONCLUSIONS: This study failed to corroborate a previously reported association between the C3435T polymorphism in the human MDR1 gene and pharmacoresistant epilepsy. Whether the C3435T polymorphism can act as a marker for the natural history of treated epilepsy remains to be determined.