Population-specific variations in KCNH2 predispose patients to delayed ventricular repolarization upon dihydroartemisinin-piperaquine therapy.

Dihydroartemisinin-piperaquine is efficacious for the treatment of uncomplicated malaria and its use is increasing globally. Despite the positive results in fighting malaria, inhibition of the Kv11.1 channel (hERG; encoded by the KCNH2 gene) by piperaquine has raised concerns about cardiac safety. Whether genetic factors could modulate the risk of piperaquine-mediated QT prolongations remained unclear. Here, we first profiled the genetic landscape of KCNH2 variability using data from 141,614 individuals. Overall, we found 1,007 exonic variants distributed over the entire gene body, 555 of which were missense. By optimizing the gene-specific parametrization of 16 partly orthogonal computational algorithms, we developed a KCNH2-specific ensemble classifier that identified a total of 116 putatively deleterious missense variations. To evaluate the clinical relevance of KCNH2 variability, we then sequenced 293 Malian patients with uncomplicated malaria and identified 13 variations within the voltage sensing and pore domains of Kv11.1 that directly interact with channel blockers. Cross-referencing of genetic and electrocardiographic data before and after piperaquine exposure revealed that carriers of two common variants, rs1805121 and rs41314375, experienced significantly higher QT prolongations (ΔQTc of 41.8 ms and 61 ms, respectively, vs 14.4 ms in controls) with more than 50% of carriers having increases in QTc >30 ms. Furthermore, we identified three carriers of rare population-specific variations who experienced clinically relevant delayed ventricular repolarization. Combined, our results map population-scale genetic variability of KCNH2 and identify genetic biomarkers for piperaquine-induced QT prolongation that could help to flag at-risk patients and optimize efficacy and adherence to antimalarial therapy.

Learning Curve for Laparoscopic Sleeve Gastrectomy: a Cumulative Summation (CUSUM) Analysis.

PURPOSE: Bariatric surgery is currently considered the most effective and durable treatment option for morbid obesity. Laparoscopic sleeve gastrectomy (LSG) has become a popular technique and may currently be the most frequently practiced surgical operation to treat obesity. However, no objective analyses of its learning curve have been reported. OBJECTIVE: to analyze the learning curve for LSG. MATERIALS AND METHODS: We included all LSGs performed in our hospital (University Hospital, Spain; Public Practice) from April 2013 to February 2016. The learning curve for LSG was evaluated using cumulative sum (CUSUM) analysis. All variables among the learning curve phases were compared. RESULTS: According to the CUSUM analysis, the learning curve was divided into three unique phases: early learning (the initial 26 patients), acquisition of skills (the middle 30 patients), and mastery of technique (the final 56 patients). The operative time and gastric stenosis significantly decreased with progression of the learning curve without differences in the 30-day postoperative complication rate, postoperative stay, or weight loss. CONCLUSION: According to this study, the learning curve for LSG can be divided into 3 distinct phases, and about 25 patients are needed to demonstrate an improvement in surgical skill.

The relationship between trial data in judicial sentences and self-reported aggression in men convicted of violence against women.

BACKGROUND: The Revised Conflict Tactics Scale (CTS-2) is widely used to assess intimate partner violence (IPV). Given the limitations preventing the collection of dyadic data, it is necessary to examine the relationship between the offender's own self-reporting and the facts established in trial proceedings. This study assesses the relationship between aggression data self-reported by participants via CTS-2 and the data contained in convictions for partner abuse. METHOD: Two groups of men convicted of abuse against their female intimate partners or ex-partners (1,998 imprisoned offenders and 804 court-referred offenders), and 590 men from the community (general population) participated. The relationship was analyzed between the scores for self-reported CTS-2 items and violent behaviors described by proven facts. An ANCOVA with post-hoc comparisons (Bonferroni) was performed to assess the differences in CTS-2 scores between the three groups. RESULTS: In the two groups of convicted participants, a significant relationship was found between CTS-2 items and the proven facts. Meanwhile, significant differences were found between the three groups in three CTS-2 subscales. CONCLUSIONS: The CTS-2 self-reported perpetrated aggression data provided by the convicted participants are related to the factual basis for convictions, and such data are therefore usable in forensic and psychological intervention contexts.