Effects of nicotine on alcohol drinking in female mice selectively-bred for high or low alcohol preference

Background Studies show that repeated nicotine use associates with high alcohol consumption in humans, and that nicotine exposure sometimes increases alcohol consumption in animal models. However, the relative roles of genetic predisposition to high alcohol consumption, the alcohol drinking patterns, and the timing of nicotine exposure both with respect to alcohol drinking and developmental stage remain unclear. The studies here manipulated all these variables, using mice selectively bred for differences in free-choice alcohol consumption to elucidate the role of genetics and nicotine exposure in alcohol consumption behaviors. Methods In Experiments 1 and 2, we assessed the effects of repeated nicotine (0, 0.5 or 1.5 mg/kg) injections immediately before binge-like (drinking-in-the-dark; Experiment 1) or during free-choice alcohol access (Experiment 2) on these alcohol drinking behaviors (immediately after injections and during re-exposure to alcohol access 14 days later) in adult high- (HAP2) and low-alcohol preferring (LAP2) female mice (co-exposure model). In Experiments 3 and 4, we assessed the effects of repeated nicotine (0, 0.5 or 1.5 mg/kg) injections 14 days prior to binge-like and free-choice alcohol access on these alcohol drinking behaviors in adolescent HAP2 and LAP2 female mice (Experiment 3) or adult HAP2 female mice (Experiment 4). Results In Experiment 1, we found that repeated nicotine (0.5 and 1.5 mg/kg) and alcohol co-exposure significantly increased binge-like drinking behavior in HAP2 but not LAP2 mice during the re-exposure phase after a 14-day abstinence period. In Experiment 2, 1.5 mg/kg nicotine injections significantly reduced free-choice alcohol intake and preference in the 3rd hour post-injection in HAP2 but not LAP2 mice. No significant effects of nicotine treatment on binge-like or free-choice alcohol drinking were observed in Experiments 3 and 4. Conclusions These results show that the temporal parameters of nicotine and alcohol exposure, pattern of alcohol access, and genetic predisposition for alcohol preference influence nicotine's effects on alcohol consumption. These findings in selectively bred mice suggest that humans with a genetic history of alcohol-use disorders may be more vulnerable to develop nicotine and alcohol co-use disorders

Evaluation of a quality improvement intervention to reduce anastomotic leak following right colectomy (EAGLE): pragmatic, batched stepped-wedge, cluster-randomized trial in 64 countries

Background Anastomotic leak affects 8 per cent of patients after right colectomy with a 10-fold increased risk of postoperative death. The EAGLE study aimed to develop and test whether an international, standardized quality improvement intervention could reduce anastomotic leaks. Methods The internationally intended protocol, iteratively co-developed by a multistage Delphi process, comprised an online educational module introducing risk stratification, an intraoperative checklist, and harmonized surgical techniques. Clusters (hospital teams) were randomized to one of three arms with varied sequences of intervention/data collection by a derived stepped-wedge batch design (at least 18 hospital teams per batch). Patients were blinded to the study allocation. Low- and middle-income country enrolment was encouraged. The primary outcome (assessed by intention to treat) was anastomotic leak rate, and subgroup analyses by module completion (at least 80 per cent of surgeons, high engagement; less than 50 per cent, low engagement) were preplanned. Results A total 355 hospital teams registered, with 332 from 64 countries (39.2 per cent low and middle income) included in the final analysis. The online modules were completed by half of the surgeons (2143 of 4411). The primary analysis included 3039 of the 3268 patients recruited (206 patients had no anastomosis and 23 were lost to follow-up), with anastomotic leaks arising before and after the intervention in 10.1 and 9.6 per cent respectively (adjusted OR 0.87, 95 per cent c.i. 0.59 to 1.30; P = 0.498). The proportion of surgeons completing the educational modules was an influence: the leak rate decreased from 12.2 per cent (61 of 500) before intervention to 5.1 per cent (24 of 473) after intervention in high-engagement centres (adjusted OR 0.36, 0.20 to 0.64; P < 0.001), but this was not observed in low-engagement hospitals (8.3 per cent (59 of 714) and 13.8 per cent (61 of 443) respectively; adjusted OR 2.09, 1.31 to 3.31). Conclusion Completion of globally available digital training by engaged teams can alter anastomotic leak rates. Registration number: NCT04270721 (http://www.clinicaltrials.gov)