Continued midazolam versus diphenhydramine in difficult-to-sedate patients: a randomized double-blind trial.

BACKGROUND AND AIMS: Current guidelines recommend diphenhydramine in patients undergoing endoscopy who are not adequately sedated with a benzodiazepine and opioid combination. Because this practice has not been adequately assessed, we performed a randomized, double-blind trial comparing diphenhydramine with continued midazolam in such patients. METHODS: Patients undergoing elective colonoscopy with moderate sedation were eligible. Sedation was measured with the Modified Observer's Assessment of Alertness/Sedation (MOAA/S) score with adequate sedation defined as 3 on a 0- to 5-point scale. Patients not adequately sedated with midazolam 5 mg and fentanyl 100 µg were randomly assigned to diphenhydramine 25 mg versus continued midazolam 1.5 mg. Adequacy of sedation was assessed 3 minutes after each study medication dose. If MOAA/S was 4 to 5, study medication was repeated, to a maximum of 3 doses. The primary endpoint was adequate sedation. RESULTS: The planned enrollment of 200 patients (100 in each study group) was attained. Adequate sedation was achieved less often with diphenhydramine than midazolam (27% vs 65%, difference = -38%; 95% CI, -50% to -24%; P < .0001). After study medications were completed, more patients required additional medication for sedation or analgesia with diphenhydramine versus midazolam (84% vs 68%, P = .008), whereas the time to discharge from the recovery unit was similar (134 vs 129 minutes). Treatment effect was consistent across subgroups including age ≤55, substance abuse, benzodiazepine use, opioid use, and psychiatric medication use. CONCLUSIONS: Endoscopists performing moderate sedation should continue midazolam rather than switching to diphenhydramine in patients who do not achieve adequate sedation with usual doses of midazolam and an opioid. (Clinical trial registration number: NCT01769586.).

Diverticular disease: paradigm shifts in pathogenesis and treatment.

OPINION STATEMENT: Colonic diverticulosis is one of the most common gastrointestinal conditions affecting the Western world and is recognized as an increasingly common condition since its first description in the 1800s. Despite its widespread prevalence, its exact pathogenesis remains unknown. Additionally, its wide spectrum of clinical manifestations has led to multiple approaches in the management of this disease. Our understanding of the condition has continued to evolve. Newer studies have challenged some long-held beliefs regarding diverticular disease (DD) and put forward some new theories. This has laid the groundwork for further research to be done in this area to improve our understanding of DD. In any individual case, diet therapy, rifaximin, mesalamine, antibiotics, or surgery may be useful depending on the clinical status.

Intermittent vs continuous proton pump inhibitor therapy for high-risk bleeding ulcers: a systematic review and meta-analysis.

IMPORTANCE: Current guidelines recommend an intravenous bolus dose of a proton pump inhibitor (PPI) followed by continuous PPI infusion after endoscopic therapy in patients with high-risk bleeding ulcers. Substitution of intermittent PPI therapy, if similarly effective as bolus plus continuous-infusion PPI therapy, would decrease the PPI dose, costs, and resource use. OBJECTIVE: To compare intermittent PPI therapy with the currently recommended bolus plus continuous-infusion PPI regimen for reduction of ulcer rebleeding. DATA SOURCES: Searches included MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials databases through December 2013; US and European gastroenterology meeting abstracts from 2009 to 2013; and bibliographies of systematic reviews. STUDY SELECTION: Randomized trials of patients with endoscopically treated high-risk bleeding ulcers (active bleeding, nonbleeding visible vessels, and adherent clots) comparing intermittent doses of PPIs and the currently recommended regimen (80-mg intravenous bolus dose of a PPI followed by an infusion of 8 mg/h for 72 hours). DATA EXTRACTION AND SYNTHESIS: Duplicate independent data extraction and risk-of-bias assessment were performed. Data were pooled using a fixed-effects model or a random effects model if statistical heterogeneity was present. MAIN OUTCOMES AND MEASURES: The primary outcome was rebleeding within 7 days; additional predefined outcomes included rebleeding within 3 and 30 days, need for urgent intervention, mortality, red blood cell transfusion, and length of hospital stay. The primary hypothesis, defined before initiation of the literature review, was that intermittent use of PPIs was noninferior to bolus plus continuous infusion of PPIs, with the noninferiority margin predefined as an absolute risk difference of 3%. RESULTS: The risk ratio of rebleeding within 7 days for intermittent vs bolus plus continuous infusion of PPIs was 0.72 (upper boundary of 1-sided 95% CI, 0.97) and the absolute risk difference was -2.64% (upper boundary of 1-sided 95% CI, -0.28%, which is well below the predefined noninferiority margin of 3%). Risk ratios for rebleeding within 30 days and 3 days, mortality, and urgent interventions were less than 1 and mean differences for blood transfusion and hospital length of stay were less than 0, indicating that no summary estimate showed an increased risk with intermittent therapy. The upper boundaries of 95% CIs for absolute risk differences were less than 1.50% for all predefined rebleeding outcomes. CONCLUSIONS AND RELEVANCE: Intermittent PPI therapy is comparable to the current guideline-recommended regimen of intravenous bolus plus a continuous infusion of PPIs in patients with endoscopically treated high-risk bleeding ulcers. Guidelines should be revised to recommend intermittent PPI therapy.

The symmetrical dimethylarginine post-translational modification of the SmD3 protein is not required for snRNP assembly and nuclear transport.

The SmB, SmD1, and SmD3 proteins have the rare symmetrical dimethylarginine post-translational modification in their C-termini. In this report, we investigate the function of this modification in the assembly and intracellular transport of the SmD3 protein. We show that the elimination of this methylation in the SmD3 protein, by mutating the modified arginines to leucines, does not interfere with the assembly and the nuclear transport of the transiently expressed SmD3 variant. This suggests this modification is not essential for maturation of the SmD3 protein.