Evaluating the efficacy of CGRP mAbs and gepants for the preventive treatment of migraine: A systematic review and network meta-analysis of phase 3 randomised controlled trials

Migraine; PreventionMigranya; PrevencióMigraña; PrevenciónBackground Several novel treatments targeting the calcitonin gene-related peptide pathway have been developed for migraine. We evaluated the efficacy of these medications, including atogepant, rimegepant, erenumab, eptinezumab, fremanezumab, and galcanezumab, for the prevention of migraine via network meta-analysis. Methods Databases, including MEDLINE via PubMed, EMBASE, and Cochrane central, were systematically reviewed, and all eligible phase 3 randomised controlled trials were included. Results Nineteen studies (n = 14,584 participants) were included. Studies included episodic (n = 11) and chronic (n = 4) migraine or both (n = 4). All interventions, except for eptinzumab 30 mg, significantly reduced mean monthly migraine days compared to placebo. All medications had a higher ≥50% responder rate than placebo and results were statistically significant in those with the subcutaneous or intravenous route of administrations, but not with the oral one. All medications significantly reduced mean monthly headache days, although no data for this outcome was available for rimegepant, and mean monthly acute medication days, with no data for eptinezumab. Conclusion The results show that medications targeting calcitonin gene-related peptide were effective in preventing migraine compared to placebo. Considering limitations of single studies, different populations such as episodic and chronic migraine, and the absence of head-to-head trials, all novel treatments decreased mean monthly migraine and headache days, and showed higher 50%, 75% and 100% responder rates than placebo

BayMAP: a Bayesian hierarchical model for the analysis of PAR-CLIP data

Motivation Photoactivatable-Ribonucleoside-Enhanced Crosslinking and Immunoprecipitation (PAR-CLIP) is a biochemical method for detecting interaction sites of proteins with mRNA. This method introduces T-to-C substitutions at sequenced cDNA that help to detect binding sites on mRNA. However, T-to-C substitutions can also occur due to other reasons such as mismatches or SNPs. Only few statistical procedures exist for detecting binding sites in PAR-CLIP data. Most of these methods do not account for other types of substitutions than those induced by PAR-CLIP, and therefore, also report positions with high T-to-C substitution rates, e.g. SNPs, as binding sites. Moreover, none of these procedures allow to include additional information, e.g. the type of mRNA region, relevant for the biology of microRNA-binding sites. Results We have developed BayMAP, a procedure based on a fully Bayesian hierarchical model that takes other sources of substitutions into account. Furthermore, this model enables the incorporation of additional information into the analysis of PAR-CLIP data. This incorporation does not only permit a better detection of binding sites, but also a better understanding of the data and the biology of binding sites. In applications to simulated PAR-CLIP data, BayMAP distinguishes binding sites from noise better than existing methods. Additionally, it yields good estimates of the influence of the additional information. We here demonstrate BayMAP's usability for real datasets even when noisy data is present. Availability and implementation BayMAP is freely available as an R package at http://stat.math.uni-duesseldorf.de/baymap. Supplementary information Supplementary data are available at Bioinformatics online

Efficacy, safety and indirect comparisons of lasmiditan, rimegepant, and ubrogepant for the acute treatment of migraine: A systematic review and network meta-analysis of the literature

Background: We performed a random-effects network meta-analysis to study the efficacy and safety of newly developed drugs for the acute treatment of migraine attacks. Methods: MEDLINE via PubMed, Embase and The Cochrane Register of Controlled Trials were searched from inception to 11 February 2022. Phase 3 randomized controlled trials examining all formulations of lasmiditan, rimegepant and ubrogepant for the acute treatment of adults with migraine, were included. Data were extracted following the PRISMA guidelines. Results: Seven studies (SAMURAI, SPARTAN, CENTURION, Study 302, Study 303, ACHIEVE I and II) involving n = 12,859 patients were included. All treatments were superior in efficacy to placebo. Lasmiditan 200 mg showed the highest two-hour pain freedom, while two-hour freedom from most bothersome symptom was equally achieved by the higher doses of lasmiditan (100 and 200 mg), rimegepant and the higher doses of ubrogepant (50 and 100 mg). The odds of treatment-emergent adverse events were greatest with all doses of lasmiditan. Conclusion: Lasmiditan 200 mg was the most effective intervention in the treatment of migraine attacks, although it was associated with high degrees of dizziness, nausea and somnolence. Rimegepant showed slightly lower, but similar efficacy rates to lasmiditan. Ubrogepant had overall the best tolerability profile. These conclusions are limited by the absence of head-to-head comparisons, limitations of individual trials and of the meta-analysis methodology itself.PROSPERO trial registration: CRD42022308224

Controlled oxygenated rewarming as novel end‐ischemic therapy for cold stored liver grafts. A randomized controlled trial

Abstract Abrupt return to normothermia has been shown a genuine factor contributing to graft dysfunction after transplantation. This study tested the concept to mitigate reperfusion injury of liver grafts by gentle warming‐up using ex vivo machine perfusion prior to reperfusion. In a single center randomized controlled study, livers were assigned to conventional static cold storage (SCS) alone or to SCS followed by 90 min of ex vivo machine perfusion including controlled oxygenated rewarming (COR) by gentle and protracted elevation of the perfusate temperature from 10°C to 20°C. Primary outcome mean peak aspartate aminotransferase (AST) was 1371 U/L (SD 2871) after SCS versus 767 U/L (SD 1157) after COR (p = 0.273). Liver function test (LiMAx) on postoperative day 1 yielded 187 μg/kg/h (SD 121) after SCS, but rose to 294 μg/kg/h (SD 106) after COR (p = 0.006). Likewise, hepatic synthesis of coagulation factor V was significantly accelerated in the COR group immediately after transplantation (103% [SD 34] vs. 66% [SD 26]; p = 0.001). Fewer severe complications (Clavien‐Dindo grade ≥3b) were reported in the COR group (8) than in the SCS group (15). Rewarming/reperfusion injury of liver grafts can be safely and effectively mitigated by controlling of the rewarming kinetics prior to blood reperfusion using end‐ischemic ex vivo machine perfusion after cold storage