Search

It is generally assumed that regions glaciated by continental ice sheets offer little promise for long paleoenvironmental records due to erosional processes associated with glaciation. We show that beneath portions of the northeastern Laurentide Ice Sheet, characterized by coldbased glaciation, sediment sequences representing multiple interglaciations have been preserved within extant lake basins. Radiocarbon and optically stimulated luminescence dating confirm the antiquity of the sediments, thereby extending the terrestrial paleoenvironmental record of the Canadian Arctic by hundreds of thousands of years. The lake sediment record presented here corroborates numerous recent cosmogenic exposure dating studies indicating complex patterns of erosion beneath polar ice sheets. It also demonstrates that the presence of intact interglacial sediments does not demand unglaciated refugia. Similarly ancient sediments may be preserved in many regions formerly covered by Pleistocene ice sheets. [ABSTRACT FROM AUTHOR]

Background: Baricitinib, an oral selective Janus kinase 1/Janus kinase 2 inhibitor, is being studied for moderate-to-severe atopic dermatitis (AD) in adults., Objective: To evaluate the efficacy and safety of baricitinib monotherapy in a North American phase 3 trial (BREEZE-AD5/NCT03435081) of adults with moderate-to-severe AD who responded inadequately or were intolerant to topical therapy., Methods: Patients (N = 440) were randomized 1:1:1 to once-daily placebo or baricitinib (1 mg or 2 mg). The primary endpoint was the proportion of patients achieving ≥75% reduction in the Eczema Area and Severity Index at week 16. A key secondary endpoint was the proportion of patients achieving a validated Investigator Global Assessment for AD score of 0 (clear)/1(almost clear) with ≥2-point improvement., Results: At week 16, the proportion of patients achieving Eczema Area and Severity Index was 8%, 13%, and 30% (P < .001, 2 mg vs placebo) and those with a validated Investigator Global Assessment for AD score of 0/1 were 5%, 13%, and 24% (P < .001, 2 mg vs placebo) for placebo, baricitinib 1 mg, and baricitinib 2 mg, respectively. Safety findings were similar to those of other baricitinib AD studies., Limitations: Short-term clinical trial results may not be generalizable to real-world settings., Conclusion: Baricitinib was efficacious for patients with moderate-to-severe AD with no new safety findings over 16 weeks., Competing Interests: Conflicts of interest Dr Simpson reports grants and fees for participation as a consultant and principal investigator from Eli Lilly and Company, LEO Pharma, Pfizer, and Regeneron; grants for participation as a principal investigator from Galderma and Merck & Co; and fees for consultant services from AbbVie, Boehringer Ingelheim, Dermavant Incyte, Forte Bio, Pierre Fabre Dermo, and Sanofi Genzyme. Dr Forman is a consultant, investigator, advisory board member, and/or speaker for and receives funding and/or honoraria from AbbVie, Aclaris Therapeutics Inc, Asana BioSciences, AstraZeneca, Athenex, Celgene Corporation, Cutanea Life Sciences, Eli Lilly and Company, Incyte Corporation, Innovaderm Research Inc, Novartis, Pfizer Inc, Promius Pharma LLC, Regeneron, UCB, Valeant Pharmaceuticals North America LLC, and XBiotech. Dr Silverberg served as a consultant and/or advisory board member for AbbVie, Arena, Asana, Bluefin, Boehringer Ingelheim, Dermavant, Dermira, Eli Lilly and Company, Galderma, GlaxoSmithKline, Glenmark, Incyte, Kiniksa, Leo, Luna, Novartis, Pfizer, RAPT, Regeneron, and Sanofi, receiving honoraria; served as a speaker for Regeneron-Sanofi; and received research grants from Galderma. Dr Zirwas is a consultant, investigator, and/or speaker for Regeneron, Sanofi, Genench, Novartis, L'Oreal, Menlo, Leo, Eli Lilly and Company, Ortho Derm, and Arcutis and is a part owner of AsepticMD. Dr Han is a consultant for Eli Lilly and Company, Regeneron, Sanofi, and Pfizer. Dr Guttman-Yassky is a consultant for AbbVie, Almirall, Amgen, Asana Biosciences, Boehringer Ingelhiem, Cara Therapeutics, Celgene, Concert, DBV, Dermira, DS Biopharma, Eli Lilly and Company, EMD Serono, Escalier, Galderma, Glenmark, Kyowa Kirin, LEO Pharma, Mitsubishi Tanabe, Pfizer, RAPT Therapeutics, Regeneron, Sanofi, Sienna Biopharma, and Union Therapeutics and reports institute grants for research from AbbVie, Almirall, Amgen, AnaptysBio, Asana Biosciences, Boehringer Ingelhiem, Celgene, Dermavant, DS Biopharma, Eli Lilly and Company, Glenmark, Galderma, Innovaderm, Janssen, Kiniska, Kyowa Kirin, Leo Pharma, Novan, Pfizer, Ralexar, Regeneron, Sienna Biopharma, UCB, and Union Therapeutics. Dr Bissonnette is an advisory board member, consultant, speaker and/or investigator for and receives honoraria and/or grant from AbbVie, Arcutis, Arena Pharma, Asana BioSciences, Bellus Health, Boehringer Ingelheim, CARA, Dermavant, Eli Lilly, EMD Serono, Galderma, Incyte, Kiniksa, Kyowa Kirin, LEO Pharma, Novan, Pfizer, Ralexar, RAPT, Regeneron, Sanofi Genzyme, and Sienna and is an employee and shareholder of Innovaderm Research. Dr Waibel is an investigator, consultant speaker for, and/or receives honoraria from AbbVie, Pfizer, Candela, Cytrellis, Dominion, Eli Lilly and Company, Novartis, Sebacia, and Sciton. Dr Papp is a consultant, speaker, investigator, scientific officer, steering committee member, and/or advisory board member for AbbVie, Akros, Amgen, Anacor, Arcutis, Astellas, Bausch Health/Valeant, Baxalta, Boehringer Ingelheim, Bristol-Myers Squibb, Can-Fite Biopharma, Celgene, Coherus, Dermira, Dow Pharma, Eli Lilly and Company, Evelo, Galapagos, Galderma, Genentech, Gilead, GSK, Janssen, Kyowa Hakko Kirin, Leo, Medimmune, Meiji Seika Pharma, Merck (MSD), Merck- Serono, Mitsubishi Pharma, Moberg Pharma, Novartis, Pfizer, PRCL Research, Regeneron, Roche, Sanofi-Aventis/Genzyme, Sun Pharma, Takeda, UCB. Drs Nunes, Holzwarth, and Janes and authors DeLozier and Angle are employees and shareholders of Eli Lilly and Company. Drs Gamalo and Goldblum were employees of Eli Lilly and Company during the study. Drs Maverakis and Marnell and author Zhong have no conflicts of interest to declare., (Copyright © 2021. Published by Elsevier Inc.)

Background: Abrocitinib, an oral selective Janus kinase 1 inhibitor, was effective and well tolerated in adults with moderate-to-severe atopic dermatitis in a phase 2b trial. We aimed to assess the efficacy and safety of abrocitinib monotherapy in adolescents and adults with moderate-to-severe atopic dermatitis., Methods: In this multicentre, double-blind, randomised phase 3 trial (JADE MONO-1), patients (aged ≥12 years) with moderate-to-severe atopic dermatitis (Investigator Global Assessment score ≥3, Eczema Area and Severity Index [EASI] score ≥16, percentage of body surface area affected ≥10%, and Peak Pruritus Numerical Rating Scale score ≥4) with a bodyweight of 40 kg or more, were enrolled at 69 sites in Australia, Canada, Europe, and the USA. Patients were randomly assigned (2:2:1) to oral abrocitinib 100 mg, abrocitinib 200 mg, or placebo once daily for 12 weeks. Randomisation was done using an interactive response technology system, stratified by baseline disease severity and age. Patients, investigators, and the funder of the study were masked to study treatment. The coprimary endpoints were the proportion of patients who had achieved an Investigator Global Assessment response (score of 0 [clear] or 1 [almost clear] with a ≥2-grade improvement from baseline), and the proportion of patients who achieved at least a 75% improvement in EASI score from baseline (EASI-75) score, both assessed at week 12. Efficacy was assessed in the full analysis set, which included all randomised patients who received at least one dose of study medication. Safety was assessed in all randomised patients. This study is registered with ClinicalTrials.gov, NCT03349060., Findings: Between Dec 7, 2017, and March 26, 2019, 387 patients were enrolled: 156 were assigned to abrocitinib 100 mg, 154 to abrocitinib 200 mg, and 77 to placebo. All enrolled patients received at least one dose of study treatment and thus were evaluable for 12-week efficacy. Of the patients with available data for the coprimary endpoints at week 12, the proportion of patients who had achieved an Investigator Global Assessment response was significantly higher in the abrocitinib 100 mg group than in the placebo group (37 [24%] of 156 patients vs six [8%] of 76 patients; p=0·0037) and in the abrocitinib 200 mg group compared with the placebo group (67 [44%] of 153 patients vs six [8%] of 76 patients; p<0·0001). Of the patients with available data for the coprimary endpoints at week 12, compared with the placebo group, the proportion of patients who had achieved an EASI-75 response was significantly higher in the abrocitinib 100 mg group (62 [40%] of 156 patients vs nine [12%] of 76 patients; p<0·0001) and abrocitinib 200 mg group (96 [63%] of 153 patients vs nine [12%] of 76 patients; p<0·0001). Adverse events were reported in 108 (69%) of 156 patients in the abrocitinib 100 mg group, 120 (78%) of 154 patients in the abrocitinib 200 mg group, and 44 (57%) of 77 patients in the placebo group. Serious adverse events were reported in five (3%) of 156 patients in the abrocitinib 100 mg group, five (3%) of 154 patients in the abrocitinib 200 mg group, and three (4%) of 77 patients in the placebo group. No treatment-related deaths were reported., Interpretation: Monotherapy with oral abrocitinib once daily was effective and well tolerated in adolescents and adults with moderate-to-severe atopic dermatitis., Funding: Pfizer., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: In the present study, we sought to determine whether opening a persistently occluded infarct-related artery (IRA) by percutaneous coronary intervention (PCI) in patients beyond the acute phase of myocardial infarction (MI) improves patency and indices of left ventricular (LV) size and function., Methods and Results: Between May 2000 and July 2005, 381 patients with an occluded native IRA 3 to 28 days after MI (median 10 days) were randomized to PCI with stenting (PCI) or optimal medical therapy alone. Repeat coronary and LV angiography was performed 1 year after randomization (n=332, 87%). Coprimary end points were IRA patency and change in LV ejection fraction. Secondary end points included change in LV end-systolic and end-diastolic volume indices and wall motion. PCI was successful in 92%. At 1 year, 83% of PCI versus 25% of medical therapy-only patients had a patent IRA (P<0.001). LV ejection fraction increased significantly (P<0.001) in both groups, with no between-group difference: PCI 4.2+/-8.9 (n=150) versus medical therapy 3.5+/-8.2 (n=136; P=0.47). Median change (interquartile range) in LV end-systolic volume index was -0.5 (-9.3 to 5.0) versus 1.0 (-5.7 to 7.3) mL/m2 (P=0.10), whereas median change (interquartile range) in LV end-diastolic volume index was 3.2 (-8.2 to 13.3) versus 5.3 (-4.6 to 23.2) mL/m2 (P=0.07) in the PCI (n=86) and medical therapy-only (n=76) groups, respectively., Conclusions: PCI with stenting of a persistently occluded IRA in the subacute phase after MI effectively maintains long-term patency but has no effect on LV ejection fraction. On the basis of these findings and the lack of clinical benefit in the main Occluded Artery Trial, routine PCI is not recommended for stable patients with a persistently occluded IRA after MI.