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AimsWhile heart failure with preserved (HFpEF) and reduced ejection fraction (HFrEF) are well described, determinants and outcomes of heart failure with mid-range ejection fraction (HFmrEF) remain unclear. We sought to examine clinical and biochemical predictors of incident HFmrEF in the community.Methods and resultsWe pooled data from four community-based longitudinal cohorts, with ascertainment of new heart failure (HF) classified into HFmrEF [ejection fraction (EF) 41-49%], HFpEF (EF ≥50%), and HFrEF (EF ≤40%). Predictors of incident HF subtypes were assessed using multivariable Cox models. Among 28 820 participants free of HF followed for a median of 12 years, there were 200 new HFmrEF cases, compared with 811 HFpEF and 1048 HFrEF. Clinical predictors of HFmrEF included age, male sex, systolic blood pressure, diabetes mellitus, and prior myocardial infarction (multivariable adjusted P ≤ 0.003 for all). Biomarkers that predicted HFmrEF included natriuretic peptides, cystatin-C, and high-sensitivity troponin (P ≤ 0.0004 for all). Natriuretic peptides were stronger predictors of HFrEF [hazard ratio (HR) 2.00 per 1 standard deviation increase, 95% confidence interval (CI) 1.81-2.20] than of HFmrEF (HR 1.51, 95% CI 1.20-1.90, P = 0.01 for difference), and did not differ in their association with incident HFmrEF and HFpEF (HR 1.56, 95% CI 1.41-1.73, P = 0.68 for difference). All-cause mortality following the onset of HFmrEF was worse than that of HFpEF (50 vs. 39 events per 1000 person-years, P = 0.02), but comparable to that of HFrEF (46 events per 1000 person-years, P = 0.78).ConclusionsWe found overlap in predictors of incident HFmrEF with other HF subtypes. In contrast, mortality risk after HFmrEF was worse than HFpEF, and similar to HFrEF.

Objective: We aimed to analyze the association between morphine and in-hospital outcomes in invasively managed ST elevation myocardial infarction (STEMI) and non-ST elevation acute coronary syndrome (NSTE-ACS) patients.Background: Morphine is commonly used for analgesia in the setting of acute coronary syndromes (ACS); however, recently its utility in ACS has come under closer scrutiny.Methods: We identified all STEMI and NSTE-ACS patients undergoing coronary angiogram +/- percutaneous intervention between January 2009 and July 2016 in our center and recorded patient characteristics and inpatient outcomes.Results: Overall, 3027 patients were examined. Overall, STEMI patients who received morphine had no difference in in-hospital mortality [4.18% vs. 7.54%, odds ratio (OR): 0.36, P = 0.19], infarct size (mean troponin level 0.75 ng/mL vs. 1.29 ng/mL, P = 0.32) or length of hospital stay (P = 0.61). The NSTE-ACS patients who received morphine had a longer hospital stay (mean 6.58 days vs. 4.78 days, P < 0.0001) and larger infarct size (mean troponin 1.16 ng/mL vs. 0.90 ng/mL, P = 0.02). Comparing matched patients, the use of morphine was associated with larger infarct size (mean troponin 1.14 ± 1.92 ng/mL vs. 0.83 ± 1.49 ng/mL, P = 0.01), longer hospital stay (6.5 ± 6.82 days vs. 4.89 ± 5.36 days, P = 0.004) and a trend towards increased mortality (5% vs. 2%, OR: 2.55, P = 0.06) in NSTE-ACS patients but morphine did not affect outcomes in the propensity matched STEMI patients.Conclusion: In a large retrospective study, morphine was associated with larger infarct size, a longer hospital stay and a trend towards increased mortality in invasively managed NSTE-ACS patients even after adjustment for clinical characteristics. [ABSTRACT FROM AUTHOR]

Our data previously revealed that chemosurviving cancer cells translate specific genes. Here, we find that the m6A-RNA-methyltransferase, METTL3, increases transiently in chemotherapy-treated breast cancer and leukemic cells in vitro and in vivo. Consistently, m6A increases on RNA from chemo-treated cells, and is needed for chemosurvival. This is regulated by eIF2α phosphorylation and mTOR inhibition upon therapy treatment. METTL3 mRNA purification reveals that eIF3 promotes METTL3 translation that is reduced by mutating a 5'UTR m6A-motif or depleting METTL3. METTL3 increase is transient after therapy treatment, as metabolic enzymes that control methylation and thus m6A levels on METTL3 RNA, are altered over time after therapy. Increased METTL3 reduces proliferation and anti-viral immune response genes, and enhances invasion genes, which promote tumor survival. Consistently, overriding phospho-eIF2α prevents METTL3 elevation, and reduces chemosurvival and immune-cell migration. These data reveal that therapy-induced stress signals transiently upregulate METTL3 translation, to alter gene expression for tumor survival., Competing Interests: Competing interests: The authors declare that they have no competing interests. SIAB and SST work at Arase and NextRNA Therapeutics respectively.

Objective: Hydrothermal duodenal mucosal resurfacing (DMR) is a safe, outpatient endoscopic procedure. REVITA-2, a double-blind, superiority randomised controlled trial, investigates safety and efficacy of DMR using the single catheter Revita system (Revita DMR (catheter and system)), on glycaemic control and liver fat content in type 2 diabetes (T2D)., Design: Eligible patients (haemoglobin A1c (HbA1c) 59-86 mmol/mol, body mass index≥24 and ≤40 kg/m 2 , fasting insulin >48.6 pmol/L, ≥1 oral antidiabetic medication) enrolled in Europe and Brazil. Primary endpoints were safety, change from baseline in HbA1c at 24 weeks, and liver MRI proton-density fat fraction (MRI-PDFF) at 12 weeks., Results: Overall mITT (DMR n=56; sham n=52), 24 weeks post DMR, median (IQR) HbA1c change was -10.4 (18.6) mmol/mol in DMR group versus -7.1 (16.4) mmol/mol in sham group (p=0.147). In patients with baseline liver MRI-PDFF >5% (DMR n=48; sham n=43), 12-week post-DMR liver-fat change was -5.4 (5.6)% in DMR group versus -2.9 (6.2)% in sham group (p=0.096). Results from prespecified interaction testing and clinical parameter assessment showed heterogeneity between European (DMR n=39; sham n=37) and Brazilian (DMR n=17; sham n=16) populations (p=0.063); therefore, results were stratified by region. In European mITT, 24 weeks post DMR, median (IQR) HbA1c change was -6.6 mmol/mol (17.5 mmol/mol) versus -3.3 mmol/mol (10.9 mmol/mol) post-sham (p=0.033); 12-week post-DMR liver-fat change was -5.4% (6.1%) versus -2.2% (4.3%) post-sham (p=0.035). Brazilian mITT results trended towards DMR benefit in HbA1c, but not liver fat, in context of a large sham effect. In overall PP, patients with high baseline fasting plasma glucose ((FPG)≥10 mmol/L) had significantly greater reductions in HbA1c post-DMR versus sham (p=0.002). Most adverse events were mild and transient., Conclusions: DMR is safe and exerts beneficial disease-modifying metabolic effects in T2D with or without non-alcoholic liver disease, particularly in patients with high FPG., Trial Registration Number: NCT02879383., Competing Interests: Competing interests: GM has received funding/grant support from Novo Nordisk, Fractyl Laboratories, Metacure, Keyron, and honorarium for consultancy from Johnson & Johnson, Novo Nordisk, and Fractyl Laboratories. JD has received research support from Fractyl Laboratories Inc for IRB-approved studies. DH has received honorarium for consultancy and/or speaker fees from Novo Nordisk, Sanofi, Astra Zeneca, Roche, Sunovion, and Fractyl Laboratories. EM has received honorarium for consultancy from Olympus do Brasil and Boston Scientific. CC has received funding/grant support from Novo Nordisk and honorarium for consultancy from Novo Nordisk and Eurofarma. DLB reports that he serves or has served on advisory boards for Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, Level Ex, Medscape Cardiology, PhaseBio, PLx Pharma and Regado Biosciences. He is or was a member of the board of directors for Boston VA Research Institute, Society of Cardiovascular Patient Care, and TobeSoft. He is or was chair for the American Heart Association Quality Oversight Committee, and is or was on data monitoring committees for Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo), and the Population Health Research Institute. He reports honoraria from the American College of Cardiology (senior associate editor, Clinical Trials and News, ACC.org; vice-chair, ACC Accreditation Committee), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (editor in chief, Harvard Heart Letter), Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (editor in chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (guest editor and associate editor), K2P (cochair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national coleader, funded by Bayer), Slack Publications (chief medical editor, Cardiology Today–Intervention), Society of Cardiovascular Patient Care (secretary/treasurer), WebMD (CME steering committees). He reports other relationships with Clinical Cardiology (deputy editor), NCDR-ACTION Registry Steering Committee (chair), and VA CART Research and Publications Committee (chair). He reports research funding from Abbott, Afimmune, Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Cardax, Chiesi, CSL Behring, Eisai, Ethicon, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Idorsia, Ironwood, Ischemix, Lexicon, Lilly, Medtronic, Pfizer, PhaseBio, PLx Pharma, Regeneron, Roche, Sanofi Aventis, Synaptic, and The Medicines Company. He reports royalties from Elsevier (editor, Cardiovascular Intervention: A Companion to Braunwald’s Heart Disease). He is or was a site coinvestigator for Biotronik, Boston Scientific, CSI, St. Jude Medical (now Abbott), and Svelte. He is or was a trustee for the American College of Cardiology. He reports unfunded research for FlowCo, Merck, Novo Nordisk, and Takeda. HR, JCL-T, KW, and VB are full-time employees of Fractyl Laboratories and may hold Fractyl stock and/or stock options. GC has received research grant support from Boston Scientific and Apollo and is on the advisory board for Cook Medical, Olympus, and Ethicon. RH has received funding/grant support/honorarium for consultancy from Cook Endoscopy, Pentax Europe, Medtronic, C2 Therapeutics, and Fractyl Laboratories to support research infrastructure. EG has received consulting fees from Fractyl Laboratories Inc, Apollo Endosurgery, and Medtronic. MGN has received honorarium for consultancy from Fractyl Laboratories, GI Windows, GI Dynamics, Apollo, and for speaker bureaus for Ethicon, Medtronic, and Olympus. GPA has been a consultant and advisory board member for Agios Pharmaceuticals, Amryt Pharma, AstraZeneca, GlaxoSmithKline and Pfizer. AR has received grant support from Norgine, Fujifilm, Boston Scientific and ERBE, and served as a member of advisory boards for Medtronic, Boston Scientific, EndoStart, EndoKey, Alfasigma and FujiFilm. AJM has received honorarium for consultancy from Fractyl Laboratories and Cook Medical. ACGvB, BH, RB, AH, MDC and NSS have nothing to disclose. AJS has been a consultant for Conatus, Gilead, Elsevier, Echosens, Malinckrodt, Immuron, Intercept, Pfizer, Salix, Uptodate, Boehringer, Ingelhiem, Novartis, Nimbus, Nitto Denko, Hemoshear, Lilly, Novo Nordisk, Fractyl Laboratories, Allergan, Chemomab, Affimmune, Teva, Ardelyx, Terns, ENYO, Birdrock, Albireo, Sanofi, Jannsen, Takeda, Zydus, BASF, Amra, Perspectum, OWL, Poxel, Servier, Second Genome, General Electric, and 89Bio. He is a stock/shareholder at Exhalenz Stock, Akarna, Durect, Indalo and Tiziana. He has received grant/research support from Novartis, Merck, Galectin, Bristol Myers, Merck, Sequana, Boehringer Ingelheim, Echosense, Salix, Malinckrodt, Cumberland, and Gilead.JJGHMB has received research support from Fractyl Laboratories for IRB-based studies and has received a consultancy fee for a single advisory board meeting for Fractyl Laboratories in September 2019., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)