Empagliflozin in Heart Failure with a Preserved Ejection Fraction.

BACKGROUND: Sodium-glucose cotransporter 2 inhibitors reduce the risk of hospitalization for heart failure in patients with heart failure and a reduced ejection fraction, but their effects in patients with heart failure and a preserved ejection fraction are uncertain. METHODS: In this double-blind trial, we randomly assigned 5988 patients with class II-IV heart failure and an ejection fraction of more than 40% to receive empagliflozin (10 mg once daily) or placebo, in addition to usual therapy. The primary outcome was a composite of cardiovascular death or hospitalization for heart failure. RESULTS: Over a median of 26.2 months, a primary outcome event occurred in 415 of 2997 patients (13.8%) in the empagliflozin group and in 511 of 2991 patients (17.1%) in the placebo group (hazard ratio, 0.79; 95% confidence interval [CI], 0.69 to 0.90; P<0.001). This effect was mainly related to a lower risk of hospitalization for heart failure in the empagliflozin group. The effects of empagliflozin appeared consistent in patients with or without diabetes. The total number of hospitalizations for heart failure was lower in the empagliflozin group than in the placebo group (407 with empagliflozin and 541 with placebo; hazard ratio, 0.73; 95% CI, 0.61 to 0.88; P<0.001). Uncomplicated genital and urinary tract infections and hypotension were reported more frequently with empagliflozin. CONCLUSIONS: Empagliflozin reduced the combined risk of cardiovascular death or hospitalization for heart failure in patients with heart failure and a preserved ejection fraction, regardless of the presence or absence of diabetes. (Funded by Boehringer Ingelheim and Eli Lilly; EMPEROR-Preserved ClinicalTrials.gov number, NCT03057951)

Reducing the environmental impact of surgery on a global scale: systematic review and co-prioritization with healthcare workers in 132 countries

Abstract Background Healthcare cannot achieve net-zero carbon without addressing operating theatres. The aim of this study was to prioritize feasible interventions to reduce the environmental impact of operating theatres. Methods This study adopted a four-phase Delphi consensus co-prioritization methodology. In phase 1, a systematic review of published interventions and global consultation of perioperative healthcare professionals were used to longlist interventions. In phase 2, iterative thematic analysis consolidated comparable interventions into a shortlist. In phase 3, the shortlist was co-prioritized based on patient and clinician views on acceptability, feasibility, and safety. In phase 4, ranked lists of interventions were presented by their relevance to high-income countries and low–middle-income countries. Results In phase 1, 43 interventions were identified, which had low uptake in practice according to 3042 professionals globally. In phase 2, a shortlist of 15 intervention domains was generated. In phase 3, interventions were deemed acceptable for more than 90 per cent of patients except for reducing general anaesthesia (84 per cent) and re-sterilization of ‘single-use’ consumables (86 per cent). In phase 4, the top three shortlisted interventions for high-income countries were: introducing recycling; reducing use of anaesthetic gases; and appropriate clinical waste processing. In phase 4, the top three shortlisted interventions for low–middle-income countries were: introducing reusable surgical devices; reducing use of consumables; and reducing the use of general anaesthesia. Conclusion This is a step toward environmentally sustainable operating environments with actionable interventions applicable to both high– and low–middle–income countries

Perfil energético e hormonal de ovelhas Santa Inês do terço médio da gestação ao pós-parto

No período periparto ocorrem importantes adequações fisiológicas que, se não forem efetivas predispõem a fêmea a enfermidades metabólicas. O conhecimento desta adaptação é relevante para que sejam implementadas, precocemente, medidas preventivas a poupar perdas produtivas. Com este objetivo foi avaliado o perfil energético e hormonal de ovelhas Santa Inês durante a gestação e puerpério. Foram utilizadas 10 ovelhas não gestantes (G0), 10 gestantes de um (G1) e 14 gestantes de dois e três fetos (G2). Foram avaliadas concentrações plasmáticas de glicose, ácidos graxos não esterificados (AGNE), betahidroxibutirato (BHB), e as concentrações séricas de insulina, glucagon, cortisol, triiodotironina (T3) e tiroxina (T4) a partir do 88º dia de gestação até o 28º dia pós-parto. No terço final de gestação, ovelhas gestantes apresentaram maiores concentrações de AGNE, T3 e T4 que as ovelhas não gestantes. No momento do parto foram observadas maiores concentrações de glicose, AGNE e T3 para todas as ovelhas gestantes em relação às não gestantes. Não houve diferença entre as ovelhas gestantes de um, dois ou três fetos. As diferenças observadas ocorreram apenas entre ovelhas gestantes e as vazias. Portanto, quando há adequada adaptação neste período de elevado desafio metabólico, os parâmetros bioquímicos aqui considerados independem do número de fetos gestados e podem ser considerados como valores de referência para ovelhas gestantes de um feto ou mais fetos do terço médio de gestação ao primeiro mês pós-parto

In vivo B(1) kinin-receptor upregulation. Evidence for involvement of protein kinases and nuclear factor κB pathways

1. Intradermal (i.d.) injection of cytokines, IL-1β and TNFα (5 ng, 60 and 30 min prior) produces a rapid onset up-regulation of des-Arg(9)-BK-mediated rat paw oedema. Here we analyse the mechanisms involved in des-Arg(9)-BK-induced oedema in animals pre-treated with IL-1β or TNFα. 2. Co-injection of anti-IL-1β, anti-TNFα and anti-IL-8 (50 ng) significantly inhibited des-Arg(9)-BK-induced oedema in animals pre-treated with IL-1β (65, 37 and 42%) or TNFα (39, 64, 25%). IL-1 receptor antagonist (IRA, 100 μg) or IL-10 (10 ng) inhibited the oedema caused by des-Arg(9)-BK, in rats that had received either IL-1β (67 and 63%) or TNFα (46 and 35%). 3. Co-injection of the PKC inhibitors, staurosporine (10 nmol) or RO 318220 (30 nmol) inhibited des-Arg(9)-BK-induced paw oedema (44 and 42% for IL-1β and, 53 and 30% for TNFα, respectively). Genistein (tyrosine kinase inhibitor, 2.5 mg kg(−1), s.c.) or PD 098059 (MAP-kinase inhibitor, 30 nmol) produced marked inhibition of des-Arg(9)-BK-induced oedema (58 and 39% for IL-1β and 31 and 35% for TNFα respectively). 4. The NF-κB inhibitors TLCK (2 mg kg(−1), i.p.) and PDCT (100 mg kg(−1), i.p.) significantly inhibited the oedema of des-Arg(9)-BK in IL-1β (27 and 83%) or TNFα (28 and 80%) pre-treated animals. 5. It is concluded that up-regulation of B(1) receptors modulated by IL-1β or TNFα involves the release of other cytokines, activation of PKC and tyrosine kinase pathways, co-ordinated with the activation of MAP-kinase and nuclear factor κB, reinforcing the view that B(1) receptors may exert a pivotal role in modulating chronic inflammatory processes

A deep learning framework for neuroscience

Systems neuroscience seeks explanations for how the brain implements a wide variety of perceptual, cognitive and motor tasks. Conversely, artificial intelligence attempts to design computational systems based on the tasks they will have to solve. In artificial neural networks, the three components specified by design are the objective functions, the learning rules and the architectures. With the growing success of deep learning, which utilizes brain-inspired architectures, these three designed components have increasingly become central to how we model, engineer and optimize complex artificial learning systems. Here we argue that a greater focus on these components would also benefit systems neuroscience. We give examples of how this optimization-based framework can drive theoretical and experimental progress in neuroscience. We contend that this principled perspective on systems neuroscience will help to generate more rapid progress

A deep learning framework for neuroscience

Systems neuroscience seeks explanations for how the brain implements a wide variety of perceptual, cognitive and motor tasks. Conversely, artificial intelligence attempts to design computational systems based on the tasks they will have to solve. In artificial neural networks, the three components specified by design are the objective functions, the learning rules and the architectures. With the growing success of deep learning, which utilizes brain-inspired architectures, these three designed components have increasingly become central to how we model, engineer and optimize complex artificial learning systems. Here we argue that a greater focus on these components would also benefit systems neuroscience. We give examples of how this optimization-based framework can drive theoretical and experimental progress in neuroscience. We contend that this principled perspective on systems neuroscience will help to generate more rapid progress

Triglyceride Lowering with Pemafibrate to Reduce Cardiovascular Risk

BACKGROUND: High triglyceride levels are associated with increased cardiovascular risk, but whether reductions in these levels would lower the incidence of cardiovascular events is uncertain. Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator, reduces triglyceride levels and improves other lipid levels. METHODS: In a multinational, double-blind, randomized, controlled trial, we assigned patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia (triglyceride level, 200 to 499 mg per deciliter), and high-density lipoprotein (HDL) cholesterol levels of 40 mg per deciliter or lower to receive pemafibrate (0.2-mg tablets twice daily) or matching placebo. Eligible patients were receiving guideline-directed lipid-lowering therapy or could not receive statin therapy without adverse effects and had low-density lipoprotein (LDL) cholesterol levels of 100 mg per deciliter or lower. The primary efficacy end point was a composite of nonfatal myocardial infarction, ischemic stroke, coronary revascularization, or death from cardiovascular causes. RESULTS: Among 10,497 patients (66.9% with previous cardiovascular disease), the median baseline fasting triglyceride level was 271 mg per deciliter, HDL cholesterol level 33 mg per deciliter, and LDL cholesterol level 78 mg per deciliter. The median follow-up was 3.4 years. As compared with placebo, the effects of pemafibrate on lipid levels at 4 months were -26.2% for triglycerides, -25.8% for very-low-density lipoprotein (VLDL) cholesterol, -25.6% for remnant cholesterol (cholesterol transported in triglyceride-rich lipoproteins after lipolysis and lipoprotein remodeling), -27.6% for apolipoprotein C-III, and 4.8% for apolipoprotein B. A primary end-point event occurred in 572 patients in the pemafibrate group and in 560 of those in the placebo group (hazard ratio, 1.03; 95% confidence interval, 0.91 to 1.15), with no apparent effect modification in any prespecified subgroup. The overall incidence of serious adverse events did not differ significantly between the groups, but pemafibrate was associated with a higher incidence of adverse renal events and venous thromboembolism and a lower incidence of nonalcoholic fatty liver disease. CONCLUSIONS: Among patients with type 2 diabetes, mild-to-moderate hypertriglyceridemia, and low HDL and LDL cholesterol levels, the incidence of cardiovascular events was not lower among those who received pemafibrate than among those who received placebo, although pemafibrate lowered triglyceride, VLDL cholesterol, remnant cholesterol, and apolipoprotein C-III levels. (Funded by the Kowa Research Institute; PROMINENT ClinicalTrials.gov number, NCT03071692.)