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In this phase 3 study involving patients with an inadequate response to biologic disease-modifying antirheumatic drugs, baricitinib, an oral JAK1 and JAK2 inhibitor, led to clinical improvement at 12 weeks. Infections were more frequent with baricitinib than with placebo. The discomfort, disability, and joint damage that characterize rheumatoid arthritis result from an autoimmune inflammatory response elicited by numerous cell populations and cytokines. Biologic therapies targeting T or B cells and cytokines, such as tumor necrosis factor α (TNF-α) or interleukin-6, have improved outcomes for patients who do not have responses to treatment with conventional, synthetic disease-modifying antirheumatic drugs (DMARDs) such as methotrexate. 1 However, since many patients do not have a sufficient response to these biologic DMARDs or have unacceptable side effects, new therapies are needed. Circulating cytokines, on binding to cell-surface receptors, signal through activation of intracellular tyrosine kinases, . . .

Objective To determine if there is a relation between aspirin “resistance” and clinical outcomes in patients with cardiovascular disease.Design Systematic review and meta-analysis.Data source Electronic literature search without language restrictions of four databases and hand search of bibliographies for other relevant articles.Review methods Inclusion criteria included a test for platelet responsiveness and clinical outcomes. Aspirin resistance was assessed, using a variety of platelet function assays.Results 20 studies totalling 2930 patients with cardiovascular disease were identified. Most studies used aspirin regimens, ranging from 75-325 mg daily, and six studies included adjunct antiplatelet therapy. Compliance was confirmed directly in 14 studies and by telephone or interviews in three. Information was insufficient to assess compliance in three studies. Overall, 810 patients (28%) were classified as aspirin resistant. A cardiovascular related event occurred in 41% of patients (odds ratio 3.85, 95% confidence interval 3.08 to 4.80), death in 5.7% (5.99, 2.28 to 15.72), and an acute coronary syndrome in 39.4% (4.06, 2.96 to 5.56). Aspirin resistant patients did not benefit from other antiplatelet treatment.Conclusion Patients who are resistant to aspirin are at a greater risk of clinically important cardiovascular morbidity long term than patients who are sensitive to aspirin.

In a phase 3 randomized trial of 1307 patients with rheumatoid arthritis receiving background methotrexate, the oral JAK1 and JAK2 inhibitor baricitinib showed superior efficacy to placebo and to the anti–tumor necrosis factor α monoclonal antibody adalimumab. Rheumatoid arthritis is a systemic autoimmune disease characterized by inflammatory synovitis and progressive joint destruction, which are associated with severe disability and increased mortality. Progress in treatment with the use of conventional synthetic disease-modifying antirheumatic drugs (DMARDs), such as methotrexate, and biologic DMARDs that target tumor necrosis factor (TNF) has made clinical remission a realistic target. 1 Activated Janus kinases (JAKs) play pivotal roles in intracellular signaling from cell-surface receptors for multiple cytokines implicated in the pathologic processes of rheumatoid arthritis. 2 Baricitinib, an orally available small molecule, provides reversible inhibition of JAK1 and JAK2 and has shown clinical efficacy in studies . . .

Objectives To investigate baricitinib (LY3009104, formerly INCB028050), a novel, oral inhibitor of JAK1/JAK2 in patients with moderate to severe rheumatoid arthritis (RA) despite treatment with methotrexate. Methods In this phase IIb study, 301 patients were randomised 2:1:1:1:1 to receive once daily doses of placebo or 1, 2, 4 or 8 mg baricitinib for 12 weeks. Patients assigned to 2, 4 and 8 mg baricitinib continued blinded treatment for an additional 12 weeks. Patients assigned to placebo or 1 mg baricitinib were reassigned to 2 mg twice daily or 4 mg once daily baricitinib between weeks 12–24. The primary endpoint was the proportion of patients in the combined 4 and 8 mg groups achieving an American College of Rheumatology 20% (ACR20) response versus placebo at week 12. Results Significantly more patients in the combined baricitinib 4 and 8 mg groups compared with placebo achieved an ACR20 response at week 12 (76% vs 41%, p<0.001). At week 12, significant differences versus placebo were also observed in patients achieving ACR50, ACR70 and remission as measured by Disease Activity Score for 28-joint counts, Clinical Disease Activity Index and Simplified Disease Activity Index. Patients receiving 2, 4, or 8 mg baricitinib maintained or improved in all measures through 24 weeks. Similar proportions of patients experienced at least one adverse event in the placebo and baricitinib groups. Serious infections developed in three patients receiving baricitinib. No cases of tuberculosis, herpes zoster, opportunistic infections or deaths were reported. Dose-dependent decreases in haemoglobin were observed with baricitinib. Conclusions Baricitinib improved the signs and symptoms of RA in methotrexate inadequate responders with active disease. Baricitinib was well tolerated with no unexpected safety findings through week 24. Trial registration number NCT01185353.

Nitrous oxide is commonly used in general anaesthesia but concerns exist that it might increase perioperative cardiovascular risk. We aimed to gather evidence to establish whether nitrous oxide affects perioperative cardiovascular risk. We did an international, randomised, assessor-blinded trial in patients aged at least 45 years with known or suspected coronary artery disease having major non-cardiac surgery. Patients were randomly assigned via automated telephone service, stratified by site, to receive a general anaesthetic with or without nitrous oxide. Attending anaesthetists were aware of patients' group assignments, but patients and assessors were not. The primary outcome measure was a composite of death and cardiovascular complications (non-fatal myocardial infarction, stroke, pulmonary embolism, or cardiac arrest) within 30 days of surgery. Our modified intention-to-treat population included all patients randomly assigned to groups and undergoing induction of general anaesthesia for surgery. This trial is registered at ClinicalTrials.gov, number NCT00430989. Of 10 102 eligible patients, we enrolled 7112 patients between May 30, 2008, and Sept 28, 2013. 3543 were assigned to receive nitrous oxide and 3569 were assigned not to receive nitrous oxide. 3483 patients receiving nitrous oxide and 3509 not receiving nitrous oxide were assessed for the primary outcome. The primary outcome occurred in 283 (8%) patients receiving nitrous oxide and in 296 (8%) patients not receiving nitrous oxide (relative risk 0·96, 95% CI 0·83–1·12; p=0·64). Surgical site infection occurred in 321 (9%) patients assigned to nitrous oxide, and in 311 (9%) patients in the no-nitrous oxide group (p=0·61), and severe nausea and vomiting occurred in 506 patients (15%) assigned to nitrous oxide and 378 patients (11%) not assigned to nitrous oxide (p<0·0001). Our findings support the safety profile of nitrous oxide use in major non-cardiac surgery. Nitrous oxide did not increase the risk of death and cardiovascular complications or surgical-site infection, the emetogenic effect of nitrous oxide can be controlled with antiemetic prophylaxis, and a desired effect of reduced volatile agent use was shown. Australian National Health and Medical Research Council; Australian and New Zealand College of Anaesthetists; Heart and Stroke Foundation of Quebec, Heart and Stroke Foundation of Ontario, Canada; General Research Fund of the Research Grant Council, Hong Kong Special Administrative Region, China.

Background/Objectives: An increasing number of older individuals require general anaesthesia for major non-cardiac surgery, with 20% displaying postoperative complications. Regional cerebral oxygen saturation (rSO2) correlates with the gold standard of mixed venous oxygen saturation, indicating global perfusion. We hypothesised that rSO2-based anaesthesia reduces organ dysfunction and morbidity after major non-cardiac surgery. Methods: In Singapore and Toronto, we conducted a prospective, double-blind, randomised controlled trial in elderly patients undergoing major non-cardiac surgery, after obtaining research ethics board permission and informed consent. This RCT followed the CONSORT guidelines. Patients received bilateral cerebral oximetry sensors, and the control group received standard care. In the intervention group, an algorithm restored rSO2 if it dropped 10% below baseline for >15 s by adjusting cerebral perfusion pressure, inspired oxygen concentration, end-tidal carbon dioxide, depth of anaesthesia, haemoglobin, and cardiac index. Postoperative complications and outcomes were noted. Categorical data were analysed using Chi-square or Fisher’s exact tests and continuous data using a t-test or a Mann–Whitney U test. The study was powered for 394 patients, but due to the COVID-19 pandemic and funding constraints, this study was terminated at 101 patients. Results: Of 101 patients, 49 were randomised to the control and 52 to the intervention group. A total of 31 (63%) patients in the control group and 30 (58%) in the interventional exhibited bilateral cerebral desaturation. Time of cumulative cerebral desaturation was longer in the control group (23 ± 48 min vs. 9 ± 15 min, respectively, p = 0.01). A total of 142 algorithm-based treatments were employed, restoring rSO2 in 29 (86%) patients. Both groups displayed equal postoperative outcomes. Conclusions: In major non-cardiac surgery, cerebral desaturation is prevalent in over 85% of patients. Although algorithm-guided therapy restored rSO2 in the majority of patients, it did not result in reduced postoperative morbidity.

Coronary artery bypass graft surgery (CABG) is associated with cardiac complications, including ischemia, acute myocardial infarction (AMI), and death. Volatile anesthetics have been shown to have a preconditioning-like effect. This systematic review assesses the effects of volatile anesthetics on cardiac ischemic complications and morbidity after CABG. Data were obtained, without language restriction, from searches of MEDLINE, Science Citation Index, PubMed, and reference lists. We included only prospective randomized controlled trials evaluating volatile anesthetics during CABG. Two reviewers independently abstracted data on myocardial ischemia, acute myocardial infarction (AMI), and death. Treatment effects were calculated as odds ratio (OR) with 95% confidence intervals (CI) for binary data, and weighted mean difference (WMD) with 95% CI for continuous data. Thirty-two studies (2,841 patients) were included. In comparison with iv anesthesia, volatile anesthetics were associated with reduced all-cause mortality (OR, 0.65; 95% CI, 0.36-1.18; P = 0.16). Enflurane was associated with increased AMI (OR, 1.34; 95% CI, 0.68-2.64; P = 0.40), whereas sevoflurane and desflurane reduced cardiac troponin I (cTnI) at six hours, 12 hr, 24 hr [WMD, -1.45; 95% CI (-1.73, -1.16); P < 0.00001], and 48 hr after operation. This meta-analysis demonstrates sevoflurane and desflurane reduce the postoperative rise in cTnI. Sevoflurane-mediated reduction in cardiac troponin was associated with improved long-term outcomes in one study. This meta-analysis was not able to show that these positive effects on troponin were translated into improved clinical outcomes. Well-designed large randomized control trials are needed to further elucidate the differential cardio-protective effects of volatile anesthetics.