Retrospective Cohort Study of Syphilis-Related Stillbirths in Winnipeg, Manitoba From 2017-2020.

OBJECTIVE: Syphilis-related stillbirths (SRSBs) disproportionately affect marginalized women with 11% of all local stillbirths having maternal syphilis as a contributory factor in 2020. This study describes the incidence and perinatal factors associated with SRSB. METHODS: This was a retrospective cohort study of all stillbirths occurring from 1 January 2017 to 31 December 2020, at a single tertiary-level referral hospital in Winnipeg, Manitoba. Cases that met criteria for SRSB were identified from hospital records and included in the final analysis. Maternal demographics, comorbidities, prenatal care attendance, sexually transmitted infection testing, treatment, and diagnostic investigations at time of stillbirth were collected from hospital charts using a standardized data collection form. Descriptive statistics were performed to present the results. RESULTS: The proportion of SRSB increased over the period of study from 0%-11%. Eleven cases were identified as SRSB, with diagnosis occurring intrapartum in 7 cases and antenatally in 4 cases. Of the 4 antenatal cases, only 2 had identifiable treatment responses indicated by microbiological and pathology workup. Commonly identified risk factors for SRSB were homelessness, mental illness, substance use, sexually transmitted co-infections, and lack of prenatal care. CONCLUSIONS: Cases of SRSB are rising in Winnipeg with 11% of all stillbirths having maternal syphilis as a contributory factor by 2020. SRSBs disproportionately affect marginalized women. The dramatic and rapid changes in the epidemiology of syphilis in Winnipeg are likely shared by other Canadian regions and warrant increased prevention strategies to improve outcomes.

Baricitinib versus Placebo or Adalimumab in Rheumatoid Arthritis.

BACKGROUND: Baricitinib is an oral, reversible inhibitor of the Janus kinases JAK1 and JAK2 that may have therapeutic value in patients with rheumatoid arthritis. METHODS: We conducted a 52-week, phase 3, double-blind, placebo- and active-controlled trial in which 1307 patients with active rheumatoid arthritis who were receiving background therapy with methotrexate were randomly assigned to one of three regimens in a 3:3:2 ratio: placebo (switched to baricitinib after 24 weeks), 4 mg of baricitinib once daily, or 40 mg of adalimumab (an anti-tumor necrosis factor α monoclonal antibody) every other week. End-point measures evaluated after adjustment for multiplicity included 20% improvement according to the criteria of the American College of Rheumatology (ACR20 response) (the primary end point), the Disease Activity Score for 28 joints (DAS28), the Health Assessment Questionnaire-Disability Index, and the Simplified Disease Activity Index at week 12, as well as radiographic progression of joint damage as measured by the van der Heijde modification of the total Sharp score (mTSS) (range, 0 to 448, with higher scores indicating greater structural joint damage) at week 24. RESULTS: More patients had an ACR20 response at week 12 with baricitinib than with placebo (primary end point, 70% vs. 40%, P<0.001). All major secondary objectives were met, including inhibition of radiographic progression of joint damage, according to the mTSS at week 24 with baricitinib versus placebo (mean change from baseline, 0.41 vs. 0.90; P<0.001) and an increased ACR20 response rate at week 12 with baricitinib versus adalimumab (70% vs. 61%, P=0.014). Adverse events, including infections, were more frequent through week 24 with baricitinib and adalimumab than with placebo. Cancers were reported in five patients (two who received baricitinib and three who received placebo). Baricitinib was associated with reductions in neutrophil counts and increases in levels of creatinine and low-density lipoprotein cholesterol. CONCLUSIONS: In patients with rheumatoid arthritis who had had an inadequate response to methotrexate, baricitinib was associated with significant clinical improvements as compared with placebo and adalimumab. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01710358 .).

Baricitinib in Patients with Refractory Rheumatoid Arthritis.

BACKGROUND: In phase 2 studies, baricitinib, an oral Janus kinase 1 and 2 inhibitor, reduced disease activity in patients with rheumatoid arthritis who had not previously received treatment with biologic disease-modifying antirheumatic drugs (DMARDs). METHODS: In this phase 3 study involving 527 patients with an inadequate response to or unacceptable side effects associated with one or more tumor necrosis factor inhibitors, other biologic DMARDs, or both, we randomly assigned the patients in a 1:1:1 ratio to baricitinib at a dose of 2 or 4 mg daily or placebo for 24 weeks. End points, tested hierarchically at week 12 to control type 1 error, were the American College of Rheumatology 20% (ACR20) response (primary end point), the Health Assessment Questionnaire-Disability Index (HAQ-DI) score, the 28-joint Disease Activity Score based on C-reactive protein level (DAS28-CRP), and a Simplified Disease Activity Index (SDAI) score of 3.3 or less (on a scale of 0.1 to 86.0, with a score of 3.3 or less indicating remission). Comparisons with placebo were made first with the 4-mg dose of baricitinib and then with the 2-mg dose. RESULTS: Significantly more patients receiving baricitinib at the 4-mg dose than those receiving placebo had an ACR20 response at week 12 (55% vs. 27%, P<0.001). Differences between the higher-dose baricitinib group and the placebo group were also significant for the HAQ-DI score and the DAS28-CRP but not for an SDAI score of 3.3 or less. Adverse-event rates through 24 weeks were higher for patients receiving the 2-mg dose of baricitinib and those receiving the 4-mg dose than for patients receiving placebo (71% and 77%, respectively, vs. 64%), including infections (44% and 40%, vs. 31%). The rates of serious adverse events were 4%, 10%, and 7% in the three groups, respectively. Two nonmelanoma skin cancers and two major adverse cardiovascular events, including a fatal stroke, occurred in the higher-dose group. Baricitinib was associated with a small reduction in neutrophil levels and increases in serum creatinine and low-density lipoprotein cholesterol levels. CONCLUSIONS: In patients with rheumatoid arthritis and an inadequate response to biologic DMARDs, baricitinib at a daily dose of 4 mg was associated with clinical improvement at 12 weeks. (Funded by Eli Lilly and Incyte; ClinicalTrials.gov number, NCT01721044.).

Baricitinib in patients with inadequate response or intolerance to conventional synthetic DMARDs: results from the RA-BUILD study.

BACKGROUND: Baricitinib is an oral, reversible, selective Janus kinase 1 and 2 inhibitor. METHODS: In this phase III, double-blind 24-week study, 684 biologic disease-modifying antirheumatic drug (DMARD)-naïve patients with rheumatoid arthritis and inadequate response or intolerance to ≥1 conventional synthetic DMARDs were randomly assigned 1:1:1 to placebo or baricitinib (2 or 4 mg) once daily, stratified by region and the presence of joint erosions. Endpoint measures included American College of Rheumatology 20% response (ACR20, primary endpoint), Disease Activity Score (DAS28) and Simplified Disease Activity Index (SDAI) score ≤3.3. RESULTS: More patients achieved ACR20 response at week 12 with baricitinib 4 mg than with placebo (62% vs 39%, p≤0.001). Compared with placebo, statistically significant improvements in DAS28, SDAI remission, Health Assessment Questionnaire-Disability Index, morning joint stiffness, worst joint pain and worst tiredness were observed. In a supportive analysis, radiographic progression of structural joint damage at week 24 was reduced with baricitinib versus placebo. Rates of adverse events during the treatment period and serious adverse events (SAEs), including serious infections, were similar among groups (SAEs: 5% for baricitinib 4 mg and placebo). One patient had an adverse event of tuberculosis (baricitinib 4 mg); one patient had an adverse event of non-melanoma skin cancer (baricitinib 4 mg). Two deaths and three major adverse cardiovascular events occurred (placebo). Baricitinib was associated with a decrease in neutrophils and increases in low-density and high-density lipoprotein. CONCLUSIONS: In patients with rheumatoid arthritis and an inadequate response or intolerance to conventional synthetic DMARDs, baricitinib was associated with clinical improvement and inhibition of progression of radiographic joint damage. TRIAL REGISTRATION NUMBER: NCT01721057; Results.

Anesthesia Technique and Mortality after Total Hip or Knee Arthroplasty: A Retrospective, Propensity Score-matched Cohort Study.

BACKGROUND: This propensity score-matched cohort study evaluates the effect of anesthetic technique on a 30-day mortality after total hip or knee arthroplasty. METHODS: All patients who had hip or knee arthroplasty between January 1, 2003, and December 31, 2014, were evaluated. The principal exposure was spinal versus general anesthesia. The primary outcome was 30-day mortality. Secondary outcomes were (1) perioperative myocardial infarction; (2) a composite of major adverse cardiac events that includes cardiac arrest, myocardial infarction, or newly diagnosed arrhythmia; (3) pulmonary embolism; (4) major blood loss; (5) hospital length of stay; and (6) operating room procedure time. A propensity score-matched-pair analysis was performed using a nonparsimonious logistic regression model of regional anesthetic use. RESULTS: We identified 10,868 patients, of whom 8,553 had spinal anesthesia and 2,315 had general anesthesia. Ninety-two percent (n = 2,135) of the patients who had general anesthesia were matched to similar patients who did not have general anesthesia. In the matched cohort, the 30-day mortality rate was 0.19% (n = 4) in the spinal anesthesia group and 0.8% (n = 17) in the general anesthesia group (risk ratio, 0.42; 95% CI, 0.21 to 0.83; P = 0.0045). Spinal anesthesia was also associated with a shorter hospital length of stay (5.7 vs. 6.6 days; P < 0.001). CONCLUSIONS: The results of this observational, propensity score-matched cohort study suggest a strong association between spinal anesthesia and lower 30-day mortality, as well as a shorter hospital length of stay, after elective joint replacement surgery.

Volatile-based short-term sedation in cardiac surgical patients: a prospective randomized controlled trial.

OBJECTIVE: To evaluate the differences in extubation times in a group of cardiac surgical patients who were anesthetized and sedated with either IV propofol or inhaled volatile anesthetic agents. DESIGN: This was a prospective randomized controlled trial performed between September 2009 and August 2011. SETTING: Cardiovascular ICU within a tertiary referral university-affiliated teaching hospital. PATIENTS: One hundred forty-one patients undergoing coronary artery bypass graft surgery with normal or mildly reduced left ventricular systolic function. INTERVENTION: Participants were randomly assigned to receive anesthesia and postoperative sedation using IV propofol (n = 74) or inhaled volatile (isoflurane or sevoflurane) anesthetic agent (n = 67). MEASUREMENTS AND MAIN RESULTS: Patients sedated using inhaled volatile agent displayed faster readiness to extubation time at 135 minutes (95-200 min) compared with those receiving IV propofol at 215 minutes (150-280 min) (p < 0.001). Extubation times were faster within the volatile group at 182 minutes (140-255 min) in comparison with propofol group at 291 minutes (210-420 min) (p < 0.001). The volatile group showed a higher prevalence of vasodilatation with hypotension and higher cardiac outputs necessitating greater use of vasoconstrictors. There was no difference in postoperative pain scores, opioid consumption, sedation score, ICU or hospital length of stay, or patient mortality. CONCLUSIONS: Inhaled volatile anesthesia and sedation facilitates faster extubation times in comparison with IV propofol for patient undergoing coronary artery bypass graft surgery.

Safety and efficacy of baricitinib at 24†weeks in patients with rheumatoid arthritis who have had an inadequate response to methotrexate.

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.

Persistent currents in spinor condensates.

We create and study persistent currents in a toroidal two-component Bose gas, consisting of 87Rb atoms in two different spin states. For a large spin-population imbalance we observe supercurrents persisting for over two minutes. However, we find that the supercurrent is unstable for spin polarization below a well-defined critical value. We also investigate the role of phase coherence between the two spin components and show that only the magnitude of the spin-polarization vector, rather than its orientation in spin space, is relevant for supercurrent stability.

Review of the Food and Drug Administration's Center for Drug Evaluation and Research Program for New Molecular Entities: Trends and Regulatory Requirements in Mid-Cycle Communications.

The United States Food and Drug Administration (FDA) implemented "the Program" in 2012 to promote greater transparency and increased communication between the FDA and applicants of New Molecular Entity (NME) New Drug Applications (NDA) and original Biologics License Applications (BLA). We examined 128 publicly available NME NDA and original BLA approval packages reviewed and approved under the Program with the goal to educate regulatory professionals about the content and timing of communications from FDA to the Sponsor. This research found that the timing of communications between FDA and the Sponsor through the Mid-Cycle Communication (MCC) was consistent with the 21st-century Desk Reference Guide (DRG); 90% of internal FDA Mid-Cycle Meetings, MCCs with the applicant, and corresponding issuance of MCC minutes were within the target date. The content and format of the MCC were also consistent with the DRG and across disciplines. Almost all MCCs reviewed included a discussion on significant review issues, including major safety concerns. FDA's preliminary opinion on the necessity of a Risk Evaluation and Mitigation Strategy (REMS), which was predictive of REMS requirement at approval. The FDA's MCC comment on advisory committee meeting plans was highly predictive; if the MCC indicated an AC was planned, an AC meeting was held 91% of the time. With respect to the MCC, this research found the DRG and relevant FDA Manual of Policies and Procedures to be reliable resources to predict the FDA's planned actions associated with the review of a NME NDA or original BLA.

Condensation dynamics in a quantum-quenched Bose gas.

By quenching the strength of interactions in a partially condensed Bose gas, we create a "supersaturated" vapor which has more thermal atoms than it can contain in equilibrium. Subsequently, the number of condensed atoms (N(0)) grows even though the temperature (T) rises and the total atom number decays. We show that the nonequilibrium evolution of the system is isoenergetic and, for small initial N(0), observe a clear separation between T and N(0) dynamics, thus explicitly demonstrating the theoretically expected "two-step" picture of condensate growth. For increasing initial N(0) values, we observe a crossover to classical relaxation dynamics. The size of the observed quench-induced effects can be explained using a simple equation of state for an interacting harmonically trapped atomic gas.

Radiographic Progression of Structural Joint Damage Over 5 Years of Baricitinib Treatment in Patients With Rheumatoid Arthritis: Results From RA-BEYOND.

OBJECTIVE: To evaluate the effect of baricitinib on inhibiting radiographic progression of structural joint damage over 5 years in patients with active rheumatoid arthritis (RA). METHODS: Patients completed 1 of 3 phase III baricitinib trials (ClinicalTrials.gov: NCT01711359, NCT01710358, or NCT01721057) and entered the long-term extension RA-BEYOND (NCT01885078), in which patients received once-daily 4 mg or 2 mg baricitinib. Across these trials, patients initially receiving methotrexate (MTX) or adalimumab (ADA) switched to baricitinib 4 mg at Week 52. Patients initially receiving placebo (PBO) switched to baricitinib 4 mg at Week 24. Radiographs were scored at baseline and Years 2, 3, 4, and 5. Change from baseline in van der Heijde modified total Sharp score (ΔmTSS) was computed. RESULTS: Overall, 2125 of 2573 (82.6%) randomized patients entered RA-BEYOND; 1837 of 2125 (86.4%) entered this analysis. From Years 3 to 5, higher proportions of disease-modifying antirheumatic drug (DMARD)-naïve patients on initial baricitinib (monotherapy or with MTX) had no progression vs initial MTX (ΔmTSS ≤ 0 at Year 5: 59.6% baricitinib 4 mg; 66.2% baricitinib 4 mg + MTX; 40.7% MTX). Higher proportions of patients with inadequate response (IR) to MTX on initial baricitinib or ADA vs PBO had no progression (ΔmTSS ≤ 0 at Year 5: 54.8% baricitinib 4 mg; 55.0% ADA; 50.3% PBO). Higher proportions of patients with conventional synthetic DMARD-IR on initial baricitinib 4 mg had less progression vs initial PBO or baricitinib 2 mg (ΔmTSS ≤ 0 at Year 5: 66.7% baricitinib 4 mg; 58.2% baricitinib 2 mg; 60.0% PBO). CONCLUSION: Oral baricitinib maintained lower levels of radiographic progression than initial conventional synthetic DMARD or PBO through 5 years in patients with active RA.

Impact of a continuous enhanced cardio-respiratory monitoring pathway on cardio-respiratory complications after bariatric surgery: A retrospective cohort study.

STUDY OBJECTIVE: To determine the impact of an enhanced monitoring pathway consisting of continuous postoperative cardio-respiratory monitoring on adverse outcomes after bariatric. DESIGN: Single-center, retrospective cohort study. PATIENTS: Adult patients who underwent bariatric surgeries between 2009 and 2016. INTERVENTIONS: We evaluated the use of an enhanced monitoring pathway consisting of a distant, continuous, non-invasive respiratory monitoring system on postoperative cardio-respiratory complications in patients undergoing bariatric surgery. Treating physicians had the option to assign patients to enhanced monitoring (intervention group) in the postoperative period for suspected or diagnosed OSA or other clinical concerns. The control group had intermittent vital sign checks as per institutional standards. MEASUREMENTS: The primary outcome was a composite of cardio-respiratory complications (rapid response team activation, intensive care admission, respiratory complications), major adverse cardiac events, and all-cause mortality. The secondary outcome was length of stay (LOS). MAIN RESULTS: Of 1450 patients, 752 patients received enhanced monitoring (intervention) and 698 patients received standard monitoring (control). Univariate analysis showed that, compared to control, enhanced monitoring was associated with lower odds of composite cardio-respiratory complications (OR: 0.41, 95%CI: 0.32-0.53, p < 0.001) and lower odds of prolonged LOS > 2 days (OR: 0.37, 95% CI: 0.28-0.49, p < 0.001. After adjusting for potential confounders, enhanced monitoring remained associated with a reduction in composite cardio-respiratory complications (OR: 0.64, 95% CI: 0.46-0.88, p = 0.005). CONCLUSIONS: Our study demonstrates that postoperative enhanced monitoring pathway was associated with a lower incidence of cardio-respiratory composite events, compared to a standard of care, in patients undergoing bariatric surgery. As our results show association rather than causation, future prospective randomized trials are needed to confirm the benefit of enhanced monitoring. Findings of our study add to the existing literature involved in clinical management pathways to reduce the incidence of adverse postoperative outcomes in high-risk patients undergoing inpatient surgeries.

Can a Bose gas be saturated?

We scrutinize the concept of saturation of the thermal component in a partially condensed trapped Bose gas. Using a 39K gas with tunable interactions, we demonstrate strong deviation from Einstein's textbook concept of a saturated vapor. However, the saturation picture can be recovered by extrapolation to the strictly noninteracting limit. We provide evidence for the universality of our observations through additional measurements with a different atomic species, 87Rb.

An interactive online 3D model of the heart assists in learning standard transesophageal echocardiography views.

PURPOSE: Transesophageal echocardiography (TEE) is becoming a standard imaging tool during cardiac surgery as well as an important diagnostic tool in cardiology and in intensive care, resulting in an increasing demand for TEE training. To address the problem of limited time for learning during TEE studies, we have developed a novel online application that allows users to visualize each of the 20 standard diagnostic TEE views in conjunction with a three-dimensional (3D) heart model that can be rotated and "cut away" above the echo plane to reveal the internal cardiac structures. This study is an evaluation of the educational benefit of this application. METHODS: The application was evaluated using a pre-test/post-test design assessing the improvement of subjects' test scores following three days of access to the application. The subjects were postgraduate fellows in anesthesia, cardiology, and cardiac surgery. RESULTS: Ten subjects showed a significant increase (31%) in their test scores after an average of 130 min of access to the application over a three-day period (P < 0.001, effect size = 1.9). Using five-point Likert scales, the users indicated that the application was a useful addition to their training (4.7), they would recommend the application to their colleagues (4.9), and they found the application easy to use (4.4). CONCLUSION: The large improvement in test scores during a short period of study and the high level of satisfaction across all of the disciplines indicates that the application is a useful adjunctive tool for learning TEE. It is now being used in TEE training worldwide.

Review of the Food and Drug Administration's Center for Drug Evaluation and Research Program for New Molecular Entities: Trends and Regulatory Requirements in Acknowledgment Letters and Filing Communications.

The United States Food and Drug Administration (FDA) implemented the PDUFA V New Molecular Entity (NME) Program (the Program) in 2012 to promote greater transparency and increased communication between the FDA review team and applicants of NME New Drug Applications (NDA) and original Biologics License Applications (BLA). We reviewed 128 publicly available NME NDA and original BLA approval packages, submitted after October 2012 and approved by July 2018. Our research had a goal to educate regulatory professionals about the content and timing of communications from FDA to the Sponsor for approved drugs reviewed under the Program. This research found that communications issued within the first 74 days were consistent with the 21st Century Desk Reference Guide (DRG) targets; forecasted dates of other projected interactions included in the Filing Communication (FC) letter were often within 4 weeks of target. The content and format of the FC letter became more consistent with time, often including templated text. Approximately half the FC letters contained at least 1 filing review issue; however, not all appeared to be substantive. The FDA's preliminary comment on advisory committee meeting plans were predictive; 95% correlated with the need (or lack thereof) for an advisory committee meeting. Approximately 62% of FC letters contained actionable labeling comments, with nearly all related to editorial changes. With respect to the FC letter, this research found the DRG and relevant FDA Manual of Policies and Procedures to be reliable resources to predict the FDA's planned actions associated with the filing and review of a NME NDA or original BLA.

Temporary interruption of baricitinib: characterization of interruptions and effect on clinical outcomes in patients with rheumatoid arthritis.

BACKGROUND: In clinical practice, temporary interruption of rheumatoid arthritis (RA) therapy is common for various reasons including side effects, non-compliance, or necessity for surgery. To characterize temporary interruptions of baricitinib and placebo-matched tablets in phase 3 studies of patients with moderate-to-severe rheumatoid arthritis (RA) and describe their impact on efficacy and safety. METHODS: During 4 baricitinib phase 3 studies, investigators documented timing, reason, and duration of investigator-initiated temporary interruptions of study drug. In 2 studies, patients recorded RA symptoms in daily diaries for 12 weeks. Post hoc analyses investigated changes in symptom scores during interruptions and resumption of treatment. Interruptions were evaluated for reoccurrence of adverse events or laboratory abnormalities after retreatment. RESULTS: Across the placebo-controlled studies, interruptions occurred in larger proportions of baricitinib- (2 mg, 18%; 4 mg, 18%) vs placebo-treated (9%) patients in only one study (bDMARD-inadequate responder patients, RA-BEACON). In the active comparator-controlled studies, the lowest rates of interruption were in the baricitinib monotherapy arm (9%) of RA-BEGIN (vs methotrexate monotherapy or combination therapy), and proportions were similar for baricitinib (10%) and adalimumab (9%) in RA-BEAM. Adverse events were the most common reason for interruption, but their reoccurrence after drug restart was infrequent. Most interruptions lasted ≤ 2 weeks. Daily diaries indicated modest symptom increases during interruption with return to pre-interruption levels or better after resumption. Interruptions had no impact on long-term efficacy outcomes. CONCLUSIONS: Consistent with its pharmacologic properties, brief interruptions of baricitinib during phase 3 studies were associated with minor increases in RA symptoms that resolved following retreatment. This analysis provides useful information for clinicians, as temporary interruption of antirheumatic therapy is common in the care of patients with RA. TRIAL REGISTRATION: ClinicalTrials.gov; NCT01710358, NCT01711359, NCT01721057, NCT01721044.

Correction to: Temporary interruption of baricitinib: characterization of interruptions and effect on clinical outcomes in patients with rheumatoid arthritis.

An amendment to this paper has been published and can be accessed via the original article.

Nitrous oxide and perioperative cardiac morbidity (ENIGMA-II) Trial: rationale and design.

BACKGROUND: Globally there are >200 million major surgical procedures undertaken annually, and about 20% of these involve patients who have coronary artery disease. Many receive nitrous oxide, which impairs methionine synthase, thus inhibiting folate synthesis and increasing postoperative homocysteine levels. Nitrous oxide anesthesia leads to postoperative endothelial dysfunction, and there is some evidence that it increases myocardial ischemia and, possibly, myocardial infarction. We have initiated the Nitrous oxide and perioperative cardiac morbidity (ENIGMA-II) Trial to test the hypothesis that in inpatients undergoing anesthesia for major noncardiac surgery, avoidance of nitrous oxide will reduce the incidence of death and major cardiovascular events. METHODS: ENIGMA-II is a 7,000-patient, international randomized trial involving patients at risk of coronary artery disease undergoing noncardiac surgery. The patients, health care providers (except for the anesthesiologists), data collectors, and outcome adjudicators are blinded to whether patients receive nitrous oxide-containing or nitrous oxide-free anesthetic. The primary outcome is a composite of death and major nonfatal events (ie, myocardial infarction, cardiac arrest, pulmonary embolism, and stroke) at 30 days after surgery. RESULTS: At present, ENIGMA-II has randomized >1,000 patients in 22 hospitals in 5 countries. To date, patients' mean age is 70 years, 66% are men, 38% have a history of coronary artery disease, 19% have a history of cerebrovascular disease, and 84% have a history of hypertension. Most patients have undergone intra-abdominal 28%, vascular 32%, and orthopedic 16% surgery. CONCLUSIONS: The ENIGMA-II Trial will be the largest study yet conducted to ascertain the benefits and risks of removing nitrous oxide from the gas mixture in anesthesia. The results of this large international trial will guide the clinical care of the hundreds of millions of adults undergoing noncardiac surgery annually.