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Aims Associations between growth differentiation factor‐15 (GDF‐15), cardiovascular outcomes, and exercise capacity among patients with a recent hospitalization for heart failure (HHF) and heart failure with reduced ejection fraction (HFrEF) are unknown. We utilized data from the ‘Functional Impact of GLP‐1 for Heart Failure Treatment’ (FIGHT) study to address these knowledge gaps. Methods and results FIGHT was a randomized clinical trial testing the effect of liraglutide (vs. placebo) among 300 participants with HFrEF and a recent HHF. Multivariable regression models evaluated associations between baseline GDF‐15 and change in GDF‐15 (per 1000 pg/mL increase from baseline to 30 days) with clinical outcomes (at 180 days) and declines in exercise capacity (6 min walk distance ≥ 45 m). At baseline (n = 249), median GDF‐15 value was 3221 pg/mL (interquartile range 1938–5511 pg/mL). Participants in the highest tertile of baseline GDF‐15 were more likely to be male and have more co‐morbidities. After adjustment, an increase in GDF‐15 over 30 days was associated with higher risk of death or HHF [hazard ratio 1.35, 95% confidence interval (CI) 1.11–1.64]. In addition, higher baseline GDF‐15 (per 1000 pg/mL until 6000 pg/mL) and an increase in GDF‐15 over 30 days were associated with declining 6 min walk distance (odds ratio 1.26, 95% CI 1.02–1.55 and odds ratio 1.37, 95% CI 1.12–1.69, respectively). GDF‐15 levels remained stable among participants randomized to liraglutide. Conclusions An increase in GDF‐15 over 30 days among patients in HFrEF was independently associated with an increased risk of cardiovascular events and declining exercise capacity. These results support the value of longitudinal GDF‐15 trajectory in informing risk of heart failure disease progression.

Robust locomotion is critical to many species' survival, yet the mechanisms by which efficient locomotion is learned and maintained are poorly understood. In mice, a common paradigm for assaying locomotor learning is the rotarod task, in which mice learn to maintain balance atop of an accelerating rod. However, the standard metric for learning in this task is improvements in latency to fall, which gives little insight into the rich kinematic adjustments that accompany locomotor learning. In this study, we developed a rotarod-like task called the RotaWheel in which changes in paw kinematics are tracked using high-speed cameras as mice learn to stay atop an accelerating wheel. Using this device, we found that learning was accompanied by stereotyped progressions of paw kinematics that correlated with early, intermediate, and late stages of performance. Within the first day, mice sharpened their interlimb coordination using a timed pause in the forward swing of their forepaws. Over the next several days, mice reduced their stride length and took shorter, quicker steps. By the second week of training, mice began to use a more variable locomotor strategy, where consecutive overshoots or undershoots in strides were selected across paws to drive forward and backward exploration of the wheel. Collectively, our results suggest that mouse locomotor learning occurs through multiple mechanisms evolving over separate time courses and involving distinct corrective actions. These data provide insights into the kinematic strategies that accompany locomotor learning and establish an experimental platform for studying locomotor skill learning in mice.

Aims Artificial intelligence (A.I) driven voice-based assistants may facilitate data capture in clinical care and trials; however, the feasibility and accuracy of using such devices in a healthcare environment are unknown. We explored the feasibility of using the Amazon Alexa (‘Alexa’) A.I. voice-assistant to screen for risk-factors or symptoms relating to SARS-CoV-2 exposure in quaternary care cardiovascular clinics. Methods We enrolled participants to be screened for signs and symptoms of SARS-CoV-2 exposure by a healthcare provider and then subsequently by the Alexa. Our primary outcome was interrater reliability of Alexa to healthcare provider screening using Cohen’s Kappa statistic. Participants rated the Alexa in a post-study survey (scale of 1 to 5 with 5 reflecting strongly agree). This study was approved by the McGill University Health Centre ethics board. Results We prospectively enrolled 215 participants. The mean age was 46 years (17.7 years standard deviation [SD]), 55% were female, and 31% were French speakers (others were English). In total, 645 screening questions were delivered by Alexa. The Alexa mis-identified one response. The simple and weighted Cohen’s kappa statistic between Alexa and healthcare provider screening was 0.989 (95% CI: 0.982, 0.997) and 0.992 (955 CI 0.985, 0.999) respectively. The participants gave an overall mean rating of 4.4 (out of 5, 0.9 SD). Conclusion Our study demonstrates the feasibility of an A.I. driven multilingual voice-based assistant to collect data in the context of SARS-CoV-2 exposure screening. Future studies integrating such devices in cardiovascular healthcare delivery and clinical trials are warranted. Registration https://clinicaltrials.gov/ct2/show/NCT04508972, Graphical Abstract Graphical Abstract

International audience; Massive animal farming for meat production poses major problems in terms of resource use, environmental impact, and biodiversity. Furthermore, excessive meat consumption has been associated with multiple deleterious health consequences. However, more and better-designed randomized trials are needed to increase the level of evidence on the health impacts of meat. Novel meat alternatives, such as plant- and cell-based meat, are much less impactful to the environment and might replace traditional animal meat in the future, but, despite promising early data, the health consequences of these novel products need further study. This manuscript focuses on the health impacts of meat over 3 main sections: 1) overview of the evidence highlighting the association of meat consumption with health; 2) novel alternatives to meat, including plant-based and cell-based alternatives; and 3) examine the rationale for randomized studies to evaluate the effects of the novel meat alternatives compared with the standard animal meat.

Women, older patients and non-White ethnic groups experience a substantial proportion of acute coronary syndromes (ACS), although they have been historically underrepresented in ACS randomized clinical trials (RCTs). To assess the influence of sex, age and race on major adverse cardiovascular events (MACE) and on heart failure events, we studied patients with type 2 diabetes in a large post-ACS trial (EXAMINE). Differences in baseline characteristics and the respective composite endpoint of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke (MACE) and cardiovascular death or heart failure hospitalization (HF events) were evaluated by subgroups in a cohort of post-ACS patients with diabetes, using unadjusted and adjusted Cox regression modelling. The EXAMINE trial enrolled 5380 patients with 35% aged > 65, 32% female and 27% non-White. The risk of MACE was higher in non-White compared to White patients after adjustment for potential confounding (HR = 1.35; 95% CI 1.04–1.75), but there were no significant differences by sex and age (HR = 1.03; 95% CI 0.87–1.22 for women; HR = 1.14; 95% CI 0.96–1.35 for patients ≥ 65 years). The risk of HF events was higher in non-White patients (HR = 1.56; 95% CI 1.13–2.14), and in patients aged > 65 (HR = 1.33; 95% CI 1.07–1.66) and nominally so in women (HR = 1.23; 95% CI 0.99–1.52). The additive risk of each demographic factor (women, older age and non-White race) was greater for HF events in comparison with MACE. Moreover, non-White elderly patients consistently had poorer prognosis regardless of sex. Older adults, women and non-White patients with diabetes who are post-ACS are often underrepresented in RCTs. The risk for HF events was higher in older and non-White patients, with a trend towards significance in women, whereas only non-White patients (and not women and older patients) were at higher risk for MACE. Future trials should enrich enrollment of these persons at risk.

Introduction While current guidelines currently recommend using warfarin, there is also a growing interest in the utilization of direct oral anticoagulants (DOACs) to treat left ventricular (LV) thrombus. Methods We performed a systematic search using PubMed, SCOPUS, EMBASE, Google Scholar, and ClinicalTrials.gov from inception to September 30th, 2020, for studies that had reported outcomes in patients with left ventricular thrombus treated with DOACs (PROSPERO registration number CRD42020219761) RESULTS: Twelve studies (n=867 patients) were included in the analysis. The pooled incidence of the systemic embolic events (SEE) with DOACs was 2.7%, while the thrombus resolution rate was 86.6%. The pooled incidence of overall bleeding (composite of major and minor bleeding) and major bleeding with DOACs were 5.6% and 1.1%, respectively. No significant difference was observed in terms of SEE (OR 0.81, 95% CI 0.44-1.52, p=0.54), major bleeding (OR 0.29, 95% CI 0.07-1.26, p=0.24), and failure of LV thrombus resolution (OR 0.86, 95% CI 0.28-2.58, p=0.68); while overall bleeding was significantly low in patients with LV thrombus treated with DOACs compared to vitamin K antagonists (VKAs) (OR 0.33, 95% CI 0.14-0.81, p=0.02) CONCLUSION: Our study demonstrates no significant difference in SEE, major bleeding, or failure of LV thrombus resolution between the two groups, thus demonstrating that DOACs are an efficacious and safe alternative for the treatment of LV thrombus compared to VKAs. However, further well-designed prospective trials are needed to answer important clinical questions - optimal dosing/duration of DOACs and its safety in the background of antiplatelet therapy. This article is protected by copyright. All rights reserved.

Background The Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (TRS-HFDM ) risk stratifies patients with type 2 diabetes mellitus (T2DM) and high cardiovascular risk for heart failure (HF) hospitalization. The utility of TRS-HFDM in risk stratification for HF outcomes requires further validation. Materials and methods We used data from the control group of The Action to Control Cardiovascular Risk in Diabetes Study Group (ACCORD) trial (n=5123; mean follow up 4.8 years). The TRS-HFDM includes: prior HF (2 points), atrial fibrillation (1 point), coronary artery disease (1 point), estimated glomerular filtration rate 300 mg/g; 2 point and 30-300 mg/g; 1 point). We evaluated discrimination (Harrell C index) and calibration (Nam-D Agostino calibration statistic) of TRS-HFDM for time to HF hospitalization or death due to HF. Results The mean age of participants was 62.8±6.6 years, and 38% were female. The prevalence of TRS-HFDM for 0, 1, 2, 3 and 4+ were 42.1%, 34.9%, 14.6%, 6.0%, and 2.5% respectively. Increasing TRS-HFDM corresponded to an increasing HF risk: 1.3/1000 person years (PY) (TRS-HFDM : 0) to 64.7/1000 PY (TRS-HFDM : 4+). TRS-HFDM demonstrated robust discrimination for HF outcomes (C-index 0.78). Furthermore, the score was well calibrated for HF outcomes (calibration statistic p=0.13). Similar results were seen in participants without baseline HF (C-index 0.75). Conclusion The TRS-HFDM discriminates for HF specific risk among people with T2DM. Using the TRS-HFDM to identify those who maximally benefit from therapies that reduce HF risk warrants evaluation. This article is protected by copyright. All rights reserved.

Aims Among patients with acute myocardial infarction (AMI) complicated by heart failure [HF; clinical HF or left ventricular (LV) systolic dysfunction], we explored the probability of subsequent non-fatal cardiovascular (CV) events and sudden cardiac death (SCD). Methods and results The high-risk myocardial infarction (HRMI) database contains 28 771 patients with signs of HF or reduced LV ejection fraction ( Conclusion Among patients with AMI complicated by HF, SCD, compared with other causes of death, was less likely to be preceded by a non-fatal CV event. As patients are less likely to have preceding non-fatal CV events to alert the healthcare team of a possible impending SCD event, additional strategies for risk stratification for SCD are needed.

Background Incidental radiographic findings, such as adrenal nodules, are commonly identified in imaging studies and documented in radiology reports. However, patients with such findings frequently do not receive appropriate follow-up, partially due to the lack of tools for the management of such findings and the time required to maintain up-to-date lists. Natural language processing (NLP) is capable of extracting information from free-text clinical documents and could provide the basis for software solutions that do not require changes to clinical workflows. Objectives In this manuscript we present (1) a machine learning algorithm we trained to identify radiology reports documenting the presence of a newly discovered adrenal incidentaloma, and (2) the web application and results database we developed to manage these clinical findings. Methods We manually annotated a training corpus of 4,090 radiology reports from across our institution with a binary label indicating whether or not a report contains a newly discovered adrenal incidentaloma. We trained a convolutional neural network to perform this text classification task. Over the NLP backbone we built a web application that allows users to coordinate clinical management of adrenal incidentalomas in real time. Results The annotated dataset included 404 positive (9.9%) and 3,686 (90.1%) negative reports. Our model achieved a sensitivity of 92.9% (95% confidence interval: 80.9–97.5%), a positive predictive value of 83.0% (69.9–91.1)%, a specificity of 97.8% (95.8–98.9)%, and an F1 score of 87.6%. We developed a front-end web application based on the model's output. Conclusion Developing an NLP-enabled custom web application for tracking and management of high-risk adrenal incidentalomas is feasible in a resource constrained, safety net hospital. Such applications can be used by an institution's quality department or its primary care providers and can easily be generalized to other types of clinical findings.

Background The EXAMINE trial tested the efficacy and safety of alogliptin, an inhibitor of dipeptidyl peptidase 4, compared with placebo in 5380 patients with type 2 diabetes and a recent acute coronary syndrome. Because alogliptin is cleared by the kidney, patients were stratified according to screening renal function within two independently randomized strata: (1) estimated glomerular filtration rate (eGFR) ≥ 60 ml/min/1.73m2 and (2) eGFR 2. We aim to assess the efficacy and safety of alogliptin vs. placebo according to the renal function strata. Methods Cox-proportional hazard models with an interaction term by renal function strata were used. The primary endpoint was a composite of cardiovascular death, nonfatal myocardial infarction (MI), or nonfatal stroke. Results Patient characteristics were balanced within each renal function strata. In total, 3946 patients were randomized within the eGFR ≥ 60 stratum, and 1434 patients within the eGFR p = 0.014. Cardiovascular death: eGFR ≥ 60 HR = 0.61, 95%CI, 0.42–0.88, and eGFR p = 0.013. Non-fatal MI: eGFR ≥ 60 HR = 0.86, 95%CI, 0.66–1.13, and eGFR p = 0.013. Conclusions Alogliptin may benefit patients with eGFR ≥ 60, but may be detrimental to patients with eGFR 2. These hypothesis-generating findings require further validation to assess the potential benefit and risk of alogliptin across the renal function spectrum among patients with type 2 diabetes and a recent acute coronary syndrome. Trial registration ClinicalTrials.gov, NCT00968708

Responding to concerns about the potential for increased risk of adverse cardiovascular outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the US Food and Drug Administration and the Committee for Medicinal Products for Human Use of the European Medicines Agency issued guidance to the pharmaceutical industry in 2008. Glucose-lowering therapies were granted regulatory approval primarily from smaller studies that have demonstrated reductions in glycated hemoglobin concentration. Such studies were overall underpowered and of insufficient duration to show any effect on cardiovascular outcomes. The 2008 guidance aimed to ensure the cardiovascular safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new cardiovascular outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated cardiovascular benefits of the newer agents, resulting in the first-ever cardiovascular protection indications for glucose-lowering therapies. Determining whether the guidance continues to have value in its current form is critically important as we move forward after the first decade of implementation. In February 2018, a think tank comprising representatives from academia, industry, and regulatory agencies convened to consider the guidance in light of the findings of the completed cardiovascular outcome trials. The group made several recommendations for future regulatory guidance and for cardiovascular outcome trials of glucose-lowering therapies. These recommendations include requiring only the 1.3 noninferiority margin for regulatory approval, conducting trials for longer durations, considering studying glucose-lowering therapies as first-line management of type 2 diabetes mellitus, considering heart failure or kidney outcomes within the primary outcome, considering head-to-head active comparator trials, increasing the diversity of patients enrolled, evaluating strategies to streamline registries and the study of unselected populations, and identifying ways to improve translation of trial results to general practice.

Aims To develop a risk model for sudden cardiac death (SCD) in high‐risk acute myocardial infarction (AMI) survivors. Methods and results Data from the Effect of Carvedilol on Outcome After Myocardial Infarction in Patients With Left Ventricular Dysfunction trial (CAPRICORN) and the Valsartan in Acute Myocardial Infarction Trial (VALIANT) were used to create a SCD risk model (with non‐SCD as a competing risk) in 13 202 patients. The risk model was validated in the Eplerenone Post‐AMI Heart Failure Efficacy and Survival Study (EPHESUS). The rate of SCD was 3.3 (95% confidence interval 3.0–3.5) per 100 person‐years over a median follow‐up of 2.0 years. Independent predictors of SCD included age > 70 years; heart rate ≥ 70 bpm; smoking; Killip class III/IV; left ventricular ejection fraction ≤30%; atrial fibrillation; history of prior myocardial infarction, heart failure or diabetes; estimated glomerular filtration rate

International audience; Aims: In heart failure with reduced ejection fraction (HFrEF), guidelines recommend up-titration of angiotensin-converting enzyme inhibitors (ACEi) and angiotensin receptors blockers (ARBs) to the maximum tolerated dose. However, some studies suggest that women might need lower doses of ACEi/ARBs than men to achieve similar treatment benefit.Methods and results: The HEAAL trial compared low vs. high dose of losartan. We reassessed the efficacy and safety of high- vs. low-dose in men vs. women using Cox models and machine learning algorithms. The mean age was 66 years and 30% of patients were women. Men appeared to have benefited more from high-dose than from low-dose losartan, whereas women appeared to have responded similarly to low and high doses [hazard ratio (95% confidence interval) comparing high- vs. low-dose losartan for the composite outcome of all-cause death or all-cause hospitalization: 0.89 (0.81-0.98) in men and 1.10 (0.95-1.28) in women; interaction P = 0.018]. Female sex clustered along with older age, ischaemic heart failure, New York Heart Association class III/IV, and estimated glomerular filtration rate

Recently, there have been many efforts to use mobile apps as an aid in contact tracing to control the spread of the SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) (COVID-19 [coronavirus disease 2019]) pandemic. However, although many apps aim to protect individual privacy, the very nature of contact tracing must reveal some otherwise protected personal information. Digital contact tracing has endemic privacy risks that cannot be removed by technological means, and which may require legal or economic solutions. In this brief communication, we discuss a few of these inherent privacy limitations of any decentralized automatic contact tracing system.

IntroductionPatients with type 2 diabetes (T2D) have an increased risk of worsening kidney function (WKF) over time compared with patients without diabetes. Data evaluating the inter-relation between WKF, cardiovascular risk, and clinical events are scarce. We aim to study the association of WKF with subsequent cardiovascular events and the probabilities of transition from WKF to hospitalization or death according to patients’ risk. We have used a large population of patients with T2D and a high cardiovascular risk enrolled in the Action to Control Cardiovascular Risk in Diabetes Study.Research design and methodsTime-updated, joint, and multistate modeling were used. WKF was defined as an estimated glomerular filtration rate (eGFR) decline greater than 40% from baseline. A total of 10 251 patients were included, of whom 1213 (11.8%) presented WKF over a median (percentile25–75) follow-up time of 5.0 (4.1–5.7) years.ResultsPatients who experienced WKF were slightly older, more frequently women, and had longer diabetes duration. Patients experiencing WKF, regardless of baseline kidney function, had a higher risk of subsequent cardiovascular events, including the composite of cardiovascular death or hospitalization for heart failure (HHF), with ≈2-fold higher risk. Joint modeling showed that renal function deterioration frequently occurs even among patients who did not experience a cardiovascular event. In multistate models, patients with a medium-high cardiovascular risk (compared with those with a low cardiovascular risk) are at higher risk of HHF or cardiovascular death first (HR=4.76, 95% CI 3.63 to 6.23) than of WKF first (HR=1.37, 95% CI 1.21 to 1.56); remarkably, the risk of cardiovascular death or HHF is highest after a WKF event (HR=6.20, 95% CI 2.71 to 14.8).ConclusionsIn patients with T2D and a high cardiovascular risk, WKF occurs in more than 10% of patients and is independently associated with risk of subsequent cardiovascular events, irrespective of baseline eGFR. Preventing serious WKF and the transition from WKF to HHF or cardiovascular death is an important objective of future trials.Trial registration numberNCT00000620.

Purpose of Review With the rising cost of cardiovascular clinical trials, there is interest in determining whether new technologies can increase cost effectiveness. This review focuses on current and potential uses of voice-based technologies, including virtual assistants, in cardiovascular clinical trials. Recent Findings Numerous potential uses for voice-based technologies have begun to emerge within cardiovascular medicine. Voice biomarkers, subtle changes in speech parameters, have emerged as a potential tool to diagnose and monitor many cardiovascular conditions, including heart failure, coronary artery disease, and pulmonary hypertension. With the increasing use of virtual assistants, numerous pilot studies have examined whether these devices can supplement initiatives to promote transitional care, physical activity, smoking cessation, and medication adherence with promising initial results. Additionally, these devices have demonstrated the ability to streamline data collection by administering questionnaires accurately and reliably. With the use of these technologies, there are several challenges that must be addressed before wider implementation including respecting patient privacy, maintaining regulatory standards, acceptance by patients and healthcare providers, determining the validity of voice-based biomarkers and endpoints, and increased accessibility. Summary Voice technology represents a novel and promising tool for cardiovascular clinical trials; however, research is still required to understand how it can be best harnessed.

Author(s): Sharma, Abhinav; Wu, Jingjing; Ezekowitz, Justin A; Felker, Gary Michael; Udell, Jacob A; Heidenreich, Paul A; Fonarow, Gregg C; Mahaffey, Kenneth W; Hernandez, Adrian F; DeVore, Adam D | Abstract: AimsSodium-glucose co-transporter (SGLT)-2 inhibitors have been shown to reduce the risk of cardiovascular death and heart failure (HF) hospitalization in patients with type 2 diabetes mellitus (DM) and high cardiovascular risk in two large clinical outcome trials: empagliflozin in EMPA-REG OUTCOME and canagliflozin in CANVAS. The scope of eligibility for SGLT-2 inhibitors (empagliflozin and canagliflozin) among patients with type 2 DM and HF, based on clinical trial criteria and current US Food and Drug Administration (FDA) labelling criteria, remains unknown.Methods and resultsUsing data from the US Get With The Guidelines (GWTG)-Heart Failure registry, we evaluated the proportion of patients with DM and HF eligible for SGLT-2 inhibitor therapy based on the clinical trial criteria and the US FDA labelling criteria. The GWTG-HF registry is a quality improvement registry of patients admitted in hospital with HF in the USA. We included GWTG-HF registry participants meeting eligibility criteria hospitalized between August 2014 and 30 June 2017 from sites fully participating in the registry. The initial inclusion time point reflects when both drugs had FDA approval. Among the 139 317 patients (out of 407 317) with DM hospitalized with HF (in 460 hospitals; 2014 to 2017), the median age was 71 years, 47% (n = 65 685) were female, and 43% (n = 59 973) had HF with reduced ejection fraction. Overall, 43% (n = 59 943) were eligible for the EMPA-REG OUTCOME trial, 45% (n = 62 818) were eligible for the CANVAS trial, and 34% (n = 47 747) of patients were eligible for either SGLT-2 inhibitors based on the FDA labelling criteria. Among the FDA-eligible patients, 91.5% (n = 43 708) were eligible for either the EMPA-REG OUTCOME trial or the CANVAS trial. Patients who were FDA eligible, compared with those who were not, were younger (70.0 vs. 72.0 years of age), more likely to be male (57.7 vs. 50.3%), and had less burden of co-morbidities.ConclusionsThe majority of patients with DM who are hospitalized with HF are not eligible for SGLT-2 inhibitor therapies. Ongoing studies evaluating the safety and efficacy of SGLT-2 inhibitors among patients with HF may potentially broaden the population that may benefit from these therapies.

Purpose of review Although type 2 diabetes (T2D) is one of the most important risk factors that leads to the development of de novo heart failure, there are limited data, particularly from a practical/qualitative standpoint, about predictors of heart failure in this population. Recent findings Sodium-glucose cotransporter-2 (SGLT-2) inhibitors have been shown to prevent the development of heart failure and the composite of heart failure and cardiovascular death in patients with T2D without known heart failure who have either established atherosclerotic vascular disease or multiple risk factors. The concept of primary prevention of heart failure has led many clinicians to inquire if there are specific risk/enrichment factors that may predict an increased risk of heart failure. Summary In this review, we identify some general and diabetes-specific risk factors that are associated with an increased risk of developing heart failure in people with T2D.

Cigarette smoking is one of the most important causes of illness and premature death. The tobacco problem in India is very complex, due to large use of an array of smoking forms well as smokeless tobacco products. Several recent publications have highlighted the requirement for the dental profession to get involved with tobacco intervention. Although approximately all of the toxicity of smoking is due to other harmful components present in cigarette smoke, the pharmacological effects of nicotine leads to tobacco addiction. Hence, all the attempts to quit smoking are aimed to remove tobacco addiction by replacing tobacco nicotine with clean nicotine. The most important cessation aid used, out of all the cessation aids, is nicotine replacement therapy or NRT. Nicotine replacement therapy (NRT) replaces much of the nicotine from tobacco, which is mixed with harmful chemicals, with clean nicotine, thus reducing motivation to consume tobacco and also lessening nicotine withdrawal symptoms, thus easing the transition from cigarette smoking to complete abstinence. NRTs show good results and have minimal adverse effects. The review aims to summarize literature on various modes of nicotine replacement therapy methods currently used and to discuss future possible approaches. Also, the safety and need of NRTs in various special conditions have been discussed. Keywords: Nicotine replacement therapy, Important cessation, Cigarette smoking.

Risk prediction following acute coronary syndrome (ACS) remains challenging. Data-driven machine-learning algorithms can potentially identify patients at high risk of clinical events. The Improved Reduction of Outcomes: Vytorin Efficacy International Trial randomized 18,144 post-ACS patients to ezetimibe + simvastatin or placebo + simvastatin. We performed hierarchical cluster analysis to identify patients at high risk of adverse events. Associations between clusters and outcomes were assessed using Cox proportional hazards models. The primary outcome was cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, unstable angina hospitalization, or coronary revascularization ≥30 days after randomization. We evaluated ezetimibe's impact on outcomes across clusters and the ability of the cluster analysis to discriminate for outcomes compared with the Global Registry of Acute Coronary Events (GRACE) score. Five clusters were identified. In cluster 1 (n = 13,252), most patients experienced a non-STEMI (54.8%). Cluster 2 patients (n = 2,719) had the highest incidence of unstable angina (n = 83.3%). Cluster 3 patients (n = 782) all identified as Spanish descent, whereas cluster 4 patients (n = 803) were primarily from South America (56.2%). In cluster 5 (n = 587), all patients had ST elevation. Cluster analysis identified patients at high risk of adverse outcomes (log-rank p0.0001); Cluster 2 (vs 1) patients had the highest risk of outcomes (hazards ratio 1.33, 95% confidence interval 1.24 to 1.43). Compared with GRACE risk, cluster analysis did not provide superior outcome discrimination. A consistent ezetimibe treatment effect was identified across clusters (interaction p = 0.882). In conclusion, cluster analysis identified significant difference in risk of outcomes across cluster groups. Data-driven strategies to identify patients who may differentially benefit from therapies and for risk stratification require further evaluation.

Background Different approaches to safety event collection influence the determination of liver toxicity within drug development programs. Herein, a description of how fasiglifam-induced liver injury was detected is provided. Methods This eight-trial drug development program was intended to evaluate fasiglifam (25 mg, 50 mg) against placebo or active comparators (glimepiride, sitagliptin) in approximately 11,000 suboptimally controlled patients with type 2 diabetes (terminated Dec 2013 due to liver toxicity). Liver safety had been pre-identified as a concern, and within the phase 3 trials, was measured through (1) adverse event reporting, (2) central predefined liver monitoring schedule with various thresholds for potential drug-induced liver injury, and (3) blinded adjudication of serious liver toxicity by a panel of experts in drug-induced liver injury. A single data monitoring committee provided safety oversight across all trials within the program. Findings Prior to program termination, 7595 of 7602 (99.9%) randomized participants across the eight trials received at least one dose of the study drug (fasiglifam, placebo, or active control). No concerning trends were noted in adverse or serious adverse event frequency, suspected unexpected serious adverse reaction, alanine or aspartate transaminase elevations, or hepatobiliary or gastrointestinal adverse events as reported by local site investigators. However, the predefined central liver safety measurements revealed a greater frequency of possible Hy’s Law cases (5 vs 2) and a 3- to 7-fold greater relative risk in alanine or aspartate transaminase elevation (with respect to upper limit of normal) within fasiglifam recipients compared with placebo/active control: alanine or aspartate transaminase > 3×: relative risk 3.34 (95% confidence interval 2.29–4.90), alanine or aspartate transaminase > 5×: relative risk 6.60 (95% confidence interval 3.03–14.38), alanine or aspartate transaminase > 8×: relative risk 6.14 (95% confidence interval 2.18–17.27), and alanine or aspartate transaminase > 10×: relative risk 6.74 (95% confidence interval 2.05, 22.14). All elevations resolved on study drug discontinuation. Drug-induced liver injury was adjudicated as highly likely or probably related in 0.64% of fasiglifam-treated versus 0.06% placebo or active control-treated patients. Conclusion In spite of clear liver toxicity detected with a systematic surveillance program, liver safety signals were not identified from investigator adverse event reporting alone. By integrating key safety monitoring processes within the randomized design of adequately sized clinical trials, the rare but serious liver toxicity signal became clear, leading to timely program termination.

Objectives The aim of the RAAS-COVID-19 randomized control trial is to evaluate whether an upfront strategy of temporary discontinuation of renin angiotensin aldosterone system (RAAS) inhibition versus continuation of RAAS inhibition among patients admitted with established COVID-19 infection has an impact on short term clinical and biomarker outcomes. We hypothesize that continuation of RAAS inhibition will be superior to temporary discontinuation with regards to the primary endpoint of a global rank sum score. The global rank sum score has been successfully used in previous cardiovascular clinical trials. Trial design This is an open label parallel two arm (1,1 ratio) randomized control superiority trial of approximately 40 COVID-19 patients who are on chronic RAAS inhibitor therapy. Participants Adults who are admitted to hospital within the McGill University Health Centre systems (MUHC) including Royal Victoria Hospital (RVH), Montreal General Hospital (MGH) and Jewish General Hospital (JGH) and who are within 96 hours of COVID-19 diagnosis (confirmed via PCR on any biological sample) will be considered for the trial. Of note, the initial protocol to screen and enrol within 48 hours of COVID-19 diagnosis was extended through an amendment, to 96 hours to increase feasibility. Participants have to be 18 years or older and would have to be on RAAS inhibitors for at least a month to be considered eligible for the study. Additionally, RAAS inhibitors should not have been held for more than 48 hours before randomization. A list of inclusion and exclusion criteria can be found in the full protocol document. In order to prevent heart failure exacerbation, patients with reduced ejection fraction were excluded from the trial. Once a patient is admitted on the ward with a diagnosis of COVID-19, we will confirm with the treating physician if the participant is suitable for the RAAS-COVID trial and meets all the inclusion and exclusion criteria. If the patient is eligible and informed consent has been obtained we will collect data on sex, age, ethnicity, past medical history and list of medications (e.g. other anti-hypertensives or anticoagulants), for further analysis. Intervention and comparator All the study participants will be randomized to a strategy of temporarily holding the RAAS inhibitor [intervention] versus continuing the RAAS inhibitor [continued standard of care]. Among participants who are randomized to the intervention arm, alternative guide-line directed anti-hypertensive medication will be provided to the treating physician team (detail in study protocol). In the intervention arm RAAS inhibitor will be withheld for a total of 7 days with the possibility of the withdrawn medication being initiated at any point after day 7 or on the day of discharge. The recommendation for re-initiating the withdrawn medication will be made to the treating physician. The re-initiation of these therapies are according to standard convention and follow-up as per Canadian guidelines. Additionally, the date of restarting the withdrawn medication or whether the medication was re-prescribed on discharge or not, will be collected. This will be used to conduct a sensitivity analysis. Furthermore, biomarkers such as troponin, c-reactive protein (CRP) and lymphocyte count will be assessed during the same time period. Samples will be collected on randomization, day 4 and day 7. Main outcomes Primary endpoint In this study the primary end point is a global rank score calculated for all participants, regardless of treatment assignment ( score from 0 to 7). Please refer to table 4 in the full protocol. In the context of the current trial, it is estimated that death is the most meaningful endpoint, and therefore has the highest score ( score of 7). This is followed by admission to ICU, the need for mechanical ventilation etc. The lowest scores ( score of 1) are assigned to biomarker changes (e.g. change in troponin, change in CRP). This strategy has been used successfully in cardiovascular disease trials and therefore is applicable to the current trial. The primary endpoint for the present trial is assessed from baseline to day 7 (or discharge). Participants are ranked across the clinical and biomarker domains. Lower values indicate better health (or stability). Participants who died during the 7th day of the study will be ranked based on all events occurring before their death and also including the fatal event in the score. Next, participants who did not die but were transferred to ICU for invasive ventilation will be ranked based on all the events occurring before the ICU entry and also including the ICU admission in the score. Those participants who did not die were not transferred to ICU for invasive ventilation, will be ranked based on the subsequent outcomes. The mean rank score will then be compared between groups. In this scheme, a lower mean rank score indicates greater overall stability for participants. Secondary endpoints : The key secondary endpoints are the individual components of the primary components and include the following: death, transfer to ICU primarily for invasive ventilation, transfer to ICU for other indication, non-fatal MACE ( any of following, MI, stroke, acute HF, new onset Afib), length of stay > 4 days, development of acute kidney injury ( > 40% decline in eGFR or doubling of serum creatinine), urgent intravenous treatment for high blood pressure, 30% increase in baseline high sensitivity troponin, 30% increase in baseline BNP, increase in CRP to > 30% in 48 hours and lymphocyte count drop> 30%. We will also look at the World Health Organization (WHO) ordinal scale for clinical improvement (in COVID-19) in our data. In this scale death will be assigned the highest score of 8. Patients with no limitation of activity will be assigned a score of 1 which indicates overall more stability (3). Additionally, we will evaluate the potential effects of discontinuing RAAS inhibition on alternative schedules (longer/shorter than 7 days, intermittent discontinuation) using a mechanistic mathematical model of COVID-19 immunopathology calibrated to data collected from our patient cohort. In particular, we will assess the impact of alternative schedules on primary and secondary endpoints including increases to baseline CRP and lymphocyte counts. Randomization Participants will be randomized in a 1:1 ratio. Randomization will be performed within an electronic database system at the time of enrolment using a random number generator, an approach that has been successfully used in other clinical trials. Neither participant, study team, or treating team will be blinded to the intervention arm. Blinding This is an open label study with no blinding. Numbers to be randomised (sample size) The approximate number of participants required for this trial is 40 patients (randomized 1:1 to continuation versus discontinuation of RAAS inhibitors). This number was calculated based on previous rates of outcomes for COVID-19 in the literature (e.g. death, ICU transfer) and statistical power calculations. Trial Status Protocol number: MP-37-2021-6641, Version 4: 01-10-2020. Trial start date September 1st 2020 and currently enrolling participants. Estimated end date for recruitment of participants : July 2021. Estimated end date for study completion: September 1st 2021. Trial registration Trial registration: ClincalTrials.gov: NCT04508985, date of registration: August 11th , 2020 Full protocol The full protocol is attached as an additional file, accessible from the Trials website (Additional file 1). In the interest in expediting dissemination of this material, the familiar formatting has been eliminated; this Letter serves as a summary of the key elements of the full protocol.

International audience; In this update of the Canadian Cardiovascular Society heart failure (HF) guidelines, we provide comprehensive recommendations and practical tips for the pharmacologic management of patients with HF with reduced ejection fraction (HFrEF). Since the 2017 comprehensive update of the Canadian Cardiovascular Society guidelines for the management of HF, substantial new evidence has emerged that has informed the care of these patients. In particular, we focus on the role of novel pharmacologic therapies for HFrEF including angiotensin receptor-neprilysin inhibitors, sinus node inhibitors, sodium glucose transport 2 inhibitors, and soluble guanylate cyclase stimulators in conjunction with other long established HFrEF therapies. Updated recommendations are also provided in the context of the clinical setting for which each of these agents might be prescribed; the potential value of each therapy is reviewed, where relevant, for chronic HF, new onset HF, and for HF hospitalization. We define a new standard of pharmacologic care for HFrEF that incorporates 4 key therapeutic drug classes as standard therapy for most patients: an angiotensin receptor-neprilysin inhibitor (as first-line therapy or after angiotensin converting enzyme inhibitor/angiotensin receptor blocker titration); a β-blocker; a mineralocorticoid receptor antagonist; and a sodium glucose transport 2 inhibitor. Additionally, many patients with HFrEF will have clinical characteristics for which we recommended other key therapies to improve HF outcomes, including sinus node inhibitors, soluble guanylate cyclase stimulators, hydralazine/nitrates in combination, and/or digoxin. Finally, an approach to management that integrates prioritized pharmacologic with nonpharmacologic and invasive therapies after a diagnosis of HFrEF is highlighted.

Funda??o Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Programa de P?s-Gradua??o em Pesquisa Cl?nica e Doen?as Infecciosas. Rio de Janeiro, RJ, Brasil / Funda??o Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laborat?rio de Bacteriologia e Bioensaios em Micobact?rias. Rio de Janeiro, RJ, Brasil / Funda??o Oswaldo Cruz. Instituto Oswaldo Cruz. Laborat?rio de Biologia Molecular Aplicada a Micobact?rias. Rio de Janeiro, RJ, Brasil. Universidade Federal do Rio Grande do Sul. Programa de P?s-Gradua??o em Biologia Celular e Molecular. Porto Alegre, RS, Brasil / Secretaria Estadual de Sa?de do Rio Grande do Sul. Centro Estadual de Vigil?ncia em Sa?de. Centro de Desenvolvimento Cient?fico e Tecnol?gico. Porto Alegre, RS, Brasil. Funda??o Oswaldo Cruz. Escola Nacional de Sa?de P?blica Sergio Arouca. Centro de Refer?ncia Professor H?lio Fraga. Laborat?rio de Refer?ncia Nacional para Tuberculose e outras Micobacterioses. Rio de Janeiro, RJ, Brasil. Universidade do Estado do Par?. Instituto de Ci?ncias Biol?gicas e da Sa?de. P?s-Gradua??o Biologia Parasit?ria na Amaz?nia. Bel?m, PA, Brasil / Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. Universidade do Estado do Par?. Instituto de Ci?ncias Biol?gicas e da Sa?de. P?s-Gradua??o Biologia Parasit?ria na Amaz?nia. Bel?m, PA, Brasil / Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Laborat?rio de Geoprocessamento. Ananindeua, PA, Brasil. International Institute of Information Technology. Department of Data Science. Bangalore, India. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. Secretaria Estadual de Sa?de do Rio Grande do Sul. Centro Estadual de Vigil?ncia em Sa?de. Centro de Desenvolvimento Cient?fico e Tecnol?gico. Porto Alegre, RS, Brasil. Universidade de S?o Paulo. Faculdade de Medicina. Departamento de Cl?nica M?dica. Ribeir?o Preto, SP, Brasil. Universidade de S?o Paulo. Faculdade de Medicina. Departamento de Cl?nica M?dica. Ribeir?o Preto, SP, Brasil. Funda??o Oswaldo Cruz. Instituto Oswaldo Cruz. Laborat?rio de Biologia Molecular Aplicada a Micobact?rias. Rio de Janeiro, RJ, Brasil / Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de G?es. Laborat?rio de Micobact?rias. Rio de Janeiro, RJ, Brasil. Universidade Federal de S?o Paulo. Departamento de Microbiologia, Imunologia e Parasitologia. S?o Paulo, SP, Brasil. Instituto Adolfo Lutz. Centro de Bacteriologia. N?cleo de Tuberculose e Micobacterioses. S?o Paulo, SP, Brasil. Universit e Paris-Saclay. Ecologie Systematique Evolution. Centre National de la Recherche Scientifique. AgroParisTech, Orsay, France. Funda??o Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laborat?rio de Bacteriologia e Bioensaios em Micobact?rias. Rio de Janeiro, RJ, Brasil. Funda??o Oswaldo Cruz. Instituto Oswaldo Cruz. Laborat?rio de Biologia Molecular Aplicada a Micobact?rias. Rio de Janeiro, RJ, Brasil. Coordena??o Geral de Vigil?ncia das Doen?as de Transmiss?o Respirat?ria de Condi??es Cr?nicas. Bras?lia, DF, Brasil. Funda??o Oswaldo Cruz. Instituto Oswaldo Cruz. Laborat?rio de Gen?tica Molecular de Microrganismos. Rio de Janeiro, RJ, Brasil. Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Paulo de G?es. Laborat?rio de Micobact?rias. Rio de Janeiro, RJ, Brasil. Funda??o Oswaldo Cruz. Instituto Oswaldo Cruz. Laborat?rio de Biologia Molecular Aplicada a Micobact?rias. Rio de Janeiro, RJ, Brasil. Universidade do Estado do Par?. Instituto de Ci?ncias Biol?gicas e da Sa?de. P?s-Gradua??o Biologia Parasit?ria na Amaz?nia. Bel?m, PA, Brasil / Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. Molecular-typing can help in unraveling epidemiological scenarios and improvement for disease control strategies. A literature review of Mycobacterium tuberculosis transmission in Brazil through genotyping on 56 studies published from 1996-2019 was performed. The clustering rate for mycobacterial interspersed repetitive units - variable tandem repeats (MIRUVNTR) of 1,613 isolates were: 73%, 33% and 28% based on 12, 15 and 24-loci, respectively; while for RFLP-IS6110 were: 84% among prison population in Rio de Janeiro, 69% among multidrug-resistant isolates in Rio Grande do Sul, and 56.2% in general population in S?o Paulo. These findings could improve tuberculosis (TB) surveillance and set up a solid basis to build a database of Mycobacterium genomes

Pathological oscillations including elevated beta activity in the subthalamic nucleus (STN) and between STN and cortical areas are a hallmark of neural activity in Parkinson’s disease (PD). Oscillations also play an important role in normal physiological processes and serve distinct functional roles at different points in time. We characterised the effect of dopaminergic medication on oscillatory whole-brain networks in PD in a time-resolved manner by employing a hidden Markov model on combined STN local field potentials and magnetoencephalography (MEG) recordings from 17 PD patients. Dopaminergic medication led to coherence within the medial and orbitofrontal cortex in the delta/theta frequency range. This is in line with known side effects of dopamine treatment such as deteriorated executive functions in Parkinson’s disease. In addition, dopamine caused the beta band activity to switch from an STN-mediated motor network to a frontoparietal-mediated one. In contrast, dopamine did not modify local STN-STN coherence in PD. STN–STN synchrony emerged both on and off medication. By providing electrophysiological evidence for the differential effects of dopaminergic medication on the discovered networks, our findings open further avenues for electrical and pharmacological interventions in PD.

Background Ultrafiltration is not commonly used because of higher incidence of worsening renal function without improved decongestion. We examined differential outcomes of high versus low fluid removal and preserved versus reduced ejection fraction (EF) in CARRESS-HF (Cardiorenal Rescue Study in Acute Decompensated Heart Failure). Methods and Results Baseline characteristics in the ultrafiltration arm were compared according to 24-hour ultrafiltration-based fluid removal above versus below the median. Patients were stratified by EF (40%). We compared clinical parameters of clinical decongestion during the hospitalization based on initial (40% group demonstrated larger increases of change in creatinine (P=0.023) and aldosterone (P=0.038) from baseline to 96 hours. Among patients with EF >40%, those with above median fluid removal (n=17) when compared with below median (n=17) had an increased rate of the combined end point (87.5% versus 47.1%, P=0.014). Conclusions In patients with acute heart failure, higher initial fluid removal with ultrafiltration had no association with worsening renal function. In patients with EF >40%, ultrafiltration was associated with worsening renal function irrespective of fluid removal rate and higher initial fluid removal was associated with higher rates of adverse clinical outcomes, highlighting variable responses to decongestive therapy. Dr. Fudim is supported by an American Heart Association Grant, 17MCPRP33460225; he consults for Coridea, AxonTherapies, Galvani, and Daxor. Dr. Greene has received research support from a Heart Failure Society of America/Emergency Medicine Foundation Acute Heart Failure Young Investigator Award funded by Novartis, Amgen, Bristol-Myers Squibb and Novartis; and serves on an advisory board for Amgen. Dr. Sharma has received research support from the Fonds de la recherche en sante du Quebec (FRSQ)-Junior 1, Jean Roy award in Cardiology (McGill University), Akcea, Pharma, Solutions, Alberta Innovates Health Solutions, Bayer-Canadian Cardiovascular Society, Boehringer-Ingelheim, Roche Diagnostics, and Takeda. Dr. Verbrugge was supported by a Fellowship of the Belgian American Educational Foundation. Dr. Martens has received consultancy fees from Astra-Zeneca, Bayer, Boehringer-Ingelheim, Novartis, and Vifor Pharma and an unrestricted research grant from Vifor Pharma. Dr. Grodin receives research support from the Texas Health Resources Clinical Scholars fund and has received consultancy fees from Pfizer, Inc. Dr. Hernandez receives Grant/Research Support; Company Relationship; AstraZeneca, Bristol-Myers Squibb, GlaxoSmithKline, Luitpold Pharmaceuticals, Merck, Novartis. Honoraria; Company Relationship; Bayer, Boston Scientific, Novartis. Dr. Felker has received research funding from Otsuka, Novartis, Roche Diagnostics, Amgen, Merck, American Heart Association, and the National Heart, Lung, and Blood Institute; and has served as a consultant for Novartis, Roche Diagnostics, Amgen, Trevena, Cytokinetics, Madeliene, Myokardia, Bristol-Myers Squibb, Stealth Biotherapeutics, and GlaxoSmithKline. Dr. Mentz receives research support from the National Institutes of Health (U01HL125511-01A1, U10HL110312, and R01AG045551-01A1), Akros, Amgen, AstraZeneca, Bayer, GlaxoSmithKline, Gilead, Luitpold, Medtronic, Merck, Novartis, Otsuka, and ResMed; honoraria from Abbott, AstraZeneca, Bayer, Janssen, Luitpold Pharmaceuticals, Medtronic, Merck, Novartis, and ResMed; and has served on an advisory board for Amgen, Luitpold, Merck, and Boehringer Ingelheim. The remaining authors have no disclosures to report. Fudim, M (corresponding author), 2301 Erwin Rd, Durham, NC 27713 USA. marat.fudim@gmail.com

Severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-19) has emerged as a public health emergency in recent times. The reported data on the mode of transmission of coronavirus disease 2019 (COVID-19) are largely through contact, droplet, airborne and fomite transmission methods with vertical transmission being a rare entity. We hereby report a case of a probable vertical transmission of SARS-CoV-19 from an infected pregnant female to her neonate. The transmission has been confirmed by a positive RT-PCR at 16 h of life along with a positive IgG antibody test for SARS-CoV-19 in the baby and after excluding the possible environmental contamination of the sample. The baby was asymptomatic during the course of hospital stay and was discharged from the facility on Day 9 of life.

Aims Heart failure with preserved ejection fraction (HFpEF) is a heterogeneous condition, and tissue congestion manifested by oedema is not present in all patients. We compared clinical characteristics, exercise capacity, and outcomes in patients with HFpEF with and without oedema. Methods and results This study was a post hoc analysis of pooled data of patients with left ventricular ejection fraction of ≥50% enrolled in the DOSE, CARRESS‐HF, RELAX, ATHENA, ROSE, INDIE, and NEAT trials. Patients were dichotomized by the severity of oedema. Cox proportional hazard regression and generalized linear regression models were used to assess associations between oedema, symptoms, and clinical outcomes. The ambulatory cohort included 393 patients (228 with and 165 without oedema), and the hospitalized cohort included 338 patients (249 with ≥moderate oedema and 89 with mild or none). Among ambulatory patients, patients with oedema had a higher body mass index (35.2 kg/m2 [inter‐quartile range, IQR 30.5, 41.6] vs. 31.6 kg/m2 [IQR 27.9, 36.3], P

CNPq (207,071/2014-4), CAPES (Finance Code 001), Swiss National Science Foundation (grants 310030_166687 and IZRJZ3_164171) Universidade do Estado do Par?. Instituto de Ci?ncias Biol?gicas e da Sa?de. P?s-Gradua??o em Biologia Parasit?ria na Amaz?nia. Bel?m, PA, Brasil / Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. International Institute of Information Technology. Department of Data Science. Bangalore, India. Universidade do Estado do Par?. Instituto de Ci?ncias Biol?gicas e da Sa?de. P?s-Gradua??o em Biologia Parasit?ria na Amaz?nia. Bel?m, PA, Brasil. University of Basel. Basel, Switzerland / Swiss Tropical & Public Health Institute. Basel, Switzerland. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Centro de Inova??es Tecnol?gicas. Ananindeua, PA, Brasil. Universidade do Estado do Par?. Instituto de Ci?ncias Biol?gicas e da Sa?de. P?s-Gradua??o em Biologia Parasit?ria na Amaz?nia. Bel?m, PA, Brasil / Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. Universidade Federal do Esp?rito Santo. N?cleo de Doen?as Infecciosas. Vit?ria, ES, Brasil. Funda??o Oswaldo Cruz. Instituto Oswaldo Cruz. Laborat?rio de Gen?tica Molecular de Microrganismos. Rio de Janeiro, RJ, Brasil. Universidade do Estado do Par?. Instituto de Ci?ncias Biol?gicas e da Sa?de. P?s-Gradua??o em Biologia Parasit?ria na Amaz?nia. Bel?m, PA, Brasil. Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Professor Paulo de G?es. Laborat?rio de Micobact?rias. Rio de Janeiro, RJ, Brasil. University of Basel. Basel, Switzerland / Swiss Tropical & Public Health Institute. Basel, Switzerland. Funda??o Oswaldo Cruz. Instituto Oswaldo Cruz. Laborat?rio de Biologia Molecular Aplicada a Micobact?rias. Rio de Janeiro, RJ, Brasil. Universidade do Estado do Par?. Instituto de Ci?ncias Biol?gicas e da Sa?de. P?s-Gradua??o em Biologia Parasit?ria na Amaz?nia. Bel?m, PA, Brasil / Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. Funda??o Oswaldo Cruz. Instituto Oswaldo Cruz. Laborat?rio de Biologia Molecular Aplicada a Micobact?rias. Rio de Janeiro, RJ, Brasil / Funda??o Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Programa de P?s-Gradua??o em Pesquisa Cl?nica e Doen?as Infecciosas. Rio de Janeiro, RJ, Brasil / Funda??o Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Laborat?rio de Bacteriologia e Bioensaios em Micobact?rias. Rio de Janeiro, RJ, Brasil. BACKGROUND The evaluation of procedures for drug susceptibility prediction of Mycobacterium tuberculosis based on genomic data against the conventional reference method test based on culture is realistic considering the scenario of growing number of tools proposals based on whole-genome sequences (WGS). OBJECTIVES This study aimed to evaluate drug susceptibility testing (DST) outcome based on WGS tools and the phenotypic methods performed on isolates of M. tuberculosis Lineage 1 from the state of Par?, Brazil, generally associated with low levels of drug resistance. METHODOLOGY Culture based DST was performed using the Proportion Method in L?wenstein-Jensen medium on 71 isolates that had been submitted to WGS. We analysed the seven main genome sequence-based tools for resistance and lineage prediction applied to M. tuberculosis and for comparison evaluation we have used the Kappa concordance test. FINDINGS When comparing the WGS-based tools against the DST, we observed the highest level of agreement using TBprofiler. Among the tools, TB-profiler, KvarQ and Mykrobe were those which identified the largest number of TB-MDR cases. Comparing the four most sensitive tools regarding resistance prediction, agreement was observed for 43 genomes. MAIN CONCLUSIONS Drug resistance profiling using next-generation sequencing offers rapid assessment of resistanceassociated mutations, therefore facilitating rapid access to effective treatment.

International audience; Background: Patients with diabetes who had a recent myocardial infarction (MI) are at high risk of cardiovascular events. Therefore, risk assessment is important for treatment and shared decisions. We used data from EXAMINE trial to investigate whether a multi-proteomic approach would provide specific proteomic signatures and also improve the prognostic capacity for determining the risk of cardiovascular death, MI, stroke, heart failure [HF], all-cause death, and combinations of these outcomes.Methods: 93 circulating proteins (92 from the Olink® CVDII plus troponin) were assessed in 5131 patients. Cox, competing risks, and reclassification measures were applied.Results: The clinical model showed good discrimination and calibration for all outcomes. On top of the clinical model that included age, sex, smoking, diabetes duration, history of MI (prior to the index MI of inclusion), history of HF hospitalization, history of stroke, atrial fibrillation, hypertension, systolic blood pressure, statin therapy, estimated glomerular filtration rate, and study treatment (alogliptin or placebo), troponin and BNP added prognostic information to the composite of cardiovascular death, MI, or stroke (∆C-index + 5%) and cardiovascular death alone (∆C-index + 7%). Troponin, BNP, and TRAILR2 added prognostic information on all-cause death and the composite of cardiovascular death or HF hospitalization. HF hospitalization alone was improved by adding BNP and Gal-9. For MI, troponin, FGF23, and AMBP added prognostic value; whereas for stroke, only troponin added prognostic value (multi-proteomics improved C-index > 3% [p < 0.001] for all the studied outcomes). The addition of the final biomarker selection to the clinical model improved event reclassification (cNRI from + 23% to + 64%). Specifically, the addition of the biomarkers allowed a better classification of patients at low risk (as having "true" low risk) and patients and high risk (as having "true" high risk). These results were consistent for all the studied outcomes with even more marked differences in the fatal events.Conclusions: The addition of multi-proteomic biomarkers to a clinical model in this population with diabetes and a recent MI allowed a better risk prediction and event reclassification, potentially helping for better risk assessment and targeted treatment decisions. T2D type 2 diabetes, MI myocardial infarction, CV cardiovascular, HFH heart failure hospitalization, Δ delta, cNRI continuous net reclassification index, BNP brain natriuretic peptide, TRAILR2 trail receptor 2 (or death receptor 5), Gal-9 galectin-9, FGF23 fibroblast growth factor 23

Background There are conflicting data regarding the benefit of primary prevention implantable cardioverter‐defibrillators ( ICD s) in patients with diabetes mellitus and heart failure (HF) with reduced ejection fraction. We aimed to assess the comparative effectiveness of ICD placement in patients with diabetes mellitus and HF with reduced ejection fraction. Methods and Results Data were obtained from the Get With the Guidelines–Health Failure registry, linked with claims from the Centers for Medicare & Medicaid Services. We used a Cox proportional hazards model censored at 5 years with propensity score matching. Of the 17 186 patients with HF with reduced ejection fraction from the Centers for Medicare & Medicaid Services claims database (6540 with diabetes mellitus; 38%), 1677 (646 with diabetes mellitus; 39%) received an ICD during their index HF hospitalization or were prescribed an ICD at discharge. Patients with diabetes mellitus and an ICD (n=646), as compared with those without an ICD (n=1031), were more likely to be younger (74 versus 78 years of age) and have coronary artery disease (68% versus 60%). After propensity matching, ICD use among patients with diabetes mellitus, as compared with those without an ICD , was associated with a reduced risk of all‐cause mortality at 5 years after HF discharge (54% versus 59%; multivariable hazard ratio, 0.73; 95% CI , 0.64–0.82; P ICD use and all‐cause mortality ( P =0.95 for interaction). Similar results were seen in patients without diabetes mellitus. Conclusions Primary prevention ICD use among older patients with HF with reduced ejection fraction and diabetes mellitus was associated with a reduced risk of all‐cause mortality. Our analysis supports current guideline recommendations for implantation of primary prevention ICD s among older patients with diabetes mellitus and HF with reduced ejection fraction.

ADA/EASD guidelines emphasize the importance of patient engagement in therapy decisions. Beyond glycemic effects of type 2 diabetes (T2D) therapies, only SGLT2i and GLP-1RA have cardiovascular (CV) benefits. Key attributes of such therapies may influence their use/adoption. We evaluated patient preferences towards three oral T2D therapies using conjoint analysis. This analysis used an online survey, completed by 553 respondents with T2D in the U.S. (mean age ±SD was 64±9; 55% had CV risk; 27% had CV disease), to present 7 hypothetical, blinded pair-wise drug profile comparison choices composed of different benefit-risk attributes and effect ranges (levels). Attributes/levels were derived from combinations of phase 3 trial data for empagliflozin 25mg (SGLT2i), oral semaglutide 14mg (GLP-1RA) and sitagliptin 100mg (DPP-4i). The predicted therapy preference outcomes and the relative importance of one attribute relative to another were calculated (in %). The preference outcome was highest for the profile matching empagliflozin, ranked first by 56% (z-test, p Disclosure G. Savarese: Advisory Panel; Self; AstraZeneca. Consultant; Self; Genesis, Societ Prodotti Antibiotici. Research Support; Self; AstraZeneca, Merck Sharp & Dohme Corp., Novartis Pharmaceuticals Corporation, Vifor Pharma Group. Speaker’s Bureau; Self; Roche Pharma, Servier, Vifor Pharma Group. A. Sharma: Advisory Panel; Self; Boehringer Ingelheim International GmbH, Roche Pharma. Research Support; Self; Bristol-Myers Squibb, Merck & Co., Inc. Speaker’s Bureau; Self; Novartis Pharmaceuticals Corporation. C. Pang: None. R. Wood: Consultant; Self; Abbott, ADOCIA, American Diabetes Association, Ascensia Diabetes Care, Boehringer Ingelheim Pharmaceuticals, Inc., CeQur Corporation, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation. Employee; Self; dQ&A Market Research Inc. J.T. George: Employee; Self; Boehringer Ingelheim International GmbH. N. Soleymanlou: Employee; Self; Boehringer Ingelheim (Canada) Ltd. Funding Boehringer Ingelheim and Eli Lilly and Company Diabetes Alliance

International audience; Background: The timing of enrolment following an acute coronary syndrome (ACS) may influence cardiovascular (CV) outcomes and potentially treatment effect in clinical trials. Understanding the timing and type of clinical events after an ACS will allow for clinicians to better tailor evidence-based treatments to optimize therapeutic effect. Using a large contemporary trial in patients with type 2 diabetes mellitus (T2DM) post-ACS, we examined the impact of timing of enrolment on subsequent CV outcomes.Methods: EXAMINE was a randomized trial of alogliptin versus placebo in 5,380 patients with T2DM and a recent ACS from October 2009 to March 2013. The primary outcome was a composite of CV death, nonfatal myocardial infarction (MI), or nonfatal stroke. The median follow-up was 18 months. In this post hoc analysis, we examined the occurrence of subsequent CV events by timing of enrollment divided by tertiles of time from ACS to randomization: 8-34, 35-56, and 57-141 days.Results: Patients randomized early (compared to the latest times) had less comorbidities at baseline including a history of heart failure (HF; 24.7% vs 33.0%), prior coronary artery bypass graft (9.6% vs 15.9%), or atrial fibrillation (5.9% vs 9.4%). Despite the reduced comorbidity burden, the risk of the primary outcome was highest in patients randomized early compared to the latest time (adjusted hazard ratio 1.47; 95% CI 1.21-1.74). Similarly, patients randomized early had an increased risk of recurrent MI (adjusted hazard ratio 1.51; 95% CI 1.17-1.96) and HF hospitalization (1.49; 95% CI 1.05-2.10).Conclusions: In a contemporary cohort of T2DM with a recent ACS, the risk for recurrent CV events including MI and HF hospitalization is elevated early after an ACS. Given the emergence of antihyperglycemic therapies that reduce the risk of MI and HF among patients with T2DM at high CV risk, future studies evaluating the initiation of these therapies in the early period following an ACS are warranted given the large burden of potentially modifiable CV events.Copyright © 2020 Elsevier Inc. All rights reserved.

Despite the reported benefits of intravenous iron therapy (IVIT) for correcting iron deficiency anemia (IDA) before any major surgery and the evidence thereof, perioperative allogenic blood transfusion (ABT) practice is still considered as the only viable option by some clinicians worldwide. As ABT increases the likelihood of infections, cardiac complications, longer hospital stays and mortality among the patients, the practice of ABT should only be reserved for critical cases (Hb level

OBJECTIVES: The aims of this study were to compare the characteristics of patients with and without diabetes and to use network analyses to compare biomarker profiles and associated pathways in patients with diabetes compared with those without diabetes, which might offer new avenues for potential therapeutic targets.BACKGROUND: Diabetes adversely affects clinical outcomes and complicates treatment in patients with heart failure (HF). A clear understanding of the pathophysiological processes associated with type 2 diabetes in HF is lacking.METHODS: Network and pathway over-representation analyses were performed to identify unique pathological pathways in patients with and without diabetes using 92 biomarkers from different pathophysiological domains measured in plasma samples from 1,572 patients with HF (31% with diabetes) with reduced ejection fraction (left ventricular ejection fraction RESULTS: Biomarker profiles were first compared between patients with HF with and without diabetes. Patients with diabetes showed higher levels of galectin-4, growth differentiation factor 15, and fatty acid binding protein 4 and lower levels of paraoxonase 3. Network analyses were then performed, revealing that epidermal growth factor receptor and galectin-3 were the most prominent connecting proteins. Translation of these networks to biologic pathways revealed that diabetes was associated with inflammatory response and neutrophil degranulation. Diabetes conferred worse outcomes after correction for an established risk model (hazard ratio: 1.20; 95% confidence interval: 1.01 to 1.42).CONCLUSIONS: Concomitant diabetes in patients with HF with reduced ejection fraction is associated with distinct pathophysiological pathways related to inflammation, protein phosphorylation, and neutrophil degranulation. These data support the evaluation of anti-inflammatory therapeutic approaches, epidermal growth factor receptor in particular, for patients with HF and diabetes.

Aim To investigate the association of the Thrombolysis In Myocardial Infarction (TIMI) Risk Score for Heart Failure in Diabetes (TRS-HFDM ) with mortality using data from the EMPA-REG OUTCOME trial. Materials and methods In EMPA-REG OUTCOME, patients with type 2 diabetes and atherosclerotic cardiovascular (CV) disease (N = 7020) received the sodium-glucose co-transporter-2 inhibitor, empagliflozin, 10 or 25 mg or placebo. Post hoc, patients were stratified into risk categories (low-intermediate, high, very-high risk scores) using baseline TRS-HFDM . Cox regression analyses evaluated the association of TRS-HFDM categories with all-cause mortality (ACM), CV death, hospitalization for heart failure (HHF) and CV death (excluding fatal stroke) or HHF, and whether empagliflozin reduced the risk of CV outcomes across these risk categories. Results In placebo patients, increasing risk category was associated with a higher risk of ACM, CV death, and HHF. Empagliflozin reduced the risk of ACM (low-intermediate HR 0.68 [95% CI 0.48, 0.97] and very-high 0.69 [0.52, 0.91]), CV death (0.75 [0.48, 1.18] and 0.56 [0.41, 0.78]), HHF (0.53 [0.28, 1.01] and 0.67 [0.48, 0.96]), and CV death or HHF (0.69 [0.46, 1.03]) and (0.64 [0.49, 0.82]) across all risk categories versus placebo. Higher absolute risk reductions (ARRs) were observed for CV death in the very-high versus low-intermediate category (P = 0.01). Conclusions Applied to EMPA-REG OUTCOME, higher TRS-HFDM was associated with increased HHF and mortality risk. Empagliflozin reduced CV outcomes across TRS-HFDM categories. Higher ARRs were associated with higher risk scores.

Background Improved heart failure ( HF ) risk stratification after a recent acute coronary syndrome may identify those who can benefit from therapies that reduce HF risk. We aimed to identify clinical and biomarker predictors for expanded HF outcomes in patients with type 2 diabetes mellitus after recent acute coronary syndrome. Methods and Results The EXAMINE ( Ex amination of Cardiovascular Outcomes with Alogliptin versus Standard of Care) trial was a multicenter, non‐inferiority, double‐masked, placebo‐controlled study which randomized 5380 patients with type 2 diabetes mellitus after recent acute coronary syndrome to alogliptin or placebo. Baseline biomarkers were measured in 5154 patients: NT‐proBNP (N‐terminal pro‐B‐type natriuretic peptide), high‐sensitivity troponin I, adiponectin, growth‐differentiation‐factor‐15, and galectin‐3. Our primary outcome was cardiovascular) death, HF hospitalization, elevated NT‐proBNP during follow‐up, or loop diuretics initiation. The association between clinical variables, biomarkers, and outcomes were assessed using Cox regression models. In the study population, the median age was 61.0 years, 67.7% were men, and 28.0% had baseline HF (median follow‐up was 18 months). In multivariable analyses, NT‐proBNP had the strongest association with the primary outcome (per log 2 , hazard ratio 1.24; Wald χ 2 67.4; P HF history (hazard ratio 1.42; Wald χ 2 20.8; P HF outcomes (C‐statistic=0.72). Discrimination results were similar for cardiovascular death or HF hospitalization. Conclusions Among patients with type 2 diabetes mellitus after recent acute coronary syndrome, the use biomarkers such as N‐terminal pro‐B‐type natriuretic peptide and clinical variables enables risk stratification for expanded HF outcomes. Clinical Trial Registration URL : https://www.clinicaltrials.gov/ . Unique identifier: NCT 00968708.

Universidade Federal de Goi?s. Hospital das Cl?nicas. Goi?nia, GO, Brazil. Funda??o Oswaldo Cruz. Instituto Nacional de Infectologia Evandro Chagas. Programa de P?s-gradua??o em Pesquisa Cl?nica e Doen?as Infecciosas. Rio de Janeiro, RJ, Brazil / Funda??o Oswaldo Cruz. Instituto Oswaldo Cruz. Laborat?rio de Biologia Molecular Aplicada em Micobacterias. Rio de Janeiro, RJ, Brazil. Universidade Federal de Goi?s. Hospital das Cl?nicas. Goi?nia, GO, Brazil. Universidade Federal de Goi?s. Hospital das Cl?nicas. Goi?nia, GO, Brazil. Funda??o Oswaldo Cruz. Instituto Oswaldo Cruz. Laborat?rio de Biologia Molecular Aplicada em Micobacterias. Rio de Janeiro, RJ, Brazil / Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Professor Paulo de G?es. Rio de Janeiro, RJ, Brazil. Instituto de Biomedicina Dr. Jacinto Convit. Instituto de Biomedicina. San Jose, Caracas, Venezuela / Universidad de Las Am?ricas. Facultad de Ciencias de La Salud. One Health Research Group. Quito, Ecuador. Funda??o Oswaldo Cruz. Centro de Refer?ncia Professor H?lio Fraga. Rio de Janeiro, RJ, Brazil. Funda??o Oswaldo Cruz. Centro de Refer?ncia Professor H?lio Fraga. Rio de Janeiro, RJ, Brazil. Funda??o Oswaldo Cruz. Centro de Refer?ncia Professor H?lio Fraga. Rio de Janeiro, RJ, Brazil. Funda??o Oswaldo Cruz. Centro de Refer?ncia Professor H?lio Fraga. Rio de Janeiro, RJ, Brazil. Funda??o Oswaldo Cruz. Centro de Refer?ncia Professor H?lio Fraga. Rio de Janeiro, RJ, Brazil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. Minist?rio da Sa?de. Secretaria de Vigil?ncia em Sa?de. Instituto Evandro Chagas. Ananindeua, PA, Brasil. International Institute of InformationTechnology - Bangalore. Department of Data Science. Bangalore, India. Corporaci?n para Investigaciones Biol?gicas. Medell?n, Colombia. Corporaci?n para Investigaciones Biol?gicas. Medell?n, Colombia. Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Professor Paulo de G?es. Rio de Janeiro, RJ, Brazil. Universidade Federal do Rio de Janeiro. Instituto de Microbiologia Professor Paulo de G?es. Rio de Janeiro, RJ, Brazil. Funda??o Oswaldo Cruz. Instituto Oswaldo Cruz. Laborat?rio de Biologia Molecular Aplicada em Micobacterias. Rio de Janeiro, RJ, Brazil. Funda??o Oswaldo Cruz. Instituto Oswaldo Cruz. Laborat?rio de Biologia Molecular Aplicada em Micobacterias. Rio de Janeiro, RJ, Brazil. Institute of Tropical Medicine. Mycobacteriology Unit. Antwerp, Belgium. Institute of Tropical Medicine. Mycobacteriology Unit. Antwerp, Belgium. Universidade Federal de Goi?s. Instituto de Patologia Tropical e Sa?de P?blica. Goi?nia, GO, Brazil. Funda??o Oswaldo Cruz. Instituto Oswaldo Cruz. Laborat?rio de Biologia Molecular Aplicada em Micobacterias. Rio de Janeiro, RJ, Brazil. Human tuberculosis (TB) is caused by members of the Mycobacterium tuberculosis complex (MTBC), including Mycobacterium tuberculosis var. tuberculosis (MTB) and Mycobacterium tuberculosis var. africanum (MAF). While MTB is isolated worldwide, MAF is almost completely restricted to the African continent, and despite the historical proximity between Brazil and Africa during the slave trade, no case of TB being caused by MAF has been reported in Brazil to date. We hereby describe the first case of TB caused by MAF in Brazil comparing its genome against the published ones. A female patient who had never visited Africa presented with clinical symptoms typical of pulmonary TB. Based on 16S rRNA gene sequencing, the cultured isolate was identified as belonging to MTBC and partial sequence of the hsp65 gene was identical to that of MAF. This was confirmed by genotyping based on detection of Single Nucleotide Polymorphism (SNP), Region of Difference (RD) and spoligotyping. The isolate presented the Shared International Typing (SIT) 181. In the whole-genome comparison against MAF genomes available on published EMBL-EBI European Nucleotide Archive (ENA), the Brazilian genome (MAFBRA00707) was identified as belonging to Lineage 6 and clustered with isolates from The Gambia. This is the first report of the isolation of MAF from a patient from Brazil, without evidence of having any contact with an African index case

Objectives Despite their essential role in collecting and organizing published medical literature, indexed search engines are unable to cover all relevant knowledge. Hence, current literature recommends the inclusion of clinical trial registries in systematic reviews (SRs). This study aims to provide an automated approach to extend a search on PubMed to the ClinicalTrials.gov database, relying on text mining and machine learning techniques. Study Design and Setting The procedure starts from a literature search on PubMed. Next, it considers the training of a classifier that can identify documents with a comparable word characterization in the ClinicalTrials.gov clinical trial repository. Fourteen SRs, covering a broad range of health conditions, are used as case studies for external validation. A cross-validated support-vector machine (SVM) model was used as the classifier. Results The sensitivity was 100% in all SRs except one (87.5%), and the specificity ranged from 97.2% to 99.9%. The ability of the instrument to distinguish on-topic from off-topic articles ranged from an area under the receiver operator characteristic curve of 93.4% to 99.9%. Conclusion The proposed machine learning instrument has the potential to help researchers identify relevant studies in the SR process by reducing workload, without losing sensitivity and at a small price in terms of specificity.

Background: Atrial fibrillation is associated with an increased risk of death. High-sensitivity troponin T, growth differentiation factor-15, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and interleukin-6 levels are predictive of cardiovascular events and total cardiovascular death in anticoagulated patients with atrial fibrillation. The prognostic utility of these biomarkers for cause-specific death is unknown. Methods: The ARISTOTLE trial (Apixaban for the Prevention of Stroke in Subjects With Atrial Fibrillation) randomized 18 201 patients with atrial fibrillation to apixaban or warfarin. Biomarkers were measured at randomization in 14 798 patients (1.9 years median follow-up). Cox models were used to identify clinical variables and biomarkers independently associated with each specific cause of death. Results: In total, 1272 patients died: 652 (51%) cardiovascular, 32 (3%) bleeding, and 588 (46%) noncardiovascular/nonbleeding deaths. Among cardiovascular deaths, 255 (39%) were sudden cardiac deaths, 168 (26%) heart failure deaths, and 106 (16%) stroke/systemic embolism deaths. Biomarkers were the strongest predictors of cause-specific death: a doubling of troponin T was most strongly associated with sudden death (hazard ratio [HR], 1.48; P P P =0.028). Prior stroke/systemic embolism (HR, 2.58; P >0.001) followed by troponin T (HR, 1.45; P Conclusions: Biomarkers were some of the strongest predictors of cause-specific death and may improve the ability to discriminate among patients’ risks for different causes of death. These data suggest a potential role of biomarkers for the identification of patients at risk for different causes of death in patients anticoagulated for atrial fibrillation. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00412984.

Purpose The purpose of this paper is to present and solve the problem of adaptive beamforming (ABF) for a uniform linear array (ULA) as an optimization problem. ABF mainly concerns with estimation of weights of antenna array so as to direct the major lobe in the direction of desired user and nulls in the direction of interfering signals with reduced side lobe level (SLL). Design/methodology/approach The potential of gravitational search algorithm is explored to optimize multi-objective fitness function for ABF using MATLAB software. Findings The performance of the algorithm has been compared by considering different number of interference signals at different power levels. The proposed algorithm presents good convergence rate and accurate steering of main lobe and nulls with reduced SLL compared to the well-known ABF technique, namely, minimum variance distortionless response (MVDR) and previously reported results. The simulation results are presented in tabular form. Research limitations/implications The present work is limited to simulation. The researchers are encouraged to solve the problem of ABF using the proposed approach in hardware. Originality/value The application of proposed algorithm is to optimize multi-objective function for ABF with reduced SLL in linear antenna arrays.

There is increasing recognition of the relationship between diabetes and heart failure (HF). Comorbid diabetes is associated with worse outcomes in patients with HF, and death from HF forms a large burden of mortality among patients with diabetes and atherosclerotic cardiovascular disease. However, there is evidence of harm relating to the risk of HF outcomes from several antihyperglycemic therapies. The absence of well-powered randomized controlled studies has resulted in significant treatment variations in the glycemic management in patients with coexisting diabetes and HF. However, there is emerging evidence from recent clinical trials suggesting that sodium-glucose–co-transporter-2 inhibitors may be used as a therapy to improve HF outcomes. In order to understand the current state of knowledge, we reviewed the evolving evidence of antihyperglycemic therapies and present strategies to optimize these therapies in patients with diabetes and HF. This analysis is based on discussions among scientists, clinical trialists, industry sponsors, and regulatory representatives who attended the 12th Global Cardiovascular Clinical Trialists Forum, Washington, DC, December 1 to 3, 2016.

Gastric outlet obstruction, afferent or efferent limb obstruction, and biliary obstruction among patients with altered anatomy often require surgical intervention which is associated with significant morbidity and mortality. Endoscopic dilation for benign etiologies requires multiple sessions, whereas self-expandable metal stents used for malignant etiologies often fail due to tumor in-growth. Lumen apposing metal stents, placed endoscopically with the intent of creating a de-novo gastrointestinal anastomosis bypassing the site of obstruction, can potentially achieve similar efficacy, with a much lower complication rate. In our study cohort (n=79), the composite technical success rate and clinical success rate was 91.1% (72/79) and 97.2% (70/72), respectively. Five different techniques were used: 43% (34/79) underwent the balloon-assisted method, 27.9% (22/79) underwent endoscopic ultrasound-guided balloon occluded gastro-jejunostomy bypass, 20.3% (16/79) underwent the direct technique, 6.3% (5/79) underwent the hybrid rendezvous technique, and 2.5% (2/79) underwent natural orifice transluminal endoscopic surgery (NOTES)-assisted procedure. All techniques required an echoendoscope except NOTES. In all, 53.2% (42/79) had non-cautery enhanced Axios stent, 44.3% (35/79) had hot Axios stent, and 2.5% (2/79) had Niti-S spaxus stent. Symptom-recurrence was seen in 2.8%, and 6.3% had a complication (bleeding, abdominal pain or peritonitis). All procedures were performed by experts at centers of excellence with adequate surgical back up.

Background Limited data exist to guide treatment for patients with heart failure with preserved ejection fraction and atrial fibrillation, including the important decision regarding rate versus rhythm control. Methods and Results We analyzed the Get With The Guidelines—Heart Failure (GWTG‐HF) registry linked to Medicare claims data from 2008 to 2014 to describe current treatments for rate versus rhythm control and subsequent outcomes in patients with heart failure with preserved ejection fraction and atrial fibrillation using inverse probability weighted analysis. Rhythm control was defined as use of an antiarrhythmic medication, cardioversion, or AF ablation or surgery. Rate control was defined as use of any combination of β‐blocker, calcium channel blocker, and digoxin without evidence of rhythm control. Among 15 682 fee‐for‐service Medicare patients, at the time of discharge, 1857 were treated with rhythm control and 13 825 with rate control, with minimal differences in baseline characteristics between groups. There was higher all‐cause death at 1 year in the rate control compared with the rhythm control group (37.5% and 30.8%, respectively, P CI , 0.75–0.98; P =0.02). Conclusions Rhythm control in patients aged 65 and older with heart failure with preserved ejection fraction and AF was associated with a lower risk of 1 year all‐cause mortality. Future prospective randomized studies are needed to explore this potential benefit.

Aims Obesity is present in up to 45% of patients with heart failure (HF). Liraglutide, a glucagon-like peptide-1 (GLP-1) receptor antagonist, facilitates weight loss in obese patients. The efficacy of liraglutide as a weight loss agent among patients with HF and reduced ejection fraction (HFrEF) and a recent acute HF hospitalization remains unknown. Methods and results The Functional Impact of GLP-1 for Heart Failure Treatment study randomized 300 patients with HFrEF (ejection fraction ≤ 40%), both with and without diabetes and a recent HF hospitalization to liraglutide or placebo. The primary outcome for this post hoc analysis was the change in weight from baseline to last study visit. We conducted an 'on-treatment' analysis of patients with at least one follow-up visit on study drug (123 on liraglutide and 124 on placebo). The median age was 61 years, 21% were female, and 69% of patients had New York Heart Association functional Class III or IV symptoms. The median ejection fraction was 25% (25th, 75th percentile 19-32%). Liraglutide use was associated with a significant weight reduction [liraglutide -1.00 lbs vs. placebo 2.00 lbs; treatment difference -4.10 lbs; 95% confidence interval (CI) -7.94, -0.25; P = 0.0367; percentage treatment difference -2.07%, 95% CI -3.86, -0.28; P = 0.0237]. Similar results were seen after multivariable adjustments. Liraglutide also significantly reduced triglyceride levels (liraglutide 7.5 mg/dL vs. placebo 12.0 mg/dL; treatment difference -33.1 mg/dL; 95% CI -60.7, -5.6; P = 0.019). Conclusions Liraglutide is an efficacious weight loss agent in patients with HFrEF. These findings will require further exploration in a well-powered cardiovascular outcomes trial.

AIM To describe differences in patient characteristics and outcomes by ethnicity in patients with diabetes mellitus (DM) and heart failure (HF) with reduced ejection fraction (HFrEF, ejection fraction ≤35%) in a multi-ethnic cohort. METHODS AND RESULTS Patient level data from two cohorts (HF-ACTION and ASIAN-HF) were combined, and patients grouped by self-reported ethnicity. DM was defined as the presence of a clinical diagnosis and/or receiving anti-diabetic therapy. A total of 6214 (1324 whites, 674 blacks, 1297 Chinese, 1510 Indians, 717 Malays, 692 Japanese/Koreans) patients were included. The overall prevalence of DM was 39.5% (n = 2454). The prevalence of DM was lowest in whites (29.3%), followed by Japanese/Koreans (34.1%), blacks (35.9%), Chinese (42.3%), Indians (44.2%), and highest in Malays (51.9%). The correlation between age, sex, body mass index, coronary artery disease, hypertension, atrial fibrillation, peripheral vascular disease and chronic kidney disease with DM differed significantly by ethnicity (P for interaction

Collagen forms fibrous networks that reinforce tissues and provide an extracellular matrix for cells. These networks exhibit remarkable strain-stiffening properties that tailor the mechanical functions of tissues and regulate cell behavior. Recent models explain this nonlinear behavior as an intrinsic feature of disordered networks of stiff fibers. Here, we experimentally validate this theoretical framework by measuring the elastic properties of collagen networks over a wide range of self-assembly conditions. We show that the model allows us to quantitatively relate both the linear and nonlinear elastic behavior of collagen networks to their underlying architecture. Specifically, we identify the local coordination number (or connectivity) [Formula: see text] as a key architectural parameter that governs the elastic response of collagen. The network elastic response reveals that [Formula: see text] decreases from 3.5 to 3 as the polymerization temperature is raised from 26 to 37°C while being weakly dependent on concentration. We furthermore infer a Young’s modulus of 1.1 MPa for the collagen fibrils from the linear modulus. Scanning electron microscopy confirms that [Formula: see text] is between three and four but is unable to detect the subtle changes in [Formula: see text] with polymerization conditions that rheology is sensitive to. Finally, we show that, consistent with the model, the initial stress-stiffening response of collagen networks is controlled by the negative normal stress that builds up under shear. Our work provides a predictive framework to facilitate future studies of the regulatory effect of extracellular matrix molecules on collagen mechanics. Moreover, our findings can aid mechanobiological studies of wound healing, fibrosis, and cancer metastasis, which require collagen matrices with tunable mechanical properties.

As we enter the information age of health care, digital health technologies offer significant opportunities to optimize both clinical care delivery and clinical research. Despite their potential, the use of such information technologies in clinical care and research faces major data quality, privacy, and regulatory concerns. In hopes of addressing both the promise and challenges facing digital health technologies in the transformation of health care, we convened a think tank meeting with academic, industry, and regulatory representatives in December 2016 in Washington, DC. In this paper, we summarize the proceedings of the think tank meeting and aim to delineate a framework for appropriately using digital health technologies in healthcare delivery and research.