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International audience; Aim: Glucagon-like peptide-1 receptor agonists (GLP1-RA) improve cardiovascular outcomes in patients with type 2 diabetes (T2D). However, some studies suggest that their effects in patients with heart failure (HF) may be attenuated. We aimed to explore the effects of the GLP1-RA albiglutide on HF outcomes in patients with and without HF history enrolled in the Harmony Outcomes trial.Methods and results: Harmony Outcomes enrolled patients with T2D and cardiovascular disease randomized to either albiglutide or placebo over a median follow-up of 1.6 years. A total of 9462 patients were included, of whom 1922 (20%) had HF history. Patients with HF had more cardiovascular comorbidities, poorer renal function, and had a three to four-fold higher risk of HF events compared to patients without HF. Compared to placebo, the effect of albiglutide on the composite of cardiovascular death or HF hospitalization was more pronounced among patients without HF (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.56-0.95) than in patients with HF (HR 1.06, 95% CI 0.79-1.43) (interaction p = 0.062). A similar pattern was observed for HF hospitalizations (interaction p = 0.025). The effect of albiglutide on cardiovascular death, sudden death or 'pump failure' death, and all-cause mortality was also attenuated among patients with HF history, but without significant interaction (p > 0.1). The benefit of albiglutide to reduce atherosclerotic events was consistent regardless of HF history.Conclusions: In patients with T2D and cardiovascular disease, albiglutide appeared to have no effect in reducing HF-related events among patients with HF history. These findings, placed in the context of other trials, suggest that GLP1-RA may not improve HF outcomes in patients with HF.

The current care model of type 2 diabetes (T2D) and its complications appears to be "asynchronous" with patient care divided by specialty. This model is associated with low use of guideline-directed medical therapies.The use of integrated care models has been well described in the management of patients with T2D; this usually includes an endocrinologist coupled with a nutritionist and nurse. However, physician-based care models are largely "asynchronous," whereby the patient requires multiple different siloed specialties to manage their health care. To date, there has been limited exploration of synchronous care delivery, i.e., whereby multi-comorbid patients with T2D are seen simultaneously by health care providers from endocrinology, cardiology, and nephrology to optimize use of guideline-directed medical therapies (GDMT). Given the rising complexity of patients with T2D, further research is needed on the role of synchronous health care delivery in optimizing the use of GDMT and improving patient outcomes.

International audience; Background: Renin-angiotensin aldosterone system inhibitors (RAASi) are commonly used among patients hospitalized with a severe acute respiratory syndrome coronavirus 2 infection (COVID-19). We evaluated whether continuation versus discontinuation of RAASi were associated with short term clinical or biochemical outcomes. Methods: The RAAS-COVID-19 trial was a randomized, open label study in adult patients previously treated with RAASi who are hospitalized with COVID-19 (NCT04508985). Participants were randomized 1:1 to discontinue or continue RAASi. The primary outcome was a global rank score calculated from baseline to day 7 (or discharge) incorporating clinical events and biomarker changes. Global rank scores were compared between groups using the Wilcoxon test statistic and the negative binomial test (using incident rate ratio [IRR]) and the intention-totreat principle. Results: Overall, 46 participants were enrolled; 21 participants were randomized to discontinue RAASi and 25 to continue. Patients' mean age was 71.5 years and 43.5% were female. Discontinuation of RAASi, versus continuation, resulted in a non-statistically different mean global rank score (discontinuation 6 [standard deviation [SD] 6.3] vs continuation 3.8 (SD 2.5); p= 0.60). The negative binomial analysis identified that discontinuation increased the risk of adverse outcomes (IRR 1.67 [95% CI 1.06 to 2.62]; p=0.027); RAASi discontinuation increased brain natriuretic peptide (BNP) levels (% change from baseline: +16.7% vs.-27.5%; p= 0.024) and the incidence of acute heart failure (33% vs. 4.2%, p=0.016). Conclusion: RAASi continuation in participants hospitalized with COVID-19 appears safe; discontinuation increased BNP levels and may increase risk of acute heart failure; where possible, RAASi should be continued.

OBJECTIVE Patients with type 2 diabetes (T2D) have a high risk for developing heart failure (HF), which is associated with poor prognosis. Fenofibrate may reduce HF events through multiple mechanisms. We sought to study the effect of fenofibrate (vs. placebo) in HF outcomes among patients with T2D receiving simvastatin enrolled in the Action to Control Cardiovascular Risk in Diabetes lipid trial (ACCORD Lipid). RESEARCH DESIGN AND METHODS We used Cox regression analysis with background glucose-lowering strategy as the stratification variable. The median follow-up was 4.7 years. RESULTS A total of 5,518 patients were included. Median age was 62 years, and 31% were women. Prior HF history was present in 5% of the patients. The composite outcome of HF hospitalization or cardiovascular death occurred in 190 (6.9%) patients in the fenofibrate group vs. 228 (8.3%) in the placebo group: HR 0.82, 95% CI 0.68–1.00 (P = 0.048). The beneficial effect of fenofibrate to reduce HF hospitalizations or cardiovascular death was present among patients receiving standard glucose-lowering strategy, HR 0.64, 95% CI 0.48–0.85, and not among patients receiving intensive glucose-lowering strategy, HR 1.02, 95% CI 0.79–1.33 (Pinteraction = 0.017). A similar pattern was observed for HF hospitalizations alone. The effect of fenofibrate on blood lipids was not influenced by background glucose-lowering therapy in a clinically important manner. Fenofibrate caused more transient worsening estimated glomerular filtration rate (eGFR) events but slowed long-term eGFR decline. CONCLUSIONS In patients with T2D treated with simvastatin, fenofibrate reduced the composite of HF hospitalizations or cardiovascular mortality, an effect that was seen predominantly in patients with standard background glucose-lowering therapy.

Worsening heart failure (WHF) is defined as persistent or worsening symptoms of heart failure that require an escalation in intravenous therapy or initiation of mechanical and ventilatory support during hospitalization. We assessed a simplified version of WHF called diuretic failure (DF), defined as an escalation of loop diuretic dosing after 48 h, and assessed its effects on mortality and rehospitalizations at 60-days.We conducted a multicenter retrospective study between December 1, 2017 and January 1, 2020. We identified 1389 patients of which 6.4% experienced DF.There was a significant relationship between DF and cumulative rates of 60-day mortality and 60-day rehospitalizations (p = 0.0002 and p = 0.0214). After multivariate adjustment, DF was associated with longer hospital stay (p 0.0001), increased rate of 60-day mortality (p = 0.026), 60-day rehospitalizations (p = 0.036), and a composite outcome of 60-day mortality and 60-day cardiac rehospitalizations (p = 0.018).DF has a strong relationship with adverse heart failure outcomes suggesting it is a simple yet robust prognostic indicator which can be used in real time to identify high-risk patients during hospitalization and beyond.

BACKGROUND Congenital gastrointestinal (GI) malformations are developmental disorders that can result in secondary intestinal failure. Nutrient intakes must be adapted according to the newborn's nutritional requirements based on frequent anthropometric and biochemical assessments. Deficiencies or excess of a macronutrient can hinder the growth of the newborn. MATERIAL AND METHODS To assess the clinical condition of newborns with GI malformations, together with the postoperative nutritional status of newborns who underwent surgery due to congenital GI malformations, we performed a case-control study. The study group comprised newborns with digestive malformations (n=51) and the control group consisted of newborns without digestive pathologies (n=102), matched by sex, gestational age, and weight at admission. RESULTS Bivariate comparisons and multiple logistic regression analyses were performed. A P value0.05 was considered to be statistically significant; these were observed in abdominal distension, gastric residue, and vomiting. The duration of hospitalization was shorter in the case group, as on average, they were transferred to the Pediatric Surgery Department on the 6th day, where they further remained admitted to treat the underlying cause. Differences between groups in administration of breast milk versus formula were not statistically significant. CONCLUSIONS We concluded that the clinical examination had a major role in early detection of digestive malformations and in the effective management of specific necessary nutrition. Proper evaluation of when to start enteral feeding can help post-surgical cases to recover faster, minimizing complications. Further studies are required to assess how financial factors affect implementation of the standardized guidelines of nutrition in children and to find possible solutions to financial constraints.

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.

We aimed to evaluate patient preferences towards three oral antihyperglycaemic therapies using conjoint analysis to determine which attributes may influence use.We used an online survey, completed by 553 US respondents with type 2 diabetes mellitus (T2DM; mean age 64 ± 9 years; 55% had cardiovascular [CV] risk; 27% had CV disease), to present hypothetical, blinded, pairwise, drug profile comparison choices, between different benefit/risk attributes and effect ranges. Attributes were derived from phase 3 trials for empagliflozin 25 mg (SGLT2 inhibitor), oral semaglutide 14 mg (GLP-1 receptor agonist) and sitagliptin 100 mg (DPP-4 inhibitor). Predicted therapy preference outcomes and relative importance of each attribute were calculated (presented as a percentage).Preference score was highest for the profile matching empagliflozin (56%), versus sitagliptin (38%; z-test, P 0.001) and oral semaglutide (6%, z-test, P 0.001). Results were overall consistent in subgroup analyses. Genital infection risk was the most important attribute (relative score: 19% [z-test, P = 0.077]). Other important attributes were fasting requirements (15%), weight reduction (15%), risk of vomiting (14%), CV benefit (12%), and risk of nausea (11%). HbA1c reduction (8%) and ability to take medication with other drugs (6%) were considered less important. While blinded to drug name/dose, respondents chose a drug profile similar to empagliflozin (41%) versus sitagliptin (31%), oral semaglutide (11%), or 'none of the options' (17%).While the drug profile comparable to empagliflozin was preferred, CV benefit was not the top patient priority. A shared physician-patient decision model and increased patient education are needed to ensure optimal use of guideline-directed T2DM therapies.

The Thrombolysis in Myocardial Infarction Risk Score for Heart Failure (HF) in Diabetes (TRS-HFThe TRS-HFIn total, HF hospitalization occurred in 193 (3.6%) patients. Based on the TRS-HFThe TRS-HF

Chronic post-thoracotomy pain (PTPS) is a frequent complication of thoracic operations. Sometimes the pain is excruciating enough to impair activities of daily living (ADL). All thoracic procedures have the potential to cause trauma to the intercostal nerves due to retractor use, chest closure techniques, and or wound healing. In our study, we analyzed the microscopic aspects of the nerves involved in the healing process, to better understand the histopathology of chronic pain.29 patients with PTPS underwent intercostal neurectomy to alleviate the symptoms. Microscopic specimens harvested during the surgeries were sent to our pathology unit for evaluation. The following data regarding the surgical procedures was collected: surgical approach, chest closure type, number of excised nerves, and time interval from previous surgery to neurectomy.A mean of 2.34±1.11 nerves were excised. Microscopy of the specimens revealed: fibrosis, hyalinization of the epineurium and perineurium, intense hyperemia of the blood capillaries, and interstitial edema. 7 cases presented with myxoid degeneration of epineurium and perineurium. In all the cases, endoneurium, myelin sheaths, and axons were interrupted. The endoneurium showed the presence of hyperemic dilated capillaries. The segmental cytoplasmic vacuolization of Schwann's cells with the total disappearance of axons was also noted. 60% of the examined specimens had intraneural myxoid degeneration, with highly dense irregular connective tissue around nerve fibers.The pathologic findings in the structure of the intercostal nerves obtained from the patients are indicative of the involvement of the wound healing mechanisms in PTPS. The negative impact of wound healing could be considered a key component in the development of intense chronic pain.

No abstract available.

Stroke is a major source of morbidity and mortality worldwide, accounting for the second largest cause of mortality and the third greatest cause of disability. Stroke is frequently preceded by a transient ischemic attack (TIA). The etiologies of 20-30% of ischemic strokes are unknown, and thus are termed "cryptogenic strokes". About 25% of ischemic strokes are cardioembolic. Strokes occur at a rate of around 2% per year in individuals with heart failure with reduced ejection fraction (HFrEF), with a strong correlation between stroke risk and the degree of ventricular impairment. Furthermore, stroke risk is augmented in the absence of anticoagulation therapy. Cardioembolic strokes, when treated inadequately, have a greater predilection for recurrences than atherothrombotic strokes, both early and late in life. The role of a patent foramen ovale in strokes, specifically in "cryptogenic strokes", is a matter of concern that deserves due attention. The use of tissue-engineered heart valves and aspirin for minimizing the risk of stroke is recommended. Transthoracic echocardiography (TTE) is advantageous for assessing heart function in the acute phase of ischemic stroke. Transesophageal echocardiography (TEE) is considered the criterion standard procedure for detecting LAA thrombi. Computed tomography (CT) scans are good imaging modalities for identifying and excluding bleeding. Magnetic resonance imaging (MRI) images are by far the most effective imaging technique available for assessing the brain parenchymal state. We conducted a thorough review of the literature on the use of imaging modalities, highlighting the important contribution of TTE, TEE, CT, and MRI in the evaluation of cardioembolic stroke.

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.

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.

The Heart Failure Academic Research Consortium is a partnership between the Heart Failure Collaboratory (HFC) and the Academic Research Consortium (ARC) composed of patients, academic investigators from the United States and Europe, the U.S. Food and Drug Administration, the National Institutes of Health, payers, and industry. Members discussed the measure, remote capture, and clinical utility of functional and quality-of-life endpoints for use in clinical trials of heart failure and cardiovascular therapeutics, with the goal of improving the efficiency of heart failure and cardiovascular clinical research, evidence generation, and thereby patient quality of life, functional status, and survival. Assessments of patient-reported outcomes and maximal and submaximal exercise tolerance are standardized and validated, but actigraphy remains inconsistent as a potential endpoint. This paper details those discussions and consensus recommendations.

Background Clinical prediction models have been developed for hospitalization for heart failure in type 2 diabetes. However, a systematic evaluation of these models’ performance, applicability, and clinical impact is absent. Methods and Results We searched Embase, MEDLINE, Web of Science, Google Scholar, and Tufts’ clinical prediction registry through February 2021. Studies needed to report the development, validation, clinical impact, or update of a prediction model for hospitalization for heart failure in type 2 diabetes with measures of model performance and sufficient information for clinical use. Model assessment was done with the Prediction Model Risk of Bias Assessment Tool, and meta‐analyses of model discrimination were performed. We included 15 model development and 3 external validation studies with data from 999 167 people with type 2 diabetes. Of the 15 models, 6 had undergone external validation and only 1 had low concern for risk of bias and applicability (Risk Equations for Complications of Type 2 Diabetes). Seven models were presented in a clinically useful manner (eg, risk score, online calculator) and 2 models were classified as the most suitable for clinical use based on study design, external validity, and point‐of‐care usability. These were Risk Equations for Complications of Type 2 Diabetes (meta‐analyzed c‐statistic, 0.76) and the Thrombolysis in Myocardial Infarction Risk Score for Heart Failure in Diabetes (meta‐analyzed c‐statistic, 0.78), which was the simplest model with only 5 variables. No studies reported clinical impact. Conclusions Most prediction models for hospitalization for heart failure in patients with type 2 diabetes have potential concerns with risk of bias or applicability, and uncertain external validity and clinical impact. Future research is needed to address these knowledge gaps.

Mobile health (mHealth) platforms can affect health behaviors but have not been rigorously tested in randomized trials.We sought to evaluate the effectiveness of a pragmatic mHealth intervention in patients with heart failure (HF) and diabetes (DM).We conducted a multicenter randomized trial in 187 patients with both HF and DM to assess an mHealth intervention to improve physical activity and medication adherence compared to usual care. The primary endpoint was change in mean daily step count from baseline through 3 months. Other outcomes included medication adherence, health-related quality of life and metabolomic profiling.The mHealth group had an increase in daily step count of 151 steps/day at 3 months, whereas the usual-care group had a decline of 162 steps/day (least squares mean between-group difference = 313 steps/day; 95% CI: 8 619; P = 0.044). Medication adherence, measured using the Voils Adherence Questionnaire, did not change from baseline to 3 months (LS-mean change -0.08 in mHealth vs -0.15 in usual care; P = 0.47). The mHealth group had an improvement in Kansas City Cardiomyopathy Questionnaire Overall Summary Score compared to the usual-care group (LS-mean difference = 5.5 points, 95% CI: 1.4, 9.6; P = 0.009). Thirteen metabolites, primarily medium- and long-chain acylcarnitines, changed differently between treatment groups from baseline to 3 months (P0.05).In patients with HF and DM, a 3-month mHealth intervention significantly improved daily physical activity, health-related quality of life and metabolomic markers of cardiovascular health but not medication adherence.Heart failure (HF) and diabetes (DM) have overlapping biological and behavioral risk factors. We conducted a multicenter randomized, clinical trial in 187 patients with both HF (regardless of ejection fraction) and DM to assess whether an mHealth intervention could improve physical activity and medication adherence. The mHealth group had an increase in mean daily step count and quality of life but not in medication adherence. Medium- and long-chain acylcarnitines changed differently in treatment groups from baseline to 3 months (P0.05). These data have important implications for designing effective lifestyle interventions in HF and DM.

The balance of microbial species in the intestine must be maintained to prevent inflammation and disease. Healthy bacteria suppress infection by pathogens and prevent disorders such as inflammatory bowel diseases (IBDs). The role of mucus in the relation between pathogens and the intestinal microbiota is poorly understood. Here, we hypothesized that healthy bacteria inhibit infection by preventing pathogens from penetrating the mucus layer and that microbial imbalance leads to inflammation by promoting the penetration of the mucosal barrier. We tested this hypothesis with an in vitro model that contains mucus, an epithelial cell layer, and resident immune cells. We found that, unlike probiotic

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

Background Unlike patients with low ejection fraction after an acute coronary syndrome (ACS), little is known about the long‐term incidence and influence of cardiovascular events before sudden death among stabilized patients after ACS. Methods and Results A total of 18 144 patients stabilized within 10 days after ACS in IMPROVE‐IT (Improved Reduction of Outcomes: Vytorin Efficacy International Trial) were studied. Cumulative incidence rates (IRs) and IRs per 100 patient‐years of sudden death were calculated. Using Cox proportional hazards, the association of ≥1 additional postrandomization cardiovascular events (myocardial infarction, stroke, and hospitalization for unstable angina or heart failure) with sudden death was examined. Early (≤1 year after ACS) and late sudden deaths (>1 year) were compared. Of 2446 total deaths, 402 (16%) were sudden. The median time to sudden death was 2.7 years, with 109 early and 293 late sudden deaths. The cumulative IR was 2.47% (95% CI, 2.23%–2.73%) at 7 years of follow‐up. The risk of sudden death following a postrandomization cardiovascular event (150/402 [37%] sudden deaths; median 1.4 years) was greater (IR/100 patient‐years, 1.45 [95% CI, 1.23–1.69]) than the risk with no postrandomization cardiovascular event (IR/100 patient‐years, 0.27 [95% CI, 0.24–0.30]). Postrandomization myocardial infarction (hazard ratio [HR], 3.64 [95% CI, 2.85–4.66]) and heart failure (HR, 4.55 [95% CI, 3.33–6.22]) significantly increased future risk of sudden death. Conclusions Patients stabilized within 10 days of an ACS remain at long‐term risk of sudden death with the greatest risk in those with an additional cardiovascular event. These results refine the long‐term risk and risk effectors of sudden death, which may help clinicians identify opportunities to improve care. Registration: URL: http://www.clinicaltrials.gov . Unique identifier: NCT00202878.

Solid‐state transistor sensors that can detect biomolecules in real time are highly attractive for emerging bioanalytical applications. However, combining upscalable manufacturing with the required performance remains challenging. Here, an alternative biosensor transistor concept is developed, which relies on a solution‐processed In2O3/ZnO semiconducting heterojunction featuring a geometrically engineered tri‐channel architecture for the rapid, real‐time detection of important biomolecules. The sensor combines a high electron mobility channel, attributed to the electronic properties of the In2O3/ZnO heterointerface, in close proximity to a sensing surface featuring tethered analyte receptors. The unusual tri‐channel design enables strong coupling between the buried electron channel and electrostatic perturbations occurring during receptor–analyte interactions allowing for robust, real‐time detection of biomolecules down to attomolar (am) concentrations. The experimental findings are corroborated by extensive device simulations, highlighting the unique advantages of the heterojunction tri‐channel design. By functionalizing the surface of the geometrically engineered channel with severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) antibody receptors, real‐time detection of the SARS‐CoV‐2 spike S1 protein down to am concentrations is demonstrated in under 2 min in physiological relevant conditions., A solution‐processed metal oxide heterojunction channel with a geometrically engineered tri‐channel architecture several millimeters in size, is developed and used as a generic platform for robust, selective, and ultrasensitive detection of various biomolecules. As a proof‐of‐concept, selective sensing of the SARS‐CoV‐2 spike protein down to attomolar concentrations in under 2 min is demonstrated.

OBJECTIVE Phenotypic heterogeneity among patients with type 2 diabetes mellitus (T2DM) and atherosclerotic cardiovascular disease (ASCVD) is ill defined. We used cluster analysis machine-learning algorithms to identify phenotypes among trial participants with T2DM and ASCVD. RESEARCH DESIGN AND METHODS We used data from the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) study (n = 14,671), a cardiovascular outcome safety trial comparing sitagliptin with placebo in patients with T2DM and ASCVD (median follow-up 3.0 years). Cluster analysis using 40 baseline variables was conducted, with associations between clusters and the primary composite outcome (cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for unstable angina) assessed by Cox proportional hazards models. We replicated the results using the Exenatide Study of Cardiovascular Event Lowering (EXSCEL) trial. RESULTS Four distinct phenotypes were identified: cluster I included Caucasian men with a high prevalence of coronary artery disease; cluster II included Asian patients with a low BMI; cluster III included women with noncoronary ASCVD disease; and cluster IV included patients with heart failure and kidney dysfunction. The primary outcome occurred, respectively, in 11.6%, 8.6%, 10.3%, and 16.8% of patients in clusters I to IV. The crude difference in cardiovascular risk for the highest versus lowest risk cluster (cluster IV vs. II) was statistically significant (hazard ratio 2.74 [95% CI 2.29–3.29]). Similar phenotypes and outcomes were identified in EXSCEL. CONCLUSIONS In patients with T2DM and ASCVD, cluster analysis identified four clinically distinct groups. Further cardiovascular phenotyping is warranted to inform patient care and optimize clinical trial designs.

Tuberculosis (TB), caused by Mycobacterium tuberculosis (MTB), is one of the top 10 causes of death worldwide. Drug-resistant tuberculosis (DR-TB) poses a major threat to the World Health Organization's “End TB” strategy which has defined its target as the year 2035. In 2019, there were close to 0.5 million cases of DRTB, of which 78% were resistant to multiple TB drugs. The traditional culture-based drug susceptibility test (DST - the current gold standard) often takes multiple weeks and the necessary laboratory facilities are not readily available in low-income countries. Whole genome sequencing (WGS) technology is rapidly becoming an important tool in clinical and research applications including transmission detection or prediction of DR-TB. For the latter, many tools have recently been developed using curated database(s) of known resistance conferring mutations. However, documenting all the mutations and their effect is a time-taking and a continuous process and therefore Machine Learning (ML) techniques can be useful for predicting the presence of DR-TB based on WGS data. This can pave the way to an earlier detection of drug resistance and consequently more efficient treatment when compared to the traditional DST.

The authors sought to characterize associations between initiation of metformin and sulfonylurea therapy and clinical outcomes among patients with comorbid heart failure (HF) and diabetes (overall and by ejection fraction [EF] phenotype).Metformin and sulfonylureas are frequently prescribed to patients with diabetes for glycemic control. The impact of these therapies on clinical outcomes among patients with comorbid HF and diabetes is unclear.The authors evaluated Medicare beneficiaries hospitalized for HF in the Get With The Guidelines-Heart Failure Registry between 2006 and 2014 with diabetes and not prescribed metformin or sulfonylurea before admission. In parallel separate analyses for metformin and sulfonylurea, patients with newly prescribed therapy within 90 days of discharge were compared with patients not prescribed therapy. Multivariable models landmarked at 90 days evaluated associations between prescription of therapy, and mortality and hospitalization for HF (HHF) at 12 months. Negative control (falsification) endpoints included hospitalization for urinary tract infection, hospitalization for gastrointestinal bleed, and influenza vaccination. Prespecified subgroup analyses were stratified by EF ≤40% versus40%.Of 5,852 patients, 454 (7.8%) were newly prescribed metformin and 504 (8.6%) were newly prescribed sulfonylurea. After adjustment, metformin prescription was independently associated with reduced risk of composite mortality/HHF (HR: 0.81; 95% CI: 0.67-0.98; P = 0.03), but individual components were not statistically significant. Findings among patients with EF40% accounted for associations with mortality/HHF (HR: 0.68; 95% CI: 0.52-0.90) and HHF (HR: 0.58; 95% CI: 0.40-0.85) endpoints (all P for interaction ≤0.04). After adjustment, sulfonylurea initiation was associated with increased risk of mortality (HR: 1.24; 95% CI: 1.00-1.52; P = 0.045) and HHF (HR: 1.22; 95% CI: 1.00-1.48; P = 0.050) with nominal statistical significance. Associations between sulfonylurea initiation and endpoints were consistent regardless of EF (all P for interaction0.11). Neither metformin initiation nor sulfonylurea initiation were associated with negative control endpoints.In this population of older U.S. adults hospitalized for HF with comorbid diabetes, metformin initiation was independently associated with substantial improvements in 12-month clinical outcomes, driven by findings among patients with EF40%. By contrast, sulfonylurea initiation was associated with excess risk of death and HF hospitalization, regardless of EF.

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.

With recent advances in the pharmacological management of type 2 diabetes mellitus (T2DM), there is a growing need to understand which patients optimally benefit from these novel therapies. Various clinical clustering methodologies have emerged that utilise data-agnostic strategies to categorise patients that have similar clinical characteristics and outcomes; broadly, this characterisation is termed phenotyping. In patients with T2DM, we aimed to describe patient characteristics from phenotype studies, their cardiovascular risk profiles and the impact of antihyperglycemic treatment.Numerous phenotypic studies have been undertaken that have utilised a combination of clinical, biochemical, imaging and genetic variables. Each of these has produced phenotypes that display a spectrum of cardiovascular risk. Studies that aimed to describe pathophysiological phenotypes generally identified five phenotypes: autoimmune phenotype, insulin-related phenotypes (including permutations of insulin deficiency and resistance), obesity phenotype, ageing phenotype, and a sex-related phenotype. Studies examining risk profiles have demonstrated that across such phenotypes there is a spectrum of risk for diabetic complications. Few studies have examined treatment effects across these phenotypes, and thus provide little insights towards making phenotype-guided treatment decisions Clustering analyses in patients with T2DM have identified distinct phenotypes with unique risk profiles. Further studies are needed that harness the use of clinical, biochemical, imaging and genetic data to explore therapeutic heterogeneity and response to antihyperglycemic treatment across the spectrum of patient phenotypes.

Purpose of review Antihyperglycemic therapies including sodium glucose contransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1 RA) have been demonstrated to confer significant cardiovascular benefit and reduce future events in patients with type 2 diabetes mellitus (T2DM). However, despite positive data from cardiovascular outcome trials, these therapies remain underutilized in a large proportion of patients who have clinical indications and meet coverage guidelines for their initiation. One of the causes of the observed gap between scientific evidence and clinical cardiology practice is therapeutic hesitancy (otherwise known as therapeutic inertia). The purpose of this review is to discuss the contributors to therapeutic hesitancy in the implementation of these evidence-based therapies and, more importantly, provide pragmatic solutions to address these barriers. Recent findings Recent studies have demonstrated that clinicians may not initiate cardiovascular protective therapies due to a reluctance to overstep perceived interdisciplinary boundaries, concerns about causing harm due to medication side effects, and a sense of unfamiliarity with the optimal choice of therapy amidst a rapidly evolving landscape of T2DM therapies. Summary Herein, we describe a multifaceted approach aimed at creating a 'permission to prescribe' culture, developing integrated multidisciplinary models of care, enhancing trainees' experiences in cardiovascular disease prevention, and utilizing technology to motivate change. Taken together, these interventions should increase the implementation of evidence-based therapies and improve the quality of life and cardiovascular outcomes of individuals with T2DM.

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.

Summary: Background: Smartphone apps might enable interventions to increase physical activity, but few randomised trials testing this hypothesis have been done. The MyHeart Counts Cardiovascular Health Study is a longitudinal smartphone-based study with the aim of elucidating the determinants of cardiovascular health. We aimed to investigate the effect of four different physical activity coaching interventions on daily step count in a substudy of the MyHeart Counts Study. Methods: In this randomised, controlled crossover trial, we recruited adults (aged ≥18 years) in the USA with access to an iPhone smartphone (Apple, Cupertino, CA, USA; version 5S or newer) who had downloaded the MyHeart Counts app (version 2.0). After completion of a 1 week baseline period of interaction with the MyHeart Counts app, participants were randomly assigned to receive one of 24 permutations (four combinations of four 7 day interventions) in a crossover design using a random number generator built into the app. Interventions consisted of either daily prompts to complete 10 000 steps, hourly prompts to stand following 1 h of sitting, instructions to read the guidelines from the American Heart Association website, or e-coaching based upon the individual's personal activity patterns from the baseline week of data collection. Participants completed the trial in a free-living setting. Due to the nature of the interventions, participants could not be masked from the intervention. Investigators were not masked to intervention allocation. The primary outcome was change in mean daily step count from baseline for each of the four interventions, assessed in the modified intention-to-treat analysis set, which included all participants who had completed 7 days of baseline monitoring and at least 1 day of one of the four interventions. This trial is registered with ClinicalTrials.gov, NCT03090321. Findings: Between Dec 12, 2016, and June 6, 2018, 2783 participants consented to enrol in the coaching study, of whom 1075 completed 7 days of baseline monitoring and at least 1 day of one of the four interventions and thus were included in the modified intention-to-treat analysis set. 493 individuals completed the full set of assigned interventions. All four interventions significantly increased mean daily step count from baseline (mean daily step count 2914 [SE 74]): mean step count increased by 319 steps (75) for participants in the American Heart Association website prompt group (p

The complexity and costs associated with traditional randomized, controlled trials have increased exponentially over time, and now threaten to stifle the development of new drugs and devices. Nevertheless, the growing use of electronic health records, mobile applications, and wearable devices offers significant promise for transforming clinical trials, making them more pragmatic and efficient. However, many challenges must be overcome before these innovations can be implemented routinely in randomized, controlled trial operations. In October of 2018, a diverse stakeholder group convened in Washington, DC, to examine how electronic health record, mobile, and wearable technologies could be applied to clinical trials. The group specifically examined how these technologies might streamline the execution of clinical trial components, delineated innovative trial designs facilitated by technological developments, identified barriers to implementation, and determined the optimal frameworks needed for regulatory oversight. The group concluded that the application of novel technologies to clinical trials provided enormous potential, yet these changes needed to be iterative and facilitated by continuous learning and pilot studies.

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.

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.

Background Actigraphy-based measurements of physiologic parameters may enable design of patient-centric heart failure (HF) clinical trials. Recently, the Heart Failure Collaboratory (HFC) focused on recommendations for meaningful change and use of actigraphy as an endpoint in HF clinical trials. We aimed to evaluate randomized controlled trials (RCTs) that have quantified the impact of HF interventions using actigraphy. Methods Using a scoping review strategy, we evaluated the use of actigraphy in HF RCTs. Studies were identified through electronic searches of Embase, OVID MEDLINE, PubMed, and Cochrane review. Data on trial characteristics and results were collected. Results We identified 11 RCTs with a total of 1,455 participants. The risk of bias across the included trials was overall high. All trials had the primary outcomes reflecting measures of either physical activity (n=8), sleep (n=2), or both (n=1). Five trials evaluated response to pharmacologic therapies compared to placebo, three evaluated physical activity interventions, two evaluated group or cognitive therapy, and one evaluated sleep-ventilation strategy. Sample sizes ranged from 30 to 619 participants. There was significant heterogeneity relating to device type, body placement site, and handling of missing actigraphy data. Duration of monitoring ranged from 48 hours to 12 weeks. None of the studies evaluating pharmacologic therapies (n=5) demonstrated a significant improvement of actigraphy-based primary endpoints measurements. Conclusions There is significant heterogeneity in the use, methodology, and results of actigraphy-based HF RCTs. Our results highlight the need to develop, standardize, and validate actigraphy-specific outcomes for use in HF clinical trials

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.

Using latent class analysis (LCA) of EMPA-REG OUTCOME (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients), this study identified distinct phenotypes in subjects with type 2 diabetes (T2D) and cardiovascular (CV) disease and explored treatment effects across phenotypes.In the EMPA-REG OUTCOME trial, empagliflozin reduced risk of CV death or hospitalization for heart failure (HHF) by 34% in subjects with T2D and CV disease. Among such subjects, there has been limited evaluation of clinical phenotypes.Overall, 7,020 participants were treated with empagliflozin 25 mg, 10 mg, or placebo. For this post hoc analysis, participants were randomly separated into training (two-thirds of patients) and validation (remaining one-third) sets. LCA identified 3 phenotype groups (n = 6,639 with complete data). The phenotype association with CV death or HHF and empagliflozin treatment effect across groups was explored by Cox regression (in training and validation sets).In the training set, phenotype group 1 (n = 1,463; 33.1%) included younger patients with shorter T2D duration and the highest estimated glomerular filtration rate (eGFR). Phenotype group 2 (n = 1,172; 26.5%) included more women with non-coronary artery disease. Phenotype group 3 (n = 1,785; 40.4%) included older patients with advanced coronary disease and the lowest eGFR. The risk of CV death varied across phenotypes (group 2 vs. 1: hazard ratio [HR]; 1.83; 95% confidence interval [CI]: 1.23 to 2.71; group 3 vs. 1: HR: 1.86; 95% CI: 1.30 to 2.67) with similar patterns for CV death or HHF. Consistent treatment effects of empagliflozin were seen across phenotypes in the training and validation sets (interaction p0.30).Among participants with T2D, this study identified 3 phenotypes with varying CV risk. The treatment effect across phenotypes reaffirms the robustness of CV death or HHF reduction with empagliflozin. (BI 10773 [Empagliflozin] Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients [EMPA-REG OUTCOME]; NCT01131676).

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.