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Abstract

Four versus six cycles of CHOP chemotherapy in combination with six applications of rituximab in patients with aggressive B-cell lymphoma with favourable prognosis (FLYER): a randomised, phase 3, non-inferiority trial.

Poeschel V, Held G, Ziepert M, Witzens-Harig M, ... ,
Background
Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis.
Methods
This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18-60 years, with stage I-II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0-1, and without bulky disease (maximal tumour diameter <7·5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m), doxorubicin (50 mg/m), and vincristine (1·4 mg/m, with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1-5. Rituximab was given at a dose of 375 mg/m of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of -5·5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421.
Findings
Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42-100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94-99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy.
Interpretation
In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population.
Funding
Deutsche Krebshilfe.

Copyright © 2019 Elsevier Ltd. All rights reserved.

Lancet: 20 Dec 2020; 394:2271-2281
Poeschel V, Held G, Ziepert M, Witzens-Harig M, ... ,
Lancet: 20 Dec 2020; 394:2271-2281 | PMID: 31868632
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Abstract

Utilization and Outcomes of Measuring Fractional Flow Reserve in Patients With Stable Ischemic Heart Disease.

Parikh RV, Liu G, Plomondon ME, Sehested TSG, ... Waldo SW, Fearon WF
Background
The use and clinical outcomes of fractional flow reserve (FFR) measurement in patients with stable ischemic heart disease (SIHD) are uncertain, as prior studies have been based on selected populations.
Objectives
This study sought to evaluate contemporary, real-world patterns of FFR use and its effect on outcomes among unselected patients with SIHD and angiographically intermediate stenoses.
Methods
The authors used data from the Veterans Affairs Clinical Assessment, Reporting, and Tracking (CART) Program to analyze patients who underwent coronary angiography between January 1, 2009, and September 30, 2017, and had SIHD with angiographically intermediate disease (40% to 69% diameter stenosis on visual inspection). The authors documented trends in FFR utilization and evaluated predictors using generalized mixed models. They applied Cox proportional hazards models to determine the association between an FFR-guided revascularization strategy and all-cause mortality at 1 year.
Results
A total of 17,989 patients at 66 sites were included. The rate of FFR use gradually increased from 14.8% to 18.5% among all patients with intermediate lesions, and from 44% to 75% among patients who underwent percutaneous coronary intervention. One-year mortality was 2.8% in the FFR group and 5.9% in the angiography-only group (p < 0.0001). After adjustment for patient, site-level, and procedural factors, FFR-guided revascularization was associated with a 43% lower risk of mortality at 1 year compared with angiography-only revascularization (hazard ratio: 0.57; 95% confidence interval: 0.45 to 0.71; p < 0.0001).
Conclusions
In patients with SIHD and angiographically intermediate stenoses, use of FFR has slowly risen, and was associated with significantly lower 1-year mortality.

Copyright © 2020 American College of Cardiology Foundation. All rights reserved.

J Am Coll Cardiol: 03 Feb 2020; 75:409-419
Parikh RV, Liu G, Plomondon ME, Sehested TSG, ... Waldo SW, Fearon WF
J Am Coll Cardiol: 03 Feb 2020; 75:409-419 | PMID: 32000953
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Abstract

Pittsburgh B Compound Positron Emission Tomography in Patients With AL Cardiac Amyloidosis.

Lee SP, Suh HY, Park S, Oh S, ... Paeng JC, Sohn DW
Background
It remains unknown whether the noninvasive evaluation of the degree of amyloid deposition in the myocardium can predict the prognosis of patients with light chain (AL) cardiac amyloidosis.
Objectives
The purpose of this study was to demonstrate that C-Pittsburgh B compound positron emission tomography (C-PiB PET) is useful for prognostication of AL cardiac amyloidosis by noninvasively imaging the myocardial AL amyloid deposition.
Methods
This study consecutively enrolled 41 chemotherapy-naïve AL cardiac amyloidosis patients. The amyloid deposit was quantitatively assessed with amyloid P immunohistochemistry in endomyocardial biopsy specimens and was compared with the degree of myocardial C-PiB uptake on PET. The primary endpoint was a composite of all-cause death, heart transplantation, and acute decompensated heart failure.
Results
The degree of myocardial C-PiB PET uptake was significantly higher in the cardiac amyloidosis patients compared with normal subjects and correlated well with the degree of amyloid deposit on histology (R = 0.343, p < 0.001). During follow-up (median: 423 days, interquartile range: 93 to 1,222 days), 24 patients experienced the primary endpoint. When the cardiac amyloidosis patients were divided into tertiles by the degree of myocardial C-PiB PET uptake, patients with the highest PiB uptake experienced the worst clinical event-free survival (log-rank p = 0.014). The degree of myocardial PiB PET uptake was a significant predictor of clinical outcome on multivariate Cox regression analysis (adjusted hazard ratio: 1.185; 95% confidence interval: 1.054 to 1.332; p = 0.005).
Conclusions
These proof-of-concept results show that noninvasive evaluation of myocardial amyloid load by C-PiB PET reflects the degree of amyloid deposit and is an independent predictor of clinical outcome in AL cardiac amyloidosis patients.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Feb 2020; 75:380-390
Lee SP, Suh HY, Park S, Oh S, ... Paeng JC, Sohn DW
J Am Coll Cardiol: 03 Feb 2020; 75:380-390 | PMID: 32000949
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Abstract

Mechanisms of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors: JACC State-of-the-Art Review.

Zelniker TA, Braunwald E

Sodium-glucose cotransporter 2 inhibitors (SGLT2i), a new drug class approved for treatment of diabetes, have been shown to possess a favorable metabolic profile and to significantly reduce atherosclerotic events, hospitalization for heart failure, cardiovascular and total mortality, and progression of chronic kidney disease. Although initially considered to be only glucose-lowering agents, the effects of SGLT2i have expanded far beyond that, and their use is now being studied in the treatment of heart failure and chronic kidney disease, even in patients without diabetes. It is therefore critical for cardiologists, diabetologists, nephrologists, and primary care physicians to be familiar with this drug class. This first part of this 2-part review provides an overview of the current understanding of the mechanisms of the cardio-metabolic-renal benefits of SGLT2i. The second part summarizes the recent clinical trials of SGLT2i.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Feb 2020; 75:422-434
Zelniker TA, Braunwald E
J Am Coll Cardiol: 03 Feb 2020; 75:422-434 | PMID: 32000955
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Abstract

Attenuated Mitral Leaflet Enlargement Contributes to Functional Mitral Regurgitation After Myocardial Infarction.

Marsit O, Clavel MA, Côté-Laroche C, Hadjadj S, ... Levine RA, Beaudoin J
Background
Mitral leaflet enlargement has been identified as an adaptive mechanism to prevent mitral regurgitation in dilated left ventricles (LVs) caused by chronic aortic regurgitation (AR). This enlargement is deficient in patients with functional mitral regurgitation, which remains frequent in the population with ischemic cardiomyopathy. Maladaptive fibrotic changes have been identified in post-myocardial infarction (MI) mitral valves. It is unknown if these changes can interfere with valve growth and whether they are present in other valves.
Objectives
This study sought to test the hypothesis that MI impairs leaflet growth, seen in AR, and induces fibrotic changes in mitral and tricuspid valves.
Methods
Sheep models of AR, AR + MI, and controls were followed for 90 days. Cardiac magnetic resonance, echocardiography, and computed tomography were performed at baseline and 90 days to assess LV volume, LV function, mitral regurgitation and mitral leaflet size. Histopathology and molecular analyses were performed in excised valves.
Results
Both experimental groups developed similar LV dilatation and dysfunction. At 90 days, mitral valve leaflet size was smaller in the AR + MI group (12.8 ± 1.3 cm vs. 15.1 ± 1.6 cm, p = 0.03). Mitral regurgitant fraction was 4% ± 7% in the AR group versus 19% ± 10% in the AR + MI group (p = 0.02). AR + MI leaflets were thicker compared with AR and control valves. Increased expression of extracellular matrix remodeling genes was found in both the mitral and tricuspid leaflets in the AR + MI group.
Conclusions
In these animal models of AR, the presence of MI was associated with impaired adaptive valve growth and more functional mitral regurgitation, despite similar LV size and function. More pronounced extracellular remodeling was observed in mitral and tricuspid leaflets, suggesting systemic valvular remodeling after MI.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Feb 2020; 75:395-405
Marsit O, Clavel MA, Côté-Laroche C, Hadjadj S, ... Levine RA, Beaudoin J
J Am Coll Cardiol: 03 Feb 2020; 75:395-405 | PMID: 32000951
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Abstract

Adverse Events, Radiation Exposure, and Reinterventions Following Transcatheter Pulmonary Valve Replacement.

Goldstein BH, Bergersen L, Armstrong AK, Boe BA, ... Goodman A, Petit CJ
Background
Transcatheter pulmonary valve replacement (TPVR) is associated with a risk of procedural serious adverse events (SAE) and exposure to ionizing radiation.
Objectives
The purpose of this study was to define the risk of, and associations with, SAE and high-dose radiation exposure using large-scale registry data.
Methods
The analysis of the multicenter C3PO-QI registry was limited to patients who underwent TPVR from January 1, 2014, to December 31, 2016. SAE were defined as the occurrence of ≥1 moderate, major, or catastrophic events. Radiation dose was reported as dose area product adjusted for weight. Associations with outcome measures were explored in univariate and multivariable analyses.
Results
A total of 530 patients (59% male) underwent TPVR at a median age of 18.3 years (interquartile range [IQR]: 12.9 to 27.3 years) and weight of 58 kg (IQR: 43 to 77 kg) at 14 centers. Implant substrate included homograft (41%), bioprosthesis (30%), native right ventricular outflow tract (RVOT) (27%) and other (2%). TPVR indications were pulmonary insufficiency (28%), stenosis (23%), and mixed (49%). AE and SAE occurred in 26% and 13% of cases, respectively, including 1 mortality. SAE were more frequent in homograft conduit than other RVOT substrates, although SAE type and severity differed between implant substrates. Median radiation dose was 198 μGy·m/kg (IQR: 94 to 350 μGy·m/kg). Higher radiation dose was associated with older age, greater RVOT obstruction, and concomitant interventions (p < 0.001). During a median follow-up duration of 1 year, 13.3% underwent catheterization, surgery, or both, unrelated to infection. Younger age, smaller size, and hemodynamic and anatomic factors indicative of greater RVOT obstruction were associated with TPV reintervention.
Conclusions
The incidence of SAE during TPVR in the C3PO-QI registry is high, but mortality is uncommon. Radiation dose is greater than for other congenital interventions and is associated with patient and procedural factors. Reintervention is common during early follow-up.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Feb 2020; 75:363-376
Goldstein BH, Bergersen L, Armstrong AK, Boe BA, ... Goodman A, Petit CJ
J Am Coll Cardiol: 03 Feb 2020; 75:363-376 | PMID: 32000947
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Abstract

Clinical Benefit of Cardiorenal Effects of Sodium-Glucose Cotransporter 2 Inhibitors: JACC State-of-the-Art Review.

Zelniker TA, Braunwald E

Changes in the regulatory guidelines by the U.S. Food and Drug Administration and the European Medical Agency requiring large-scale trials that study the cardiovascular safety of new glucose-lowering drugs have improved our understanding of type 2 diabetes mellitus. Unexpectedly, these trials demonstrated that sodium-glucose cotransporter 2 inhibitors reduce adverse cardiovascular outcomes. This second part of this 2-part review summarizes the findings of recent clinical trials and their clinical implications and describes ongoing trials and future areas of research.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Feb 2020; 75:435-447
Zelniker TA, Braunwald E
J Am Coll Cardiol: 03 Feb 2020; 75:435-447 | PMID: 32000956
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Abstract

Short-Term Hemodynamic and Electrophysiological Effects of Cardiac Resynchronization by Left Ventricular Septal Pacing.

Salden FCWM, Luermans JGLM, Westra SW, Weijs B, ... Prinzen FW, Vernooy K
Background
Cardiac resynchronization therapy (CRT) is usually performed by biventricular (BiV) pacing. Previously, feasibility of transvenous implantation of a lead at the left ventricular (LV) endocardial side of the interventricular septum, referred to as LV septal (LVs) pacing, was demonstrated.
Objectives
The authors sought to compare the acute electrophysiological and hemodynamic effects of LVs with BiV and His bundle (HB) pacing in CRT patients.
Methods
Temporary LVs pacing (transaortic approach) alone or in combination with right ventricular (RV) (LVs+RV), BiV, and HB pacing was performed in 27 patients undergoing CRT implantation. Electrophysiological changes were assessed using electrocardiography (QRS duration), vectorcardiography (QRS area), and multielectrode body surface mapping (standard deviation of activation times [SDAT]). Hemodynamic changes were assessed as the first derivative of LV pressure (LVdP/dtmax).
Results
As compared with baseline, LVs pacing resulted in a larger reduction in QRS area (to 73 ± 22 μVs) and SDAT (to 26 ± 7 ms) than BiV (to 93 ± 26 μVs and 31 ± 7 ms; both p < 0.05) and LVs+RV pacing (to 108 ± 37 μVs; p < 0.05; and 29 ± 8 ms; p = 0.05). The increase in LVdP/dtmax was similar during LVs and BiV pacing (17 ± 10% vs. 17 ± 9%, respectively) and larger than during LVs+RV pacing (11 ± 9%; p < 0.05). There were no significant differences between basal, mid-, or apical LVs levels in LVdP/dtmax and SDAT. In a subgroup of 16 patients, changes in QRS area, SDAT, and LVdP/dtmax were comparable between LVs and HB pacing.
Conclusions
LVs pacing provides short-term hemodynamic improvement and electrical resynchronization that is at least as good as during BiV and possibly HB pacing. These results indicate that LVs pacing may serve as a valuable alternative for CRT.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 03 Feb 2020; 75:347-359
Salden FCWM, Luermans JGLM, Westra SW, Weijs B, ... Prinzen FW, Vernooy K
J Am Coll Cardiol: 03 Feb 2020; 75:347-359 | PMID: 32000945
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Abstract

Cardiometabolic-Based Chronic Disease, Adiposity and Dysglycemia Drivers: JACC State-of-the-Art Review.

Mechanick JI, Farkouh ME, Newman JD, Garvey WT

A new cardiometabolic-based chronic disease (CMBCD) model is presented that provides a basis for early and sustainable, evidence-based therapeutic targeting to promote cardiometabolic health and mitigate the development and ravages of cardiovascular disease. In the first part of this JACC State-of-the-Art Review, a framework is presented for CMBCD, focusing on 3 primary drivers (genetics, environment, and behavior) and 2 metabolic drivers (adiposity and dysglycemia) with applications to 3 cardiovascular endpoints (coronary heart disease, heart failure, and atrial fibrillation). Specific mechanistic pathways are presented configuring early primary drivers with subsequent adiposity, insulin resistance, β-cell dysfunction, and metabolic syndrome, leading to cardiovascular disease. The context for building this CMBCD model is to expose actionable targets for prevention to achieve optimal cardiovascular outcomes. The tactical implementation of this CMBCD model is the subject of second part of this JACC State-of-the-Art Review.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Feb 2020; 75:525-538
Mechanick JI, Farkouh ME, Newman JD, Garvey WT
J Am Coll Cardiol: 10 Feb 2020; 75:525-538 | PMID: 32029136
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Abstract

Oral Anticoagulation for Patients With Atrial Fibrillation on Long-Term Hemodialysis.

Kuno T, Takagi H, Ando T, Sugiyama T, ... Burger A, Bangalore S
Background
Patients on long-term dialysis are at increased risk of bleeding. Although oral anticoagulants (OACs) are recommended for atrial fibrillation (AF) to reduce the risk of stroke, randomized trials have excluded these populations. As such, the net clinical benefit of OACs among patients on dialysis is unknown.
Objectives
This study aimed to investigate the efficacy and safety of OACs in patients with AF on long-term dialysis.
Methods
MEDLINE and EMBASE were searched through June 10, 2019, for studies that investigated the efficacy and safety of different OAC strategies in patients with AF on long-term dialysis. The efficacy outcomes were ischemic stroke and/or systemic thromboembolism, all-cause mortality, and the safety outcome was major bleeding.
Results
This study identified 16 eligible observational studies (N = 71,877) regarding patients on long-term dialysis who had AF. Only 2 of 16 studies investigated direct OACs. Outcomes for dabigatran and rivaroxaban were limited to major bleeding events. Compared with no anticoagulants, apixaban and warfarin were not associated with a significant decrease in stroke and/or systemic thromboembolism (apixaban 5 mg, hazard ratio [HR]: 0.59; 95% confidence interval [CI]: 0.30 to 1.17; apixaban 2.5 mg, HR: 1.00; 95% CI: 0.52 to 1.93; warfarin, HR: 0.91; 95% CI: 0.72 to 1.16). Apixaban 5 mg was associated with a significantly lower risk of mortality (vs. warfarin, HR: 0.65; 95% CI: 0.45 to 0.93; vs. apixaban 2.5 mg, HR: 0.62; 95% CI: 0.42 to 0.90; vs. no anticoagulant, HR: 0.61; 95% CI: 0.41 to 0.90). Warfarin was associated with a significantly higher risk of major bleeding than apixaban 5 min/2.5 mg and no anticoagulant (vs. apixaban 5 mg, HR: 1.41; 95% CI: 1.07 to 1.88; vs. apixaban 2.5 mg, HR: 1.40; 95% CI: 1.07 to 1.82; vs. no anticoagulant, HR: 1.31; 95% CI: 1.15 to 1.50). Dabigatran and rivaroxaban were also associated with significantly higher risk of major bleeding than apixaban and no anticoagulant.
Conclusions
This meta-analysis showed that OACs were not associated with a reduced risk of thromboembolism in patients with AF on long-term dialysis. Warfarin, dabigatran, and rivaroxaban were associated with significantly higher bleeding risk compared with apixaban and no anticoagulant. The benefit-to-risk ratio of OACs in patients with AF on long-term dialysis warrants validation in randomized clinical trials.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Jan 2020; 75:273-285
Kuno T, Takagi H, Ando T, Sugiyama T, ... Burger A, Bangalore S
J Am Coll Cardiol: 27 Jan 2020; 75:273-285 | PMID: 31976865
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Abstract

Marijuana Use in Patients With Cardiovascular Disease: JACC Review Topic of the Week.

DeFilippis EM, Bajaj NS, Singh A, Malloy R, ... Bhatt DL, Vaduganathan M

Marijuana use is increasing as more states are legalizing cannabis for both medicinal and recreational purposes. National survey data estimate that >2 million Americans with established cardiovascular diseases currently use or have used marijuana in its variety of forms, including inhalation and vaping. Cannabinoid receptors are distributed in multiple tissue beds and cells, including platelets, adipose tissue, and myocytes. Observational data suggest associations between marijuana and a broad range of adverse cardiovascular risks. Marijuana is becoming increasingly potent, and smoking marijuana carries many of the same cardiovascular health hazards as smoking tobacco. Synthetic cannabinoids have been linked to more sustained and deleterious pharmacodynamic effects. Marijuana is classified as a Schedule I substance, thus limiting its rigorous study for cardiovascular health effects. This review summarizes cardiovascular considerations related to marijuana use, pharmacological interactions, and future steps to provide clearer guidance regarding its cardiovascular safety. Screening for marijuana use is encouraged, especially in young patients presenting with cardiovascular disease.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Jan 2020; 75:320-332
DeFilippis EM, Bajaj NS, Singh A, Malloy R, ... Bhatt DL, Vaduganathan M
J Am Coll Cardiol: 27 Jan 2020; 75:320-332 | PMID: 31976871
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Abstract

Cardiometabolic-Based Chronic Disease, Addressing Knowledge and Clinical Practice Gaps: JACC State-of-the-Art Review.

Mechanick JI, Farkouh ME, Newman JD, Garvey WT

In the second part of this JACC State-of-the-Art Review, an early and sustainable preventive care plan is described for cardiometabolic-based chronic disease. This plan can improve cardiometabolic health by targeting early mechanistic events to decrease the risk for certain cardiovascular diseases (e.g., coronary heart disease, heart failure, and atrial fibrillation). Included are various prevention modalities, intensive lifestyle interventions, pharmacotherapy and cardiovascular outcome trial evidence, and bariatric/metabolic procedures. A tactical approach of implementing published clinical practice guidelines/algorithms for early behavioral, adiposity, and dysglycemia targeting is emphasized, as well as relevant educational and research implications.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Feb 2020; 75:539-555
Mechanick JI, Farkouh ME, Newman JD, Garvey WT
J Am Coll Cardiol: 10 Feb 2020; 75:539-555 | PMID: 32029137
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Abstract

Extracellular Myocardial Volume in Patients With Aortic Stenosis.

Everett RJ, Treibel TA, Fukui M, Lee H, ... Moon JC, Dweck MR
Background
Myocardial fibrosis is a key mechanism of left ventricular decompensation in aortic stenosis and can be quantified using cardiovascular magnetic resonance (CMR) measures such as extracellular volume fraction (ECV%). Outcomes following aortic valve intervention may be linked to the presence and extent of myocardial fibrosis.
Objectives
This study sought to determine associations between ECV% and markers of left ventricular decompensation and post-intervention clinical outcomes.
Methods
Patients with severe aortic stenosis underwent CMR, including ECV% quantification using modified Look-Locker inversion recovery-based T1 mapping and late gadolinium enhancement before aortic valve intervention. A central core laboratory quantified CMR parameters.
Results
Four-hundred forty patients (age 70 ± 10 years, 59% male) from 10 international centers underwent CMR a median of 15 days (IQR: 4 to 58 days) before aortic valve intervention. ECV% did not vary by scanner manufacturer, magnetic field strength, or T1 mapping sequence (all p > 0.20). ECV% correlated with markers of left ventricular decompensation including left ventricular mass, left atrial volume, New York Heart Association functional class III/IV, late gadolinium enhancement, and lower left ventricular ejection fraction (p < 0.05 for all), the latter 2 associations being independent of all other clinical variables (p = 0.035 and p < 0.001). After a median of 3.8 years (IQR: 2.8 to 4.6 years) of follow-up, 52 patients had died, 14 from adjudicated cardiovascular causes. A progressive increase in all-cause mortality was seen across tertiles of ECV% (17.3, 31.6, and 52.7 deaths per 1,000 patient-years; log-rank test; p = 0.009). Not only was ECV% associated with cardiovascular mortality (p = 0.003), but it was also independently associated with all-cause mortality following adjustment for age, sex, ejection fraction, and late gadolinium enhancement (hazard ratio per percent increase in ECV%: 1.10; 95% confidence interval [1.02 to 1.19]; p = 0.013).
Conclusions
In patients with severe aortic stenosis scheduled for aortic valve intervention, an increased ECV% is a measure of left ventricular decompensation and a powerful independent predictor of mortality.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Jan 2020; 75:304-316
Everett RJ, Treibel TA, Fukui M, Lee H, ... Moon JC, Dweck MR
J Am Coll Cardiol: 27 Jan 2020; 75:304-316 | PMID: 31976869
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Abstract

Coronary Artery Target Selection and Survival After Bilateral Internal Thoracic Artery Grafting.

Bakaeen FG, Ravichandren K, Blackstone EH, Houghtaling PL, ... Gillinov AM, Svensson LG
Background
The importance of a coronary artery, based on the myocardial mass it perfuses, is well documented, but little is known about the importance of a vessel that has been bypassed and its effect on survival in the context of bilateral internal thoracic artery (BITA) grafting.
Objectives
This study determined the effect of a dominant left anterior descending (LAD) artery and important non-LAD targets on outcomes after BITA grafting.
Methods
From January 1972 to January 2011, of 6,127 patients who underwent BITA grafting, 2,551 received 1 ITA grafted to the LAD and had an evaluable coronary angiogram. A dominant LAD was defined as one that was wrapped around the left ventricular apex. Non-LAD targets were graded based on their terminal reach toward the apex: important: >75% (n = 1,698); and less important: ≤75% (n = 853). Mean follow-up was 14 ± 8.7 years. Multivariable analysis was performed to identify risk factors for time-related mortality.
Results
A dominant LAD was present more frequently in patients with less important additional targets (51% vs. 35%; p < 0.0001). A total of 179 patients (7.0%) received a second ITA to multiple targets, 77 (43%) of which were to multiple important target vessels. Unadjusted late survival was similar regardless of degree of importance of the second ITA target-77% at 15 years (p = 0.70) for the important and less important targets, respectively. In the multivariable model, grafting the second ITA to multiple important targets was associated with better long-term survival (p = 0.005). In patients with a nondominant LAD, a second ITA grafted to a less important artery was associated with higher risk of operative mortality (2.4% vs. 0.51%; p = 0.007). A saphenous vein graft to an important or less important target did not influence long-term survival.
Conclusions
In BITA grafting, bypassing multiple important targets to maximize myocardium supplied by ITAs improved long-term survival. In patients with a nondominant LAD, selecting an important target for the second ITA lowered operative mortality.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Jan 2020; 75:258-268
Bakaeen FG, Ravichandren K, Blackstone EH, Houghtaling PL, ... Gillinov AM, Svensson LG
J Am Coll Cardiol: 27 Jan 2020; 75:258-268 | PMID: 31976863
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Abstract

A Contemporary Picture of Enterococcal Endocarditis.

Pericàs JM, Llopis J, Muñoz P, Gálvez-Acebal J, ... Miró JM,
Background
Enterococcal endocarditis (EE) is a growing entity in Western countries. However, quality data from large studies is lacking.
Objectives
The purpose of this study was to describe the characteristics and analyze the prognostic factors of EE in the GAMES cohort.
Methods
This was a post hoc analysis of a prospectively collected cohort of patients from 35 Spanish centers from 2008 to 2016. Characteristics and outcomes of 516 cases of EE were compared with those of 3,308 cases of nonenterococcal endocarditis (NEE). Logistic regression and Cox proportional hazards regression analysis were performed to investigate risk factors for in-hospital and 1-year mortality, as well as relapses.
Results
Patients with EE were significantly older; more frequently presented chronic lung disease, chronic heart failure, prior endocarditis, and degenerative valve disease; and had higher median age-adjusted Charlson score. EE more frequently involved the aortic valve and prosthesis (64.3% vs. 46.7%; p < 0.001; and 35.9% vs. 28.9%; p = 0.002, respectively) but less frequently pacemakers/defibrillators (1.5% vs. 10.5%; p < 0.001), and showed higher rates of acute heart failure (45% vs. 38.3%; p = 0.005). Cardiac surgery was less frequently performed in EE (40.7% vs. 45.9%; p = 0.024). No differences in in-hospital and 1-year mortality were found, whereas relapses were significantly higher in EE (3.5% vs. 1.7%; p = 0.035). Increasing Charlson score, LogEuroSCORE, acute heart failure, septic shock, and paravalvular complications were risk factors for mortality, whereas prior endocarditis was protective and persistent bacteremia constituted the sole risk factor for relapse.
Conclusions
Besides other baseline and clinical differences, EE more frequently affects prosthetic valves and less frequently pacemakers/defibrillators. EE presents higher rates of relapse than NEE.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Feb 2020; 75:482-494
Pericàs JM, Llopis J, Muñoz P, Gálvez-Acebal J, ... Miró JM,
J Am Coll Cardiol: 10 Feb 2020; 75:482-494 | PMID: 32029130
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Impact:
Abstract

Haptoglobin Phenotype Modifies the Influence of Intensive Glycemic Control on Cardiovascular Outcomes.

Carew AS, Levy AP, Ginsberg HN, Coca S, ... Gardner M, Cahill LE
Background
Whereas there exists a direct relationship between glycated hemoglobin and cardiovascular disease (CVD), clinical trials targeting glycated hemoglobin to near-normal levels using intensive therapy have failed to prevent CVD and have even increased mortality, making clinical decision making difficult. A common polymorphism at the haptoglobin (Hp) genetic locus is associated with CVD, especially coronary heart disease, in the setting of hyperglycemia.
Objectives
This study sought to determine whether the treatment difference of intensive versus standard glucose-lowering therapy on risk of CVD events in the ACCORD (Action to Control Cardiovascular Risk in Diabetes) study depended on Hp phenotype.
Methods
Hp phenotype was measured within 5,806 non-Hispanic white ACCORD participants using a validated assay. Adjusted hazard ratios (aHR) with 95% confidence intervals (CI) estimated from stratified Cox regression models were used to quantify the association between intensive therapy and incident CVD for the 2 different Hp phenotype groups (Hp2-2, Hp1 carriers).
Results
Compared with standard therapy, intensive therapy was associated with a lower risk of incident coronary heart disease among participants with the Hp2-2 phenotype (n = 2,133; aHR: 0.71; 95% CI: 0.55 to 0.91; p = 0.006), but not among the other 2 phenotypes (Hp1 allele carriers) (n = 3,673; aHR: 0.95; 95% CI: 0.79 to 1.13; p = 0.550). The same pattern was observed for CVD. Conversely, intensive therapy was associated with an increased risk of fatal CVD (aHR: 1.50; 95% CI: 1.00 to 2.25; p = 0.049) and total mortality (aHR: 1.40; 95% CI: 1.08 to 1.81; p = 0.011) among the Hp1 carriers, whereas this risk was not increased in the Hp2-2 phenotype (fatal CVD: aHR: 1.02; 95% CI: 0.59 to 1.77; p = 0.931; total mortality: aHR: 0.98; 95% CI: 0.68 to 1.41; p = 0.908).
Conclusions
Intensive glucose-lowering therapy was effective at preventing incident coronary heart disease and CVD events in ACCORD study participants with the Hp2-2 phenotype but not in Hp1 carriers, who had increased mortality risk from intensive therapy.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Feb 2020; 75:512-521
Carew AS, Levy AP, Ginsberg HN, Coca S, ... Gardner M, Cahill LE
J Am Coll Cardiol: 10 Feb 2020; 75:512-521 | PMID: 32029134
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Impact:
Abstract

Morphine and Cardiovascular Outcomes Among Patients With Non-ST-Segment Elevation Acute Coronary Syndromes Undergoing Coronary Angiography.

Furtado RHM, Nicolau JC, Guo J, Im K, ... Newby LK, Giugliano RP
Background
Mechanistic studies have shown that morphine blunts the antiplatelet effects of oral adenosine diphosphate receptor blockers. However, the clinical relevance of this interaction is controversial.
Objectives
This study sought to explore the association between morphine and ischemic events in 5,438 patients treated with concomitant clopidogrel presenting with non-ST-segment elevation acute coronary syndromes (NSTEACS) in the EARLY ACS (Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome) trial. Patients not treated with clopidogrel (n = 3,462) were used as negative controls.
Methods
Endpoints were the composite of death, myocardial infarction (MI), recurrent ischemia, or thrombotic bailout at 96 h (4-way endpoint) and the composite of death or MI at 30 days.
Results
In patients treated with clopidogrel, morphine use was associated with higher rates of the 4-way endpoint at 96 h (adjusted odds ratio [OR]: 1.40; 95% confidence interval [CI]: 1.04 to 1.87; p = 0.026). There was a trend for higher rates of death or MI at 30 days (adjusted OR: 1.29; 95% CI: 0.98 to 1.70; p = 0.072), driven by events in the first 48 h (adjusted hazard ratio: 1.54; 95% CI: 1.07 to 2.23; p = 0.021). In patients not treated with clopidogrel, morphine was not associated with either the 4-way endpoint at 96 h (adjusted OR: 1.05; 95% CI: 0.74 to 1.49; p = 0.79; p = 0.36 ) or death or MI at 30 days (adjusted OR: 1.07; 95% CI: 0.77 to 1.48; p = 0.70; p = 0.46).
Conclusions
When used concomitantly with clopidogrel pre-treatment, morphine was associated with higher rates of ischemic events in patients with NSTEACS. (EARLY ACS: Early Glycoprotein IIb/IIIa Inhibition in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome; NCT00089895).

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Jan 2020; 75:289-300
Furtado RHM, Nicolau JC, Guo J, Im K, ... Newby LK, Giugliano RP
J Am Coll Cardiol: 27 Jan 2020; 75:289-300 | PMID: 31976867
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Impact:
Abstract

Long-Term Outcomes and Associations With Major Adverse Limb Events After Peripheral Artery Revascularization.

Hess CN, Wang TY, Weleski Fu J, Gundrum J, ... Rogers RK, Hiatt WR
Background
Long-term cardiovascular and limb outcomes after revascularization for peripheral artery disease and, in particular, prognosis after post-procedure major adverse limb events (MALE) are not well-studied.
Objectives
This study sought to describe outcomes after peripheral revascularization and assess relationships between post-procedure MALE hospitalization and subsequent events.
Methods
Patients undergoing peripheral artery revascularization between January 1, 2009, and September 30, 2015, in the Premier Healthcare Database were examined for the co-primary outcomes of interest, composite myocardial infarction (MI) or stroke and composite major amputation or peripheral revascularization. Multivariable adjusted Cox proportional hazards models with post-procedure MALE hospitalization included as a time-dependent covariate were developed to estimate hazard ratios for outcomes.
Results
Among 393,017 revascularized patients followed for a median of 2.7 years (interquartile range: 1.3 to 4.4 years), the cumulative incidence of MI or stroke was 9.8% and that of major amputation or peripheral revascularization was 41.9%. A total of 50,750 patients (12.9%) had at least 1 post-procedure MALE hospitalization. In time-dependent covariate adjusted models, post-procedure MALE hospitalization was associated with greater risk of subsequent MI or stroke (hazard ratio: 1.34; 95% confidence interval: 1.28 to 1.40) and major amputation or peripheral revascularization (hazard ratio: 8.13; 95% confidence interval: 7.96 to 8.29). After peripheral revascularization with or without post-procedure MALE hospitalization, risk of limb events increased rapidly post-procedure and more slowly after the first year, whereas cardiac risk increased steadily during follow-up.
Conclusions
Revascularized peripheral artery disease patients face earlier limb and later cardiovascular ischemic risk that is heightened among patients with post-procedure MALE hospitalization. Increased provider awareness of these long-term risks may guide efforts to improve post-procedural outcomes.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Feb 2020; 75:498-508
Hess CN, Wang TY, Weleski Fu J, Gundrum J, ... Rogers RK, Hiatt WR
J Am Coll Cardiol: 10 Feb 2020; 75:498-508 | PMID: 32029132
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Impact:
Abstract

Embolic Stroke of Undetermined Source: JACC Review Topic of the Week.

Ntaios G

The term embolic stroke of undetermined source (ESUS) was introduced in 2014 to describe patients with a nonlacunar ischemic stroke and no convincing etiology. The terms ESUS and cryptogenic stroke are not synonyms, as the latter also includes patients with multiple stroke etiologies or incomplete diagnostic work-up. ESUS involves approximately 17% of all ischemic stroke patients, and these patients are typically younger with mild strokes and an annual rate of stroke recurrence of 4% to 5%. It was hypothesized that oral anticoagulation may decrease the risk of stroke recurrence in ESUS, which was tested in 2 large randomized controlled trials: the NAVIGATE ESUS (Rivaroxaban Versus Aspirin in Secondary Prevention of Stroke and Prevention of Systemic Embolism in Patients With Recent Embolic Stroke of Undetermined Source) and the RE-SPECT ESUS (Dabigatran Etexilate for Secondary Stroke Prevention in Patients With Embolic Stroke of Undetermined Source). The present review discusses the trials of anticoagulation in patients with ESUS, suggests potential explanations for their neutral results, and highlights the rationale that supports ongoing and future research in this population aiming to reduce the associated risk for stroke recurrence.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 27 Jan 2020; 75:333-340
Ntaios G
J Am Coll Cardiol: 27 Jan 2020; 75:333-340 | PMID: 31976872
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Impact:
Abstract

Coronary CT Angiography in Patients With Non-ST-Segment Elevation Acute Coronary Syndrome.

Linde JJ, Kelbæk H, Hansen TF, Sigvardsen PE, ... Køber LV, Kofoed KF
Background
In patients with non-ST-segment elevation acute coronary syndrome (NSTEACS), coronary pathology may range from structurally normal vessels to severe coronary artery disease.
Objectives
The purpose of this study was to test if coronary computed tomography angiography (CTA) may be used to exclude coronary artery stenosis ≥50% in patients with NSTEACS.
Methods
The VERDICT (Very Early Versus Deferred Invasive Evaluation Using Computerized Tomography in Patients With Acute Coronary Syndromes) trial (NCT02061891) evaluated the outcome of patients with confirmed NSTEACS randomized 1:1 to very early (within 12 h) or standard (48 to 72 h) invasive coronary angiography (ICA). As an observational component of the trial, a clinically blinded coronary CTA was conducted prior to ICA in both groups. The primary endpoint was the ability of coronary CTA to rule out coronary artery stenosis (≥50% stenosis) in the entire population, expressed as the negative predictive value (NPV), using ICA as the reference standard.
Results
Coronary CTA was conducted in 1,023 patients-very early, 2.5 h (interquartile range [IQR]: 1.8 to 4.2 h), n = 583; and standard, 59.9 h (IQR: 38.9 to 86.7 h); n = 440 after the diagnosis of NSTEACS was made. A coronary stenosis ≥50% was found by coronary CTA in 68.9% and by ICA in 67.4% of the patients. Per-patient NPV of coronary CTA was 90.9% (95% confidence interval [CI]: 86.8% to 94.1%) and the positive predictive value, sensitivity, and specificity were 87.9% (95% CI: 85.3% to 90.1%), 96.5% (95% CI: 94.9% to 97.8%) and 72.4% (95% CI: 67.2% to 77.1%), respectively. NPV was not influenced by patient characteristics or clinical risk profile and was similar in the very early and the standard strategy group.
Conclusions
Coronary CTA has a high diagnostic accuracy to rule out clinically significant coronary artery disease in patients with NSTEACS.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Feb 2020; 75:453-463
Linde JJ, Kelbæk H, Hansen TF, Sigvardsen PE, ... Køber LV, Kofoed KF
J Am Coll Cardiol: 10 Feb 2020; 75:453-463 | PMID: 32029126
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Impact:
Abstract

Global Longitudinal Strain and Cardiac Events in Patients With Immune Checkpoint Inhibitor-Related Myocarditis.

Awadalla M, Mahmood SS, Groarke JD, Hassan MZO, ... Fradley MG, Neilan TG
Background
There is a need for improved methods for detection and risk stratification of myocarditis associated with immune checkpoint inhibitors (ICIs). Global longitudinal strain (GLS) is a sensitive marker of cardiac toxicity among patients receiving standard chemotherapy. There are no data on the use of GLS in ICI myocarditis.
Objectives
This study sought to evaluate the role of GLS and assess its association with cardiac events among patients with ICI myocarditis.
Methods
This study retrospectively compared echocardiographic GLS by speckle tracking at presentation with ICI myocarditis (cases, n = 101) to that from patients receiving an ICI who did not develop myocarditis (control subjects, n = 92). Where available, GLS was also measured pre-ICI in both groups. Major adverse cardiac events (MACE) were defined as a composite of cardiogenic shock, arrest, complete heart block, and cardiac death.
Results
Cases and control subjects were similar in age, sex, and cancer type. At presentation with myocarditis, 61 cases (60%) had a normal ejection fraction (EF). Pre-ICI, GLS was similar between cases and control subjects (20.3 ± 2.6% vs. 20.6 ± 2.0%; p = 0.60). There was no change in GLS among control subjects on an ICI without myocarditis (pre-ICI vs. on ICI, 20.6 ± 2.0% vs. 20.5 ± 1.9%; p = 0.41); in contrast, among cases, GLS decreased to 14.1 ± 2.8% (p < 0.001). The GLS at presentation with myocarditis was lower among cases presenting with either a reduced (12.3 ± 2.7%) or preserved EF (15.3 ± 2.0%; p < 0.001). Over a median follow-up of 162 days, 51 (51%) experienced MACE. The risk of MACE was higher with a lower GLS among patients with either a reduced or preserved EF. After adjustment for EF, each percent reduction in GLS was associated with a 1.5-fold increase in MACE among patients with a reduced EF (hazard ratio: 1.5; 95% confidence interval: 1.2 to 1.8) and a 4.4-fold increase with a preserved EF (hazard ratio: 4.4; 95% confidence interval: 2.4 to 7.8).
Conclusions
GLS decreases with ICI myocarditis and, compared with control subjects, was lower among cases presenting with either a preserved or reduced EF. Lower GLS was strongly associated with MACE in ICI myocarditis presenting with either a preserved or reduced EF.

Crown Copyright © 2020. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 10 Feb 2020; 75:467-478
Awadalla M, Mahmood SS, Groarke JD, Hassan MZO, ... Fradley MG, Neilan TG
J Am Coll Cardiol: 10 Feb 2020; 75:467-478 | PMID: 32029128
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Impact:
Abstract

Five-Year Outcomes of Transcatheter or Surgical Aortic-Valve Replacement.

Makkar RR, Thourani VH, Mack MJ, Kodali SK, ... Leon MB,
Background
There are scant data on long-term clinical outcomes and bioprosthetic-valve function after transcatheter aortic-valve replacement (TAVR) as compared with surgical aortic-valve replacement in patients with severe aortic stenosis and intermediate surgical risk.
Methods
We enrolled 2032 intermediate-risk patients with severe, symptomatic aortic stenosis at 57 centers. Patients were stratified according to intended transfemoral or transthoracic access (76.3% and 23.7%, respectively) and were randomly assigned to undergo either TAVR or surgical replacement. Clinical, echocardiographic, and health-status outcomes were followed for 5 years. The primary end point was death from any cause or disabling stroke.
Results
At 5 years, there was no significant difference in the incidence of death from any cause or disabling stroke between the TAVR group and the surgery group (47.9% and 43.4%, respectively; hazard ratio, 1.09; 95% confidence interval [CI], 0.95 to 1.25; P = 0.21). Results were similar for the transfemoral-access cohort (44.5% and 42.0%, respectively; hazard ratio, 1.02; 95% CI, 0.87 to 1.20), but the incidence of death or disabling stroke was higher after TAVR than after surgery in the transthoracic-access cohort (59.3% vs. 48.3%; hazard ratio, 1.32; 95% CI, 1.02 to 1.71). At 5 years, more patients in the TAVR group than in the surgery group had at least mild paravalvular aortic regurgitation (33.3% vs. 6.3%). Repeat hospitalizations were more frequent after TAVR than after surgery (33.3% vs. 25.2%), as were aortic-valve reinterventions (3.2% vs. 0.8%). Improvement in health status at 5 years was similar for TAVR and surgery.
Conclusions
Among patients with aortic stenosis who were at intermediate surgical risk, there was no significant difference in the incidence of death or disabling stroke at 5 years after TAVR as compared with surgical aortic-valve replacement. (Funded by Edwards Lifesciences; PARTNER 2 ClinicalTrials.gov number, NCT01314313.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 26 Mar 2020; 382
Makkar RR, Thourani VH, Mack MJ, Kodali SK, ... Leon MB,
N Engl J Med: 26 Mar 2020; 382 | PMID: 31995682
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Abstract

Stent-Related Adverse Events >1 Year After Percutaneous Coronary Intervention.

Madhavan MV, Kirtane AJ, Redfors B, Généreux P, ... Pocock SJ, Stone GW
Background
The majority of stent-related major adverse cardiovascular events (MACE) after percutaneous coronary intervention (PCI) are believed to occur within the first year. Very-late (>1-year) stent-related MACE have not been well described.
Objectives
The purpose of this study was to assess the frequency and predictors of very-late stent-related events or MACE by stent type.
Methods
Individual patient data from 19 prospective, randomized metallic stent trials maintained at a leading academic research organization were pooled. Very-late MACE (a composite of cardiac death, myocardial infarction [MI], or ischemia-driven target lesion revascularization [ID-TLR]), and target lesion failure (cardiac death, target-vessel MI, or ID-TLR) were assessed within year 1 and between 1 and 5 years after PCI with bare-metal stents (BMS), first-generation drug-eluting stents (DES1) and second-generation drug-eluting stents (DES2). A network meta-analysis was performed to evaluate direct and indirect comparisons.
Results
Among 25,032 total patients, 3,718, 7,934, and 13,380 were treated with BMS, DES1, and DES2, respectively. MACE rates within 1 year after PCI were progressively lower after treatment with BMS versus DES1 versus DES2 (17.9% vs. 8.2% vs. 5.1%, respectively, p < 0.0001). Between years 1 and 5, very-late MACE occurred in 9.4% of patients (including 2.9% cardiac death, 3.1% MI, and 5.1% ID-TLR). Very-late MACE occurred in 9.7%, 11.0%, and 8.3% of patients treated with BMS, DES1, and DES2, respectively (p < 0.0001), linearly increasing between 1 and 5 years. Similar findings were observed for target lesion failure in 19,578 patients from 12 trials. Findings were confirmed in the network meta-analysis.
Conclusions
In this large-scale, individual patient data pooled study, very-late stent-related events occurred between 1 and 5 years after PCI at a rate of ∼2%/year with all stent types, with no plateau evident. New approaches are required to improve long-term outcomes after PCI.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 17 Feb 2020; 75:590-604
Madhavan MV, Kirtane AJ, Redfors B, Généreux P, ... Pocock SJ, Stone GW
J Am Coll Cardiol: 17 Feb 2020; 75:590-604 | PMID: 32057373
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Impact:
Abstract

Sex-Specific Risks of Major Cardiovascular and Limb Events in Patients With Symptomatic Peripheral Artery Disease.

Haine A, Kavanagh S, Berger JS, Hess CN, ... Baumgartner I,
Background
Patients with peripheral artery disease (PAD) have a higher risk of major adverse cardiovascular events (MACE) compared with those without PAD.
Objectives
The aim of this post hoc analysis was to evaluate sex-specific differences in MACE and limb events in the EUCLID (Examining Use of Ticagrelor in PAD) trial.
Methods
Cox proportional hazards models were used to compare time-to-event outcomes stratified by sex. Covariates were introduced after adjusted model selection.
Results
EUCLID enrolled 13,885 patients with PAD (28% women [n = 3,888]). PAD severity and medical treatment were comparable between sexes, whereas prior lower extremity revascularization was reported less frequently in women (54.8% vs. 57.3%; p = 0.006). Women were older (mean ± SD age: 67.8 ± 8.9 vs. 66.1 ± 8.2 years; p < 0.001) and more likely to have diabetes mellitus (p = 0.004), hypertension, hyperlipidemia, and chronic kidney disease (all p < 0.001). Over a mean follow-up of 30 months, women had a lower risk of MACE (9.5% vs. 11.2%; adjusted hazard ratio: 0.77; 95% confidence interval: 0.68 to 0.88; p < 0.001) and all-cause-mortality (7.6% vs. 9.7%; adjusted hazard ratio: 0.61; 95% confidence interval: 0.53 to 0.71; p < 0.001). In contrast, risk for major adverse limb events (2.6% vs. 3.0%) and hospitalization for acute limb ischemia (1.6% vs. 1.7%) were not different by sex.
Conclusions
Although women with PAD are at lower risk for MACE and all-cause mortality, risk for limb events was similar between sexes over a mean follow-up of 30 months. Understanding sex-specific differences and dissociation between baseline cardiovascular risk and subsequent cardiovascular events requires further investigation. (A Study Comparing Cardiovascular Effects of Ticagrelor and Clopidogrel in Patients With Peripheral Artery Disease [EUCLID]; NCT01732822).

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 17 Feb 2020; 75:608-617
Haine A, Kavanagh S, Berger JS, Hess CN, ... Baumgartner I,
J Am Coll Cardiol: 17 Feb 2020; 75:608-617 | PMID: 32057375
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Impact:
Abstract

Reporting of Cardiovascular Events in Clinical Trials Supporting FDA Approval of Contemporary Cancer Therapies.

Bonsu JM, Guha A, Charles L, Yildiz VO, ... Paskett ED, Addison D
Background
Cardiovascular disease (CVD) has become an increasingly common limitation to effective anticancer therapy. Yet, whether CVD events were consistently reported in pivotal trials supporting contemporary anticancer drugs is unknown.
Objectives
The authors sought to evaluate the incidence, consistency, and nature of CVD event reporting in cancer drug trials.
Methods
From the [email protected], clinicaltrials.gov, MEDLINE, and publicly available U.S. Food and Drug Administration (FDA) drug reviews, all reported CVD events across latter-phase (II and III) trials supporting FDA approval of anticancer drugs from 1998 to 2018 were evaluated. The primary outcome was the report of major adverse cardiovascular events (MACE), defined as incident myocardial infarction, stroke, heart failure, coronary revascularization, atrial fibrillation, or CVD death, irrespective of treatment arm. The secondary outcome was report of any CVD event. Pooled reported annualized incidence rates of MACE in those without baseline CVD were compared with reported large contemporary population rates using relative risks. Population risk differences for MACE were estimated. Differences in drug efficacy using pooled binary endpoint hazard ratios on the basis of the presence or absence of reported CVD were also assessed.
Results
Overall, there were 189 trials, evaluating 123 drugs, enrolling 97,365 participants (58.5 ± 5 years, 46.0% female, 72.5% on biologic, targeted, or immune-based therapies) with 148,138 person-years of follow-up. Over a median follow-up of 30 months, 1,148 incidents of MACE (375 heart failure, 253 myocardial infarction, 180 strokes, 65 atrial fibrillation, 29 revascularizations, and 246 CVD deaths; 792 in the intervention vs. 356 in the control arm; p < 0.01) were reported from the 62.4% of trials noting any CVD. The overall weighted-average incidence was 542 events per 100,000 person-years (716 per 100,000 in the intervention arm), compared with 1,408 among similar-aged non-cancer trial subjects (relative risk: 0.38; p < 0.01), translating into a risk difference of 866. There was no association between reporting CVD events and drug efficacy (hazard ratio: 0.68 vs. 0.67; p = 0.22).
Conclusions
Among pivotal clinical trials linked to contemporary FDA-approved cancer drugs, reported CVD event rates trail expected population rates.

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 17 Feb 2020; 75:620-628
Bonsu JM, Guha A, Charles L, Yildiz VO, ... Paskett ED, Addison D
J Am Coll Cardiol: 17 Feb 2020; 75:620-628 | PMID: 32057377
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Impact:
Abstract

Salt Reduction to Prevent Hypertension and Cardiovascular Disease: JACC State-of-the-Art Review.

He FJ, Tan M, Ma Y, MacGregor GA

There is strong evidence for a causal relationship between salt intake and blood pressure. Randomized trials demonstrate that salt reduction lowers blood pressure in both individuals who are hypertensive and those who are normotensive, additively to antihypertensive treatments. Methodologically robust studies with accurate salt intake assessment have shown that a lower salt intake is associated with a reduced risk of cardiovascular disease, all-cause mortality, and other conditions, such as kidney disease, stomach cancer, and osteoporosis. Multiple complex and interconnected physiological mechanisms are implicated, including fluid homeostasis, hormonal and inflammatory mechanisms, as well as more novel pathways such as the immune response and the gut microbiome. High salt intake is a top dietary risk factor. Salt reduction programs are cost-effective and should be implemented or accelerated in all countries. This review provides an update on the evidence relating salt to health, with a particular focus on blood pressure and cardiovascular disease, as well as the potential mechanisms.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 17 Feb 2020; 75:632-647
He FJ, Tan M, Ma Y, MacGregor GA
J Am Coll Cardiol: 17 Feb 2020; 75:632-647 | PMID: 32057379
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Impact:
Abstract

Long-Term Evolocumab in Patients With Familial Hypercholesterolemia.

Santos RD, Stein EA, Hovingh GK, Blom DJ, ... Hamer AW, Raal FJ
Background
Proprotein convertase subtilisin/kexin type 9 inhibitor therapy is a treatment option for patients with familial hypercholesterolemia (FH) who are unable to reach low-density lipoprotein cholesterol (LDL-C) goals.
Objectives
The aim of this study was to provide long-term safety and efficacy data for evolocumab in patients with homozygous FH (HoFH) and severe heterozygous FH (HeFH).
Methods
In this open-label, single-arm study, patients with HoFH or severe HeFH ≥12 years of age and on stable lipid-lowering therapy began subcutaneous evolocumab 420 mg monthly or 420 mg every 2 weeks if on lipoprotein apheresis. After 12 weeks, those not on apheresis could be up-titrated to 420 mg every 2 weeks. The primary endpoint was the incidence of treatment-emergent adverse events; secondary endpoints were changes in LDL-C and other lipids.
Results
In total, 300 patients (106 with HoFH, including 14 <18 years of age at enrollment) received evolocumab for a median of 4.1 years. Adverse events occurred in 89.3% of patients, the most common of which were nasopharyngitis, influenza, upper respiratory tract infection, and headache. Mean change in LDL-C from baseline to week 12 was -21.2% (-59.8 mg/dl) in patients with HoFH and -54.9% (-104.4 mg/dl) in those with severe HeFH and was sustained over time. Of 48 patients with HoFH who were up-titrated, mean change in LDL-C improved from -19.6% at week 12 to -29.7% after 12 weeks of 420 mg every 2 weeks. The adjudicated cardiovascular event rate was 2.7% per year. Of 61 patients receiving apheresis at enrollment, 16 discontinued apheresis.
Conclusions
Evolocumab was well tolerated and effectively reduced plasma LDL-C levels in patients with HoFH and severe HeFH over a median of 4.1 years.

Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 17 Feb 2020; 75:565-574
Santos RD, Stein EA, Hovingh GK, Blom DJ, ... Hamer AW, Raal FJ
J Am Coll Cardiol: 17 Feb 2020; 75:565-574 | PMID: 32057369
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Impact:
Abstract

Carotid Artery Stenting in Asymptomatic Carotid Artery Stenosis: JACC Review Topic of the Week.

Beckman JA, Ansel GM, Lyden SP, Das TS

The advance of therapies to reduce the stroke impact of asymptomatic carotid artery stenosis has proved difficult over the last decade. Disagreement concerning the underlying randomized control trials has limited entry into the care arena of endovascular therapies. Recently, advances in percutaneous therapies for carotid artery disease have been reported and provide a substantial database supporting the further incorporation of endovascular-based therapies in patients who need revascularization and meet selection criteria. With a second randomized control trial now published, it is time for a re-evaluation of endovascular therapy as a component of carotid artery care. This review describes the advances in the field in the last 5 years, clarifying the current position of these therapies in the care of the patient with asymptomatic carotid artery disease.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 17 Feb 2020; 75:648-656
Beckman JA, Ansel GM, Lyden SP, Das TS
J Am Coll Cardiol: 17 Feb 2020; 75:648-656 | PMID: 32057380
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Abstract

Ticagrelor With or Without Aspirin After PCI: The TWILIGHT Platelet Substudy.

Baber U, Zafar MU, Dangas G, Escolar G, ... Mehran R, Badimon JJ
Background
An evolving strategy in the setting of percutaneous coronary intervention (PCI) involves withdrawal of acetylsalicylic acid (ASA), or aspirin, while maintaining P2Y inhibition. However, the pharmacodynamic effects of this approach on blood thrombogenicity and platelet reactivity remain unknown.
Objectives
This study sought to compare the antithrombotic potency of ticagrelor alone versus ticagrelor plus ASA among high-risk patients undergoing PCI with drug-eluting stents.
Methods
This was a mechanistic substudy within the TWILIGHT (Ticagrelor With Aspirin or Alone in High-Risk Patients After Coronary Intervention) trial, which randomized patients undergoing PCI to ticagrelor plus placebo versus ticagrelor plus ASA following 3 months of dual antiplatelet therapy. Substudy participants were enrolled after randomization, at which time ex vivo assays to quantify thrombus size under dynamic flow conditions and platelet reactivity were performed. Pharmacodynamic assessments were repeated 1 to 6 months thereafter. The primary endpoint was thrombus size at the post-randomization visit with platelet reactivity following stimuli to arachidonic acid, collagen, adenosine diphosphate, and thrombin as secondary endpoints. Results were analyzed using analysis of covariance.
Results
A total of 51 patients were enrolled, among whom 42 underwent perfusion assays at baseline and follow-up with a median time between studies of 1.5 months. The adjusted mean difference in post-randomization thrombus area was similar between groups: -218.2 μm (95% confidence interval [CI]: -575.9 to 139.9 μm; p = 0.22). Markers sensitive to cyclo-oxygenase-1 blockade, including platelet reactivity in response to arachidonic acid (mean difference: 10.9 U; 95% CI: 1.9 to 19.9 U) and collagen (mean difference: 9.8 U; 95% CI: 0.8 to 18.8 U) stimuli were higher among patients receiving placebo, whereas levels of platelet reactivity were similar with adenosine diphosphate and thrombin.
Conclusions
Among high-risk patients receiving drug-eluting stents, the antithrombotic potency of ticagrelor monotherapy is similar to that of ticagrelor plus ASA with respect to ex vivo blood thrombogenicity, whereas markers sensitive to cyclo-oxygenase-1 blockade are increased in the absence of ASA. (Platelet Substudy of the TWILIGHT Trial; NCT04001374).

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 17 Feb 2020; 75:578-586
Baber U, Zafar MU, Dangas G, Escolar G, ... Mehran R, Badimon JJ
J Am Coll Cardiol: 17 Feb 2020; 75:578-586 | PMID: 32057371
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Abstract

Fracture risks among patients with atrial fibrillation receiving different oral anticoagulants: a real-world nationwide cohort study.

Huang HK, Liu PP, Hsu JY, Lin SM, ... Wang JH, Loh CH
Aims
To evaluate the fracture risk among patients with atrial fibrillation (AF) treated with non-vitamin K antagonist oral anticoagulants (NOACs) or warfarin.
Methods and results
We conducted a real-world nationwide retrospective cohort study using Taiwan\'s National Health Insurance Research Database. All adult patients in Taiwan newly diagnosed with AF between 2012 and 2016 who received NOACs or warfarin were enrolled and followed up until 2017. Patients treated with NOACs were sub-grouped according to the NOAC used (dabigatran, rivaroxaban, and apixaban). Propensity score matching was performed for each head-to-head comparison. Cox regression analysis, with a shared frailty model, was used to calculate the adjusted hazard ratios (aHRs) for hip, vertebral, and humerus/forearm/wrist fractures. After matching, 19 414 patients were included (9707 in each NOAC and warfarin groups). The median follow-up time was 2.4 years. Compared with warfarin, NOACs were associated with a reduced fracture risk [aHR = 0.84, 95% confidence interval (CI) = 0.77-0.93; P < 0.001]. Sub-analyses revealed that each NOAC, namely dabigatran (aHR = 0.88, 95% CI = 0.78-0.99; P = 0.027), rivaroxaban (aHR = 0.81, 95% CI = 0.72-0.90; P < 0.001), and apixaban (aHR = 0.67, 95% CI = 0.52-0.87; P = 0.003), had a reduced fracture risk. Analyses including all eligible patients, without propensity score matching, generated similar results.
Conclusion
Compared with warfarin, NOAC was associated with a reduced fracture risk among AF patients. Therefore, if oral anticoagulants are indicated, NOACs rather than warfarin should be considered to lower the risk of fractures. However, further studies are needed to investigate the underlying mechanisms and elucidate causality.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 31 Jan 2020; epub ahead of print
Huang HK, Liu PP, Hsu JY, Lin SM, ... Wang JH, Loh CH
Eur Heart J: 31 Jan 2020; epub ahead of print | PMID: 32006423
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Abstract

Soluble Urokinase Receptor and Acute Kidney Injury.

Hayek SS, Leaf DE, Samman Tahhan A, Raad M, ... Quyyumi AA, Reiser J
Background
Acute kidney injury is common, with a major effect on morbidity and health care utilization. Soluble urokinase plasminogen activator receptor (suPAR) is a signaling glycoprotein thought to be involved in the pathogenesis of kidney disease. We investigated whether a high level of suPAR predisposed patients to acute kidney injury in multiple clinical contexts, and we used experimental models to identify mechanisms by which suPAR acts and to assess it as a therapeutic target.
Methods
We measured plasma levels of suPAR preprocedurally in patients who underwent coronary angiography and patients who underwent cardiac surgery and at the time of admission to the intensive care unit in critically ill patients. We assessed the risk of acute kidney injury at 7 days as the primary outcome and acute kidney injury or death at 90 days as a secondary outcome, according to quartile of suPAR level. In experimental studies, we used a monoclonal antibody to urokinase plasminogen activator receptor (uPAR) as a therapeutic strategy to attenuate acute kidney injury in transgenic mice receiving contrast material. We also assessed cellular bioenergetics and generation of reactive oxygen species in human kidney proximal tubular (HK-2) cells that were exposed to recombinant suPAR.
Results
The suPAR level was assessed in 3827 patients who were undergoing coronary angiography, 250 who were undergoing cardiac surgery, and 692 who were critically ill. Acute kidney injury developed in 318 patients (8%) who had undergone coronary angiography. The highest suPAR quartile (vs. the lowest) had an adjusted odds ratio of 2.66 (95% confidence interval [CI], 1.77 to 3.99) for acute kidney injury and 2.29 (95% CI, 1.71 to 3.06) for acute kidney injury or death at 90 days. Findings were similar in the surgical and critically ill cohorts. The suPAR-overexpressing mice that were given contrast material had greater functional and histologic evidence of acute kidney injury than wild-type mice. The suPAR-treated HK-2 cells showed heightened energetic demand and mitochondrial superoxide generation. Pretreatment with a uPAR monoclonal antibody attenuated kidney injury in suPAR-overexpressing mice and normalized bioenergetic changes in HK-2 cells.
Conclusions
High suPAR levels were associated with acute kidney injury in various clinical and experimental contexts. (Funded by the National Institutes of Health and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Jan 2020; 382:416-426
Hayek SS, Leaf DE, Samman Tahhan A, Raad M, ... Quyyumi AA, Reiser J
N Engl J Med: 29 Jan 2020; 382:416-426 | PMID: 31995687
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Abstract

Development of an international standard set of outcome measures for patients with atrial fibrillation: a report of the International Consortium for Health Outcomes Measurement (ICHOM) atrial fibrillation working group.

Seligman WH, Das-Gupta Z, Jobi-Odeneye AO, Arbelo E, ... Yutao G, Camm AJ
Aims
As health systems around the world increasingly look to measure and improve the value of care that they provide to patients, being able to measure the outcomes that matter most to patients is vital. To support the shift towards value-based health care in atrial fibrillation (AF), the International Consortium for Health Outcomes Measurement (ICHOM) assembled an international Working Group (WG) of 30 volunteers, including health professionals and patient representatives to develop a standardized minimum set of outcomes for benchmarking care delivery in clinical settings.
Methods and results
Using an online-modified Delphi process, outcomes important to patients and health professionals were selected and categorized into (i) long-term consequences of disease outcomes, (ii) complications of treatment outcomes, and (iii) patient-reported outcomes. The WG identified demographic and clinical variables for use as case-mix risk adjusters. These included baseline demographics, comorbidities, cognitive function, date of diagnosis, disease duration, medications prescribed and AF procedures, as well as smoking, body mass index (BMI), alcohol intake, and physical activity. Where appropriate, and for ease of implementation, standardization of outcomes and case-mix variables was achieved using ICD codes. The standard set underwent an open review process in which over 80% of patients surveyed agreed with the outcomes captured by the standard set.
Conclusion
Implementation of these consensus recommendations could help institutions to monitor, compare and improve the quality and delivery of chronic AF care. Their consistent definition and collection, using ICD codes where applicable, could also broaden the implementation of more patient-centric clinical outcomes research in AF.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 28 Jan 2020; epub ahead of print
Seligman WH, Das-Gupta Z, Jobi-Odeneye AO, Arbelo E, ... Yutao G, Camm AJ
Eur Heart J: 28 Jan 2020; epub ahead of print | PMID: 31995195
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Abstract

Fatal Cytomegalovirus Infection in an Adult with Inherited NOS2 Deficiency.

Drutman SB, Mansouri D, Mahdaviani SA, Neehus AL, ... Nathan C, Casanova JL
Background
Cytomegalovirus (CMV) can cause severe disease in children and adults with a variety of inherited or acquired T-cell immunodeficiencies, who are prone to multiple infections. It can also rarely cause disease in otherwise healthy persons. The pathogenesis of idiopathic CMV disease is unknown. Inbred mice that lack the gene encoding nitric oxide synthase 2 () are susceptible to the related murine CMV infection.
Methods
We studied a previously healthy 51-year-old man from Iran who after acute CMV infection had an onset of progressive CMV disease that led to his death 29 months later. We hypothesized that the patient may have had a novel type of inborn error of immunity. Thus, we performed whole-exome sequencing and tested candidate mutant alleles experimentally.
Results
We found a homozygous frameshift mutation inencoding a truncated NOS2 protein that did not produce nitric oxide, which determined that the patient had autosomal recessive NOS2 deficiency. Moreover, allvariants that we found in homozygosity in public databases encoded functional proteins, as did all other variants with an allele frequency greater than 0.001.
Conclusions
These findings suggest that inherited NOS2 deficiency was clinically silent in this patient until lethal infection with CMV. Moreover, NOS2 appeared to be redundant for control of other pathogens in this patient. (Funded by the National Center for Advancing Translational Sciences and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Jan 2020; 382:437-445
Drutman SB, Mansouri D, Mahdaviani SA, Neehus AL, ... Nathan C, Casanova JL
N Engl J Med: 29 Jan 2020; 382:437-445 | PMID: 31995689
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Abstract

Conservative versus Interventional Treatment for Spontaneous Pneumothorax.

Brown SGA, Ball EL, Perrin K, Asha SE, ... Beasley R,
Background
Whether conservative management is an acceptable alternative to interventional management for uncomplicated, moderate-to-large primary spontaneous pneumothorax is unknown.
Methods
In this open-label, multicenter, noninferiority trial, we recruited patients 14 to 50 years of age with a first-known, unilateral, moderate-to-large primary spontaneous pneumothorax. Patients were randomly assigned to immediate interventional management of the pneumothorax (intervention group) or a conservative observational approach (conservative-management group) and were followed for 12 months. The primary outcome was lung reexpansion within 8 weeks.
Results
A total of 316 patients underwent randomization (154 patients to the intervention group and 162 to the conservative-management group). In the conservative-management group, 25 patients (15.4%) underwent interventions to manage the pneumothorax, for reasons prespecified in the protocol, and 137 (84.6%) did not undergo interventions. In a complete-case analysis in which data were not available for 23 patients in the intervention group and 37 in the conservative-management group, reexpansion within 8 weeks occurred in 129 of 131 patients (98.5%) with interventional management and in 118 of 125 (94.4%) with conservative management (risk difference, -4.1 percentage points; 95% confidence interval [CI], -8.6 to 0.5; P = 0.02 for noninferiority); the lower boundary of the 95% confidence interval was within the prespecified noninferiority margin of -9 percentage points. In a sensitivity analysis in which all missing data after 56 days were imputed as treatment failure (with reexpansion in 129 of 138 patients [93.5%] in the intervention group and in 118 of 143 [82.5%] in the conservative-management group), the risk difference of -11.0 percentage points (95% CI, -18.4 to -3.5) was outside the prespecified noninferiority margin. Conservative management resulted in a lower risk of serious adverse events or pneumothorax recurrence than interventional management.
Conclusions
Although the primary outcome was not statistically robust to conservative assumptions about missing data, the trial provides modest evidence that conservative management of primary spontaneous pneumothorax was noninferior to interventional management, with a lower risk of serious adverse events. (Funded by the Emergency Medicine Foundation and others; PSP Australian New Zealand Clinical Trials Registry number, ACTRN12611000184976.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Jan 2020; 382:405-415
Brown SGA, Ball EL, Perrin K, Asha SE, ... Beasley R,
N Engl J Med: 29 Jan 2020; 382:405-415 | PMID: 31995686
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Abstract

Family History of Gastric Cancer and Treatment.

Choi IJ, Kim CG, Lee JY, Kim YI, ... Park B, Joo J
Background
infection and a family history of gastric cancer are the main risk factors for gastric cancer. Whether treatment to eradicatecan reduce the risk of gastric cancer in persons with a family history of gastric cancer in first-degree relatives is unknown.
Methods
In this single-center, double-blind, placebo-controlled trial, we screened 3100 first-degree relatives of patients with gastric cancer. We randomly assigned 1838 participants withinfection to receive either eradication therapy (lansoprazole [30 mg], amoxicillin [1000 mg], and clarithromycin [500 mg], each taken twice daily for 7 days) or placebo. The primary outcome was development of gastric cancer. A prespecified secondary outcome was development of gastric cancer according toeradication status, assessed during the follow-up period.
Results
A total of 1676 participants were included in the modified intention-to-treat population for the analysis of the primary outcome (832 in the treatment group and 844 in the placebo group). During a median follow-up of 9.2 years, gastric cancer developed in 10 participants (1.2%) in the treatment group and in 23 (2.7%) in the placebo group (hazard ratio, 0.45; 95% confidence interval [CI], 0.21 to 0.94; P = 0.03 by log-rank test). Among the 10 participants in the treatment group in whom gastric cancer developed, 5 (50.0%) had persistentinfection. Gastric cancer developed in 0.8% of participants (5 of 608) in whominfection was eradicated and in 2.9% of participants (28 of 979) who had persistent infection (hazard ratio, 0.27; 95% CI, 0.10 to 0.70). Adverse events were mild and were more common in the treatment group than in the placebo group (53.0% vs. 19.1%; P<0.001).
Conclusions
Among persons withinfection who had a family history of gastric cancer in first-degree relatives,eradication treatment reduced the risk of gastric cancer. (Funded by the National Cancer Center, South Korea; ClinicalTrials.gov number, NCT01678027.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 29 Jan 2020; 382:427-436
Choi IJ, Kim CG, Lee JY, Kim YI, ... Park B, Joo J
N Engl J Med: 29 Jan 2020; 382:427-436 | PMID: 31995688
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Abstract

Early Transmission Dynamics in Wuhan, China, of Novel Coronavirus-Infected Pneumonia.

Li Q, Guan X, Wu P, Wang X, ... Leung GM, Feng Z
Background
The initial cases of novel coronavirus (2019-nCoV)-infected pneumonia (NCIP) occurred in Wuhan, Hubei Province, China, in December 2019 and January 2020. We analyzed data on the first 425 confirmed cases in Wuhan to determine the epidemiologic characteristics of NCIP.
Methods
We collected information on demographic characteristics, exposure history, and illness timelines of laboratory-confirmed cases of NCIP that had been reported by January 22, 2020. We described characteristics of the cases and estimated the key epidemiologic time-delay distributions. In the early period of exponential growth, we estimated the epidemic doubling time and the basic reproductive number.
Results
Among the first 425 patients with confirmed NCIP, the median age was 59 years and 56% were male. The majority of cases (55%) with onset before January 1, 2020, were linked to the Huanan Seafood Wholesale Market, as compared with 8.6% of the subsequent cases. The mean incubation period was 5.2 days (95% confidence interval [CI], 4.1 to 7.0), with the 95th percentile of the distribution at 12.5 days. In its early stages, the epidemic doubled in size every 7.4 days. With a mean serial interval of 7.5 days (95% CI, 5.3 to 19), the basic reproductive number was estimated to be 2.2 (95% CI, 1.4 to 3.9).
Conclusions
On the basis of this information, there is evidence that human-to-human transmission has occurred among close contacts since the middle of December 2019. Considerable efforts to reduce transmission will be required to control outbreaks if similar dynamics apply elsewhere. Measures to prevent or reduce transmission should be implemented in populations at risk. (Funded by the Ministry of Science and Technology of China and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 28 Jan 2020; epub ahead of print
Li Q, Guan X, Wu P, Wang X, ... Leung GM, Feng Z
N Engl J Med: 28 Jan 2020; epub ahead of print | PMID: 31995857
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Abstract

COMPARE: prospective, randomized, non-inferiority trial of high- vs. low-dose paclitaxel drug-coated balloons for femoropopliteal interventions.

Steiner S, Schmidt A, Zeller T, Tepe G, ... Weiss N, Scheinert D
Aims
Drug-coated balloons (DCBs) for femoropopliteal interventions have not been tested against each other. We aimed to directly compare efficacy and safety of a high-dose (In.Pact™) vs. low-dose (Ranger™) DCB with nominal paclitaxel densities of 3.5 vs. 2.0 μg/mm2.
Methods and results
Within a prospective, multicentre, non-inferiority, clinical trial 414 patients with symptomatic femoropopliteal lesions (Rutherford classification 2-4) were randomly assigned in a 1:1 ratio to endovascular treatment with either high- or low-dose DCB after stratification for lesion length. Primary efficacy and safety endpoints comprised primary patency and freedom from major adverse events (i.e. device and procedure-related deaths through 1 month, major amputations, and clinically driven target lesion revascularization through 12 months). We set a non-inferiority margin of -10% at 12 months. Total occlusions were observed frequently (>40%) and provisional stenting was performed in every fourth intervention. Non-inferiority was determined for both primary efficacy and safety endpoints at 12 months. Primary patency was 81.5% in the high-dose and 83.0% in low-dose DCB group {difference: 1.5% [lower bound of the 90% two-sided confidence interval (CI) -5.2%]; Pnon-inferiority < 0.01}. Freedom from major adverse events was determined in 92.6% in high-dose and in 91.0% in low-dose DCB group [difference -1.6% (lower bound of the 90% two-sided CI -6.5%); Pnon-inferiority < 0.01]. Overall death rate was low (2.0%) and no major amputation occurred.
Conclusion
Two DCBs with different coating characteristics exhibited comparable results with excellent effectiveness and safety through 12 months for femoropopliteal interventions including a wide range of lesion lengths.
Clinical trial registration
The trial is registered with ClinicalTrials.gov (NCT02701543).

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 27 Jan 2020; epub ahead of print
Steiner S, Schmidt A, Zeller T, Tepe G, ... Weiss N, Scheinert D
Eur Heart J: 27 Jan 2020; epub ahead of print | PMID: 31989155
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Abstract

Reduced Lung-Cancer Mortality with Volume CT Screening in a Randomized Trial.

de Koning HJ, van der Aalst CM, de Jong PA, Scholten ET, ... Oudkerk M,
Background
There are limited data from randomized trials regarding whether volume-based, low-dose computed tomographic (CT) screening can reduce lung-cancer mortality among male former and current smokers.
Methods
A total of 13,195 men (primary analysis) and 2594 women (subgroup analyses) between the ages of 50 and 74 were randomly assigned to undergo CT screening at T0 (baseline), year 1, year 3, and year 5.5 or no screening. We obtained data on cancer diagnosis and the date and cause of death through linkages with national registries in the Netherlands and Belgium, and a review committee confirmed lung cancer as the cause of death when possible. A minimum follow-up of 10 years until December 31, 2015, was completed for all participants.
Results
Among men, the average adherence to CT screening was 90.0%. On average, 9.2% of the screened participants underwent at least one additional CT scan (initially indeterminate). The overall referral rate for suspicious nodules was 2.1%. At 10 years of follow-up, the incidence of lung cancer was 5.58 cases per 1000 person-years in the screening group and 4.91 cases per 1000 person-years in the control group; lung-cancer mortality was 2.50 deaths per 1000 person-years and 3.30 deaths per 1000 person-years, respectively. The cumulative rate ratio for death from lung cancer at 10 years was 0.76 (95% confidence interval [CI], 0.61 to 0.94; P = 0.01) in the screening group as compared with the control group, similar to the values at years 8 and 9. Among women, the rate ratio was 0.67 (95% CI, 0.38 to 1.14) at 10 years of follow-up, with values of 0.41 to 0.52 in years 7 through 9.
Conclusions
In this trial involving high-risk persons, lung-cancer mortality was significantly lower among those who underwent volume CT screening than among those who underwent no screening. There were low rates of follow-up procedures for results suggestive of lung cancer. (Funded by the Netherlands Organization of Health Research and Development and others; NELSON Netherlands Trial Register number, NL580.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 28 Jan 2020; epub ahead of print
de Koning HJ, van der Aalst CM, de Jong PA, Scholten ET, ... Oudkerk M,
N Engl J Med: 28 Jan 2020; epub ahead of print | PMID: 31995683
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Abstract

Inflamm-ageing: the role of inflammation in age-dependent cardiovascular disease.

Liberale L, Montecucco F, Tardif JC, Libby P, Camici GG

The ongoing worldwide increase in life expectancy portends a rising prevalence of age-related cardiovascular (CV) diseases in the coming decades that demands a deeper understanding of their molecular mechanisms. Inflammation has recently emerged as an important contributor for CV disease development. Indeed, a state of chronic sterile low-grade inflammation characterizes older organisms (also known as inflamm-ageing) and participates pivotally in the development of frailty, disability, and most chronic degenerative diseases including age-related CV and cerebrovascular afflictions. Due to chronic activation of inflammasomes and to reduced endogenous anti-inflammatory mechanisms, inflamm-ageing contributes to the activation of leucocytes, endothelial, and vascular smooth muscle cells, thus accelerating vascular ageing and atherosclerosis. Furthermore, inflamm-ageing promotes the development of catastrophic athero-thrombotic complications by enhancing platelet reactivity and predisposing to plaque rupture and erosion. Thus, inflamm-ageing and its contributors or molecular mediators might furnish targets for novel therapeutic strategies that could promote healthy ageing and conserve resources for health care systems worldwide. Here, we discuss recent findings in the pathophysiology of inflamm-ageing, the impact of these processes on the development of age-related CV diseases, results from clinical trials targeting its components and the potential implementation of these advances into daily clinical practice.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 31 Jan 2020; epub ahead of print
Liberale L, Montecucco F, Tardif JC, Libby P, Camici GG
Eur Heart J: 31 Jan 2020; epub ahead of print | PMID: 32006431
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Abstract

First Case of 2019 Novel Coronavirus in the United States.

Holshue ML, DeBolt C, Lindquist S, Lofy KH, ... Pillai SK,

An outbreak of novel coronavirus (2019-nCoV) that began in Wuhan, China, has spread rapidly, with cases now confirmed in multiple countries. We report the first case of 2019-nCoV infection confirmed in the United States and describe the identification, diagnosis, clinical course, and management of the case, including the patient\'s initial mild symptoms at presentation with progression to pneumonia on day 9 of illness. This case highlights the importance of close coordination between clinicians and public health authorities at the local, state, and federal levels, as well as the need for rapid dissemination of clinical information related to the care of patients with this emerging infection.

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 30 Jan 2020; epub ahead of print
Holshue ML, DeBolt C, Lindquist S, Lofy KH, ... Pillai SK,
N Engl J Med: 30 Jan 2020; epub ahead of print | PMID: 32004427
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Abstract

Classification, prevalence, and outcomes of anticancer therapy-induced cardiotoxicity: the CARDIOTOX registry.

López-Sendón J, Álvarez-Ortega C, Zamora Auñon P, Buño Soto A, ... Cadenas Chamorro R, López Fernández T
Aim
Cardiotoxicity (CTox) is a major side effect of cancer therapies, but uniform diagnostic criteria to guide clinical and research practices are lacking.
Methods and results
We prospectively studied 865 patients, aged 54.7 ± 13.9; 16.3% men, scheduled for anticancer therapy related with moderate/high CTox risk. Four groups of progressive myocardial damage/dysfunction were considered according to current guidelines: normal, normal biomarkers (high-sensitivity troponin T and N-terminal natriuretic pro-peptide), and left ventricular (LV) function; mild, abnormal biomarkers, and/or LV dysfunction (LVD) maintaining an LV ejection fraction (LVEF) ≥50%; moderate, LVD with LVEF 40-49%; and severe, LVD with LVEF ≤40% or symptomatic heart failure. Cardiotoxicity was defined as new or worsening of myocardial damage/ventricular function from baseline during follow-up. Patients were followed for a median of 24 months. Cardiotoxicity was identified in 37.5% patients during follow-up [95% confidence interval (CI) 34.22-40.8%], 31.6% with mild, 2.8% moderate, and 3.1% with severe myocardial damage/dysfunction. The mortality rate in the severe CTox group was 22.9 deaths per 100 patients-year vs. 2.3 deaths per 100 patients-year in the rest of groups, hazard ratio of 10.2 (95% CI 5.5-19.2) (P < 0.001).
Conclusions
The majority of patients present objective data of myocardial injury/dysfunction during or after cancer therapy. Nevertheless, severe CTox, with a strong prognostic relationship, was comparatively rare. This should be reflected in protocols for clinical and research practices.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 03 Feb 2020; epub ahead of print
López-Sendón J, Álvarez-Ortega C, Zamora Auñon P, Buño Soto A, ... Cadenas Chamorro R, López Fernández T
Eur Heart J: 03 Feb 2020; epub ahead of print | PMID: 32016393
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Abstract

Understanding the use of observational and randomized data in cardiovascular medicine.

Bowman L, Baras A, Bombien R, Califf RM, ... Wallentin L, Casadei B

The availability of large datasets from multiple sources [e.g. registries, biobanks, electronic health records (EHRs), claims or billing databases, implantable devices, wearable sensors, and mobile apps], coupled with advances in computing and analytic technologies, have provided new opportunities for conducting innovative health research. Equally, improved digital access to health information has facilitated the conduct of efficient randomized controlled trials (RCTs) upon which clinical management decisions can be based, for instance, by permitting the identification of eligible patients for recruitment and/or linkage for follow-up via their EHRs. Given these advances in cardiovascular data science and the complexities they behold, it is important that health professionals have clarity on the appropriate use and interpretation of observational, so-called \'real-world\', and randomized data in cardiovascular medicine. The Cardiovascular Roundtable of the European Society of Cardiology (ESC) held a workshop to explore the future of RCTs and the current and emerging opportunities for gathering and exploiting complex observational datasets in cardiovascular research. The aim of this article is to provide a perspective on the appropriate use of randomized and observational data and to outline the ESC plans for supporting the collection and availability of clinical data to monitor and improve the quality of care of patients with cardiovascular disease in Europe and provide an infrastructure for undertaking pragmatic RCTs. Moreover, the ESC continues to campaign for greater engagement amongst regulators, industry, patients, and health professionals in the development and application of a more efficient regulatory framework that is able to take maximal advantage of new opportunities for improving the design and efficiency of observational studies and RCT in patients with cardiovascular disease.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 03 Feb 2020; epub ahead of print
Bowman L, Baras A, Bombien R, Califf RM, ... Wallentin L, Casadei B
Eur Heart J: 03 Feb 2020; epub ahead of print | PMID: 32016367
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Abstract

Lower versus Traditional Treatment Threshold for Neonatal Hypoglycemia.

van Kempen AAMW, Eskes PF, Nuytemans DHGM, van der Lee JH, ... Boluyt N,
Background
Worldwide, many newborns who are preterm, small or large for gestational age, or born to mothers with diabetes are screened for hypoglycemia, with a goal of preventing brain injury. However, there is no consensus on a treatment threshold that is safe but also avoids overtreatment.
Methods
In a multicenter, randomized, noninferiority trial involving 689 otherwise healthy newborns born at 35 weeks of gestation or later and identified as being at risk for hypoglycemia, we compared two threshold values for treatment of asymptomatic moderate hypoglycemia. We sought to determine whether a management strategy that used a lower threshold (treatment administered at a glucose concentration of <36 mg per deciliter [2.0 mmol per liter]) would be noninferior to a traditional threshold (treatment at a glucose concentration of <47 mg per deciliter [2.6 mmol per liter]) with respect to psychomotor development at 18 months, assessed with the Bayley Scales of Infant and Toddler Development, third edition, Dutch version (Bayley-III-NL; scores range from 50 to 150 [mean {±SD}, 100±15]), with higher scores indicating more advanced development and 7.5 points (one half the SD) representing a clinically important difference). The lower threshold would be considered noninferior if scores were less than 7.5 points lower than scores in the traditional-threshold group.
Results
Bayley-III-NL scores were assessed in 287 of the 348 children (82.5%) in the lower-threshold group and in 295 of the 341 children (86.5%) in the traditional-threshold group. Cognitive and motor outcome scores were similar in the two groups (mean scores [±SE], 102.9±0.7 [cognitive] and 104.6±0.7 [motor] in the lower-threshold group and 102.2±0.7 [cognitive] and 104.9±0.7 [motor] in the traditional-threshold group). The prespecified inferiority limit was not crossed. The mean glucose concentration was 57±0.4 mg per deciliter (3.2±0.02 mmol per liter) in the lower-threshold group and 61±0.5 mg per deciliter (3.4±0.03 mmol per liter) in the traditional-threshold group. Fewer and less severe hypoglycemic episodes occurred in the traditional-threshold group, but that group had more invasive diagnostic and treatment interventions. Serious adverse events in the lower-threshold group included convulsions (during normoglycemia) in one newborn and one death.
Conclusions
In otherwise healthy newborns with asymptomatic moderate hypoglycemia, a lower glucose treatment threshold (36 mg per deciliter) was noninferior to a traditional threshold (47 mg per deciliter) with regard to psychomotor development at 18 months. (Funded by the Netherlands Organization for Health Research and Development; HypoEXIT Current Controlled Trials number, ISRCTN79705768.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 05 Feb 2020; 382:534-544
van Kempen AAMW, Eskes PF, Nuytemans DHGM, van der Lee JH, ... Boluyt N,
N Engl J Med: 05 Feb 2020; 382:534-544 | PMID: 32023373
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Impact:
Abstract

Six-Year Follow-up of a Trial of Antenatal Vitamin D for Asthma Reduction.

Litonjua AA, Carey VJ, Laranjo N, Stubbs BJ, ... Hollis BW, Weiss ST
Background
We previously reported the results of a trial of prenatal vitamin D supplementation to prevent asthma and recurrent wheeze in young children, which suggested that supplementation provided a protective effect at the age of 3 years. We followed the children through the age of 6 years to determine the course of asthma and recurrent wheeze.
Methods
In this follow-up study, investigators and participants remained unaware of the treatment assignments through the children\'s sixth birthday. We aimed to determine whether, when maternal levels of 25-hydroxyvitamin D were taken into account, children born to mothers who had received 4400 IU of vitamin D per day during pregnancy (vitamin D group) would have a lower incidence of asthma and recurrent wheeze at the age of 6 years than would those born to mothers who had received 400 IU of vitamin D per day (control group). Time-to-event methods were used to compare the treatment groups with respect to time to the onset of asthma or recurrent wheeze. Multivariate methods were used to compare longitudinal measures of lung function between the treatment groups.
Results
There was no effect of maternal vitamin D supplementation on asthma and recurrent wheeze in either an intention-to-treat analysis or an analysis with stratification according to the maternal 25-hydroxyvitamin D level during pregnancy. There was no effect of prenatal vitamin D supplementation on most of the prespecified secondary outcomes. We found no effects of prenatal supplementation on spirometric indexes. Although there was a very small effect on airway resistance as measured by impulse oscillometry, this finding was of uncertain significance.
Conclusions
Vitamin D supplementation during the prenatal period alone did not influence the 6-year incidence of asthma and recurrent wheeze among children who were at risk for asthma. (Funded by the National Heart, Lung, and Blood Institute; VDAART ClinicalTrials.gov number, NCT00920621.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 05 Feb 2020; 382:525-533
Litonjua AA, Carey VJ, Laranjo N, Stubbs BJ, ... Hollis BW, Weiss ST
N Engl J Med: 05 Feb 2020; 382:525-533 | PMID: 32023372
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Abstract

Use of CAR-Transduced Natural Killer Cells in CD19-Positive Lymphoid Tumors.

Liu E, Marin D, Banerjee P, Macapinlac HA, ... Shpall EJ, Rezvani K
Background
Anti-CD19 chimeric antigen receptor (CAR) T-cell therapy has shown remarkable clinical efficacy in B-cell cancers. However, CAR T cells can induce substantial toxic effects, and the manufacture of the cells is complex. Natural killer (NK) cells that have been modified to express an anti-CD19 CAR have the potential to overcome these limitations.
Methods
In this phase 1 and 2 trial, we administered HLA-mismatched anti-CD19 CAR-NK cells derived from cord blood to 11 patients with relapsed or refractory CD19-positive cancers (non-Hodgkin\'s lymphoma or chronic lymphocytic leukemia [CLL]). NK cells were transduced with a retroviral vector expressing genes that encode anti-CD19 CAR, interleukin-15, and inducible caspase 9 as a safety switch. The cells were expanded ex vivo and administered in a single infusion at one of three doses (1×10, 1×10, or 1×10 CAR-NK cells per kilogram of body weight) after lymphodepleting chemotherapy.
Results
The administration of CAR-NK cells was not associated with the development of cytokine release syndrome, neurotoxicity, or graft-versus-host disease, and there was no increase in the levels of inflammatory cytokines, including interleukin-6, over baseline. The maximum tolerated dose was not reached. Of the 11 patients who were treated, 8 (73%) had a response; of these patients, 7 (4 with lymphoma and 3 with CLL) had a complete remission, and 1 had remission of the Richter\'s transformation component but had persistent CLL. Responses were rapid and seen within 30 days after infusion at all dose levels. The infused CAR-NK cells expanded and persisted at low levels for at least 12 months.
Conclusions
Among 11 patients with relapsed or refractory CD19-positive cancers, a majority had a response to treatment with CAR-NK cells without the development of major toxic effects. (Funded by the M.D. Anderson Cancer Center CLL and Lymphoma Moonshot and the National Institutes of Health; ClinicalTrials.gov number, NCT03056339.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 05 Feb 2020; 382:545-553
Liu E, Marin D, Banerjee P, Macapinlac HA, ... Shpall EJ, Rezvani K
N Engl J Med: 05 Feb 2020; 382:545-553 | PMID: 32023374
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Abstract

Gastrointestinal bleeding and the risk of colorectal cancer in anticoagulated patients with atrial fibrillation.

Rasmussen PV, Dalgaard F, Gislason GH, Brandes A, ... Pallisgaard JL, Hansen ML
Aims
Gastrointestinal bleeding (GI-bleeding) is frequent in patients with atrial fibrillation (AF) treated with oral anticoagulation (OAC) therapy. We sought to investigate to what extent lower GI-bleeding represents the unmasking of an occult colorectal cancer.
Methods and results
A total of 125 418 Danish AF patients initiating OAC therapy were identified using Danish administrative registers. Non-parametric estimation and semi-parametric absolute risk regression were used to estimate the absolute risks of colorectal cancer in patients with and without lower GI-bleeding. During a maximum of 3 years of follow-up, we identified 2576 patients with lower GI-bleeding of whom 140 patients were subsequently diagnosed with colorectal cancer within the first year of lower GI-bleeding. In all age groups, we observed high risks of colorectal cancer after lower GI-bleeding. The absolute 1-year risk ranged from 3.7% [95% confidence interval (CI) 2.2-6.2] to 8.1% (95% CI 6.1-10.6) in the age groups ≤65 and 76-80 years of age, respectively. When comparing patients with and without lower GI-bleeding, we found increased risk ratios of colorectal cancer across all age groups with a risk ratio of 24.2 (95% CI 14.5-40.4) and 12.3 (95% CI 7.9-19.0) for the youngest and oldest age group of ≤65 and >85 years, respectively.
Conclusion
In anticoagulated AF patients, lower GI-bleeding conferred high absolute risks of incident colorectal cancer. Lower GI-bleeding should not be dismissed as a benign consequence of OAC therapy but always examined for a potential underlying malignant cause.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 06 Feb 2020; epub ahead of print
Rasmussen PV, Dalgaard F, Gislason GH, Brandes A, ... Pallisgaard JL, Hansen ML
Eur Heart J: 06 Feb 2020; epub ahead of print | PMID: 32030399
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Abstract

Impact of myocardial fibrosis on left ventricular remodelling, recovery, and outcome after transcatheter aortic valve implantation in different haemodynamic subtypes of severe aortic stenosis.

Puls M, Beuthner BE, Topci R, Vogelgesang A, ... Jacobshagen C, Hasenfuß G
Aims
Myocardial fibrosis (MF) might represent a key player in pathophysiology of heart failure in aortic stenosis (AS). We aimed to assess its impact on left ventricular (LV) remodelling, recovery, and mortality after transcatheter aortic valve implantation (TAVI) in different AS subtypes.
Methods and results
One hundred patients with severe AS were prospectively characterized clinically and echocardiographically at baseline (BL), 6 months, 1 year, and 2 years following TAVI. Left ventricular biopsies were harvested after valve deployment. Myocardial fibrosis was assessed after Masson\'s trichrome staining, and fibrotic area was calculated as percentage of total tissue area. Patients were stratified according to MF above (MF+) or below (MF-) median percentage MF (≥11% or <11%). Myocardial fibrosis burden differed significantly between AS subtypes, with highest levels in low ejection fraction (EF), low-gradient AS and lowest levels in normal EF, high-gradient AS (29.5 ± 26.4% vs. 13.5 ± 16.1%, P = 0.003). In the entire cohort, MF+ was significantly associated with poorer LV function, higher extent of pathological LV remodelling, and more pronounced clinical heart failure at BL. After TAVI, MF+ was associated with a delay in normalization of LV geometry and function but not per se with absence of reverse remodelling and clinical improvement. However, 22 patients died during follow-up (mean, 11 months), and 14 deaths were classified as cardiovascular (CV) (n = 9 arrhythmia-associated). Importantly, 13 of 14 CV deaths occurred in MF+ patients (CV mortality 26.5% in MF+ vs. 2% in MF- patients, P = 0.0003). Multivariate analysis identified MF+ as independent predictor of CV mortality [hazard ratio (HR) 27.4 (2.0-369), P = 0.01].
Conclusion
Histological MF is associated with AS-related pathological LV remodelling and independently predicts CV mortality after TAVI.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 11 Feb 2020; epub ahead of print
Puls M, Beuthner BE, Topci R, Vogelgesang A, ... Jacobshagen C, Hasenfuß G
Eur Heart J: 11 Feb 2020; epub ahead of print | PMID: 32049275
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Abstract

Comparison of newer generation self-expandable vs. balloon-expandable valves in transcatheter aortic valve implantation: the randomized SOLVE-TAVI trial.

Thiele H, Kurz T, Feistritzer HJ, Stachel G, ... de Waha-Thiele S, Desch S
Aims
Transcatheter aortic valve implantation (TAVI) has emerged as established treatment option in patients with symptomatic aortic stenosis. Technical developments in valve design have addressed previous limitations such as suboptimal deployment, conduction disturbances, and paravalvular leakage. However, there are only limited data available for the comparison of newer generation self-expandable valve (SEV) and balloon-expandable valve (BEV).
Methods and results
SOLVE-TAVI is a multicentre, open-label, 2 × 2 factorial, randomized trial of 447 patients with aortic stenosis undergoing transfemoral TAVI comparing SEV (Evolut R, Medtronic Inc., Minneapolis, MN, USA) with BEV (Sapien 3, Edwards Lifesciences, Irvine, CA, USA). The primary efficacy composite endpoint of all-cause mortality, stroke, moderate/severe prosthetic valve regurgitation, and permanent pacemaker implantation at 30 days was powered for equivalence (equivalence margin 10% with significance level 0.05). The primary composite endpoint occurred in 28.4% of SEV patients and 26.1% of BEV patients meeting the prespecified criteria of equivalence [rate difference -2.39 (90% confidence interval, CI -9.45 to 4.66); Pequivalence = 0.04]. Event rates for the individual components were as follows: all-cause mortality 3.2% vs. 2.3% [rate difference -0.93 (90% CI -4.78 to 2.92); Pequivalence < 0.001], stroke 0.5% vs. 4.7% [rate difference 4.20 (90% CI 0.12 to 8.27); Pequivalence = 0.003], moderate/severe paravalvular leak 3.4% vs. 1.5% [rate difference -1.89 (90% CI -5.86 to 2.08); Pequivalence = 0.0001], and permanent pacemaker implantation 23.0% vs. 19.2% [rate difference -3.85 (90% CI -10.41 to 2.72) in SEV vs. BEV patients; Pequivalence = 0.06].
Conclusion
In patients with aortic stenosis undergoing transfemoral TAVI, newer generation SEV and BEV are equivalent for the primary valve-related efficacy endpoint. These findings support the safe application of these newer generation percutaneous valves in the majority of patients with some specific preferences based on individual valve anatomy.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 11 Feb 2020; epub ahead of print
Thiele H, Kurz T, Feistritzer HJ, Stachel G, ... de Waha-Thiele S, Desch S
Eur Heart J: 11 Feb 2020; epub ahead of print | PMID: 32049283
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Abstract

Physical activity, cardiorespiratory fitness, and cardiovascular outcomes in individuals with atrial fibrillation: the HUNT study.

Garnvik LE, Malmo V, Janszky I, Ellekjær H, ... Loennechen JP, Nes BM
Aims
Atrial fibrillation (AF) confers higher risk of mortality and morbidity, but the long-term impact of physical activity (PA) and cardiorespiratory fitness (CRF) on outcomes in AF patients is unknown. We, therefore, examined the prospective associations of PA and estimated CRF (eCRF) with all-cause mortality, cardiovascular disease (CVD) mortality, morbidity and stroke in individuals with AF.
Methods and results
We followed 1117 AF patients from the HUNT3 study in 2006-08 until first occurrence of the outcomes or end of follow-up in November 2015. We used Cox proportional hazard regression to examine the prospective associations of self-reported PA and eCRF with the outcomes. Atrial fibrillation patients meeting PA guidelines had lower risk of all-cause [hazard ratio (HR) 0.55, 95% confidence interval (CI) 0.41-0.75] and CVD mortality (HR 0.54, 95% CI 0.34-0.86) compared with inactive patients. The respective HRs for CVD morbidity and stroke were 0.78 (95% CI 0.58-1.04) and 0.70 (95% CI 0.42-1.15). Each 1-metabolic equivalent task (MET) higher eCRF was associated with a lower risk of all-cause (HR 0.88, 95% CI 0.81-0.95), CVD mortality (HR 0.85, 95% CI 0.76-0.95), and morbidity (HR 0.88, 95% CI 0.82-0.95).
Conclusion
Higher PA and CRF are associated with lower long-term risk of CVD and all-cause mortality in individuals with AF. The findings support a role for regular PA and improved CRF in AF patients, in order to combat the elevated risk for mortality and morbidity.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 10 Feb 2020; epub ahead of print
Garnvik LE, Malmo V, Janszky I, Ellekjær H, ... Loennechen JP, Nes BM
Eur Heart J: 10 Feb 2020; epub ahead of print | PMID: 32047884
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Abstract

Polymer-based or Polymer-free Stents in Patients at High Bleeding Risk.

Windecker S, Latib A, Kedhi E, Kirtane AJ, ... Stone GW,
Background
Polymer-free drug-coated stents provide superior clinical outcomes to bare-metal stents in patients at high bleeding risk who undergo percutaneous coronary intervention (PCI) and are treated with 1 month of dual antiplatelet therapy. Data on the use of polymer-based drug-eluting stents, as compared with polymer-free drug-coated stents, in such patients are limited.
Methods
In an international, randomized, single-blind trial, we compared polymer-based zotarolimus-eluting stents with polymer-free umirolimus-coated stents in patients at high bleeding risk. After PCI, patients were treated with 1 month of dual antiplatelet therapy, followed by single antiplatelet therapy. The primary outcome was a safety composite of death from cardiac causes, myocardial infarction, or stent thrombosis at 1 year. The principal secondary outcome was target-lesion failure, an effectiveness composite of death from cardiac causes, target-vessel myocardial infarction, or clinically indicated target-lesion revascularization. Both outcomes were powered for noninferiority.
Results
A total of 1996 patients at high bleeding risk were randomly assigned in a 1:1 ratio to receive zotarolimus-eluting stents (1003 patients) or polymer-free drug-coated stents (993 patients). At 1 year, the primary outcome was observed in 169 of 988 patients (17.1%) in the zotarolimus-eluting stent group and in 164 of 969 (16.9%) in the polymer-free drug-coated stent group (risk difference, 0.2 percentage points; upper boundary of the one-sided 97.5% confidence interval [CI], 3.5; noninferiority margin, 4.1; P = 0.01 for noninferiority). The principal secondary outcome was observed in 174 patients (17.6%) in the zotarolimus-eluting stent group and in 169 (17.4%) in the polymer-free drug-coated stent group (risk difference, 0.2 percentage points; upper boundary of the one-sided 97.5% CI, 3.5; noninferiority margin, 4.4; P = 0.007 for noninferiority).
Conclusions
Among patients at high bleeding risk who received 1 month of dual antiplatelet therapy after PCI, use of polymer-based zotarolimus-eluting stents was noninferior to use of polymer-free drug-coated stents with regard to safety and effectiveness composite outcomes. (Funded by Medtronic; ONYX ONE ClinicalTrials.gov number, NCT03344653.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 11 Feb 2020; epub ahead of print
Windecker S, Latib A, Kedhi E, Kirtane AJ, ... Stone GW,
N Engl J Med: 11 Feb 2020; epub ahead of print | PMID: 32050061
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Abstract

Aetiology and outcomes of severe right ventricular dysfunction.

Padang R, Chandrashekar N, Indrabhinduwat M, Scott CG, ... Pellikka PA, Kane GC
Aims
Right ventricular dysfunction (RVD) is an important determinant of functional status and survival in various diseases states. Data are sparse on the epidemiology and outcome of patients with severe RVD. This study examined the characteristics, aetiology, and survival of patients with severe RVD.
Methods and results
Retrospective study of consecutive patients with severe RVD diagnosed by transthoracic echocardiography (TTE) between 2011 and 2015 in a single tertiary referral institution. Patients with prior cardiac surgery, mechanical assist devices, and congenital heart disease were excluded. Primary endpoint was all-cause mortality. In 64 728 patients undergoing TTE, the prevalence of ≥mild RVD was 21%. This study focused on the cohort of 1299 (4%) patients with severe RVD; age 64 ± 16 years; 61% male. The most common causes of severe RVD were left-sided heart diseases (46%), pulmonary thromboembolic disease (18%), chronic lung disease/hypoxia (CLD; 17%), and pulmonary arterial hypertension (PAH; 11%). After 2 ± 2 years of follow-up, 701 deaths occurred, 66% within the first year of diagnosis. The overall probability of survival at 1- and 5 years for the entire cohort were 61% [95% confidence interval (CI) 58-64%] and 35% (95% CI 31-38%), respectively. In left-sided heart diseases, 1- and 5-year survival rates were 61% (95% CI 57-65%) and 33% (95% CI 28-37%), respectively; vs. 76% (95% CI 68-82%) and 50% (95% CI 40-59%) in PAH, vs. 71% (95% CI 64-76%) and 49% (95% CI 41-58%) in thromboembolic diseases, vs. 42% (95% CI 35-49%) and 8% (95% CI 4-15%) in CLD (log-rank P < 0.0001). Presence of ≥moderate tricuspid regurgitation portended worse survival in severe RVD.
Conclusion
One-year mortality of patients with severe RVD was high (∼40%) and dependent on the aetiology of RVD. Left-sided heart diseases is the most common cause of severe RVD but prognosis was worst in CLD.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 10 Feb 2020; epub ahead of print
Padang R, Chandrashekar N, Indrabhinduwat M, Scott CG, ... Pellikka PA, Kane GC
Eur Heart J: 10 Feb 2020; epub ahead of print | PMID: 32047900
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Abstract

Outbreak of Listeriosis in South Africa Associated with Processed Meat.

Thomas J, Govender N, McCarthy KM, Erasmus LK, ... Smith AM, Blumberg LH
Background
An outbreak of listeriosis was identified in South Africa in 2017. The source was unknown.
Methods
We conducted epidemiologic, trace-back, and environmental investigations and used whole-genome sequencing to typeisolates. A case was defined as laboratory-confirmedinfection during the period from June 11, 2017, to April 7, 2018.
Results
A total of 937 cases were identified, of which 465 (50%) were associated with pregnancy; 406 of the pregnancy-associated cases (87%) occurred in neonates. Of the 937 cases, 229 (24%) occurred in patients 15 to 49 years of age (excluding those who were pregnant). Among the patients in whom human immunodeficiency virus (HIV) status was known, 38% of those with pregnancy-associated cases (77 of 204) and 46% of the remaining patients (97 of 211) were infected with HIV. Among 728 patients with a known outcome, 193 (27%) died. Clinical isolates from 609 patients were sequenced, and 567 (93%) were identified as sequence type 6 (ST6). In a case-control analysis, patients with ST6 infections were more likely to have eaten polony (a ready-to-eat processed meat) than those with non-ST6 infections (odds ratio, 8.55; 95% confidence interval, 1.66 to 43.35). Polony and environmental samples also yielded ST6 isolates, which, together with the isolates from the patients, belonged to the same core-genome multilocus sequence typing cluster with no more than 4 allelic differences; these findings showed that polony produced at a single facility was the outbreak source. A recall of ready-to-eat processed meat products from this facility was associated with a rapid decline in the incidence ofST6 infections.
Conclusions
This investigation showed that in a middle-income country with a high prevalence of HIV infection,caused disproportionate illness among pregnant girls and women and HIV-infected persons. Whole-genome sequencing facilitated the detection of the outbreak and guided the trace-back investigations that led to the identification of the source.

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 12 Feb 2020; 382:632-643
Thomas J, Govender N, McCarthy KM, Erasmus LK, ... Smith AM, Blumberg LH
N Engl J Med: 12 Feb 2020; 382:632-643 | PMID: 32053299
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Impact:
Abstract

Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis.

Walsh M, Merkel PA, Peh CA, Szpirt WM, ... Jayne DRW,
Background
More effective and safer treatments are needed for antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis.
Methods
We conducted a randomized trial with a 2-by-2 factorial design to evaluate the use of plasma exchange and two regimens of oral glucocorticoids in patients with severe ANCA-associated vasculitis (defined by an estimated glomerular filtration rate of <50 ml per minute per 1.73 m of body-surface area or diffuse pulmonary hemorrhage). Patients were randomly assigned to undergo plasma exchange (seven plasma exchanges within 14 days after randomization) or no plasma exchange (control group). Patients were also randomly assigned to follow either a standard-dose regimen or a reduced-dose regimen of oral glucocorticoids. Patients were followed for up to 7 years for the primary composite outcome of death from any cause or end-stage kidney disease (ESKD).
Results
Death from any cause or ESKD occurred in 100 of 352 patients (28.4%) in the plasma-exchange group and in 109 of 352 patients (31.0%) in the control group (hazard ratio, 0.86; 95% confidence interval [CI], 0.65 to 1.13; P = 0.27). The results were similar in subgroup analyses and in analyses of secondary outcomes. We also assessed the noninferiority of a reduced-dose regimen of glucocorticoids to a standard-dose regimen, using a noninferiority margin of 11 percentage points. Death from any cause or ESKD occurred in 92 of 330 patients (27.9%) in the reduced-dose group and in 83 of 325 patients (25.5%) in the standard-dose group (absolute risk difference, 2.3 percentage points; 90% CI, -3.4 to 8.0), which met the criterion for noninferiority. Serious infections at 1 year were less common in the reduced-dose group than in the standard-dose group (incidence rate ratio, 0.69; 95% CI, 0.52 to 0.93), but other secondary outcomes were similar in the two groups.
Conclusions
Among patients with severe ANCA-associated vasculitis, the use of plasma exchange did not reduce the incidence of death or ESKD. A reduced-dose regimen of glucocorticoids was noninferior to a standard-dose regimen with respect to death or ESKD. (Funded by the U.K. National Institute for Health Research and others; PEXIVAS Current Controlled Trials number, ISRCTN07757494; ClinicalTrials.gov number, NCT00987389.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 12 Feb 2020; 382:622-631
Walsh M, Merkel PA, Peh CA, Szpirt WM, ... Jayne DRW,
N Engl J Med: 12 Feb 2020; 382:622-631 | PMID: 32053298
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Impact:
Abstract

Effect of Dapagliflozin on Atrial Fibrillation in Patients with Type 2 Diabetes Mellitus: Insights from the DECLARE-TIMI 58 Trial.

Zelniker TA, Bonaca MP, Furtado R, Mosenzon O, ... Sabatine MS, Wiviott SD

Atrial fibrillation (AF) and atrial flutter (AFL) are associated with both diabetes and its related comorbidities including hypertension, obesity, and heart failure (HF). SGLT2i have been shown to lower blood pressure, reduce weight, have salutary effects on left ventricular remodeling and reduce hospitalization for HF and cardiovascular death in patients with type 2 diabetes (T2DM). We therefore investigated whether SGLT2i may also reduce the risk of AF/AFL.DECLARE-TIMI 58 studied the efficacy and safety of the SGLT2i dapagliflozin versus placebo in 17160 patients with T2DM and either multiple risk factors for (MRF, n=10186) or known atherosclerotic cardiovascular disease (ASCVD, n=6974). Here, we explore the effect of dapagliflozin on the first and total number of AF/AFL events in patients with (n=1,116) and without prevalent AF/AFL using Cox and negative binomial models, respectively. AF/AFL events were identified by search of the safety database using the MedDRA Preferred Terms (\"atrial fibrillation\", \"atrial flutter\").Dapagliflozin reduced the risk of AF/AFL events by 19% (264 versus 325 events, 7.8 versus 9.6 events per 1000 patient-years, hazard ratio 0.81, 95% CI 0.68 to 0.95, P=0.009). The reduction in AF/AFL events was consistent regardless of presence or absence of a history of AF/AFL at baseline (Prior AF/AFL: HR 0.79, 95% CI 0.58-1.09, No AF/AFL: HR 0.81, 95% CI 0.67-0.98; P-INT 0.89). Similarly, presence of ASCVD (HR 0.83, 95% CI 0.66-1.04) versus MRF (HR 0.78, 95% CI 0.62-0.99; P-INT 0.72), or a history of HF (HF: HR 0.78, 95% CI 0.55-1.11, No HF: HR 0.81, 95% CI 0.68-0.97; P-INT 0.88) did not modify the reduction in AF/AFL events observed with dapagliflozin. Moreover, there was no effect modification by sex, history of ischemic stroke, HbA1c, body mass index, blood pressure, or eGFR (all P-INT>0.20). Dapagliflozin also reduced the total number (first and recurrent) of AF/AFL events (337 versus 432; incidence rate ratio 0.77, 95% CI 0.64-0.92, P=0.005).Dapagliflozin decreased the incidence of reported episodes of AF/AFL adverse events in high-risk patients with T2DM. This effect was consistent regardless of the patients\' prior history of AF, ASCVD, or HF.URL: https://clinicaltrials.gov Unique Identifier: NCT01730534.



Circulation: 26 Jan 2020; epub ahead of print
Zelniker TA, Bonaca MP, Furtado R, Mosenzon O, ... Sabatine MS, Wiviott SD
Circulation: 26 Jan 2020; epub ahead of print | PMID: 31983236
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Impact:
Abstract

Regulatory RNAs in Heart Failure.

Gomes CPDC, Schroen B, Kuster GM, Robinson EL, ... Devaux Y,

Cardiovascular disease is an enormous socioeconomic burden worldwide and remains a leading cause of mortality and disability despite significant efforts to improve treatments and personalize healthcare. Heart failure is the main manifestation of cardiovascular disease and has reached epidemic proportions. Heart failure follows a loss of cardiac homeostasis, which relies on a tight regulation of gene expression. This regulation is under the control of multiple types of RNA molecules, some encoding proteins (the so-called messenger RNAs) and others lacking protein-coding potential, named noncoding RNAs. In this review article, we aim to revisit the notion of regulatory RNA, which has been thus far mainly confined to noncoding RNA. Regulatory RNA, which we propose to abbreviate as regRNA, can include both protein-coding RNAs and noncoding RNAs, as long as they contribute, directly or indirectly, to the regulation of gene expression. We will address the regulation and functional role of messenger RNAs, microRNAs, long noncoding RNAs, and circular RNAs (ie, regRNAs) in heart failure. We will debate the utility of regRNAs to diagnose, prognosticate, and treat heart failure, and we will provide directions for future work.



Circulation: 27 Jan 2020; 141:313-328
Gomes CPDC, Schroen B, Kuster GM, Robinson EL, ... Devaux Y,
Circulation: 27 Jan 2020; 141:313-328 | PMID: 31986093
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Impact:
Abstract

Myosin Sequestration Regulates Sarcomere Function, Cardiomyocyte Energetics, and Metabolism, Informing the Pathogenesis of Hypertrophic Cardiomyopathy.

Toepfer CN, Garfinkel AC, Venturini G, Wakimoto H, ... Seidman JG, Seidman CE

Hypertrophic cardiomyopathy (HCM) is caused by pathogenic variants in sarcomere protein genes that evoke hypercontractility, poor relaxation, and increased energy consumption by the heart and increased patient risks for arrhythmias and heart failure. Recent studies show that pathogenic missense variants in myosin, the molecular motor of the sarcomere, are clustered in residues that participate in dynamic conformational states of sarcomere proteins. We hypothesized that these conformations are essential to adapt contractile output for energy conservation and that pathophysiology of HCM results from destabilization of these conformations.We assayed myosin ATP binding to define the proportions of myosin in SRX or DRX conformations in healthy rodent and human hearts, at baseline and in response to reduced hemodynamic demands of hibernation or pathogenic HCM variants. To determine the relationships between myosin conformations, sarcomere function, and cell biology we assessed contractility, relaxation, and cardiomyocyte morphology and metabolism, with and without an allosteric modulator of myosin ATPase activity. We then tested whether the positions of myosin variants with unknown clinical significance (VUS) that were identified in HCM patients, predicted functional consequences and associations with heart failure and arrhythmias.Myosins undergo physiologic shifts between SRX conformations that maximized energy-conservation and active states (DRX) that enable cross-bridge formation with greater ATP consumption. Systemic hemodynamic requirements, pharmacologic modulators of myosin, and pathogenic myosin missense mutations influenced the proportions of these conformations. Hibernation increased SRX conformations while pathogenic variants destabilized these and increased the proportion of DRX myosins, which enhanced cardiomyocyte contractility but impaired relaxation, and evoked hypertrophic remodeling with increased energetic stress. Using structural locations to stratify VUS, we showed that variants that unbalanced myosin conformations were associated with higher rates of heart failure and arrhythmias in HCM patients.Myosin conformations establish work-energy equipoise that is essential for life-long cellular homeostasis and heart function. Destabilization of myosin energy conserving states promotes contractile abnormalities, morphological and metabolic remodeling and adverse clinical outcomes in HCM patients. Therapeutic restabilization corrects cellular contractile and metabolic phenotypes and may limit these adverse clinical outcomes in HCM patients.



Circulation: 26 Jan 2020; epub ahead of print
Toepfer CN, Garfinkel AC, Venturini G, Wakimoto H, ... Seidman JG, Seidman CE
Circulation: 26 Jan 2020; epub ahead of print | PMID: 31983222
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Abstract

Heart Disease and Stroke Statistics-2020 Update: A Report From the American Heart Association.

Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, ... Tsao CW,
Background
The American Heart Association, in conjunction with the National Institutes of Health, annually reports on the most up-to-date statistics related to heart disease, stroke, and cardiovascular risk factors, including core health behaviors (smoking, physical activity, diet, and weight) and health factors (cholesterol, blood pressure, and glucose control) that contribute to cardiovascular health. The Statistical Update presents the latest data on a range of major clinical heart and circulatory disease conditions (including stroke, congenital heart disease, rhythm disorders, subclinical atherosclerosis, coronary heart disease, heart failure, valvular disease, venous disease, and peripheral artery disease) and the associated outcomes (including quality of care, procedures, and economic costs).
Methods
The American Heart Association, through its Statistics Committee, continuously monitors and evaluates sources of data on heart disease and stroke in the United States to provide the most current information available in the annual Statistical Update. The 2020 Statistical Update is the product of a full year\'s worth of effort by dedicated volunteer clinicians and scientists, committed government professionals, and American Heart Association staff members. This year\'s edition includes data on the monitoring and benefits of cardiovascular health in the population, metrics to assess and monitor healthy diets, an enhanced focus on social determinants of health, a focus on the global burden of cardiovascular disease, and further evidence-based approaches to changing behaviors, implementation strategies, and implications of the American Heart Association\'s 2020 Impact Goals.
Results
Each of the 26 chapters in the Statistical Update focuses on a different topic related to heart disease and stroke statistics.
Conclusions
The Statistical Update represents a critical resource for the lay public, policy makers, media professionals, clinicians, healthcare administrators, researchers, health advocates, and others seeking the best available data on these factors and conditions.



Circulation: 28 Jan 2020:CIR0000000000000757; epub ahead of print
Virani SS, Alonso A, Benjamin EJ, Bittencourt MS, ... Tsao CW,
Circulation: 28 Jan 2020:CIR0000000000000757; epub ahead of print | PMID: 31992061
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Impact:
Abstract

Impact of Regulatory Guidance on Evaluating Cardiovascular Risk of New Glucose-Lowering Therapies to Treat Type 2 Diabetes Mellitus: Lessons Learned and Future Directions.

Sharma A, Pagidipati NJ, Califf RM, McGuire DK, ... McMurray JJV, Granger CB

Responding to concerns about the potential for increased risk of adverse cardiovascular (CV) outcomes, specifically myocardial infarction, associated with certain glucose-lowering therapies, the U.S. 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 primarily granted regulatory approval 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 CV outcomes. The 2008 guidance aimed to ensure CV safety of new glucose-lowering therapies to treat patients with type 2 diabetes mellitus. This resulted in a plethora of new CV outcome trials, most designed primarily as placebo-controlled noninferiority trials, but with many also powered for superiority. Several of these outcome trials demonstrated CV benefits of the newer agents, resulting in the first-ever CV 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 CV outcome trials. The group made several recommendations for future regulatory guidance and for CV outcome trials regarding 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, 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.



Circulation: 28 Jan 2020; epub ahead of print
Sharma A, Pagidipati NJ, Califf RM, McGuire DK, ... McMurray JJV, Granger CB
Circulation: 28 Jan 2020; epub ahead of print | PMID: 31992065
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Abstract

Altering Sphingolipid Metabolism Attenuates Cell Death and Inflammatory Response after Myocardial Infarction.

Hadas Y, Vincek AS, Youssef E, Żak MM, ... Eliyahu E, Zangi L

Sphingolipids have recently emerged as a biomarker of recurrence and mortality after myocardial infarction (MI). The increased ceramide levels in mammalian heart tissues during acute MI, as demonstrated by several groups, is associated with higher cell death rates in the left ventricle (LV) and deteriorated cardiac function. Ceramidase, the only enzyme known to hydrolyze pro-apoptotic ceramide, generates sphingosine, which is then phosphorylated by sphingosine kinase (Sphk) to produce the pro-survival molecule sphingosine-1-phosphate (S1P). We hypothesized that Acid Ceramidase (AC) overexpression would counteract the negative effects of elevated ceramide and promote cell survival, thereby providing cardioprotection after MI.We performed transcriptomic, sphingolipid and protein analyses to evaluate sphingolipid metabolism and signaling post MI. We investigated the effect of altering ceramide metabolism through a loss (chemical inhibitors) or gain (modified mRNA (modRNA)) of AC function post hypoxia or MI.We found that several genes involved inceramide synthesis were upregulated and that ceramide (C16, C20, C20:1 and C24) levels had significantly increased 24 hours after MI. AC inhibition post hypoxia or MI resulted in reduced AC activity and increased cell death; by contrast, enhancing AC activity via AC modRNA treatment increased cell survival post hypoxia or MI. AC modRNA-treated mice had significantly better heart function, longer survival and smaller scar size than control mice 28 days post MI. We attributed the improvement in heart function post MI following AC modRNA delivery to decreased ceramide levels, lower cell death rates and changes in the composition of the immune cell population in the LV manifested by lowered abundance of pro-inflammatory detrimental neutrophils.Our findings suggest that transiently altering sphingolipid metabolism through AC overexpression is sufficient and necessary to induce cardioprotection post MI, thereby highlighting the therapeutic potential of AC modRNA in ischemic heart disease.



Circulation: 28 Jan 2020; epub ahead of print
Hadas Y, Vincek AS, Youssef E, Żak MM, ... Eliyahu E, Zangi L
Circulation: 28 Jan 2020; epub ahead of print | PMID: 31992066
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Abstract

Recommendations for Cardiovascular Health and Disease Surveillance for 2030 and Beyond: A Policy Statement From the American Heart Association.

Roger VL, Sidney S, Fairchild AL, Howard VJ, ... Rosamond WD,

The release of the American Heart Association\'s 2030 Impact Goal and associated metrics for success underscores the importance of cardiovascular health and cardiovascular disease surveillance systems for the acquisition of information sufficient to support implementation and evaluation. The aim of this policy statement is to review and comment on existing recommendations for and current approaches to cardiovascular surveillance, identify gaps, and formulate policy implications and pragmatic recommendations for transforming surveillance of cardiovascular disease and cardiovascular health in the United States. The development of community platforms coupled with widespread use of digital technologies, electronic health records, and mobile health has created new opportunities that could greatly modernize surveillance if coordinated in a pragmatic matter. However, technology and public health and scientific mandates must be merged into action. We describe the action and components necessary to create the cardiovascular health and cardiovascular disease surveillance system of the future, steps in development, and challenges that federal, state, and local governments will need to address. Development of robust policies and commitment to collaboration among professional organizations, community partners, and policy makers are critical to ultimately reduce the burden of cardiovascular disease and improve cardiovascular health and to evaluate whether national health goals are achieved.



Circulation: 28 Jan 2020:CIR0000000000000756; epub ahead of print
Roger VL, Sidney S, Fairchild AL, Howard VJ, ... Rosamond WD,
Circulation: 28 Jan 2020:CIR0000000000000756; epub ahead of print | PMID: 31992050
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Abstract

Reevaluating the Genetic Contribution of Monogenic Dilated Cardiomyopathy.

Mazzarotto F, Tayal U, Buchan RJ, Midwinter W, ... Ware JS, Walsh R

Dilated cardiomyopathy (DCM) is genetically heterogeneous, with >100 purported disease genes tested in clinical laboratories. However, many genes were originally identified based on candidate-gene studies that did not adequately account for background population variation. Here we define the frequency of rare variation in 2538 patients with DCM across protein-coding regions of 56 commonly tested genes and compare this to both 912 confirmed healthy controls and a reference population of 60706 individuals to identify clinically interpretable genes robustly associated with dominant monogenic DCM.We used the TruSight Cardio sequencing panel to evaluate the burden of rare variants in 56 putative DCM genes in 1040 patients with DCM and 912 healthy volunteers processed with identical sequencing and bioinformatics pipelines. We further aggregated data from 1498 patients with DCM sequenced in diagnostic laboratories and the Exome Aggregation Consortium database for replication and meta-analysis.Truncating variants inandwere associated with DCM in all comparisons. Variants inandwere significantly enriched in specific patient subsets, with the last 2 genes potentially contributing primarily to earlyonset forms of DCM. Overall, rare variants in these 12 genes potentially explained 17% of cases in the outpatient clinic cohort representing a broad range of adult patients with DCM and 26% of cases in the diagnostic referral cohort enriched in familial and early-onset DCM. Although the absence of a significant excess in other genes cannot preclude a limited role in disease, such genes have limited diagnostic value because novel variants will be uninterpretable and their diagnostic yield is minimal.In the largest sequenced DCM cohort yet described, we observe robust disease association with 12 genes, highlighting their importance in DCM and translating into high interpretability in diagnostic testing. The other genes analyzed here will need to be rigorously evaluated in ongoing curation efforts to determine their validity as Mendelian DCM genes but have limited value in diagnostic testing in DCM at present. This data will contribute to community gene curation efforts and will reduce erroneous and inconclusive findings in diagnostic testing.



Circulation: 26 Jan 2020; epub ahead of print
Mazzarotto F, Tayal U, Buchan RJ, Midwinter W, ... Ware JS, Walsh R
Circulation: 26 Jan 2020; epub ahead of print | PMID: 31983221
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Abstract

Preventive or Deferred Ablation of Ventricular Tachycardia in Patients with Ischemic Cardiomyopathy and Implantable Defibrillator (BERLIN VT): A Multicenter Randomized Trial.

Willems S, Tilz RR, Steven D, Kääb S, ... Kuck KH,

Catheter ablation for ventricular tachycardia (VT) reduces the recurrence of VT in patients with implanted cardioverter-defibrillators (ICDs). The appropriate timing of VT ablation and its effects on mortality and heart failure progression remain a matter of debate. In patients with life-threatening arrhythmias necessitating ICD implantation, we compared outcomes of preventive VT ablation (undertaken before ICD implantation in order to prevent ICD shocks for VT) and deferred ablation after three ICD shocks for VT.The Preventive Ablation of Ventricular Tachycardia in Patients with Myocardial Infarction (BERLIN VT) study was a prospective, open, parallel, randomized trial performed at 26 centers. Patients with stable ischemic cardiomyopathy, a left ventricular ejection fraction between 30% and 50%, and documented VT were randomly assigned 1:1 to a preventive or deferred ablation strategy. The primary outcome was a composite of all-cause death and unplanned hospitalization for either symptomatic ventricular arrhythmia or worsening heart failure. Secondary outcomes included sustained ventricular tachyarrhythmia and appropriate ICD therapy. We hypothesized that preventive ablation strategy would be superior to deferred ablation strategy in the intention-to-treat population.During a mean follow-up of 396{plus minus}284 days, the primary endpoint occurred in 25 (32.9%) of 76 patients in the preventive ablation group and 23 (27.7%) of 83 patients in the deferred ablation group (hazard ratio, 1.09; 95% CI, 0.62-1.92; P=0.77). Using prespecified criteria for interim analyses, the study was terminated early for futility. In the preventive versus deferred ablation group, six versus two patients died (7.9% vs. 2.4%; P=0.18), eight versus two patients were admitted for worsening heart failure (10.4% vs. 2.3%; P=0.062), and 15 versus 21 patients were hospitalized for symptomatic ventricular arrhythmia (19.5% vs. 25.3%; P=0.27). Among secondary outcomes, the proportions of patients with sustained ventricular tachyarrhythmia (39.7% vs. 48.2%; P=0.050) and appropriate ICD therapy (34.2% vs. 47.0%; P=0.030) were numerically reduced in the preventive ablation group.Preventive VT ablation before ICD implantation did not reduce mortality or hospitalization for arrhythmia or worsening heart failure during 1 year of follow-up when compared to the deferred ablation strategy.URL: https://www.clinicaltrials.gov. Unique identifier: NCT02501005.



Circulation: 30 Jan 2020; epub ahead of print
Willems S, Tilz RR, Steven D, Kääb S, ... Kuck KH,
Circulation: 30 Jan 2020; epub ahead of print | PMID: 32000514
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Abstract

Long-Term Safety and Efficacy of Durable Polymer Cobalt-Chromium Everolimus-Eluting Stents in Patients at High Bleeding Risk: A Patient-Level Stratified Analysis from Four Post-Approval Studies.

Sorrentino S, Claessen BE, Chandiramani R, Guedeney P, ... Valgimigli M, Mehran R

Long-term outcomes in patients at high bleeding risk (HBR) undergoing percutaneous coronary intervention (PCI) with a drug-eluting stent are unclear. Therefore, we aimed to evaluate long-term adverse events in HBR patients undergoing PCI with cobalt-chromium (CoCr) everolimus-eluting stent implantation.We analyzed stratified data from four all-comers post-approval registries. Patients with at least one of the following criteria were categorized as HBR: age ≥75 years, history of major bleeding (MB), history of stroke, chronic oral anticoagulant use, chronic kidney disease (CKD), anemia, or thrombocytopenia. Additionally, in a separate analysis, patients were categorized according to the recently published Academic Research Consortium (ARC) HBR criteria. The Kaplan-Meier method was used for time-to-event analyses. Coronary thrombotic events (CTE) included myocardial infarction or definite/probable stent thrombosis. MB was defined according to the TIMI or GUSTO scales. Impact of CTE and MB on subsequent risk of mortality was assessed using multivariable Cox regression with MB and CTE included as time-updated covariates.Of the total 10,502 patients included, 3,507 (33%) were identified as HBR. Compared to non-HBR patients, those at HBR had more comorbidities, higher lesion complexity and a higher risk of 4-year mortality (HR 4.38, 95% CI 3.76-5.11). Results were qualitatively similar when using ARC criteria to define HBR. Risk of mortality was increased after CTE (HR 5.02, 95% CI 3.93-6.41), as well as after MB (HR 4.92, 95% CI 3.82-6.35). Of note, this effect was consistent across the spectrum of bleeding risk (p-interaction test 0.97 and 0.06, respectively).Compared to the non-HBR population, HBR patients experienced worse 4-year outcomes after PCI with CoCr everolimus-eluting stent. Both CTE and MB had a significant impact on subsequent risk of mortality irrespective of bleeding risk.



Circulation: 28 Jan 2020; epub ahead of print
Sorrentino S, Claessen BE, Chandiramani R, Guedeney P, ... Valgimigli M, Mehran R
Circulation: 28 Jan 2020; epub ahead of print | PMID: 31992063
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Abstract

The American Heart Association 2030 Impact Goal: A Presidential Advisory From the American Heart Association.

Angell SY, McConnell MV, Anderson CAM, Bibbins-Domingo K, ... Saha S, Warner JJ

Each decade, the American Heart Association (AHA) develops an Impact Goal to guide its overall strategic direction and investments in its research, quality improvement, advocacy, and public health programs. Guided by the AHA\'s new Mission Statement, to be a relentless force for a world of longer, healthier lives, the 2030 Impact Goal is anchored in an understanding that to achieve cardiovascular health for all, the AHA must include a broader vision of health and well-being and emphasize health equity. In the next decade, by 2030, the AHA will strive to equitably increase healthy life expectancy beyond current projections, with global and local collaborators, from 66 years of age to at least 68 years of age across the United States and from 64 years of age to at least 67 years of age worldwide. The AHA commits to developing additional targets for equity and well-being to accompany this overarching Impact Goal. To attain the 2030 Impact Goal, we recommend a thoughtful evaluation of interventions available to the public, patients, providers, healthcare delivery systems, communities, policy makers, and legislators. This presidential advisory summarizes the task force\'s main considerations in determining the 2030 Impact Goal and the metrics to monitor progress. It describes the aspiration that these goals will be achieved by working with a diverse community of volunteers, patients, scientists, healthcare professionals, and partner organizations needed to ensure success.



Circulation: 28 Jan 2020:CIR0000000000000758; epub ahead of print
Angell SY, McConnell MV, Anderson CAM, Bibbins-Domingo K, ... Saha S, Warner JJ
Circulation: 28 Jan 2020:CIR0000000000000758; epub ahead of print | PMID: 31992057
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Abstract

Electrical versus pharmacological cardioversion for emergency department patients with acute atrial fibrillation (RAFF2): a partial factorial randomised trial.

Stiell IG, Sivilotti MLA, Taljaard M, Birnie D, ... Wells GA, Perry JJ
Background
Acute atrial fibrillation is the most common arrythmia treated in the emergency department. Our primary aim was to compare conversion to sinus rhythm between pharmacological cardioversion followed by electrical cardioversion (drug-shock), and electrical cardioversion alone (shock-only). Our secondary aim was to compare the effectiveness of two pad positions for electrical cardioversion.
Methods
We did a partial factorial trial of two protocols for patients with acute atrial fibrillation at 11 academic hospital emergency departments in Canada. We enrolled adult patients with acute atrial fibrillation. Protocol 1 was a randomised, blinded, placebo-controlled comparison of attempted pharmacological cardioversion with intravenous procainamide (15 mg/kg over 30 min) followed by electrical cardioversion if necessary (up to three shocks, each of ≥200 J), and placebo infusion followed by electrical cardioversion. For patients having electrical cardioversion, we used Protocol 2, a randomised, open-label, nested comparison of anteroposterior versus anterolateral pad positions. Patients were randomly assigned (1:1, stratified by study site) for Protocol 1 by on-site research personnel using an online electronic data capture system. Randomisation for Protocol 2 occurred 30 min after drug infusion for patients who had not converted and was stratified by site and Protocol 1 allocation. Patients and all research and emergency department staff were masked to treatment allocation for Protocol 1. The primary outcome was conversion to normal sinus rhythm for at least 30 min at any time after randomisation and up to a point immediately after three shocks. Protocol 1 was analysed by intention to treat and Protocol 2 excluded patients who did not receive electrical cardioversion. This study is registered at ClinicalTrials.gov, number NCT01891058.
Findings
Between July 18, 2013, and Oct 17, 2018, we enrolled 396 patients, and none were lost to follow-up. In the drug-shock group (n=204), conversion to sinus rhythm occurred in 196 (96%) patients and in the shock-only group (n=192), conversion occurred in 176 (92%) patients (absolute difference 4%; 95% CI 0-9; p=0·07). The proportion of patients discharged home was 97% (n=198) versus 95% (n=183; p=0·60). 106 (52%) patients in the drug-shock group converted after drug infusion only. No patients had serious adverse events in follow-up. The different pad positions in Protocol 2 (n=244), had similar conversions to sinus rhythm (119 [94%] of 127 in anterolateral group vs 108 [92%] of 117 in anteroposterior group; p=0·68).
Interpretation
Both the drug-shock and shock-only strategies were highly effective, rapid, and safe in restoring sinus rhythm for patients in the emergency department with acute atrial fibrillation, avoiding the need for return to hospital. The drug infusion worked for about half of patients and avoided the resource intensive procedural sedation required for electrical cardioversion. We also found no significant difference between the anterolateral and anteroposterior pad positions for electrical cardioversion. Immediate rhythm control for patients in the emergency department with acute atrial fibrillation leads to excellent outcomes.
Funding
Heart and Stroke Foundation of Canada and the Canadian Institutes of Health Research.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 31 Jan 2020; 395:339-349
Stiell IG, Sivilotti MLA, Taljaard M, Birnie D, ... Wells GA, Perry JJ
Lancet: 31 Jan 2020; 395:339-349 | PMID: 32007169
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Abstract

Spin current from sub-terahertz-generated antiferromagnetic magnons.

Li J, Wilson CB, Cheng R, Lohmann M, ... Sherwin MS, Shi J

Spin dynamics in antiferromagnets has much shorter timescales than in ferromagnets, offering attractive properties for potential applications in ultrafast devices. However, spin-current generation via antiferromagnetic resonance and simultaneous electrical detection by the inverse spin Hall effect in heavy metals have not yet been explicitly demonstrated. Here we report sub-terahertz spin pumping in heterostructures of a uniaxial antiferromagnetic CrO crystal and a heavy metal (Pt or Ta in its β phase). At 0.240 terahertz, the antiferromagnetic resonance in CrO occurs at about 2.7 tesla, which excites only right-handed magnons. In the spin-canting state, another resonance occurs at 10.5 tesla from the precession of induced magnetic moments. Both resonances generate pure spin currents in the heterostructures, which are detected by the heavy metal as peaks or dips in the open-circuit voltage. The pure-spin-current nature of the electrically detected signals is unambiguously confirmed by the reversal of the voltage polarity observed under two conditions: when switching the detector metal from Pt to Ta, reversing the sign of the spin Hall angle, and when flipping the magnetic-field direction, reversing the magnon chirality. The temperature dependence of the electrical signals at both resonances suggests that the spin current contains both coherent and incoherent magnon contributions, which is further confirmed by measurements of the spin Seebeck effect and is well described by a phenomenological theory. These findings reveal the unique characteristics of magnon excitations in antiferromagnets and their distinctive roles in spin-charge conversion in the high-frequency regime.



Nature: 26 Jan 2020; epub ahead of print
Li J, Wilson CB, Cheng R, Lohmann M, ... Sherwin MS, Shi J
Nature: 26 Jan 2020; epub ahead of print | PMID: 31988510
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Abstract

2020 Focused Update of the 2017 ACC Expert Consensus Decision Pathway on the Management of Mitral Regurgitation.

Bonow RO, O\'Gara PT, Adams DH, Badhwar V, ... Whisenant B, Woo YJ

Mitral regurgitation (MR) is a complex valve lesion that can pose significant management challenges. This Expert Consensus Decision Pathway emphasizes that recognition of MR should prompt an assessment of its etiology, mechanism, and severity, as well as consideration of the indications for treatment. The document is a focused update of the 2017 ACC Expert Consensus Decision Pathway on the Management of Mitral Regurgitation, with some sections updated and others added in light of the publication of new trial data related to secondary MR, among other developments. A structured approach to evaluation based on clinical findings, accurate echocardiographic imaging, and, when necessary, adjunctive testing, can help clarify decision making. Treatment goals include timely intervention by an experienced multidisciplinary heart team to prevent left ventricular dysfunction, heart failure, reduced quality of life, and premature death.

Copyright © 2020 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.

J Am Coll Cardiol: 09 Feb 2020; epub ahead of print
Bonow RO, O'Gara PT, Adams DH, Badhwar V, ... Whisenant B, Woo YJ
J Am Coll Cardiol: 09 Feb 2020; epub ahead of print | PMID: 32068084
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Abstract

Nonsedation or Light Sedation in Critically Ill, Mechanically Ventilated Patients.

Olsen HT, Nedergaard HK, Strøm T, Oxlund J, ... Lauridsen JT, Toft P
Background
In critically ill, mechanically ventilated patients, daily interruption of sedation has been shown to reduce the time on ventilation and the length of stay in the intensive care unit (ICU). Data on whether a plan of no sedation, as compared with a plan of light sedation, has an effect on mortality are lacking.
Methods
In a multicenter, randomized, controlled trial, we assigned, in a 1:1 ratio, mechanically ventilated ICU patients to a plan of no sedation (nonsedation group) or to a plan of light sedation (i.e., to a level at which the patient was arousable, defined as a score of -2 to -3 on the Richmond Agitation and Sedation Scale [RASS], on which scores range from -5 [unresponsive] to +4 [combative]) (sedation group) with daily interruption. The primary outcome was mortality at 90 days. Secondary outcomes were the number of major thromboembolic events, the number of days free from coma or delirium, acute kidney injury according to severity, the number of ICU-free days, and the number of ventilator-free days. Between-group differences were calculated as the value in the nonsedation group minus the value in the sedation group.
Results
A total of 710 patients underwent randomization, and 700 were included in the modified intention-to-treat analysis. The characteristics of the patients at baseline were similar in the two trial groups, except for the score on the Acute Physiology and Chronic Health Evaluation (APACHE) II, which was 1 point higher in the nonsedation group than in the sedation group, indicating a greater chance of in-hospital death. The mean RASS score in the nonsedation group increased from -1.3 on day 1 to -0.8 on day 7 and, in the sedation group, from -2.3 on day 1 to -1.8 on day 7. Mortality at 90 days was 42.4% in the nonsedation group and 37.0% in the sedated group (difference, 5.4 percentage points; 95% confidence interval [CI], -2.2 to 12.2; P = 0.65). The number of ICU-free days and of ventilator-free days did not differ significantly between the trial groups. The patients in the nonsedation group had a median of 27 days free from coma or delirium, and those in the sedation group had a median of 26 days free from coma or delirium. A major thromboembolic event occurred in 1 patient (0.3%) in the nonsedation group and in 10 patients (2.8%) in the sedation group (difference, -2.5 percentage points; 95% CI, -4.8 to -0.7 [unadjusted for multiple comparisons]).
Conclusions
Among mechanically ventilated ICU patients, mortality at 90 days did not differ significantly between those assigned to a plan of no sedation and those assigned to a plan of light sedation with daily interruption. (Funded by the Danish Medical Research Council and others; NONSEDA ClinicalTrials.gov number, NCT01967680.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 15 Feb 2020; epub ahead of print
Olsen HT, Nedergaard HK, Strøm T, Oxlund J, ... Lauridsen JT, Toft P
N Engl J Med: 15 Feb 2020; epub ahead of print | PMID: 32068366
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Impact:
Abstract

Local Peroxynitrite Impairs Endothelial TRPV4 Channels and Elevates Blood Pressure in Obesity.

Ottolini M, Hong K, Cope EL, Daneva Z, ... Isakson BE, Sonkusare SK

Impaired endothelium-dependent vasodilation is a hallmark of obesity-induced hypertension. The recognition that Ca signaling in endothelial cells promotes vasodilation has led to the hypothesis that endothelial Ca signaling is compromised during obesity, but the underlying abnormality is unknown. In this regard, TRPV4 ion channels are a major Ca influx pathway in endothelial cells, and regulatory protein AKAP150 enhances the activity of TRPV4 channels.We used endothelium-specific knockout mice and high fat diet-fed mice to assess the role of endothelial AKAP150-TRPV4 signaling in blood pressure regulation under normal and obese conditions. We further determined the role of peroxynitrite, an oxidant molecule generated from the reaction between nitric oxide (NO) and superoxide radicals, in impairing endothelial AKAP150-TRPV4 signaling in obesity, and assessed the effectiveness of peroxynitrite inhibition in rescuing endothelial AKAP150-TRPV4 signaling in obesity. The clinical relevance of our findings was evaluated in arteries from non-obese and obese individuals.We show that Ca influx through TRPV4 channels at myoendothelial projections (MEPs) to smooth muscle cells decreases resting blood pressure in non-obese mice, a response that is diminished in obese mice. Counterintuitively, release of the vasodilator molecule NO attenuated endothelial TRPV4 channel activity and vasodilation in obese animals. Increased activities of iNOS and NOX1 enzymes at MEPs in obese mice generated higher levels of NO and superoxide radicals, resulting in increased local peroxynitrite formation and subsequent oxidation of the regulatory protein AKAP150 at cysteine 36, to impair AKAP150-TRPV4 channel signaling at MEPs. Strategies that lowered peroxynitrite levels prevented cysteine 36 oxidation of AKAP150, and rescued endothelial AKAP150-TRPV4 signaling, vasodilation, and blood pressure in obesity. Importantly, peroxynitrite-dependent impairment of endothelial TRPV4 channel activity and vasodilation was also observed in the arteries from obese patients.These data suggest that a spatially restricted impairment of endothelial TRPV4 channels contributes to obesity-induced hypertension, and imply that inhibiting peroxynitrite might represent a strategy for normalizing endothelial TRPV4 channel activity, vasodilation, and blood pressure in obesity.



Circulation: 02 Feb 2020; epub ahead of print
Ottolini M, Hong K, Cope EL, Daneva Z, ... Isakson BE, Sonkusare SK
Circulation: 02 Feb 2020; epub ahead of print | PMID: 32008372
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Impact:
Abstract

Processive extrusion of polypeptide loops by a Hsp100 disaggregase.

Avellaneda MJ, Franke KB, Sunderlikova V, Bukau B, Mogk A, Tans SJ

The ability to reverse protein aggregation is vital to cells. Hsp100 disaggregases such as ClpB and Hsp104 are proposed to catalyse this reaction by translocating polypeptide loops through their central pore. This model of disaggregation is appealing, as it could explain how polypeptides entangled within aggregates can be extracted and subsequently refolded with the assistance of Hsp70. However, the model is also controversial, as the necessary motor activity has not been identified and recent findings indicate non-processive mechanisms such as entropic pulling or Brownian ratcheting. How loop formation would be accomplished is also obscure. Indeed, cryo-electron microscopy studies consistently show single polypeptide strands in the Hsp100 pore. Here, by following individual ClpB-substrate complexes in real time, we unambiguously demonstrate processive translocation of looped polypeptides. We integrate optical tweezers with fluorescent-particle tracking to show that ClpB translocates both arms of the loop simultaneously and switches to single-arm translocation when encountering obstacles. ClpB is notably powerful and rapid; it exerts forces of more than 50 pN at speeds of more than 500 residues per second in bursts of up to 28 residues. Remarkably, substrates refold while exiting the pore, analogous to co-translational folding. Our findings have implications for protein-processing phenomena including ubiquitin-mediated remodelling by Cdc48 (or its mammalian orthologue p97) and degradation by the 26S proteasome.



Nature: 28 Jan 2020; epub ahead of print
Avellaneda MJ, Franke KB, Sunderlikova V, Bukau B, Mogk A, Tans SJ
Nature: 28 Jan 2020; epub ahead of print | PMID: 31996849
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Abstract

Zucchini consensus motifs determine the mechanism of pre-piRNA production.

Izumi N, Shoji K, Suzuki Y, Katsuma S, Tomari Y

PIWI-interacting RNAs (piRNAs) of between approximately 24 and 31 nucleotides in length guide PIWI proteins to silence transposons in animal gonads, thereby ensuring fertility. In the biogenesis of piRNAs, PIWI proteins are first loaded with 5\'-monophosphorylated RNA fragments called pre-pre-piRNAs, which then undergo endonucleolytic cleavage to produce pre-piRNAs. Subsequently, the 3\'-ends of pre-piRNAs are trimmed by the exonuclease Trimmer (PNLDC1 in mouse) and 2\'-O-methylated by the methyltransferase Hen1 (HENMT1 in mouse), generating mature piRNAs. It is assumed that the endonuclease Zucchini (MitoPLD in mouse) is a major enzyme catalysing the cleavage of pre-pre-piRNAs into pre-piRNAs. However, direct evidence for this model is lacking, and how pre-piRNAs are generated remains unclear. Here, to analyse pre-piRNA production, we established a Trimmer-knockout silkworm cell line and derived a cell-free system that faithfully recapitulates Zucchini-mediated cleavage of PIWI-loaded pre-pre-piRNAs. We found that pre-piRNAs are generated by parallel Zucchini-dependent and -independent mechanisms. Cleavage by Zucchini occurs at previously unrecognized consensus motifs on pre-pre-piRNAs, requires the RNA helicase Armitage, and is accompanied by 2\'-O-methylation of pre-piRNAs. By contrast, slicing of pre-pre-piRNAs with weak Zucchini motifs is achieved by downstream complementary piRNAs, producing pre-piRNAs without 2\'-O-methylation. Regardless of the endonucleolytic mechanism, pre-piRNAs are matured by Trimmer and Hen1. Our findings highlight multiplexed processing of piRNA precursors that supports robust and flexible piRNA biogenesis.



Nature: 28 Jan 2020; epub ahead of print
Izumi N, Shoji K, Suzuki Y, Katsuma S, Tomari Y
Nature: 28 Jan 2020; epub ahead of print | PMID: 31996847
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Abstract

Gram-scale bottom-up flash graphene synthesis.

Luong DX, Bets KV, Algozeeb WA, Stanford MG, ... Yakobson BI, Tour JM

Most bulk-scale graphene is produced by a top-down approach, exfoliating graphite, which often requires large amounts of solvent with high-energy mixing, shearing, sonication or electrochemical treatment. Although chemical oxidation of graphite to graphene oxide promotes exfoliation, it requires harsh oxidants and leaves the graphene with a defective perforated structure after the subsequent reduction step. Bottom-up synthesis of high-quality graphene is often restricted to ultrasmall amounts if performed by chemical vapour deposition or advanced synthetic organic methods, or it provides a defect-ridden structure if carried out in bulk solution. Here we show that flash Joule heating of inexpensive carbon sources-such as coal, petroleum coke, biochar, carbon black, discarded food, rubber tyres and mixed plastic waste-can afford gram-scale quantities of graphene in less than one second. The product, named flash graphene (FG) after the process used to produce it, shows turbostratic arrangement (that is, little order) between the stacked graphene layers. FG synthesis uses no furnace and no solvents or reactive gases. Yields depend on the carbon content of the source; when using a high-carbon source, such as carbon black, anthracitic coal or calcined coke, yields can range from 80 to 90 per cent with carbon purity greater than 99 per cent. No purification steps are necessary. Raman spectroscopy analysis shows a low-intensity or absent D band for FG, indicating that FG has among the lowest defect concentrations reported so far for graphene, and confirms the turbostratic stacking of FG, which is clearly distinguished from turbostratic graphite. The disordered orientation of FG layers facilitates its rapid exfoliation upon mixing during composite formation. The electric energy cost for FG synthesis is only about 7.2 kilojoules per gram, which could render FG suitable for use in bulk composites of plastic, metals, plywood, concrete and other building materials.



Nature: 26 Jan 2020; epub ahead of print
Luong DX, Bets KV, Algozeeb WA, Stanford MG, ... Yakobson BI, Tour JM
Nature: 26 Jan 2020; epub ahead of print | PMID: 31988511
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Abstract

Cell stress in cortical organoids impairs molecular subtype specification.

Bhaduri A, Andrews MG, Mancia Leon W, Jung D, ... Nowakowski TJ, Kriegstein AR

Cortical organoids are self-organizing three-dimensional cultures that model features of the developing human cerebral cortex. However, the fidelity of organoid models remains unclear. Here we analyse the transcriptomes of individual primary human cortical cells from different developmental periods and cortical areas. We find that cortical development is characterized by progenitor maturation trajectories, the emergence of diverse cell subtypes and areal specification of newborn neurons. By contrast, organoids contain broad cell classes, but do not recapitulate distinct cellular subtype identities and appropriate progenitor maturation. Although the molecular signatures of cortical areas emerge in organoid neurons, they are not spatially segregated. Organoids also ectopically activate cellular stress pathways, which impairs cell-type specification. However, organoid stress and subtype defects are alleviated by transplantation into the mouse cortex. Together, these datasets and analytical tools provide a framework for evaluating and improving the accuracy of cortical organoids as models of human brain development.



Nature: 28 Jan 2020; epub ahead of print
Bhaduri A, Andrews MG, Mancia Leon W, Jung D, ... Nowakowski TJ, Kriegstein AR
Nature: 28 Jan 2020; epub ahead of print | PMID: 31996853
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Abstract

Coherent laser spectroscopy of highly charged ions using quantum logic.

Micke P, Leopold T, King SA, Benkler E, ... Crespo López-Urrutia JR, Schmidt PO

Precision spectroscopy of atomic systems is an invaluable tool for the study of fundamental interactions and symmetries. Recently, highly charged ions have been proposed to enable sensitive tests of physics beyond the standard model and the realization of high-accuracy atomic clocks, owing to their high sensitivity to fundamental physics and insensitivity to external perturbations, which result from the high binding energies of their outer electrons. However, the implementation of these ideas has been hindered by the low spectroscopic accuracies (of the order of parts per million) achieved so far. Here we cool trapped, highly charged argon ions to the lowest temperature reported so far, and study them using coherent laser spectroscopy, achieving an increase in precision of eight orders of magnitude. We use quantum logic spectroscopy to probe the forbidden optical transition in Ar at a wavelength of 441 nanometres and measure its excited-state lifetime and g-factor. Our work unlocks the potential of highly charged ions as ubiquitous atomic systems for use in quantum information processing, as frequency standards and in highly sensitive tests of fundamental physics, such as searches for dark-matter candidates or violations of fundamental symmetries.



Nature: 28 Jan 2020; epub ahead of print
Micke P, Leopold T, King SA, Benkler E, ... Crespo López-Urrutia JR, Schmidt PO
Nature: 28 Jan 2020; epub ahead of print | PMID: 31996851
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Abstract

Intersection of biology and therapeutics: type 2 targeted therapeutics for adult asthma.

Peters MC, Wenzel SE

Asthma is a disease of reversible airflow obstruction characterised clinically by wheezing, shortness of breath, and coughing. Increases in airway type 2 cytokine activity, including interleukin-4 (IL-4), IL-5, and IL-13, are now established biological mechanisms in asthma. Inhaled corticosteroids have been the foundation for asthma treatment, in a large part because they decrease airway type 2 inflammation. However, inhaled or systemic corticosteroids are ineffective treatments in many patients with asthma and few treatment options exist for patients with steroid resistant asthma. Although mechanisms for corticosteroid refractory asthma are likely to be numerous, the development of a new class of biologic agents that target airway type 2 inflammation has provided a new model for treating some patients with corticosteroid refractory asthma. The objective of this Therapeutic paper is to summarise the new type 2 therapeutics, with an emphasis on the biological rationale and clinical efficacy of this new class of asthma therapeutics.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 31 Jan 2020; 395:371-383
Peters MC, Wenzel SE
Lancet: 31 Jan 2020; 395:371-383 | PMID: 32007172
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Abstract

Advancing Healthcare Reform: The American Heart Association\'s 2020 Statement of Principles for Adequate, Accessible, and Affordable Health Care: A Presidential Advisory From the American Heart Association.

Warner JJ, Benjamin IJ, Churchwell K, Firestone G, ... Harrington RA,

The mission of the American Heart Association is to be a relentless force for a world of longer, healthier lives. The American Heart Association has consistently prioritized the needs and perspective of the patient in taking positions on healthcare reform while recognizing the importance of biomedical research, providers, and healthcare delivery systems in advancing the care of patients and the prevention of disease. The American Heart Association\'s vision for healthcare reform describes the foundational changes needed for the health system to serve the best interests of patients and to achieve health care and coverage that are adequate, accessible, and affordable for everyone living in the United States. The American Heart Association is committed to advancing the dialogue around healthcare reform and has prepared this updated statement of our principles, placed in the context of the advances in coverage and care that have occurred after the passage of the Affordable Care Act, the rapidly changing landscape of healthcare delivery systems, and our evolving recognition that efforts to prevent cardiovascular disease can have synergistic benefit in preventing other diseases and improving overall well-being. These updated principles focus on expanding access to affordable health care and coverage; enhancing the availability of evidence-based preventive services; eliminating disparities that limit the availability and equitable delivery of health care; strengthening the public health infrastructure to respond to social determinants of health; prioritizing and accelerating investments in biomedical research; and growing a diverse, culturally competent health and healthcare workforce prepared to meet the challenges of delivering high-value health care.



Circulation: 02 Feb 2020:CIR0000000000000759; epub ahead of print
Warner JJ, Benjamin IJ, Churchwell K, Firestone G, ... Harrington RA,
Circulation: 02 Feb 2020:CIR0000000000000759; epub ahead of print | PMID: 32008369
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Abstract

The pheromone darcin drives a circuit for innate and reinforced behaviours.

Demir E, Li K, Bobrowski-Khoury N, Sanders JI, ... Kepecs A, Axel R

Organisms have evolved diverse behavioural strategies that enhance the likelihood of encountering and assessing mates. Many species use pheromones to communicate information about the location, sexual and social status of potential partners. In mice, the major urinary protein darcin-which is present in the urine of males-provides a component of a scent mark that elicits approach by females and drives learning. Here we show that darcin elicits a complex and variable behavioural repertoire that consists of attraction, ultrasonic vocalization and urinary scent marking, and also serves as a reinforcer in learning paradigms. We identify a genetically determined circuit-extending from the accessory olfactory bulb to the posterior medial amygdala-that is necessary for all behavioural responses to darcin. Moreover, optical activation of darcin-responsive neurons in the medial amygdala induces both the innate and the conditioned behaviours elicited by the pheromone. These neurons define a topographically segregated population that expresses neuronal nitric oxide synthase. We suggest that this darcin-activated neural circuit integrates pheromonal information with internal state to elicit both variable innate behaviours and reinforced behaviours that may promote mate encounters and mate selection.



Nature: 28 Jan 2020; epub ahead of print
Demir E, Li K, Bobrowski-Khoury N, Sanders JI, ... Kepecs A, Axel R
Nature: 28 Jan 2020; epub ahead of print | PMID: 31996852
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Abstract

PIK3CA variants selectively initiate brain hyperactivity during gliomagenesis.

Yu K, Lin CJ, Hatcher A, Lozzi B, ... Scott KL, Deneen B

Glioblastoma is a universally lethal form of brain cancer that exhibits an array of pathophysiological phenotypes, many of which are mediated by interactions with the neuronal microenvironment. Recent studies have shown that increases in neuronal activity have an important role in the proliferation and progression of glioblastoma. Whether there is reciprocal crosstalk between glioblastoma and neurons remains poorly defined, as the mechanisms that underlie how these tumours remodel the neuronal milieu towards increased activity are unknown. Here, using a native mouse model of glioblastoma, we develop a high-throughput in vivo screening platform and discover several driver variants of PIK3CA. We show that tumours driven by these variants have divergent molecular properties that manifest in selective initiation of brain hyperexcitability and remodelling of the synaptic constituency. Furthermore, secreted members of the glypican (GPC) family are selectively expressed in these tumours, and GPC3 drives gliomagenesis and hyperexcitability. Together, our studies illustrate the importance of functionally interrogating diverse tumour phenotypes driven by individual, yet related, variants and reveal how glioblastoma alters the neuronal microenvironment.



Nature: 28 Jan 2020; epub ahead of print
Yu K, Lin CJ, Hatcher A, Lozzi B, ... Scott KL, Deneen B
Nature: 28 Jan 2020; epub ahead of print | PMID: 31996845
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Abstract

ATP13A2 deficiency disrupts lysosomal polyamine export.

van Veen S, Martin S, Van den Haute C, Benoy V, ... Eggermont J, Vangheluwe P

ATP13A2 (PARK9) is a late endolysosomal transporter that is genetically implicated in a spectrum of neurodegenerative disorders, including Kufor-Rakeb syndrome-a parkinsonism with dementia-and early-onset Parkinson\'s disease. ATP13A2 offers protection against genetic and environmental risk factors of Parkinson\'s disease, whereas loss of ATP13A2 compromises lysosomes. However, the transport function of ATP13A2 in lysosomes remains unclear. Here we establish ATP13A2 as a lysosomal polyamine exporter that shows the highest affinity for spermine among the polyamines examined. Polyamines stimulate the activity of purified ATP13A2, whereas ATP13A2 mutants that are implicated in disease are functionally impaired to a degree that correlates with the disease phenotype. ATP13A2 promotes the cellular uptake of polyamines by endocytosis and transports them into the cytosol, highlighting a role for endolysosomes in the uptake of polyamines into cells. At high concentrations polyamines induce cell toxicity, which is exacerbated by ATP13A2 loss due to lysosomal dysfunction, lysosomal rupture and cathepsin B activation. This phenotype is recapitulated in neurons and nematodes with impaired expression of ATP13A2 or its orthologues. We present defective lysosomal polyamine export as a mechanism for lysosome-dependent cell death that may be implicated in neurodegeneration, and shed light on the molecular identity of the mammalian polyamine transport system.



Nature: 28 Jan 2020; epub ahead of print
van Veen S, Martin S, Van den Haute C, Benoy V, ... Eggermont J, Vangheluwe P
Nature: 28 Jan 2020; epub ahead of print | PMID: 31996848
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Abstract

Tobacco smoking and somatic mutations in human bronchial epithelium.

Yoshida K, Gowers KHC, Lee-Six H, Chandrasekharan DP, ... Janes SM, Campbell PJ

Tobacco smoking causes lung cancer, a process that is driven by more than 60 carcinogens in cigarette smoke that directly damage and mutate DNA. The profound effects of tobacco on the genome of lung cancer cells are well-documented, but equivalent data for normal bronchial cells are lacking. Here we sequenced whole genomes of 632 colonies derived from single bronchial epithelial cells across 16 subjects. Tobacco smoking was the major influence on mutational burden, typically adding from 1,000 to 10,000 mutations per cell; massively increasing the variance both within and between subjects; and generating several distinct mutational signatures of substitutions and of insertions and deletions. A population of cells in individuals with a history of smoking had mutational burdens that were equivalent to those expected for people who had never smoked: these cells had less damage from tobacco-specific mutational processes, were fourfold more frequent in ex-smokers than current smokers and had considerably longer telomeres than their more-mutated counterparts. Driver mutations increased in frequency with age, affecting 4-14% of cells in middle-aged subjects who had never smoked. In current smokers, at least 25% of cells carried driver mutations and 0-6% of cells had two or even three drivers. Thus, tobacco smoking increases mutational burden, cell-to-cell heterogeneity and driver mutations, but quitting promotes replenishment of the bronchial epithelium from mitotically quiescent cells that have avoided tobacco mutagenesis.



Nature: 28 Jan 2020; epub ahead of print
Yoshida K, Gowers KHC, Lee-Six H, Chandrasekharan DP, ... Janes SM, Campbell PJ
Nature: 28 Jan 2020; epub ahead of print | PMID: 31996850
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Abstract

The molecular basis for sugar import in malaria parasites.

Qureshi AA, Suades A, Matsuoka R, Brock J, ... Delemotte L, Drew D

Elucidating the mechanism of sugar import requires a molecular understanding of how transporters couple sugar binding and gating events. Whereas mammalian glucose transporters (GLUTs) are specialists, the hexose transporter from the malaria parasite Plasmodium falciparum PfHT1 has acquired the ability to transport both glucose and fructose sugars as efficiently as the dedicated glucose (GLUT3) and fructose (GLUT5) transporters. Here, to establish the molecular basis of sugar promiscuity in malaria parasites, we determined the crystal structure of PfHT1 in complex with D-glucose at a resolution of 3.6 Å. We found that the sugar-binding site in PfHT1 is very similar to those of the distantly related GLUT3 and GLUT5 structures. Nevertheless, engineered PfHT1 mutations made to match GLUT sugar-binding sites did not shift sugar preferences. The extracellular substrate-gating helix TM7b in PfHT1 was positioned in a fully occluded conformation, providing a unique glimpse into how sugar binding and gating are coupled. We determined that polar contacts between TM7b and TM1 (located about 15 Å from D-glucose) are just as critical for transport as the residues that directly coordinate D-glucose, which demonstrates a strong allosteric coupling between sugar binding and gating. We conclude that PfHT1 has achieved substrate promiscuity not by modifying its sugar-binding site, but instead by evolving substrate-gating dynamics.



Nature: 28 Jan 2020; epub ahead of print
Qureshi AA, Suades A, Matsuoka R, Brock J, ... Delemotte L, Drew D
Nature: 28 Jan 2020; epub ahead of print | PMID: 31996846
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Abstract

Application of the 2019 ESC/EAS dyslipidaemia guidelines to nationwide data of patients with a recent myocardial infarction: a simulation study.

Allahyari A, Jernberg T, Hagström E, Leosdottir M, Lundman P, Ueda P
Aims
To estimate the proportion of patients with a recent myocardial infarction (MI) who would be eligible for additional lipid-lowering therapy according to the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines for the management of dyslipidaemias, and to simulate the effects of expanded lipid-lowering therapy on attainment of the low-density lipoprotein cholesterol (LDL-C) target as recommended by the guidelines.
Methods and results
Using the nationwide SWEDEHEART register, we included 25 466 patients who had attended a follow-up visit 6-10 weeks after an MI event, 2013-17. While most patients (86.6%) were receiving high-intensity statins, 82.9% of the patients would be eligible for expanded lipid-lowering therapy, as they had not attained the target of an LDL-C level of <1.4 mmol and a ≥50% LDL-C level reduction. When maximized use of high-intensity statins followed by add-on therapy with ezetimibe was simulated using a Monte Carlo model, the LDL-C target was reached in 19.9% using high-intensity statin monotherapy and in another 28.5% with high-intensity statins and ezetimibe, while 50.7% would still be eligible for proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. When use of alirocumab or evolocumab was simulated in those who were eligible for PCSK9 inhibitors, around 90% of all patients attained the LDL-C target.
Conclusion 
Our study suggests that, even with maximized use of high-intensity statins and ezetimibe, around half of patients with MI would be eligible for treatment with PCSK9 inhibitors according to the 2019 ESC/EAS guidelines. Considering the current cost of PCSK9 inhibitors, the financial implications of the new guidelines may be substantial.

© The Author(s) 2020. Published by Oxford University Press on behalf of the European Society of Cardiology.

Eur Heart J: 17 Feb 2020; epub ahead of print
Allahyari A, Jernberg T, Hagström E, Leosdottir M, Lundman P, Ueda P
Eur Heart J: 17 Feb 2020; epub ahead of print | PMID: 32072178
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Abstract

Trial of Nemolizumab in Moderate-to-Severe Prurigo Nodularis.

Ständer S, Yosipovitch G, Legat FJ, Lacour JP, ... Ahmad F, Piketty C
Background
Prurigo nodularis is a chronic pruritic skin disease with multiple nodular skin lesions. Nemolizumab is a monoclonal antibody targeting the interleukin-31 receptor, which is involved in the pathogenesis of prurigo nodularis.
Methods
We conducted a 12-week, randomized, double-blind, phase 2 trial of nemolizumab (at a dose of 0.5 mg per kilogram of body weight) administered subcutaneously at baseline, week 4, and week 8, as compared with placebo, in patients with moderate-to-severe prurigo nodularis and severe pruritus. Moderate-to-severe prurigo nodularis was defined as 20 or more nodules, and severe pruritus was defined as a mean score of at least 7 for the worst daily intensity of pruritus on the numerical rating scale (scores range from 0 [no itch] to 10 [worst itch imaginable]). The primary outcome was the percent change from baseline in the mean peak score for pruritus on the numerical rating scale at week 4. Secondary outcomes included additional measures of itching and disease severity. Safety assessments were performed through week 18.
Results
A total of 70 patients were randomly assigned in a 1:1 ratio to receive nemolizumab (34 patients) or placebo (36). The initial pruritus score on the numerical rating scale was 8.4 in each group. At week 4, the peak pruritus score on the numerical rating scale was reduced from baseline by 4.5 points (change, -53.0%) in the nemolizumab group, as compared with a reduction of 1.7 points (change, -20.2%) in the placebo group (difference, -32.8 percentage points; 95% confidence interval, -46.8 to -18.8; P<0.001). Results for secondary outcomes were in the same direction as for the primary outcome. Nemolizumab was associated with gastrointestinal symptoms (abdominal pain and diarrhea) and musculoskeletal symptoms.
Conclusions
Nemolizumab resulted in a greater reduction in pruritus and severity of skin lesions than placebo in patients with prurigo nodularis but was associated with adverse events. Larger and longer trials are needed to determine the durability and safety of nemolizumab for the treatment of prurigo nodularis. (Funded by Galderma; ClinicalTrials.gov number, NCT03181503.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 19 Feb 2020; 382:706-716
Ständer S, Yosipovitch G, Legat FJ, Lacour JP, ... Ahmad F, Piketty C
N Engl J Med: 19 Feb 2020; 382:706-716 | PMID: 32074418
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Abstract

A Community-Based Intervention for Managing Hypertension in Rural South Asia.

Jafar TH, Gandhi M, de Silva HA, Jehan I, ... Feng L,
Background
The burden of hypertension is escalating, and control rates are poor in low- and middle-income countries. Cardiovascular mortality is high in rural areas.
Methods
We conducted a cluster-randomized, controlled trial in rural districts in Bangladesh, Pakistan, and Sri Lanka. A total of 30 communities were randomly assigned to either a multicomponent intervention (intervention group) or usual care (control group). The intervention involved home visits by trained government community health workers for blood-pressure monitoring and counseling, training of physicians, and care coordination in the public sector. A total of 2645 adults with hypertension were enrolled. The primary outcome was reduction in systolic blood pressure at 24 months. Follow-up at 24 months was completed for more than 90% of the participants.
Results
At baseline, the mean systolic blood pressure was 146.7 mm Hg in the intervention group and 144.7 mm Hg in the control group. At 24 months, the mean systolic blood pressure fell by 9.0 mm Hg in the intervention group and by 3.9 mm Hg in the control group; the mean reduction was 5.2 mm Hg greater with the intervention (95% confidence interval [CI], 3.2 to 7.1; P<0.001). The mean reduction in diastolic blood pressure was 2.8 mm Hg greater in the intervention group than in the control group (95% CI, 1.7 to 3.9). Blood-pressure control (<140/90 mm Hg) was achieved in 53.2% of the participants in the intervention group, as compared with 43.7% of those in the control group (relative risk, 1.22; 95% CI, 1.10 to 1.35). All-cause mortality was 2.9% in the intervention group and 4.3% in the control group.
Conclusions
In rural communities in Bangladesh, Pakistan, and Sri Lanka, a multicomponent intervention that was centered on proactive home visits by trained government community health workers who were linked with existing public health care infrastructure led to a greater reduction in blood pressure than usual care among adults with hypertension. (Funded by the Joint Global Health Trials scheme; COBRA-BPS ClinicalTrials.gov number, NCT02657746.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 19 Feb 2020; 382:717-726
Jafar TH, Gandhi M, de Silva HA, Jehan I, ... Feng L,
N Engl J Med: 19 Feb 2020; 382:717-726 | PMID: 32074419
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Impact:
Abstract

Deep learning for prediction of colorectal cancer outcome: a discovery and validation study.

Skrede OJ, De Raedt S, Kleppe A, Hveem TS, ... Kerr DJ, Danielsen HE
Background
Improved markers of prognosis are needed to stratify patients with early-stage colorectal cancer to refine selection of adjuvant therapy. The aim of the present study was to develop a biomarker of patient outcome after primary colorectal cancer resection by directly analysing scanned conventional haematoxylin and eosin stained sections using deep learning.
Methods
More than 12 000 000 image tiles from patients with a distinctly good or poor disease outcome from four cohorts were used to train a total of ten convolutional neural networks, purpose-built for classifying supersized heterogeneous images. A prognostic biomarker integrating the ten networks was determined using patients with a non-distinct outcome. The marker was tested on 920 patients with slides prepared in the UK, and then independently validated according to a predefined protocol in 1122 patients treated with single-agent capecitabine using slides prepared in Norway. All cohorts included only patients with resectable tumours, and a formalin-fixed, paraffin-embedded tumour tissue block available for analysis. The primary outcome was cancer-specific survival.
Findings
828 patients from four cohorts had a distinct outcome and were used as a training cohort to obtain clear ground truth. 1645 patients had a non-distinct outcome and were used for tuning. The biomarker provided a hazard ratio for poor versus good prognosis of 3·84 (95% CI 2·72-5·43; p<0·0001) in the primary analysis of the validation cohort, and 3·04 (2·07-4·47; p<0·0001) after adjusting for established prognostic markers significant in univariable analyses of the same cohort, which were pN stage, pT stage, lymphatic invasion, and venous vascular invasion.
Interpretation
A clinically useful prognostic marker was developed using deep learning allied to digital scanning of conventional haematoxylin and eosin stained tumour tissue sections. The assay has been extensively evaluated in large, independent patient populations, correlates with and outperforms established molecular and morphological prognostic markers, and gives consistent results across tumour and nodal stage. The biomarker stratified stage II and III patients into sufficiently distinct prognostic groups that potentially could be used to guide selection of adjuvant treatment by avoiding therapy in very low risk groups and identifying patients who would benefit from more intensive treatment regimes.
Funding
The Research Council of Norway.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 31 Jan 2020; 395:350-360
Skrede OJ, De Raedt S, Kleppe A, Hveem TS, ... Kerr DJ, Danielsen HE
Lancet: 31 Jan 2020; 395:350-360 | PMID: 32007170
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Impact:
Abstract

Epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in Wuhan, China: a descriptive study.

Chen N, Zhou M, Dong X, Qu J, ... Zhang X, Zhang L
Background
In December, 2019, a pneumonia associated with the 2019 novel coronavirus (2019-nCoV) emerged in Wuhan, China. We aimed to further clarify the epidemiological and clinical characteristics of 2019-nCoV pneumonia.
Methods
In this retrospective, single-centre study, we included all confirmed cases of 2019-nCoV in Wuhan Jinyintan Hospital from Jan 1 to Jan 20, 2020. Cases were confirmed by real-time RT-PCR and were analysed for epidemiological, demographic, clinical, and radiological features and laboratory data. Outcomes were followed up until Jan 25, 2020.
Findings
Of the 99 patients with 2019-nCoV pneumonia, 49 (49%) had a history of exposure to the Huanan seafood market. The average age of the patients was 55·5 years (SD 13·1), including 67 men and 32 women. 2019-nCoV was detected in all patients by real-time RT-PCR. 50 (51%) patients had chronic diseases. Patients had clinical manifestations of fever (82 [83%] patients), cough (81 [82%] patients), shortness of breath (31 [31%] patients), muscle ache (11 [11%] patients), confusion (nine [9%] patients), headache (eight [8%] patients), sore throat (five [5%] patients), rhinorrhoea (four [4%] patients), chest pain (two [2%] patients), diarrhoea (two [2%] patients), and nausea and vomiting (one [1%] patient). According to imaging examination, 74 (75%) patients showed bilateral pneumonia, 14 (14%) patients showed multiple mottling and ground-glass opacity, and one (1%) patient had pneumothorax. 17 (17%) patients developed acute respiratory distress syndrome and, among them, 11 (11%) patients worsened in a short period of time and died of multiple organ failure.
Interpretation
The 2019-nCoV infection was of clustering onset, is more likely to affect older males with comorbidities, and can result in severe and even fatal respiratory diseases such as acute respiratory distress syndrome. In general, characteristics of patients who died were in line with the MuLBSTA score, an early warning model for predicting mortality in viral pneumonia. Further investigation is needed to explore the applicability of the MuLBSTA score in predicting the risk of mortality in 2019-nCoV infection.
Funding
National Key R&D Program of China.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 29 Jan 2020; epub ahead of print
Chen N, Zhou M, Dong X, Qu J, ... Zhang X, Zhang L
Lancet: 29 Jan 2020; epub ahead of print | PMID: 32007143
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Impact:
Abstract

Genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding.

Lu R, Zhao X, Li J, Niu P, ... Shi W, Tan W
Background
In late December, 2019, patients presenting with viral pneumonia due to an unidentified microbial agent were reported in Wuhan, China. A novel coronavirus was subsequently identified as the causative pathogen, provisionally named 2019 novel coronavirus (2019-nCoV). As of Jan 26, 2020, more than 2000 cases of 2019-nCoV infection have been confirmed, most of which involved people living in or visiting Wuhan, and human-to-human transmission has been confirmed.
Methods
We did next-generation sequencing of samples from bronchoalveolar lavage fluid and cultured isolates from nine inpatients, eight of whom had visited the Huanan seafood market in Wuhan. Complete and partial 2019-nCoV genome sequences were obtained from these individuals. Viral contigs were connected using Sanger sequencing to obtain the full-length genomes, with the terminal regions determined by rapid amplification of cDNA ends. Phylogenetic analysis of these 2019-nCoV genomes and those of other coronaviruses was used to determine the evolutionary history of the virus and help infer its likely origin. Homology modelling was done to explore the likely receptor-binding properties of the virus.
Findings
The ten genome sequences of 2019-nCoV obtained from the nine patients were extremely similar, exhibiting more than 99·98% sequence identity. Notably, 2019-nCoV was closely related (with 88% identity) to two bat-derived severe acute respiratory syndrome (SARS)-like coronaviruses, bat-SL-CoVZC45 and bat-SL-CoVZXC21, collected in 2018 in Zhoushan, eastern China, but were more distant from SARS-CoV (about 79%) and MERS-CoV (about 50%). Phylogenetic analysis revealed that 2019-nCoV fell within the subgenus Sarbecovirus of the genus Betacoronavirus, with a relatively long branch length to its closest relatives bat-SL-CoVZC45 and bat-SL-CoVZXC21, and was genetically distinct from SARS-CoV. Notably, homology modelling revealed that 2019-nCoV had a similar receptor-binding domain structure to that of SARS-CoV, despite amino acid variation at some key residues.
Interpretation
2019-nCoV is sufficiently divergent from SARS-CoV to be considered a new human-infecting betacoronavirus. Although our phylogenetic analysis suggests that bats might be the original host of this virus, an animal sold at the seafood market in Wuhan might represent an intermediate host facilitating the emergence of the virus in humans. Importantly, structural analysis suggests that 2019-nCoV might be able to bind to the angiotensin-converting enzyme 2 receptor in humans. The future evolution, adaptation, and spread of this virus warrant urgent investigation.
Funding
National Key Research and Development Program of China, National Major Project for Control and Prevention of Infectious Disease in China, Chinese Academy of Sciences, Shandong First Medical University.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 29 Jan 2020; epub ahead of print
Lu R, Zhao X, Li J, Niu P, ... Shi W, Tan W
Lancet: 29 Jan 2020; epub ahead of print | PMID: 32007145
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Impact:
Abstract

Impact of HPV vaccination and cervical screening on cervical cancer elimination: a comparative modelling analysis in 78 low-income and lower-middle-income countries.

Brisson M, Kim JJ, Canfell K, Drolet M, ... Broutet N, Hutubessy R
Background
The WHO Director-General has issued a call for action to eliminate cervical cancer as a public health problem. To help inform global efforts, we modelled potential human papillomavirus (HPV) vaccination and cervical screening scenarios in low-income and lower-middle-income countries (LMICs) to examine the feasibility and timing of elimination at different thresholds, and to estimate the number of cervical cancer cases averted on the path to elimination.
Methods
The WHO Cervical Cancer Elimination Modelling Consortium (CCEMC), which consists of three independent transmission-dynamic models identified by WHO according to predefined criteria, projected reductions in cervical cancer incidence over time in 78 LMICs for three standardised base-case scenarios: girls-only vaccination; girls-only vaccination and once-lifetime screening; and girls-only vaccination and twice-lifetime screening. Girls were vaccinated at age 9 years (with a catch-up to age 14 years), assuming 90% coverage and 100% lifetime protection against HPV types 16, 18, 31, 33, 45, 52, and 58. Cervical screening involved HPV testing once or twice per lifetime at ages 35 years and 45 years, with uptake increasing from 45% (2023) to 90% (2045 onwards). The elimination thresholds examined were an average age-standardised cervical cancer incidence of four or fewer cases per 100 000 women-years and ten or fewer cases per 100 000 women-years, and an 85% or greater reduction in incidence. Sensitivity analyses were done, varying vaccination and screening strategies and assumptions. We summarised results using the median (range) of model predictions.
Findings
Girls-only HPV vaccination was predicted to reduce the median age-standardised cervical cancer incidence in LMICs from 19·8 (range 19·4-19·8) to 2·1 (2·0-2·6) cases per 100 000 women-years over the next century (89·4% [86·2-90·1] reduction), and to avert 61·0 million (60·5-63·0) cases during this period. Adding twice-lifetime screening reduced the incidence to 0·7 (0·6-1·6) cases per 100 000 women-years (96·7% [91·3-96·7] reduction) and averted an extra 12·1 million (9·5-13·7) cases. Girls-only vaccination was predicted to result in elimination in 60% (58-65) of LMICs based on the threshold of four or fewer cases per 100 000 women-years, in 99% (89-100) of LMICs based on the threshold of ten or fewer cases per 100 000 women-years, and in 87% (37-99) of LMICs based on the 85% or greater reduction threshold. When adding twice-lifetime screening, 100% (71-100) of LMICs reached elimination for all three thresholds. In regions in which all countries can achieve cervical cancer elimination with girls-only vaccination, elimination could occur between 2059 and 2102, depending on the threshold and region. Introducing twice-lifetime screening accelerated elimination by 11-31 years. Long-term vaccine protection was required for elimination.
Interpretation
Predictions were consistent across our three models and suggest that high HPV vaccination coverage of girls can lead to cervical cancer elimination in most LMICs by the end of the century. Screening with high uptake will expedite reductions and will be necessary to eliminate cervical cancer in countries with the highest burden.
Funding
WHO, UNDP, UN Population Fund, UNICEF-WHO-World Bank Special Program of Research, Development and Research Training in Human Reproduction, Canadian Institute of Health Research, Fonds de recherche du Québec-Santé, Compute Canada, National Health and Medical Research Council Australia Centre for Research Excellence in Cervical Cancer Control.

Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Lancet: 29 Jan 2020; epub ahead of print
Brisson M, Kim JJ, Canfell K, Drolet M, ... Broutet N, Hutubessy R
Lancet: 29 Jan 2020; epub ahead of print | PMID: 32007141
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Abstract

High-sensitivity cardiac troponin assays for cardiovascular risk stratification in the general population.

Farmakis D, Mueller C, Apple FS

Cardiac troponins (cTns) I and T have long been the most successful cardiac-specific circulating biomarkers in cardiovascular (CV) medicine, having changed dramatically the diagnosis of acute myocardial infarction, while being independent predictors of outcome in several cardiac conditions and non-cardiac conditions. The latest-generation high-sensitivity (hs) cTn assays demonstrate both enhanced diagnostic performance and improved analytical performance, with the ability to measure detectable concentrations in a substantial proportion of the asymptomatic and presumably healthy populations. Given this unique analytical feature, recent evidence suggests that hs-cTn can be used for the stratification of CV risk in the general population. High-sensitivity cTn predicts future CV events, are responsive to preventive pharmacological or lifestyle interventions, change in parallel to risk modifications, and offer incremental risk prediction when added to well-established prognosticators. The implementation of CV risk stratification and prevention strategies incorporating hs-cTn requires further investigation to define the optimal target populations, timing of measurement, and preventive interventions.

Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2020. For permissions, please email: [email protected]

Eur Heart J: 19 Feb 2020; epub ahead of print
Farmakis D, Mueller C, Apple FS
Eur Heart J: 19 Feb 2020; epub ahead of print | PMID: 32077940
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Abstract

Mortality impact of achieving WHO cervical cancer elimination targets: a comparative modelling analysis in 78 low-income and lower-middle-income countries.

Canfell K, Kim JJ, Brisson M, Keane A, ... Broutet N, Hutubessy R
Background
WHO is developing a global strategy towards eliminating cervical cancer as a public health problem, which proposes an elimination threshold of four cases per 100 000 women and includes 2030 triple-intervention coverage targets for scale-up of human papillomavirus (HPV) vaccination to 90%, twice-lifetime cervical screening to 70%, and treatment of pre-invasive lesions and invasive cancer to 90%. We assessed the impact of achieving the 90-70-90 triple-intervention targets on cervical cancer mortality and deaths averted over the next century. We also assessed the potential for the elimination initiative to support target 3.4 of the UN Sustainable Development Goals (SDGs)-a one-third reduction in premature mortality from non-communicable diseases by 2030.
Methods
The WHO Cervical Cancer Elimination Modelling Consortium (CCEMC) involves three independent, dynamic models of HPV infection, cervical carcinogenesis, screening, and precancer and invasive cancer treatment. Reductions in age-standardised rates of cervical cancer mortality in 78 low-income and lower-middle-income countries (LMICs) were estimated for three core scenarios: girls-only vaccination at age 9 years with catch-up for girls aged 10-14 years; girls-only vaccination plus once-lifetime screening and cancer treatment scale-up; and girls-only vaccination plus twice-lifetime screening and cancer treatment scale-up. Vaccination was assumed to provide 100% lifetime protection against infections with HPV types 16, 18, 31, 33, 45, 52, and 58, and to scale up to 90% coverage in 2020. Cervical screening involved HPV testing at age 35 years, or at ages 35 years and 45 years, with scale-up to 45% coverage by 2023, 70% by 2030, and 90% by 2045, and we assumed that 50% of women with invasive cervical cancer would receive appropriate surgery, radiotherapy, and chemotherapy by 2023, which would increase to 90% by 2030. We summarised results using the median (range) of model predictions.
Findings
In 2020, the estimated cervical cancer mortality rate across all 78 LMICs was 13·2 (range 12·9-14·1) per 100 000 women. Compared to the status quo, by 2030, vaccination alone would have minimal impact on cervical cancer mortality, leading to a 0·1% (0·1-0·5) reduction, but additionally scaling up twice-lifetime screening and cancer treatment would reduce mortality by 34·2% (23·3-37·8), averting 300 000 (300 000-400 000) deaths by 2030 (with similar results for once-lifetime screening). By 2070, scaling up vaccination alone would reduce mortality by 61·7% (61·4-66·1), averting 4·8 million (4·1-4·8) deaths. By 2070, additionally scaling up screening and cancer treatment would reduce mortality by 88·9% (84·0-89·3), averting 13·3 million (13·1-13·6) deaths (with once-lifetime screening), or by 92·3% (88·4-93·0), averting 14·6 million (14·1-14·6) deaths (with twice-lifetime screening). By 2120, vaccination alone would reduce mortality by 89·5% (86·6-89·9), averting 45·8 million (44·7-46·4) deaths. By 2120, additionally scaling up screening and cancer treatment would reduce mortality by 97·9% (95·0-98·0), averting 60·8 million (60·2-61·2) deaths (with once-lifetime screening), or by 98·6% (96·5-98·6), averting 62·6 million (62·1-62·8) deaths (with twice-lifetime screening). With the WHO triple-intervention strategy, over the next 10 years, about half (48% [45-55]) of deaths averted would be in sub-Saharan Africa and almost a third (32% [29-34]) would be in South Asia; over the next 100 years, almost 90% of deaths averted would be in these regions. For premature deaths (age 30-69 years), the WHO triple-intervention strategy would result in rate reductions of 33·9% (24·4-37·9) by 2030, 96·2% (94·3-96·8) by 2070, and 98·6% (96·9-98·8) by 2120.
Interpretation
These findings emphasise the importance of acting immediately on three fronts to scale up vaccination, screening, and treatment for pre-invasive and invasive cervical cancer. In the next 10 years, a one-third reduction in the rate of premature mortality from cervical cancer in LMICs is possible, contributing to the realisation of the 2030 UN SDGs. Over the next century, successful implementation of the WHO elimination strategy would reduce cervical cancer mortality by almost 99% and save more than 62 million women\'s lives.
Funding
WHO, UNDP, UN Population Fund, UNICEF-WHO-World Bank Special Program of Research, Development and Research Training in Human Reproduction, Germany Federal Ministry of Health, National Health and Medical Research Council Australia, Centre for Research Excellence in Cervical Cancer Control, Canadian Institute of Health Research, Compute Canada, and Fonds de recherche du Québec-Santé.

Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY-NC-ND 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Lancet: 29 Jan 2020; epub ahead of print
Canfell K, Kim JJ, Brisson M, Keane A, ... Broutet N, Hutubessy R
Lancet: 29 Jan 2020; epub ahead of print | PMID: 32007142
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
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