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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

Infections Associated with Resterilized Pacemakers and Defibrillators.

Khairy TF, Lupien MA, Nava S, Baez FV, ... Macle L, Khairy P
Background
Access to pacemakers and defibrillators is problematic in places with limited resources. Resterilization and reuse of implantable cardiac devices obtained post mortem from patients in wealthier nations have been undertaken, but uncertainty around the risk of infection is a concern.
Methods
A multinational program was initiated in 1983 to provide tested and resterilized pacemakers and defibrillators to underserved nations; a prospective registry was established in 2003. Patients who received reused devices in this program were matched in a 1:3 ratio with control patients who received new devices implanted in Canada. The primary outcome was infection or device-related death, with mortality from other causes modeled as a competing risk.
Results
Resterilized devices were implanted in 1051 patients (mean [±SD] age, 63.2±18.5 years; 43.6% women) in Mexico (36.0%), the Dominican Republic (28.1%), Guatemala (26.6%), and Honduras (9.3%). Overall, 85% received pacemakers and 15% received defibrillators, with one (55.5%), two (38.8%), or three (5.7%) leads. Baseline characteristics did not differ between these patients and the 3153 matched control patients. At 2 years of follow-up, infections had occurred in 21 patients (2.0%) with reused devices and in 38 (1.2%) with new devices (hazard ratio, 1.66; 95% confidence interval, 0.97 to 2.83; P = 0.06); there were no device-related deaths. The most common implicated pathogens wereand .
Conclusions
Among patients in underserved countries who received a resterilized and reused pacemaker or defibrillator, the incidence of infection or device-related death at 2 years was 2.0%, an incidence that did not differ significantly from that seen among matched control patients with new devices in Canada.

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 06 May 2020; 382:1823-1831
Khairy TF, Lupien MA, Nava S, Baez FV, ... Macle L, Khairy P
N Engl J Med: 06 May 2020; 382:1823-1831 | PMID: 32374963
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Abstract

Cost-Effectiveness of Alirocumab in Patients With Acute Coronary Syndromes: The ODYSSEY OUTCOMES Trial.

Bhatt DL, Briggs AH, Reed SD, Annemans L, ... Gabriel Steg P,
Background
Cholesterol reduction with proprotein convertase subtilisin-kexin type 9 inhibitors reduces ischemic events; however, the cost-effectiveness in statin-treated patients with recent acute coronary syndrome remains uncertain.
Objectives
This study sought to determine whether further cholesterol reduction with alirocumab would be cost-effective in patients with a recent acute coronary syndrome on optimal statin therapy.
Methods
A cost-effectiveness model leveraging patient-level data from ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) was developed to estimate costs and outcomes over a lifetime horizon. Patients (n = 18,924) had a recent acute coronary syndrome and were on high-intensity or maximum-tolerated statin therapy, with a baseline low-density lipoprotein cholesterol (LDL-C) level ≥70 mg/dl, non-high-density lipoprotein cholesterol ≥100 mg/dl, or apolipoprotein B ≥80 mg/l. Alirocumab 75 mg or placebo was administered subcutaneously every 2 weeks. Alirocumab was blindly titrated to 150 mg if LDL-C remained ≥50 mg/dl or switched to placebo if 2 consecutive LDL-C levels were <15 mg/dl. Incremental cost per quality-adjusted life-year (QALY) was determined with the addition of alirocumab versus placebo and, based on clinical efficacy findings from the trial, was stratified by baseline LDL-C levels ≥100 mg/dl and <100 mg/dl.
Results
Across the overall population recruited to the ODYSSEY OUTCOMES trial, using an annual treatment cost of US$5,850, the mean overall incremental cost-effectiveness ratio was US$92,200 per QALY (base case). The cost was US$41,800 per QALY in patients with baseline LDL-C ≥100 mg/dl, whereas in those with LDL-C <100 mg/dl the cost per QALY was US$299,400. Among patients with LDL-C ≥100 mg/dl, incremental cost-effectiveness ratios remained below US$100,000 per QALY across a wide variety of sensitivity analyses.
Conclusions
In patients with a recent acute coronary syndrome on optimal statin therapy, alirocumab improves cardiovascular outcomes at costs considered intermediate value, with good value in patients with baseline LDL-C ≥100 mg/dl but less economic value with LDL-C <100 mg/dl. (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab [ODYSSEY OUTCOMES]; NCT01663402).

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

J Am Coll Cardiol: 11 May 2020; 75:2297-2308
Bhatt DL, Briggs AH, Reed SD, Annemans L, ... Gabriel Steg P,
J Am Coll Cardiol: 11 May 2020; 75:2297-2308 | PMID: 32381160
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Abstract

Incidence and Long-Term Outcomes of Hypertensive Disorders of Pregnancy.

Garovic VD, White WM, Vaughan L, Saiki M, ... Weaver A, Mielke MM
Background
Hypertensive disorders of pregnancy (HDP) are associated with increased risks for cardiovascular disease later in life. The HDP incidence is commonly assessed using diagnostic codes, which are not reliable; and typically are expressed per-pregnancy, which may underestimate the number of women with an HDP history after their reproductive years.
Objectives
This study sought to determine the incidence of HDP expressed as both per-pregnancy and per-woman, and to establish their associations with future chronic conditions and multimorbidity, a measure of accelerated aging, in a population-based cohort study.
Methods
Using the Rochester Epidemiology Project medical record-linkage system, the authors identified residents of Olmsted County, Minnesota, who delivered between 1976 and 1982. The authors classified pregnancies into normotensive, gestational hypertension, pre-eclampsia, eclampsia, pre-eclampsia superimposed on chronic hypertension, and chronic hypertension using a validated electronic algorithm, and calculated the incidence of HDP both per-pregnancy and per-woman. The risk of chronic conditions between women with versus those without a history of HDP (age and parity 1:2 matched) was quantified using the hazard ratio and corresponding 95% confidence interval estimated from a Cox model.
Results
Among 9,862 pregnancies, we identified 719 (7.3%) with HDP and 324 (3.3%) with pre-eclampsia. The incidence of HDP and pre-eclampsia doubled when assessed on a per-woman basis: 15.3% (281 of 1,839) and 7.5% (138 of 1,839), respectively. Women with a history of HDP were at increased risk for subsequent diagnoses of stroke (hazard ratio [HR]: 2.27; 95% confidence interval [CI]: 1.37 to 3.76), coronary artery disease (HR: 1.89; 95% CI: 1.26 to 2.82), cardiac arrhythmias (HR: 1.62; 95% CI: 1.28 to 2.05), chronic kidney disease (HR: 2.41; 95% CI: 1.54 to 3.78), and multimorbidity (HR: 1.25; 95% CI: 1.15 to 1.35).
Conclusions
The HDP population-based incidence expressed per-pregnancy underestimates the number of women affected by this condition during their reproductive years. A history of HDP confers significant increase in risks for future chronic conditions and multimorbidity.

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

J Am Coll Cardiol: 11 May 2020; 75:2323-2334
Garovic VD, White WM, Vaughan L, Saiki M, ... Weaver A, Mielke MM
J Am Coll Cardiol: 11 May 2020; 75:2323-2334 | PMID: 32381164
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Abstract

Atrial Septal Aneurysm, Shunt Size, and Recurrent Stroke Risk in Patients With Patent Foramen Ovale.

Turc G, Lee JY, Brochet E, Kim JS, ... Mas JL,
Background
In patients with patent foramen ovale (PFO)-associated stroke, the presence of large shunt or atrial septal aneurysm (ASA) has been suggested to convey a high risk of stroke recurrence.
Objectives
The purpose of this study was to assess the respective influence of PFO size and ASA status on stroke recurrence under medical therapy in patients with recent PFO-associated stroke without alternative cause.
Methods
The authors pooled individual patient data from 2 prospective observational studies and the medical arms of 2 randomized trials, in which shunt size and ASA status was assessed by independent reading of echocardiographic images. Associations between PFO anatomical features and recurrent ischemic stroke were assessed by mixed effects Cox models.
Results
Of 898 patients (mean age 45.3 years), 178 (19.8%) had ASA with large PFO, 71 (7.9%) ASA with nonlarge PFO, 397 (44.2%) large PFO without ASA, and 252 (28.1%) nonlarge PFO without ASA. Over a median follow-up of 3.8 years (interquartile range: 2.6 to 5.5 years), 47 (5.2%) patients experienced a recurrent stroke. There was a heterogeneity across studies for the association between PFO size and stroke recurrence (p = 0.01). In a model accounting for age, hypertension, antithrombotic therapy, and PFO anatomy, ASA was independently associated with recurrent stroke (adjusted hazard ratio: 3.27; 95% confidence interval: 1.82 to 5.86; p < 0.0001), whereas large PFO was not (average adjusted hazard ratio across studies: 1.43; 95% confidence interval: 0.50 to 4.03; p = 0.50).
Conclusions
In patients with PFO-associated stroke, ASA is a more important predictor of recurrent stroke than shunt size. These results can help to better identify those patients with a high risk of stroke recurrence under medical therapy who may derive the most benefit from PFO closure. (Patent Foramen Ovale Closure or Anticoagulants Versus Antiplatelet Therapy to Prevent Stroke Recurrence [CLOSE]; NCT00562289) (Device Closure versus Medical Therapy in Patients with Cryptogenic Stroke and High-Risk Patent Foramen Ovale [DEFENSE-PFO]; NCT01550588).

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

J Am Coll Cardiol: 11 May 2020; 75:2312-2320
Turc G, Lee JY, Brochet E, Kim JS, ... Mas JL,
J Am Coll Cardiol: 11 May 2020; 75:2312-2320 | PMID: 32381162
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Abstract

Emapalumab in Children with Primary Hemophagocytic Lymphohistiocytosis.

Locatelli F, Jordan MB, Allen C, Cesaro S, ... Ballabio M, de Min C
Background
Primary hemophagocytic lymphohistiocytosis is a rare syndrome characterized by immune dysregulation and hyperinflammation. It typically manifests in infancy and is associated with high mortality.
Methods
We investigated the efficacy and safety of emapalumab (a human anti-interferon-γ antibody), administered with dexamethasone, in an open-label, single-group, phase 2-3 study involving patients who had received conventional therapy before enrollment (previously treated patients) and previously untreated patients who were 18 years of age or younger and had primary hemophagocytic lymphohistiocytosis. The patients could enter a long-term follow-up study until 1 year after allogeneic hematopoietic stem-cell transplantation or until 1 year after the last dose of emapalumab, if transplantation was not performed. The planned 8-week treatment period could be shortened or extended if needed according to the timing of transplantation. The primary efficacy end point was the overall response, which was assessed in the previously treated patients according to objective clinical and laboratory criteria.
Results
At the cutoff date of July 20, 2017, a total of 34 patients (27 previously treated patients and 7 previously untreated patients) had received emapalumab; 26 patients completed the study. A total of 63% of the previously treated patients and 65% of the patients who received an emapalumab infusion had a response; these percentages were significantly higher than the prespecified null hypothesis of 40% (P = 0.02 and P = 0.005, respectively). In the previously treated group, 70% of the patients were able to proceed to transplantation, as were 65% of the patients who received emapalumab. At the last observation, 74% of the previously treated patients and 71% of the patients who received emapalumab were alive. Emapalumab was not associated with any organ toxicity. Severe infections developed in 10 patients during emapalumab treatment. Emapalumab was discontinued in 1 patient because of disseminated histoplasmosis.
Conclusions
Emapalumab was an efficacious targeted therapy for patients with primary hemophagocytic lymphohistiocytosis. (Funded by NovImmune and the European Commission; NI-0501-04 and NI-0501-05 ClinicalTrials.gov numbers, NCT01818492 and NCT02069899.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 06 May 2020; 382:1811-1822
Locatelli F, Jordan MB, Allen C, Cesaro S, ... Ballabio M, de Min C
N Engl J Med: 06 May 2020; 382:1811-1822 | PMID: 32374962
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Abstract

Cognition After Lowering LDL-Cholesterol With Evolocumab.

Gencer B, Mach F, Guo J, Im K, ... Giugliano RP,
Background
The EBBINGHAUS (Evaluating PCSK9 Binding Antibody Influence on Cognitive Health in High Cardiovascular Risk Subjects) trial demonstrated that evolocumab added to a background statin did not affect cognitive performance in a subset of 1,204 patients enrolled in FOURIER (Further Cardiovascular Outcomes Research With PCSK9 inhibitors in Subjects With Elevated Risk).
Objectives
The authors describe patient-reported cognition in the entire FOURIER trial using a self-survey.
Methods
FOURIER was a randomized, double-blind, placebo-controlled trial involving patients with atherosclerotic cardiovascular disease and low-density lipoprotein cholesterol (LDL-C) levels ≥70 mg/dl or non-high-density cholesterol ≥100 mg/dl despite statin therapy. At the final visit, patients completed a 23-item survey on memory and executive domains from the Everyday Cognition (ECog) scale. Patients compared their levels of everyday function at the end of the trial with their levels at the beginning and scored as 1 (no change or improvement), 2 (occasionally worse), 3 (consistently little worse), or 4 (consistently much worse). ECog scores were compared by the 2 randomized treatment arms and by achieved LDL-C at 4 weeks.
Results
A total of 22,655 patients completed ECog after a median duration of 2.2 years. The proportions of patients reporting cognitive decline (ECog score ≥2) at the end of the study were similar for placebo versus evolocumab, both for total score 3.6% versus 3.7% (p = 0.62) and for subdomains (memory, 5.8% vs. 6.0%; total executive, 3.6% vs. 3.7%). The proportion of patients reporting a decline in total cognitive score was similar among the 2,338 patients who achieved very low LDL-C levels (<20 mg/dl) compared to the 3,613 patients with LDL-C ≥100 mg/dl (3.8% vs. 4.5%, p = 0.57).
Conclusions
The addition of evolocumab to maximally tolerated statin therapy had no impact on patient-reported cognition after an average of 2.2 years of treatment, even among patients who achieved LDL-C <20 mg/dl.

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

J Am Coll Cardiol: 11 May 2020; 75:2283-2293
Gencer B, Mach F, Guo J, Im K, ... Giugliano RP,
J Am Coll Cardiol: 11 May 2020; 75:2283-2293 | PMID: 32381158
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Abstract

Characteristics and outcomes of patients hospitalized for COVID-19 and cardiac disease in Northern Italy.

Inciardi RM, Adamo M, Lupi L, Cani DS, ... Bezzi M, Metra M
Aims
To compare demographic characteristics, clinical presentation, and outcomes of patients with and without concomitant cardiac disease, hospitalized for COVID-19 in Brescia, Lombardy, Italy.
Methods and results
The study population includes 99 consecutive patients with COVID-19 pneumonia admitted to our hospital between 4 March and 25 March 2020. Fifty-three patients with a history of cardiac disease were compared with 46 without cardiac disease. Among cardiac patients, 40% had a history of heart failure, 36% had atrial fibrillation, and 30% had coronary artery disease. Mean age was 67 ± 12 years, and 80 (81%) patients were males. No differences were found between cardiac and non-cardiac patients except for higher values of serum creatinine, N-terminal probrain natriuretic peptide, and high sensitivity troponin T in cardiac patients. During hospitalization, 26% patients died, 15% developed thrombo-embolic events, 19% had acute respiratory distress syndrome, and 6% had septic shock. Mortality was higher in patients with cardiac disease compared with the others (36% vs. 15%, log-rank P = 0.019; relative risk 2.35; 95% confidence interval 1.08-5.09). The rate of thrombo-embolic events and septic shock during the hospitalization was also higher in cardiac patients (23% vs. 6% and 11% vs. 0%, respectively).
Conclusions
Hospitalized patients with concomitant cardiac disease and COVID-19 have an extremely poor prognosis compared with subjects without a history of cardiac disease, with higher mortality, thrombo-embolic events, and septic shock rates.

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: 07 May 2020; epub ahead of print
Inciardi RM, Adamo M, Lupi L, Cani DS, ... Bezzi M, Metra M
Eur Heart J: 07 May 2020; epub ahead of print | PMID: 32383763
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Abstract

Observational Study of Hydroxychloroquine in Hospitalized Patients with Covid-19.

Geleris J, Sun Y, Platt J, Zucker J, ... Sobieszczyk ME, Schluger NW
Background
Hydroxychloroquine has been widely administered to patients with Covid-19 without robust evidence supporting its use.
Methods
We examined the association between hydroxychloroquine use and intubation or death at a large medical center in New York City. Data were obtained regarding consecutive patients hospitalized with Covid-19, excluding those who were intubated, died, or discharged within 24 hours after presentation to the emergency department (study baseline). The primary end point was a composite of intubation or death in a time-to-event analysis. We compared outcomes in patients who received hydroxychloroquine with those in patients who did not, using a multivariable Cox model with inverse probability weighting according to the propensity score.
Results
Of 1446 consecutive patients, 70 patients were intubated, died, or discharged within 24 hours after presentation and were excluded from the analysis. Of the remaining 1376 patients, during a median follow-up of 22.5 days, 811 (58.9%) received hydroxychloroquine (600 mg twice on day 1, then 400 mg daily for a median of 5 days); 45.8% of the patients were treated within 24 hours after presentation to the emergency department, and 85.9% within 48 hours. Hydroxychloroquine-treated patients were more severely ill at baseline than those who did not receive hydroxychloroquine (median ratio of partial pressure of arterial oxygen to the fraction of inspired oxygen, 223 vs. 360). Overall, 346 patients (25.1%) had a primary end-point event (180 patients were intubated, of whom 66 subsequently died, and 166 died without intubation). In the main analysis, there was no significant association between hydroxychloroquine use and intubation or death (hazard ratio, 1.04, 95% confidence interval, 0.82 to 1.32). Results were similar in multiple sensitivity analyses.
Conclusions
In this observational study involving patients with Covid-19 who had been admitted to the hospital, hydroxychloroquine administration was not associated with either a greatly lowered or an increased risk of the composite end point of intubation or death. Randomized, controlled trials of hydroxychloroquine in patients with Covid-19 are needed. (Funded by the National Institutes of Health.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 06 May 2020; epub ahead of print
Geleris J, Sun Y, Platt J, Zucker J, ... Sobieszczyk ME, Schluger NW
N Engl J Med: 06 May 2020; epub ahead of print | PMID: 32379955
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Abstract

Long-Term Outcomes of Primary Cardiac Malignancies: Multi-Institutional Results From the National Cancer Database.

Sultan I, Bianco V, Habertheuer A, Kilic A, ... Arnaoutakis G, Okusanya O
Background
Data on primary cardiac malignancies are limited to small single-center studies.
Objectives
The aim of the current study was to provide detailed outcomes for treatment of primary cardiac malignancies from a multi-institutional database.
Methods
Outcomes were acquired from the National Cancer Database for all solid primary cardiac malignancies from 2004 to 2016. The primary outcome was long-term survival. Logistic regression was used to determine factors associated with mortality.
Results
A total of 100,317 cardiac tumors were identified, of which 826 (0.8%) were primary malignant tumors. After exclusion criteria, the cohort consisted of 747 patients (median age 53 years, 47.5% women). Most tumors were primary sarcomas (88.5%), the majority of which were hemangiosarcoma (40.4%). A total of 136 patients received no therapy, 113 received just chemotherapy, and 20 received just radiation. Surgery was performed in 442 (59.2%) patients including 255 patients undergoing multimodal therapy (surgery with chemotherapy, radiation, or chemoradiation). With surgery alone, 90-day mortality was 29.4%. Overall 30-day, 1-year, and 5-year survival rates were 81.2%, 45.3%, and 11.5%, respectively. The surgery group as compared with the no surgery groups had significantly better long-term survival (p < 0.0001). For stage III disease, there was a statistically significant improvement in survival with the addition of chemotherapy to surgery.
Conclusions
Primary cardiac malignancies are rare cancers with dismal long-term survival despite mode of treatment. Patients who underwent surgery and those with stage III disease who received peri-operative chemotherapy had better survival compared with those who did not. However, there was likely a significant selection bias in patients chosen for surgical or medical therapy.

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

J Am Coll Cardiol: 11 May 2020; 75:2338-2347
Sultan I, Bianco V, Habertheuer A, Kilic A, ... Arnaoutakis G, Okusanya O
J Am Coll Cardiol: 11 May 2020; 75:2338-2347 | PMID: 32381166
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Abstract

Deleterious effects of viral pneumonia on cardiovascular system.

Duan J, Wu Y, Liu C, Yang C, Yang L

Viral pneumonia has a significant effect on the cardiovascular system through various mechanisms; even though it is traditionally regarded as a pulmonary disease characterized by dyspnoea and hypoxaemia. Recent research works have shown that cardiovascular events outweigh all other causes of death in various influenza pandemics. Therefore, the exploration of the effects of viral pneumonia on cardiovascular system becomes increasingly essential. The objective of this review is three-fold: first, to summarize the knowledge about the epidemiological characteristics and clinical manifestations of viral infections that are the recent causes of global pandemics; second, to explore the cardiovascular response to these infections; and third, to attempt in identifying the possible coping strategies of the Wuhan epidemic and the future viral infection pandemics.

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: 07 May 2020; epub ahead of print
Duan J, Wu Y, Liu C, Yang C, Yang L
Eur Heart J: 07 May 2020; epub ahead of print | PMID: 32383765
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Abstract

Cardiovascular outcomes, bleeding risk, and achieved blood pressure in patients on long-term anticoagulation with the thrombin antagonist dabigatran or warfarin: data from the RE-LY trial.

Böhm M, Brueckmann M, Eikelboom JW, Ezekowitz M, ... Wallentin L, Yusuf S
Aims 
A J-shaped association of cardiovascular events to achieved systolic (SBP) and diastolic (DBP) blood pressure was shown in high-risk patients. This association on oral anticoagulation is unknown. This analysis from RELY assessed the risks of death, stroke or systemic emboli, and bleeding according to mean achieved SBP and DBP in atrial fibrillation on oral anticoagulation.
Methods and results 
RE-LY patients were followed for 2 years and recruited between 22 December 2005 until 15 December 2007. 18.113 patients were randomized in 951 centres in 54 countries and 18,107 patients with complete blood pressure (BP) data were analysed with a median follow-up of 2.0 years and a complete follow-up in 99.9%. The association between achieved mean SBP and DBP on all-cause death, stroke and systemic embolic events (SSE), major, and any bleeding were explored. On treatment, SBP >140 mmHg and <120 mmHg was associated with all-cause death compared with SBP 120-130 mmHg (reference). For SSE, risk was unchanged at SBP <110 mmHg but increased at 140-160 mmHg (adjusted hazard ratio (HR) 1.81; 1.40-2.33) and SBP ≥160 mmHg (HR 3.35; 2.09-5.36). Major bleeding events were also increased at <110 mmHg and at 110 to <120 mmHg. Interestingly, there was no increased risk of major bleeding at SBP >130 mmHg. Similar patterns were observed for DBP with an increased risk at <70 mmHg (HR 1.55; 1.35-1.78) and >90 mmHg (HR 1.88; 1.43-2.46) for all-cause death compared to 70 to <80 mmHg (reference). Risk for any bleeding was increased at low DBP <70 mmHg (HR 1.46; 1.37-1.56) at DBP 80 to <90 mmHg (HR 1.13; 1.06-1.31) without increased risk at higher achieved DBP. Dabigatran 150 mg twice daily showed an advantage in all patients for all-cause death and SSE and there was an advantage for 110 mg dabigatran twice daily for major bleeding and any bleeding irrespective of SBP or DBP achieved. Similar results were obtained for baseline BP, time-updated BP, and BP as time-varying covariate.
Conclusion 
Low achieved SBP associates with increased risk of death, SSE, and bleeding in patients with atrial fibrillation on oral anticoagulation. Major bleeding events did not occur at higher BP. Low BP might identify high-risk patients not only for death but also for high bleeding risks.
Clinical trial registration
 ClinicalTrials.gov-Identifier: NCT00262600.

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: 07 May 2020; epub ahead of print
Böhm M, Brueckmann M, Eikelboom JW, Ezekowitz M, ... Wallentin L, Yusuf S
Eur Heart J: 07 May 2020; epub ahead of print | PMID: 32385506
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Abstract

Circulating plasma concentrations of angiotensin-converting enzyme 2 in men and women with heart failure and effects of renin-angiotensin-aldosterone inhibitors.

Sama IE, Ravera A, Santema BT, van Goor H, ... van Veldhuisen DJ, Voors AA
Aims
The current pandemic coronavirus SARS-CoV-2 infects a wide age group but predominantly elderly individuals, especially men and those with cardiovascular disease. Recent reports suggest an association with use of renin-angiotensin-aldosterone system (RAAS) inhibitors. Angiotensin-converting enzyme 2 (ACE2) is a functional receptor for coronaviruses. Higher ACE2 concentrations might lead to increased vulnerability to SARS-CoV-2 in patients on RAAS inhibitors.
Methods
We measured ACE2 concentrations in 1485 men and 537 women with heart failure (index cohort). Results were validated in 1123 men and 575 women (validation cohort).
Results
The median age was 69 years for men and 75 years for women. The strongest predictor of elevated concentrations of ACE2 in both cohorts was male sex (estimate = 0.26, P < 0.001; and 0.19, P < 0.001, respectively). In the index cohort, use of ACE inhibitors, angiotensin receptor blockers (ARBs), or mineralocorticoid receptor antagonists (MRAs) was not an independent predictor of plasma ACE2. In the validation cohort, ACE inhibitor (estimate = -0.17, P = 0.002) and ARB use (estimate = -0.15, P = 0.03) were independent predictors of lower plasma ACE2, while use of an MRA (estimate = 0.11, P = 0.04) was an independent predictor of higher plasma ACE2 concentrations.
Conclusion
In two independent cohorts of patients with heart failure, plasma concentrations of ACE2 were higher in men than in women, but use of neither an ACE inhibitor nor an ARB was associated with higher plasma ACE2 concentrations. These data might explain the higher incidence and fatality rate of COVID-19 in men, but do not support previous reports suggesting that ACE inhibitors or ARBs increase the vulnerability for COVID-19 through increased plasma ACE2 concentrations.

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: 09 May 2020; epub ahead of print
Sama IE, Ravera A, Santema BT, van Goor H, ... van Veldhuisen DJ, Voors AA
Eur Heart J: 09 May 2020; epub ahead of print | PMID: 32388565
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Abstract

Vulnerable plaques and patients: state-of-the-art.

Tomaniak M, Katagiri Y, Modolo R, Silva R, ... Serruys PW, Onuma Y

Despite advanced understanding of the biology of atherosclerosis, coronary heart disease remains the leading cause of death worldwide. Progress has been challenging as half of the individuals who suffer sudden cardiac death do not experience premonitory symptoms. Furthermore, it is well-recognized that also a plaque that does not cause a haemodynamically significant stenosis can trigger a sudden cardiac event, yet the majority of ruptured or eroded plaques remain clinically silent. In the past 30 years since the term \'vulnerable plaque\' was introduced, there have been major advances in the understanding of plaque pathogenesis and pathophysiology, shifting from pursuing features of \'vulnerability\' of a specific lesion to the more comprehensive goal of identifying patient \'cardiovascular vulnerability\'. It has been also recognized that aside a thin-capped, lipid-rich plaque associated with plaque rupture, acute coronary syndromes (ACS) are also caused by plaque erosion underlying between 25% and 60% of ACS nowadays, by calcified nodule or by functional coronary alterations. While there have been advances in preventive strategies and in pharmacotherapy, with improved agents to reduce cholesterol, thrombosis, and inflammation, events continue to occur in patients receiving optimal medical treatment. Although at present the positive predictive value of imaging precursors of the culprit plaques remains too low for clinical relevance, improving coronary plaque imaging may be instrumental in guiding pharmacotherapy intensity and could facilitate optimal allocation of novel, more aggressive, and costly treatment strategies. Recent technical and diagnostic advances justify continuation of interdisciplinary research efforts to improve cardiovascular prognosis by both systemic and \'local\' diagnostics and therapies. The present state-of-the-art document aims to present and critically appraise the latest evidence, developments, and future perspectives in detection, prevention, and treatment of \'high-risk\' plaques occurring in \'vulnerable\' patients.

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: 12 May 2020; epub ahead of print
Tomaniak M, Katagiri Y, Modolo R, Silva R, ... Serruys PW, Onuma Y
Eur Heart J: 12 May 2020; epub ahead of print | PMID: 32402086
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Abstract

Characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019.

Shi S, Qin M, Cai Y, Liu T, ... Yang B, Huang C
Aims
To investigate the characteristics and clinical significance of myocardial injury in patients with severe coronavirus disease 2019 (COVID-19).
Methods and results
We enrolled 671 eligible hospitalized patients with severe COVID-19 from 1 January to 23 February 2020, with a median age of 63 years. Clinical, laboratory, and treatment data were collected and compared between patients who died and survivors. Risk factors of death and myocardial injury were analysed using multivariable regression models. A total of 62 patients (9.2%) died, who more often had myocardial injury (75.8% vs. 9.7%; P < 0.001) than survivors. The area under the receiver operating characteristic curve of initial cardiac troponin I (cTnI) for predicting in-hospital mortality was 0.92 [95% confidence interval (CI), 0.87-0.96; sensitivity, 0.86; specificity, 0.86; P < 0.001]. The single cut-off point and high level of cTnI predicted risk of in-hospital death, hazard ratio (HR) was 4.56 (95% CI, 1.28-16.28; P = 0.019) and 1.25 (95% CI, 1.07-1.46; P = 0.004), respectively. In multivariable logistic regression, senior age, comorbidities (e.g. hypertension, coronary heart disease, chronic renal failure, and chronic obstructive pulmonary disease), and high level of C-reactive protein were predictors of myocardial injury.
Conclusion
The risk of in-hospital death among patients with severe COVID-19 can be predicted by markers of myocardial injury, and was significantly associated with senior age, inflammatory response, and cardiovascular comorbidities.

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 May 2020; epub ahead of print
Shi S, Qin M, Cai Y, Liu T, ... Yang B, Huang C
Eur Heart J: 10 May 2020; epub ahead of print | PMID: 32391877
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Abstract

Challenges and Special Aspects of Pulmonary Hypertension in Middle- to Low-Income Regions: JACC State-of-the-Art Review.

Hasan B, Hansmann G, Budts W, Heath A, ... Kumar RK,

Challenges and special aspects related to the management and prognosis of pulmonary hypertension (PH) in middle- to low-income regions (MLIRs) range from late presentation to comorbidities, lack of resources and expertise, cost, and rare options of lung transplantation. Expert consensus recommendations addressing the specific challenges for prevention and therapy of PH in MLIRs with limited resources have been lacking. To date, 6 MLIR-PH registries containing mostly adult patients with PH exist. Importantly, the global prevalence of PH is much higher in MLIRs compared with high-income regions: group 2 PH (left heart disease), pulmonary arterial hypertension associated with unrepaired congenital heart disease, human immunodeficiency virus, or schistosomiasis are highly prevalent. This consensus statement provides selective, tailored modifications to the current PH guidelines to address the specific challenges faced in MLIRs, resulting in the first pragmatic and cost-effective consensus recommendations for PH care providers, patients, and their families.

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

J Am Coll Cardiol: 18 May 2020; 75:2463-2477
Hasan B, Hansmann G, Budts W, Heath A, ... Kumar RK,
J Am Coll Cardiol: 18 May 2020; 75:2463-2477 | PMID: 32408981
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Abstract

Regression of Left Ventricular Mass After Transcatheter Aortic Valve Replacement: The PARTNER Trials and Registries.

Chau KH, Douglas PS, Pibarot P, Hahn RT, ... Leon MB, Lindman BR
Background
Greater early left ventricular mass index (LVMi) regression is associated with fewer hospitalizations 1 year after transcatheter aortic valve replacement (TAVR). The association between LVMi regression and longer-term post-TAVR outcomes is unclear.
Objectives
The purpose of this study was to determine the association between LVMi regression at 1-year post-TAVR and clinical outcomes between 1 and 5 years.
Methods
Among intermediate- and high-risk patients who received TAVR in the PARTNER (Placement of Aortic Transcatheter Valves) I, II, and S3 trials or registries and were alive at 1 year, we included patients with baseline moderate or severe left ventricular hypertrophy (LVH) and paired measurements of LVMi at baseline and 1 year. The associations between LVMi regression (percent change between baseline and 1 year) and death or rehospitalization from 1 to 5 years were examined.
Results
Among 1,434 patients, LVMi was 146 g/m (interquartile range [IQR]: 133 to 168 g/m) at baseline and decreased 14.5% (IQR: 4.2% to 26.1%) to 126 g/m (IQR: 106 to 148 g/m) at 1 year. After adjustment, greater LVMi regression at 1 year was associated with lower all-cause death (adjusted hazard ratio [aHR]: 0.95 per 10% decrease in LVMi; 95% confidence interval [CI]: 0.91 to 0.98; p = 0.004; aHR of the quartile with greatest vs. least LVMi regression: 0.61; 95% CI: 0.43 to 0.86; p = 0.005). Severe LVH at 1 year was observed in 39%, which was independently associated with increased all-cause death (aHR of severe LVH vs. no LVH: 1.71; 95% CI: 1.20 to 2.44; p = 0.003). Similar associations were found for rates of cardiovascular mortality and rehospitalization.
Conclusions
Among patients with moderate or severe LVH treated with TAVR who are alive at 1 year, greater LVMi regression at 1 year is associated with lower death and hospitalization rates to 5 years. These findings may have implications for the timing of valve replacement and the role of adjunctive medical therapy after TAVR.

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

J Am Coll Cardiol: 18 May 2020; 75:2446-2458
Chau KH, Douglas PS, Pibarot P, Hahn RT, ... Leon MB, Lindman BR
J Am Coll Cardiol: 18 May 2020; 75:2446-2458 | PMID: 32408979
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Abstract

Obesity and weight loss are inversely related to mortality and cardiovascular outcome in prediabetes and type 2 diabetes: data from the ORIGIN trial.

Doehner W, Gerstein HC, Ried J, Jung H, ... Hess S, Anker SD
Aims
The association of body weight and weight change with mortality and cardiovascular (CV) outcome in patients with diabetes mellitus (DM) is not clearly established. We assessed the relationship between weight, weight change, and outcomes in patients with established CV risk factors and type 2 DM or pre-diabetes.
Methods and results
A total of 12 521 participants from the ORIGIN trial were grouped in BMI categories of low body weight [body mass index (BMI) < 22 kg/m2] normal (22-24.9), overweight (25-29.9), obesity Grades 1-3 (30-34.9, 35-39.9, ≥40 kg/m2, respectively). Outcome variables included total and CV mortality and composite outcomes of CV death, non-fatal stroke, or myocardial infarction plus revascularization or heart failure hospitalization. Follow-up was 6.2 years (interquartile range 5.8-6.7 years). After multivariable adjustment, lowest risks were seen in patients with overweight and mild obesity for total mortality [overweight: hazard ratio (HR) 0.80 (95% confidence interval (CI) 0.69-0.91); obesity Grade 1: HR 0.82 (0.71-0.95), both P < 0.01)] and CV mortality [overweight: HR 0.79 (0.66-0.94); obesity Grade 1: 0.79 (0.65-0.95), all compared to patients with normal BMI, P < 0.05]. Obesity of any severity was not associated with higher mortality. Low body weight was related to higher mortality [HR 1.28 (1.02-1.61); CV mortality: HR 1.34 (1.01-1.79), P < 0.05]. A continued 2-year weight loss was associated with higher risk of mortality [HR 1.32 (1.18-1.46), P < 0.0001] and CV mortality [HR 1.18 (1.02-1.35), compared to patients without weight loss, P < 0.05]. In turn, weight gain was not related to any adverse outcome.
Conclusion
Obesity in patients with DM or pre-diabetes and CV risk profile was not associated with higher mortality or adverse CV outcome. The lowest mortality risk was seen in patients with overweight and moderate obesity (BMI 25-35 kg/m2). Weight loss was an independent risk factor for higher mortality compared to no weight loss.

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

Eur Heart J: 12 May 2020; epub ahead of print
Doehner W, Gerstein HC, Ried J, Jung H, ... Hess S, Anker SD
Eur Heart J: 12 May 2020; epub ahead of print | PMID: 32402060
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Abstract

Personalized iPSC-Derived Dopamine Progenitor Cells for Parkinson\'s Disease.

Schweitzer JS, Song B, Herrington TM, Park TY, ... Carter BS, Kim KS

We report the implantation of patient-derived midbrain dopaminergic progenitor cells, differentiated in vitro from autologous induced pluripotent stem cells (iPSCs), in a patient with idiopathic Parkinson\'s disease. The patient-specific progenitor cells were produced under Good Manufacturing Practice conditions and characterized as having the phenotypic properties of substantia nigra pars compacta neurons; testing in a humanized mouse model (involving peripheral-blood mononuclear cells) indicated an absence of immunogenicity to these cells. The cells were implanted into the putamen (left hemisphere followed by right hemisphere, 6 months apart) of a patient with Parkinson\'s disease, without the need for immunosuppression. Positron-emission tomography with the use of fluorine-18-L-dihydroxyphenylalanine suggested graft survival. Clinical measures of symptoms of Parkinson\'s disease after surgery stabilized or improved at 18 to 24 months after implantation. (Funded by the National Institutes of Health and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 13 May 2020; 382:1926-1932
Schweitzer JS, Song B, Herrington TM, Park TY, ... Carter BS, Kim KS
N Engl J Med: 13 May 2020; 382:1926-1932 | PMID: 32402162
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Abstract

The Mediterranean diet, plasma metabolome, and cardiovascular disease risk.

Li J, Guasch-Ferré M, Chung W, Ruiz-Canela M, ... Hu FB, Liang L
Aims
To investigate whether metabolic signature composed of multiple plasma metabolites can be used to characterize adherence and metabolic response to the Mediterranean diet and whether such a metabolic signature is associated with cardiovascular disease (CVD) risk.
Methods and results
Our primary study cohort included 1859 participants from the Spanish PREDIMED trial, and validation cohorts included 6868 participants from the US Nurses\' Health Studies I and II, and Health Professionals Follow-up Study (NHS/HPFS). Adherence to the Mediterranean diet was assessed using a validated Mediterranean Diet Adherence Screener (MEDAS), and plasma metabolome was profiled by liquid chromatography-tandem mass spectrometry. We observed substantial metabolomic variation with respect to Mediterranean diet adherence, with nearly one-third of the assayed metabolites significantly associated with MEDAS (false discovery rate < 0.05). Using elastic net regularized regressions, we identified a metabolic signature, comprised of 67 metabolites, robustly correlated with Mediterranean diet adherence in both PREDIMED and NHS/HPFS (r = 0.28-0.37 between the signature and MEDAS; P = 3 × 10-35 to 4 × 10-118). In multivariable Cox regressions, the metabolic signature showed a significant inverse association with CVD incidence after adjusting for known risk factors (PREDIMED: hazard ratio [HR] per standard deviation increment in the signature = 0.71, P < 0.001; NHS/HPFS: HR = 0.85, P = 0.001), and the association persisted after further adjustment for MEDAS scores (PREDIMED: HR = 0.73, P = 0.004; NHS/HPFS: HR = 0.85, P = 0.004). Further genome-wide association analysis revealed that the metabolic signature was significantly associated with genetic loci involved in fatty acids and amino acids metabolism. Mendelian randomization analyses showed that the genetically inferred metabolic signature was significantly associated with risk of coronary heart disease (CHD) and stroke (odds ratios per SD increment in the genetically inferred metabolic signature = 0.92 for CHD and 0.91 for stroke; P < 0.001).
Conclusions
We identified a metabolic signature that robustly reflects adherence and metabolic response to a Mediterranean diet, and predicts future CVD risk independent of traditional risk factors, in Spanish and US cohorts.

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: 13 May 2020; epub ahead of print
Li J, Guasch-Ferré M, Chung W, Ruiz-Canela M, ... Hu FB, Liang L
Eur Heart J: 13 May 2020; epub ahead of print | PMID: 32406924
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Abstract

Blood Pressure Variation and Subclinical Brain Disease.

Ma Y, Yilmaz P, Bos D, Blacker D, ... Vernooij MW, Ikram MK
Background
Large blood pressure (BP) variability may contribute to stroke and dementia, but the mechanisms are largely unknown.
Objectives
This study investigated the association of BP variation, considering its magnitude and direction, with the presence and progression of subclinical brain disease in the general population.
Methods
This study included 2,348 participants age ≥55 years from a prospective cohort study. BP was measured at each visit every 3 to 4 years from 1990 onward. Brain magnetic resonance imaging (MRI) was performed at all visits from 2005 onward. The authors primarily assessed variation as the absolute difference in BP divided by the mean over 2 sequential visits for both systolic BP (SBP) and diastolic BP (DBP), and further assessed the direction of the variation. The authors investigated the multivariate-adjusted associations of BP variation with subsequent measurements of MRI markers of cerebral small vessel disease, brain tissue volumes, and white matter microstructural integrity. Longitudinal changes in these markers also were assessed.
Results
A large SBP variation (top vs. bottom tertiles), measured on average 7 years preceding brain MRI, was associated with higher odds of having severe white matter hyperintensities (WMH) (odds ratio [OR]: 1.32; 95% confidence interval [CI]: 1.21 to 1.43), lacunes (OR: 1.25; 95% CI: 1.04 to 1.48), and microbleeds (OR: 1.16; 95% CI: 1.03 to 1.31). Similarly, this variation was associated with smaller total brain volume and worse white matter microstructural integrity (all p < 0.001). A large SBP variation was also associated with the progression of WMH (rate ratio [RR]: 1.14; 95% CI: 1.02 to 1.27). Higher burdens of these brain imaging markers were observed with both large rises and falls in SBP. Similar findings were observed for DBP variation.
Conclusions
Elevated BP variation was associated with a wide range of subclinical brain structural changes, including MRI markers of cerebral small vessel disease, smaller brain tissue volumes, and worse white matter microstructural integrity. These subclinical brain changes could be the underlying mechanisms linking BP variation to dementia and stroke.

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

J Am Coll Cardiol: 18 May 2020; 75:2387-2399
Ma Y, Yilmaz P, Bos D, Blacker D, ... Vernooij MW, Ikram MK
J Am Coll Cardiol: 18 May 2020; 75:2387-2399 | PMID: 32408975
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Abstract

Randomized Trial of Lactin-V to Prevent Recurrence of Bacterial Vaginosis.

Cohen CR, Wierzbicki MR, French AL, Morris S, ... Parks T, Hemmerling A
Background
Bacterial vaginosis affects 15 to 50% of women of reproductive age, and recurrence is common after treatment with an antibiotic agent. The high incidence of recurrence suggests the need for new treatments to prevent recurrent bacterial vaginosis.
Methods
We conducted a randomized, double-blind, placebo-controlled, phase 2b trial to evaluate the ability ofCTV-05 (Lactin-V) to prevent the recurrence of bacterial vaginosis. Women 18 to 45 years of age who had received a diagnosis of bacterial vaginosis and who had completed a course of vaginal metronidazole gel as part of the eligibility requirements were randomly assigned, in a 2:1 ratio, to receive vaginally administered Lactin-V or placebo for 11 weeks; follow-up occurred through week 24. The primary outcome was the percentage of women who had a recurrence of bacterial vaginosis by week 12.
Results
A total of 228 women underwent randomization: 152 to the Lactin-V group and 76 to the placebo group; of these participants, 88% in the Lactin-V group and 84% in the placebo group could be evaluated for the primary outcome. In the intention-to-treat population, recurrence of bacterial vaginosis by week 12 occurred in 46 participants (30%) in the Lactin-V group and in 34 participants (45%) in the placebo group (risk ratio after multiple imputation for missing responses, 0.66; 95% confidence interval [CI], 0.44 to 0.87; P = 0.01). The risk ratio for recurrence by week 24 (also calculated with multiple imputation for missing responses) was 0.73 (95% CI, 0.54 to 0.92). At the 12-week visit,CTV-05 was detected in 79% of participants in the Lactin-V group. The percentage of participants who had at least one adverse event related to Lactin-V or placebo by week 24 did not differ significantly between the groups. The percentage of participants with local or systemic adverse events was similar in the two groups.
Conclusions
The use of Lactin-V after treatment with vaginal metronidazole resulted in a significantly lower incidence of recurrence of bacterial vaginosis than placebo at 12 weeks. (Funded by the National Institutes of Health; ClinicalTrials.gov number, NCT02766023.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 13 May 2020; 382:1906-1915
Cohen CR, Wierzbicki MR, French AL, Morris S, ... Parks T, Hemmerling A
N Engl J Med: 13 May 2020; 382:1906-1915 | PMID: 32402161
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Abstract

Atezolizumab plus Bevacizumab in Unresectable Hepatocellular Carcinoma.

Finn RS, Qin S, Ikeda M, Galle PR, ... Cheng AL,
Background
The combination of atezolizumab and bevacizumab showed encouraging antitumor activity and safety in a phase 1b trial involving patients with unresectable hepatocellular carcinoma.
Methods
In a global, open-label, phase 3 trial, patients with unresectable hepatocellular carcinoma who had not previously received systemic treatment were randomly assigned in a 2:1 ratio to receive either atezolizumab plus bevacizumab or sorafenib until unacceptable toxic effects occurred or there was a loss of clinical benefit. The coprimary end points were overall survival and progression-free survival in the intention-to-treat population, as assessed at an independent review facility according to Response Evaluation Criteria in Solid Tumors, version 1.1 (RECIST 1.1).
Results
The intention-to-treat population included 336 patients in the atezolizumab-bevacizumab group and 165 patients in the sorafenib group. At the time of the primary analysis (August 29, 2019), the hazard ratio for death with atezolizumab-bevacizumab as compared with sorafenib was 0.58 (95% confidence interval [CI], 0.42 to 0.79; P<0.001). Overall survival at 12 months was 67.2% (95% CI, 61.3 to 73.1) with atezolizumab-bevacizumab and 54.6% (95% CI, 45.2 to 64.0) with sorafenib. Median progression-free survival was 6.8 months (95% CI, 5.7 to 8.3) and 4.3 months (95% CI, 4.0 to 5.6) in the respective groups (hazard ratio for disease progression or death, 0.59; 95% CI, 0.47 to 0.76; P<0.001). Grade 3 or 4 adverse events occurred in 56.5% of 329 patients who received at least one dose of atezolizumab-bevacizumab and in 55.1% of 156 patients who received at least one dose of sorafenib. Grade 3 or 4 hypertension occurred in 15.2% of patients in the atezolizumab-bevacizumab group; however, other high-grade toxic effects were infrequent.
Conclusions
In patients with unresectable hepatocellular carcinoma, atezolizumab combined with bevacizumab resulted in better overall and progression-free survival outcomes than sorafenib. (Funded by F. Hoffmann-La Roche/Genentech; ClinicalTrials.gov number, NCT03434379.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 13 May 2020; 382:1894-1905
Finn RS, Qin S, Ikeda M, Galle PR, ... Cheng AL,
N Engl J Med: 13 May 2020; 382:1894-1905 | PMID: 32402160
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Abstract

EAPCI Position Statement on Invasive Management of Acute Coronary Syndromes during the COVID-19 pandemic.

Chieffo A, Stefanini GG, Price S, Barbato E, ... Dudek D, Baumbach A

The coronavirus disease 2019 (COVID-19) pandemic poses an unprecedented challenge to healthcare worldwide. The infection can be life threatening and require intensive care treatment. The transmission of the disease poses a risk to both patients and healthcare workers. The number of patients requiring hospital admission and intensive care may overwhelm health systems and negatively affect standard care for patients presenting with conditions needing emergency interventions. This position statements aims to assist cardiologists in the invasive management of acute coronary syndrome (ACS) patients in the context of the COVID-19 pandemic. To that end, we assembled a panel of interventional cardiologists and acute cardiac care specialists appointed by the European Association of Percutaneous Cardiovascular Interventions (EAPCI) and from the Acute Cardiovascular Care Association (ACVC) and included the experience from the first and worst affected areas in Europe. Modified diagnostic and treatment algorithms are proposed to adapt evidence-based protocols for this unprecedented challenge. Various clinical scenarios, as well as management algorithms for patients with a diagnosed or suspected COVID-19 infection, presenting with ST- and non-ST-segment elevation ACS are described. In addition, we address the need for re-organization of ACS networks, with redistribution of hub and spoke hospitals, as well as for in-hospital reorganization of emergency rooms and cardiac units, with examples coming from multiple European countries. Furthermore, we provide a guidance to reorganization of catheterization laboratories and, importantly, measures for protection of healthcare providers involved with invasive procedures.

This article has been co-published with permission in the European Heart Journal and EuroIntervention. All rights reserved. © 2020 European Society of Cardiology. These articles are identical except for minor stylistic and spelling differences in keeping with each journal\'s style. Either citation can be used when citing this article.

Eur Heart J: 13 May 2020; epub ahead of print
Chieffo A, Stefanini GG, Price S, Barbato E, ... Dudek D, Baumbach A
Eur Heart J: 13 May 2020; epub ahead of print | PMID: 32405641
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Abstract

Reduction of hospitalizations for myocardial infarction in Italy in the COVID-19 era.

De Rosa S, Spaccarotella C, Basso C, Calabrò MP, ... Indolfi C,
Aims
To evaluate the impact of the COVID-19 pandemic on patient admissions to Italian cardiac care units (CCUs).
Methods and results
We conducted a multicentre, observational, nationwide survey to collect data on admissions for acute myocardial infarction (AMI) at Italian CCUs throughout a 1 week period during the COVID-19 outbreak, compared with the equivalent week in 2019. We observed a 48.4% reduction in admissions for AMI compared with the equivalent week in 2019 (P < 0.001). The reduction was significant for both ST-segment elevation myocardial infarction [STEMI; 26.5%, 95% confidence interval (CI) 21.7-32.3; P = 0.009] and non-STEMI (NSTEMI; 65.1%, 95% CI 60.3-70.3; P < 0.001). Among STEMIs, the reduction was higher for women (41.2%; P = 0.011) than men (17.8%; P = 0.191). A similar reduction in AMI admissions was registered in North Italy (52.1%), Central Italy (59.3%), and South Italy (52.1%). The STEMI case fatality rate during the pandemic was substantially increased compared with 2019 [risk ratio (RR) = 3.3, 95% CI 1.7-6.6; P < 0.001]. A parallel increase in complications was also registered (RR = 1.8, 95% CI 1.1-2.8; P = 0.009).
Conclusion
Admissions for AMI were significantly reduced during the COVID-19 pandemic across Italy, with a parallel increase in fatality and complication rates. This constitutes a serious social issue, demanding attention by the scientific and healthcare communities and public regulatory agencies.

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: 14 May 2020; epub ahead of print
De Rosa S, Spaccarotella C, Basso C, Calabrò MP, ... Indolfi C,
Eur Heart J: 14 May 2020; epub ahead of print | PMID: 32412631
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Abstract

Summary of Updated Recommendations for Primary Prevention of Cardiovascular Disease in Women: JACC State-of-the-Art Review.

Cho L, Davis M, Elgendy I, Epps K, ... Volgman AS,

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality for women in the United States and worldwide. There has been no American College of Cardiology (ACC)/American Heart Association guideline update specifically for the prevention of CVD in women since 2011. Since then, the body of sex-specific data has grown, in addition to updated hypertension, cholesterol, diabetes, atrial fibrillation, and primary prevention guidelines. The ACC CVD in Women Committee undertook a review of the recent guidelines and major studies to summarize recommendations pertinent to women. In this update, the authors address special topics, particularly the risk factors and treatments that have led to some controversies and confusion. Specifically, sex-related risk factors, hypertension, diabetes, hyperlipidemia, anticoagulation for atrial fibrillation, use of aspirin, perimenopausal hormone therapy, and psychosocial issues are highlighted.

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

J Am Coll Cardiol: 25 May 2020; 75:2602-2618
Cho L, Davis M, Elgendy I, Epps K, ... Volgman AS,
J Am Coll Cardiol: 25 May 2020; 75:2602-2618 | PMID: 32439010
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Abstract

Worldwide Prevalence of Familial Hypercholesterolemia: Meta-Analyses of 11 Million Subjects.

Beheshti SO, Madsen CM, Varbo A, Nordestgaard BG
Background
Despite the greater prevalence of familial hypercholesterolemia (FH) in subjects with ischemic heart disease (IHD), premature IHD, and severe hypercholesterolemia (low-density lipoprotein ≥190 mg/dl), overall prevalence estimates are not available.
Objectives
The aim of this study was to provide worldwide estimates of FH prevalence in subjects with IHD, premature IHD, and severe hypercholesterolemia compared with those in the general population.
Methods
In this systematic review and meta-analyses, Embase, PubMed, and the Web of Science were searched until June 3, 2019, for peer-reviewed papers and conference abstracts reporting heterozygous FH prevalence in nonfounder populations, revealing 104 studies eligible for inclusion.
Results
Estimates of FH prevalence were pooled using random-effects meta-analyses and were 0.32% (95% confidence interval [CI]: 0.26% to 0.39% [corresponding to 1:313]) among 10,921,310 unique subjects in the general population (33,036 patients with FH) on the basis of 44 studies, 3.2% (95% CI: 2.2% to 4.3% [1:31]) among 84,479 unique subjects with IHD (2,103 patients with FH) on the basis of 28 studies, 6.7% (95% CI: 4.9% to 8.7% [1:15]) among 31,316 unique subjects with premature IHD (1,471 patients with FH) on the basis of 32 studies, and 7.2% (95% CI: 4.6% to 10.8% [1:14]) among 17,728 unique subjects with severe hypercholesterolemia (920 patients with FH) on the basis of 7 studies. FH prevalence in the general population was similar using genetic versus clinical diagnoses. Seventeen of 195 countries (9%) in the world have reported FH prevalence for the general population, leaving 178 (91%) countries in the world with unknown prevalence.
Conclusions
Compared with 1:313 among subjects in the general population, FH prevalence is 10-fold higher among those with IHD, 20-fold higher among those with premature IHD, and 23-fold higher among those with severe hypercholesterolemia. The prevalence of FH is unknown in 90% of countries in the world.

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

J Am Coll Cardiol: 25 May 2020; 75:2553-2566
Beheshti SO, Madsen CM, Varbo A, Nordestgaard BG
J Am Coll Cardiol: 25 May 2020; 75:2553-2566 | PMID: 32439005
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Impact:
Abstract

Allocating Scarce Resources and Triaging Patients during the COVID-19 Pandemic.

Kirkpatrick JN, Hull SC, Fedson S, Mullen B, Goodlin SJ

The COVID-19 pandemic and its sequelae have created scenarios of scarce medical resources, leading to the prospect that healthcare systems have faced or will face difficult decisions about triage, allocation and reallocation. These decisions should be guided by ethical principles and values, should not be made before crisis standards have been declared by authorities, and, in most cases, will not be made by bedside clinicians. Do not attempt resuscitation (DNAR) and withholding and withdrawing decisions should be made according to standard determination of medical appropriateness and futility, but there are unique considerations during a pandemic. Transparent and clear communication is crucial, coupled with dedication to provide the best possible care to patients, including palliative care. As medical knowledge about COVID-19 grows, more will be known about prognostic factors that can guide these difficult decisions.

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 07 May 2020; epub ahead of print
Kirkpatrick JN, Hull SC, Fedson S, Mullen B, Goodlin SJ
J Am Coll Cardiol: 07 May 2020; epub ahead of print | PMID: 32407772
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Impact:
Abstract

Associations Between Cardiovascular Risk, Structural Brain Changes, and Cognitive Decline.

Song R, Xu H, Dintica CS, Pan KY, ... Bennett DA, Xu W
Background
The impact of cardiovascular risk burden on cognitive trajectories and brain structure changes remains unclear.
Objectives
This study aimed to examine whether cardiovascular risk burden assessed by the Framingham General Cardiovascular Risk Score (FGCRS) is associated with cognitive decline and structural brain differences.
Methods
Within the Rush Memory and Aging Project, 1,588 dementia-free participants (mean age: 79.5 years) were followed for up to 21 years. FGCRS was assessed at baseline and categorized into tertiles (lowest, middle, and highest). Episodic memory, semantic memory, working memory, visuospatial ability, and perceptual speed were assessed annually with a battery of 19 tests, from which composite scores were derived. A subsample (n = 378) of participants underwent magnetic resonance imaging. Structural total and regional brain volumes were estimated. Data were analyzed using linear mixed-effects models and linear regression models.
Results
In all participants, FGCRS ranged from 4 to 28 (mean score: 15.6 ± 3.7). Compared with the lowest tertile of FGCRS, the highest tertile was associated with faster decline in global cognition (β = -0.019; 95% confidence interval [CI]: -0.035 to -0.003), episodic memory (β = -0.023; 95% CI: -0.041 to -0.004), working memory (β = -0.021; 95% CI: -0.035 to -0.007), and perceptual speed (β = -0.027; 95% CI: -0.042 to -0.011) over the follow-up. In magnetic resonance imaging data analyses, higher FGCRS was related to smaller volumes of the hippocampus (β = -0.021; 95% CI: -0.042 to -0.000), gray matter (β = -1.569; 95% CI: -2.757 to -0.382), and total brain (β = -1.588; 95% CI: -2.832 to -0.344), and greater volume of white matter hyperintensities (β = 0.035; 95% CI: 0.001 to 0.069).
Conclusions
Higher cardiovascular risk burden may predict decline in episodic memory, working memory, and perceptual speed and is associated with neurodegeneration and vascular lesions in the brain.

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

J Am Coll Cardiol: 25 May 2020; 75:2525-2534
Song R, Xu H, Dintica CS, Pan KY, ... Bennett DA, Xu W
J Am Coll Cardiol: 25 May 2020; 75:2525-2534 | PMID: 32439001
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Abstract

Prevention of aortic dissection and aneurysm via an ALDH2-mediated switch in vascular smooth muscle cell phenotype.

Yang K, Ren J, Li X, Wang Z, ... Chen Y, Xu F
Aims
Aortic aneurysm/dissection (AAD) is a life-threatening disorder lacking effective pharmacotherapeutic remedies. Aldehyde dehydrogenase 2 (ALDH2) polymorphism is tied with various risk factors for AAD including hypertension, atherosclerosis, and hypercholesterolaemia although direct correlation between the two remains elusive.
Methods and results
Two independent case-control studies were conducted involving 307 AAD patients and 399 healthy controls in two geographically distinct areas in China. Our data revealed that subjects carrying mutant ALDH2 gene possessed a ∼50% reduced risk of AAD compared with wild-type (WT) alleles. Using 3-aminopropionitrile fumarate (BAPN)- and angiotensin II (Ang II)-induced AAD animal models, inhibition of ALDH2 was found to retard development of AAD. Mechanistically, ALDH2 inhibition ablated pathological vascular smooth muscle cell (VSMC) phenotypical switch through interaction with myocardin, a determinant of VSMC contractile phenotype. Using microarray and bioinformatics analyses, ALDH2 deficiency was found to down-regulate miR-31-5p, which further altered myocardin mRNA level. Gain-of-function and loss-of-function studies verified that miR-31-5p significantly repressed myocardin level and aggravated pathological VSMC phenotypical switch and AAD, an effect that was blunted by ALDH2 inhibition. We next noted that ALDH2 deficiency increased Max expression and decreased miR-31-5p level. Moreover, ALDH2 mutation or inhibition down-regulated levels of miR-31-5p while promoting myocardin downstream contractile genes in the face of Ang II in primary human VSMCs.
Conclusions
ALDH2 deficiency is associated with a lower risk of AAD in patients and mice, possibly via suppressing VSMC phenotypical switch in a miR-31-5p-myocardin-dependent manner. These findings favour a role for ALDH2 and miR-31-5p as novel targets for AAD therapy.

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: 17 May 2020; epub ahead of print
Yang K, Ren J, Li X, Wang Z, ... Chen Y, Xu F
Eur Heart J: 17 May 2020; epub ahead of print | PMID: 32428930
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Impact:
Abstract

The thrombotic risk of spaceflight: has a serious problem been overlooked for more than half of a century?

Limper U, Tank J, Ahnert T, Maegele M, ... Hein M, Jordan J

The first ever venous thrombotic condition associated with spaceflight, an internal jugular vein thrombus requiring anticoagulation, has recently been reported. Systematic investigation of space travel-associated thrombotic risk has not been conducted. Cellular, animal, and human studies performed in ground-based models and in actual weightlessness revealed influences of weightlessness and gravity on the blood coagulation system. However, human study populations were small and limited to highly selected participants. Evidence in individuals with medical conditions and older persons is lacking. Evidence for thrombotic risk in spaceflight is unsatisfactory. This issue deserves further study in heterogeneous, high risk populations to find prevention strategies and to enable safe governmental and touristic human spaceflight.

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: 17 May 2020; epub ahead of print
Limper U, Tank J, Ahnert T, Maegele M, ... Hein M, Jordan J
Eur Heart J: 17 May 2020; epub ahead of print | PMID: 32428936
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Impact:
Abstract

Pulmonary Vascular Endothelialitis, Thrombosis, and Angiogenesis in Covid-19.

Ackermann M, Verleden SE, Kuehnel M, Haverich A, ... Mentzer SJ, Jonigk D
Background
Progressive respiratory failure is the primary cause of death in the coronavirus disease 2019 (Covid-19) pandemic. Despite widespread interest in the pathophysiology of the disease, relatively little is known about the associated morphologic and molecular changes in the peripheral lung of patients who die from Covid-19.
Methods
We examined 7 lungs obtained during autopsy from patients who died from Covid-19 and compared them with 7 lungs obtained during autopsy from patients who died from acute respiratory distress syndrome (ARDS) secondary to influenza A(H1N1) infection and 10 age-matched, uninfected control lungs. The lungs were studied with the use of seven-color immunohistochemical analysis, micro-computed tomographic imaging, scanning electron microscopy, corrosion casting, and direct multiplexed measurement of gene expression.
Results
In patients who died from Covid-19-associated or influenza-associated respiratory failure, the histologic pattern in the peripheral lung was diffuse alveolar damage with perivascular T-cell infiltration. The lungs from patients with Covid-19 also showed distinctive vascular features, consisting of severe endothelial injury associated with the presence of intracellular virus and disrupted cell membranes. Histologic analysis of pulmonary vessels in patients with Covid-19 showed widespread thrombosis with microangiopathy. Alveolar capillary microthrombi were 9 times as prevalent in patients with Covid-19 as in patients with influenza (P<0.001). In lungs from patients with Covid-19, the amount of new vessel growth - predominantly through a mechanism of intussusceptive angiogenesis - was 2.7 times as high as that in the lungs from patients with influenza (P<0.001).
Conclusions
In our small series, vascular angiogenesis distinguished the pulmonary pathobiology of Covid-19 from that of equally severe influenza virus infection. The universality and clinical implications of our observations require further research to define. (Funded by the National Institutes of Health and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 20 May 2020; epub ahead of print
Ackermann M, Verleden SE, Kuehnel M, Haverich A, ... Mentzer SJ, Jonigk D
N Engl J Med: 20 May 2020; epub ahead of print | PMID: 32437596
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Impact:
Abstract

Subcutaneous Selatogrel Inhibits Platelet Aggregation in Patients With Acute Myocardial Infarction.

Sinnaeve P, Fahrni G, Schelfaut D, Spirito A, ... Atar S, Valgimigli M
Background
Oral P2Y receptor antagonists exhibit delayed onset of platelet inhibition in patients with acute myocardial infarction (AMI). Selatogrel is a potent, highly selective, and reversible P2Y receptor antagonist with a rapid onset and short duration of action.
Objectives
This study sought to assess inhibition of platelet aggregation following subcutaneous administration of selatogrel in patients with AMI.
Methods
Patients with AMI were randomized to a single subcutaneous dose of selatogrel of 8 or 16 mg. The primary endpoint was response to treatment (P2Y reaction units <100; measured by VerifyNow) at 30 min post-dose. Safety was assessed up to 48 h post-injection.
Results
Forty-seven patients received selatogrel 8 mg (n = 24) or 16 mg (n = 23) followed by ticagrelor (n = 43) or clopidogrel (n = 1). The proportion of responders 30 min post-dose was 91% (one-sided 97.5% confidence interval [CI]: 80% to 100%) and 96% (97.5% CI: 87% to 100%) with 8 and 16 mg, respectively (p values for responders >85% target; p = 0.142 and p = 0.009, respectively). Response rates were independent from type of AMI presentation, age, or sex. A similar response rate was observed at 15 min (8 mg: 75% [97.5% CI: 58% to 100%]; 16 mg: 91% [97.5% CI: 80% to 100%]), which was sustained at 60 min post-dose (8 mg: 75% [97.5% CI: 58% to 100%]; 16 mg: 96% [97.5% CI: 87% to 100%]). At 15 min, median P2Y reaction units was 51 (range: 4 to 208) for 8 mg and 9 (range: 2 to 175) for 16 mg. Selatogrel was well tolerated, without major bleeding complications.
Conclusions
Single-dose subcutaneous administration of selatogrel in patients with AMI was safe and induced a profound, rapid, and dose-related antiplatelet response. (A Medical Research Study to Evaluate the Effects of ACT-246475 in Adults With Heart Attack; NCT03487445, 2018-000765-36 [EudraCT]).

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 25 May 2020; 75:2588-2597
Sinnaeve P, Fahrni G, Schelfaut D, Spirito A, ... Atar S, Valgimigli M
J Am Coll Cardiol: 25 May 2020; 75:2588-2597 | PMID: 32439008
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Impact:
Abstract

Physiological Stratification of Patients With Angina Due to Coronary Microvascular Dysfunction.

Rahman H, Demir OM, Khan F, Ryan M, ... Webb A, Perera D
Background
Coronary microvascular dysfunction (CMD) is defined by diminished flow reserve. Functional and structural CMD endotypes have recently been described, with normal and elevated minimal microvascular resistance, respectively.
Objectives
This study determined the mechanism of altered resting and maximal flow in CMD endotypes.
Methods
A total of 86 patients with angina but no obstructive coronary disease underwent coronary pressure and flow measurement during rest, exercise, and adenosine-mediated hyperemia and were classified as the reference group or as patients with CMD by a coronary flow reserve threshold of 2.5; functional or structural endotypes were distinguished by a hyperemic microvascular resistance threshold of 2.5 mm Hg/cm/s. Endothelial function was assessed by forearm blood flow (FBF) response to acetylcholine, and nitric oxide synthase (NOS) activity was defined as the inverse of FBF reserve to N-monomethyl-L-arginine.
Results
Of the 86 patients, 46 had CMD (28 functional, 18 structural), and 40 patients formed the reference group. Resting coronary blood flow (CBF) (24.6 ± 2.0 cm/s vs. 16.6 ± 3.9 cm/s vs. 15.1 ± 4.7 cm/s; p < 0.001) and NOS activity (2.27 ± 0.96 vs. 1.77 ± 0.59 vs. 1.30 ± 0.16; p < 0.001) were higher in the functional group compared with the structural CMD and reference groups, respectively. The structural group had lower acetylcholine FBF augmentation than the functional or reference group (2.1 ± 1.8 vs. 4.1 ± 1.7 vs. 4.5 ± 2.0; p < 0.001). On exercise, oxygen demand was highest (rate-pressure product: 22,157 ± 5,497 beats/min/mm Hg vs. 19,519 ± 4,653 beats/min/mm Hg vs. 17,530 ± 4,678 beats/min/mm Hg; p = 0.004), but peak CBF was lowest in patients with structural CMD compared with the functional and reference groups.
Conclusions
Functional CMD is characterized by elevated resting flow that is linked to enhanced NOS activity. Patients with structural CMD have endothelial dysfunction, which leads to diminished peak CBF augmentation and increased demand during exercise. The value of pathophysiologically stratified therapy warrants investigation.

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

J Am Coll Cardiol: 25 May 2020; 75:2538-2549
Rahman H, Demir OM, Khan F, Ryan M, ... Webb A, Perera D
J Am Coll Cardiol: 25 May 2020; 75:2538-2549 | PMID: 32439003
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Impact:
Abstract

Remdesivir for the Treatment of Covid-19 - Preliminary Report.

Beigel JH, Tomashek KM, Dodd LE, Mehta AK, ... Lane HC,
Background
Although several therapeutic agents have been evaluated for the treatment of coronavirus disease 2019 (Covid-19), none have yet been shown to be efficacious.
Methods
We conducted a double-blind, randomized, placebo-controlled trial of intravenous remdesivir in adults hospitalized with Covid-19 with evidence of lower respiratory tract involvement. Patients were randomly assigned to receive either remdesivir (200 mg loading dose on day 1, followed by 100 mg daily for up to 9 additional days) or placebo for up to 10 days. The primary outcome was the time to recovery, defined by either discharge from the hospital or hospitalization for infection-control purposes only.
Results
A total of 1063 patients underwent randomization. The data and safety monitoring board recommended early unblinding of the results on the basis of findings from an analysis that showed shortened time to recovery in the remdesivir group. Preliminary results from the 1059 patients (538 assigned to remdesivir and 521 to placebo) with data available after randomization indicated that those who received remdesivir had a median recovery time of 11 days (95% confidence interval [CI], 9 to 12), as compared with 15 days (95% CI, 13 to 19) in those who received placebo (rate ratio for recovery, 1.32; 95% CI, 1.12 to 1.55; P<0.001). The Kaplan-Meier estimates of mortality by 14 days were 7.1% with remdesivir and 11.9% with placebo (hazard ratio for death, 0.70; 95% CI, 0.47 to 1.04). Serious adverse events were reported for 114 of the 541 patients in the remdesivir group who underwent randomization (21.1%) and 141 of the 522 patients in the placebo group who underwent randomization (27.0%).
Conclusions
Remdesivir was superior to placebo in shortening the time to recovery in adults hospitalized with Covid-19 and evidence of lower respiratory tract infection. (Funded by the National Institute of Allergy and Infectious Diseases and others; ACCT-1 ClinicalTrials.gov number, NCT04280705.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 21 May 2020; epub ahead of print
Beigel JH, Tomashek KM, Dodd LE, Mehta AK, ... Lane HC,
N Engl J Med: 21 May 2020; epub ahead of print | PMID: 32445440
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Impact:
Abstract

Comparison of in-hospital outcomes and readmissions for valve-in-valve transcatheter aortic valve replacement vs. reoperative surgical aortic valve replacement: a contemporary assessment of real-world outcomes.

Hirji SA, Percy ED, Zogg CK, Malarczyk A, ... Yazdchi F, Kaneko T
Aims
We sought to perform a head-to-head comparison of contemporary 30-day outcomes and readmissions between valve-in-valve transcatheter aortic valve replacement (VIV-TAVR) patients and a matched cohort of high-risk reoperative surgical aortic valve replacement (re-SAVR) patients using a large, multicentre, national database.
Methods and results
We utilized the nationally weighted 2012-16 National Readmission Database claims to identify all US adult patients with degenerated bioprosthetic aortic valves who underwent either VIV-TAVR (n = 3443) or isolated re-SAVR (n = 3372). Thirty-day outcomes were compared using multivariate analysis and propensity score matching (1:1). Unadjusted, VIV-TAVR patients had significantly lower 30-day mortality (2.7% vs. 5.0%), 30-day morbidity (66.4% vs. 79%), and rates of major bleeding (35.8% vs. 50%). On multivariable analysis, re-SAVR was a significant risk factor for both 30-day mortality [adjusted odds ratio (aOR) of VIV-SAVR (vs. re-SAVR) 0.48, 95% confidence interval (CI) 0.28-0.81] and 30-day morbidity [aOR for VIV-TAVR (vs. re-SAVR) 0.54, 95% CI 0.43-0.68]. After matching (n = 2181 matched pairs), VIV-TAVR was associated with lower odds of 30-day mortality (OR 0.41, 95% CI 0.23-0.74), 30-day morbidity (OR 0.53, 95% CI 0.43-0.72), and major bleeding (OR 0.66, 95% CI 0.51-0.85). Valve-in-valve TAVR was also associated with shorter length of stay (median savings of 2 days, 95% CI 1.3-2.7) and higher odds of routine home discharges (OR 2.11, 95% CI 1.61-2.78) compared to re-SAVR.
Conclusion
In this large, nationwide study of matched high-risk patients with degenerated bioprosthetic aortic valves, VIV-TAVR appears to confer an advantage over re-SAVR in terms of 30-day mortality, morbidity, and bleeding complications. Further studies are warranted to benchmark in low- and intermediate-risk patients and to adequately assess longer-term efficacy.

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: 22 May 2020; epub ahead of print
Hirji SA, Percy ED, Zogg CK, Malarczyk A, ... Yazdchi F, Kaneko T
Eur Heart J: 22 May 2020; epub ahead of print | PMID: 32445575
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Impact:
Abstract

Call to Action to Prevent Venous Thromboembolism in Hospitalized Patients: A Policy Statement From the American Heart Association.

Henke PK, Kahn SR, Pannucci CJ, Secemksy EA, ... Pradhan AD,

Venous thromboembolism (VTE) is a major preventable disease that affects hospitalized inpatients. Risk stratification and prophylactic measures have good evidence supporting their use, but multiple reasons exist that prevent full adoption, compliance, and efficacy that may underlie the persistence of VTE over the past several decades. This policy statement provides a focused review of VTE, risk scoring systems, prophylaxis, and tracking methods. From this summary, 5 major areas of policy guidance are presented that the American Heart Association believes will lead to better implementation, tracking, and prevention of VTE events. They include performing VTE risk assessment and reporting the level of VTE risk in all hospitalized patients, integrating preventable VTE as a benchmark for hospital comparison and pay-for-performance programs, supporting appropriations to improve public awareness of VTE, tracking VTE nationwide with the use of standardized definitions, and developing a centralized data steward for data tracking on VTE risk assessment, prophylaxis, and rates.



Circulation: 06 May 2020:CIR0000000000000769; epub ahead of print
Henke PK, Kahn SR, Pannucci CJ, Secemksy EA, ... Pradhan AD,
Circulation: 06 May 2020:CIR0000000000000769; epub ahead of print | PMID: 32375490
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Impact:
Abstract

The pathogenicity of SARS-CoV-2 in hACE2 transgenic mice.

Bao L, Deng W, Huang B, Gao H, ... Wu G, Qin C

Severe acute respiratory syndrome CoV-2 (SARS-CoV-2) caused the corona virus disease 2019 (COVID-19) cases in China and has become a public health emergency of international concern. Because angiotensin-converting enzyme 2 (ACE2) is the cell entry receptor of SARS-CoV, we used transgenic mice bearing human ACE2 and infected with SARS-CoV-2 to study the pathogenicity of the virus. Weight loss and virus replication in lung were observed in hACE2 mice infected with SARS-CoV-2. The typical histopathology was interstitial pneumonia with infiltration of significant macrophages and lymphocytes into the alveolar interstitium, and accumulation of macrophages in alveolar cavities. Viral antigens were observed in the bronchial epithelial cells, macrophages and alveolar epithelia. The phenomenon was not found in wild-type mice with SARS-CoV-2 infection. Notably, we have confirmed the pathogenicity of SARS-CoV-2 in hACE2 mice. The mouse model with SARS-CoV-2 infection will be valuable for evaluating antiviral therapeutics and vaccines as well as understanding the pathogenesis of COVID-19.



Nature: 06 May 2020; epub ahead of print
Bao L, Deng W, Huang B, Gao H, ... Wu G, Qin C
Nature: 06 May 2020; epub ahead of print | PMID: 32380511
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Impact:
Abstract

Inherited Thoracic Aortic Disease: New Insights and Translational Targets.

Fletcher AJ, Syed MBJ, Aitman TJ, Newby DE, Walker NL

Inherited thoracic aortopathies denote a group of congenital conditions that predispose to disease of the thoracic aorta. Aortic wall weakness and abnormal aortic hemodynamic profiles predispose these patients to dilatation of the thoracic aorta, which is generally silent but can precipitate aortic dissection or rupture with devastating and often fatal consequences. Current strategies to assess the future risk of aortic dissection or rupture are based primarily on monitoring aortic diameter. However, diameter alone is a poor predictor of risk, with many patients experiencing dissection or rupture below current intervention thresholds. Developing tools that improve the risk assessment of those with aortopathy is internationally regarded as a research priority. A robust understanding of the molecular pathways that lead to aortic wall weakness is required to identify biomarkers and therapeutic targets that could improve patient management. Here, we summarize the current understanding of the genetically determined mechanisms underlying inherited aortopathies and critically appraise the available blood biomarkers, imaging techniques, and therapeutic targets that have shown promise for improving the management of patients with these important and potentially fatal conditions.



Circulation: 11 May 2020; 141:1570-1587
Fletcher AJ, Syed MBJ, Aitman TJ, Newby DE, Walker NL
Circulation: 11 May 2020; 141:1570-1587 | PMID: 32392100
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Impact:
Abstract

Isolation of SARS-CoV-2-related coronavirus from Malayan pangolins.

Xiao K, Zhai J, Feng Y, Zhou N, ... Xiao L, Shen Y

The outbreak of COVID-19 poses unprecedent challenges to global health. The new coronavirus, SARS-CoV-2, shares high sequence identity to SARS-CoV and a bat coronavirus RaTG13. While bats may be the reservoir host for various coronaviruses, whether SARS-CoV-2 has other hosts remains ambiguous. In this study, one coronavirus isolated from a Malayan pangolin showed 100%, 98.6%, 97.8% and 90.7% amino acid identity with SARS-CoV-2 in the E, M, N and S genes, respectively. In particular, the receptor-binding domain within the S protein of the Pangolin-CoV is virtually identical to that of SARS-CoV-2, with one noncritical amino acid difference. Results of comparative genomic analysis suggest that SARS-CoV-2 might have originated from the recombination of a Pangolin-CoV-like virus with a Bat-CoV-RaTG13-like virus. The Pangolin-CoV was detected in 17 of 25 Malayan pangolins analyzed. Infected pangolins showed clinical signs and histological changes, and circulating antibodies against Pangolin-CoV reacted with the S protein of SARS-CoV-2. The isolation of a coronavirus that is highly related to SARS-CoV-2 in pangolins suggests that they have the potential to act as the intermediate host of SARS-CoV-2. The newly identified coronavirus in the most-trafficked mammal could represent a future threat to public health if wildlife trade is not effectively controlled.



Nature: 06 May 2020; epub ahead of print
Xiao K, Zhai J, Feng Y, Zhou N, ... Xiao L, Shen Y
Nature: 06 May 2020; epub ahead of print | PMID: 32380510
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Impact:
Abstract

Monotherapy with a P2Y inhibitor or aspirin for secondary prevention in patients with established atherosclerosis: a systematic review and meta-analysis.

Chiarito M, Sanz-Sánchez J, Cannata F, Cao D, ... Ferrante G, Stefanini GG
Background
Antiplatelet therapy is recommended among patients with established atherosclerosis. We compared monotherapy with a P2Y inhibitor versus aspirin for secondary prevention.
Methods
In this systematic review and meta-analysis, all randomised trials comparing P2Y inhibitor with aspirin monotherapy for secondary prevention in patients with cerebrovascular, coronary, or peripheral artery disease were evaluated for inclusion. On Dec 18, 2019, we searched PubMed, Embase, BioMedCentral, Google Scholar, and the Cochrane Central Register of Controlled Trials. Additionally, we reviewed references from identified articles and searched abstracts from 2017 to 2019 presented at relevant scientific meetings. Data about year of publication, inclusion and exclusion criteria, sample size, baseline patients\' features including the baseline condition determining study inclusion (ie, cerebrovascular, coronary, or peripheral artery disease), P2Y inhibitor type and dosage, aspirin dosage, endpoint definitions, effect estimates, follow-up duration, and percentage of patients lost to follow-up were collected. Odds ratios (ORs) and 95% CIs were used as metric of choice for treatment effects with random-effects models. Co-primary endpoints were myocardial infarction and stroke. Key secondary endpoints were all-cause death and vascular death. Heterogeneity was assessed with the I index. This study is registered with PROSPERO (CRD42018115037).
Findings
A total of nine randomised trials were identified and included in this study, and 42 108 patients randomly allocated to a P2Y inhibitor (n=21 043) or aspirin (n=21 065) were included in our analyses. Patients who received a P2Y inhibitor had a borderline reduction for the risk of myocardial infarction compared with those who received aspirin (OR 0·81 [95% CI 0·66-0·99]; I=10·9%). Risks of stroke (OR 0·93 [0·82-1·06]; I=34·5%), all-cause death (OR 0·98 [0·89-1·08]; I=0%), and vascular death (OR 0·97 [0·86-1·09]; I=0%) did not differ between patients who received a P2Y inhibitor and those who received aspirin. Similarly, the risk of major bleeding (OR 0·90 [0·74-1·10]; I=3·9%) did not differ between patients who received a P2Y inhibitor and those who received aspirin. The number needed to treat to prevent one myocardial infarction with P2Y inhibitor monotherapy was 244 patients. Findings were consistent regardless of the type of P2Y inhibitor used.
Interpretation
Compared with aspirin monotherapy, P2Y inhibitor monotherapy is associated with a risk reduction for myocardial infarction and a comparable risk of stroke in the setting of secondary prevention. The benefit of P2Y inhibitor monotherapy is of debatable clinical relevance, in view of the high number needed to treat to prevent a myocardial infarction and the absence of any effect on all-cause and vascular mortality.
Funding
Italian Ministry of Education.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 08 May 2020; 395:1487-1495
Chiarito M, Sanz-Sánchez J, Cannata F, Cao D, ... Ferrante G, Stefanini GG
Lancet: 08 May 2020; 395:1487-1495 | PMID: 32386592
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Impact:
Abstract

Longevity genes, cardiac ageing, and the pathogenesis of cardiomyopathy: implications for understanding the effects of current and future treatments for heart failure.

Packer M

The two primary molecular regulators of lifespan are sirtuin-1 (SIRT1) and mammalian target of rapamycin complex 1 (mTORC1). Each plays a central role in two highly interconnected pathways that modulate the balance between cellular growth and survival. The activation of SIRT1 [along with peroxisome proliferator-activated receptor-gamma coactivator (PGC-1α) and adenosine monophosphate-activated protein kinase (AMPK)] and the suppression of mTORC1 (along with its upstream regulator, Akt) act to prolong organismal longevity and retard cardiac ageing. Both activation of SIRT1/PGC-1α and inhibition of mTORC1 shifts the balance of cellular priorities so as to promote cardiomyocyte survival over growth, leading to cardioprotective effects in experimental models. These benefits may be related to direct actions to modulate oxidative stress, organellar function, proinflammatory pathways, and maladaptive hypertrophy. In addition, a primary shared benefit of both SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 inhibition is the enhancement of autophagy, a lysosome-dependent degradative pathway, which clears the cytosol of dysfunctional organelles and misfolded proteins that drive the ageing process by increasing oxidative and endoplasmic reticulum stress. Autophagy underlies the ability of SIRT1/PGC-1α/AMPK activation and Akt/mTORC1 suppression to extend lifespan, mitigate cardiac ageing, alleviate cellular stress, and ameliorate the development and progression of cardiomyopathy; silencing of autophagy genes abolishes these benefits. Loss of SIRT1/PGC-1α/AMPK function or hyperactivation of Akt/mTORC1 is a consistent feature of experimental cardiomyopathy, and reversal of these abnormalities mitigates the development of heart failure. Interestingly, most treatments that have been shown to be clinically effective in the treatment of chronic heart failure with a reduced ejection fraction have been reported experimentally to exert favourable effects to activate SIRT1/PGC-1α/AMPK and/or suppress Akt/mTORC1, and thereby, to promote autophagic flux. Therefore, the impairment of autophagy resulting from derangements in longevity gene signalling is likely to represent a seminal event in the evolution and progression of cardiomyopathy.

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

Eur Heart J: 26 May 2020; epub ahead of print
Packer M
Eur Heart J: 26 May 2020; epub ahead of print | PMID: 32460327
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Abstract

WWP1 Gain-of-Function Inactivation of PTEN in Cancer Predisposition.

Lee YR, Yehia L, Kishikawa T, Ni Y, ... Eng C, Pandolfi PP
Background
Patients withhamartoma tumor syndrome (PHTS) have germline mutations in the tumor-suppressor gene encoding phosphatase and tensin homologue (). Such mutations have been associated with a hereditary predisposition to multiple types of cancer, including the Cowden syndrome. However, a majority of patients who have PHTS-related phenotypes have tested negative formutations. In a previous study, we found that the E3 ubiquitin ligase WWP1 negatively regulates the function of PTEN.
Methods
In a prospective cohort study conducted from 2005 through 2015, we enrolled 431 patients with wild-typewho met at least the relaxed diagnostic criteria of the International Cowden Consortium. Patients were scanned forgermline variants. We used the Cancer Genome Atlas (TCGA) data set as representative of apparently sporadic cancers and the Exome Aggregation Consortium data set excluding TCGA (non-TCGA ExAC) and the noncancer Genome Aggregation Database (gnomAD) as representative of population controls without a reported cancer diagnosis. We established both in vitro and murine in vivo models to functionally characterize representativevariants.
Results
The existence of germlinevariants was first established in a family with wild-typewho had oligopolyposis and early-onset colon cancers. A validation series indicated thatgermline variants occurred in 5 of 126 unrelated patients (4%) with oligopolyposis as a predominant phenotype. Germlinevariants, particularly theK740N and N745S alleles, were enriched in patients who did not have PHTS but had prevalent sporadic cancers, including related cancer types in TCGA (odds ratio, 1.5; 95% confidence interval, 1.1 to 2.1; P = 0.01). The prioritizedvariants resulted in gain-of-function effects, which led to aberrant enzymatic activation with consequent PTEN inactivation, thereby triggering hyperactive growth-promoting PI3K signaling in cellular and murine models.
Conclusions
In this study involving patients with disorders resulting in a predisposition to the development of multiple malignant neoplasms withoutgermline mutations, we confirmed the function ofas a cancer-susceptibility gene through direct aberrant regulation of the PTEN-PI3K signaling axis. (Funded by the National Institutes of Health and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 27 May 2020; 382:2103-2116
Lee YR, Yehia L, Kishikawa T, Ni Y, ... Eng C, Pandolfi PP
N Engl J Med: 27 May 2020; 382:2103-2116 | PMID: 32459922
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Abstract

Remdesivir for 5 or 10 Days in Patients with Severe Covid-19.

Goldman JD, Lye DCB, Hui DS, Marks KM, ... Subramanian A,
Background
Remdesivir is an RNA polymerase inhibitor with potent antiviral activity in vitro and efficacy in animal models of coronavirus disease 2019 (Covid-19).
Methods
We conducted a randomized, open-label, phase 3 trial involving hospitalized patients with confirmed SARS-CoV-2 infection, oxygen saturation of 94% or less while they were breathing ambient air, and radiologic evidence of pneumonia. Patients were randomly assigned in a 1:1 ratio to receive intravenous remdesivir for either 5 days or 10 days. All patients received 200 mg of remdesivir on day 1 and 100 mg once daily on subsequent days. The primary end point was clinical status on day 14, assessed on a 7-point ordinal scale.
Results
In total, 397 patients underwent randomization and began treatment (200 patients for 5 days and 197 for 10 days). The median duration of treatment was 5 days (interquartile range, 5 to 5) in the 5-day group and 9 days (interquartile range, 5 to 10) in the 10-day group. At baseline, patients randomly assigned to the 10-day group had significantly worse clinical status than those assigned to the 5-day group (P = 0.02). By day 14, a clinical improvement of 2 points or more on the ordinal scale occurred in 64% of patients in the 5-day group and in 54% in the 10-day group. After adjustment for baseline clinical status, patients in the 10-day group had a distribution in clinical status at day 14 that was similar to that among patients in the 5-day group (P = 0.14). The most common adverse events were nausea (9% of patients), worsening respiratory failure (8%), elevated alanine aminotransferase level (7%), and constipation (7%).
Conclusions
In patients with severe Covid-19 not requiring mechanical ventilation, our trial did not show a significant difference between a 5-day course and a 10-day course of remdesivir. With no placebo control, however, the magnitude of benefit cannot be determined. (Funded by Gilead Sciences; GS-US-540-5773 ClinicalTrials.gov number, NCT04292899.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 26 May 2020; epub ahead of print
Goldman JD, Lye DCB, Hui DS, Marks KM, ... Subramanian A,
N Engl J Med: 26 May 2020; epub ahead of print | PMID: 32459919
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Abstract

FDA Initiative for Drug Facts Label for Over-the-Counter Naloxone.

Cohen BR, Mahoney KM, Baro E, Squire C, ... Izem R, Woodcock J
Background
The opioid crisis highlights the need to increase access to naloxone, possibly through regulatory approval for over-the-counter sales. To address industry-perceived barriers to such access, the Food and Drug Administration (FDA) developed a model drug facts label for such sales to assess whether consumers understood the key statements for safe and effective use.
Methods
In this label-comprehension study, we conducted individual structured interviews with 710 adults and adolescents, including 430 adults who use opioids and their family and friends. Eight primary end points were developed to assess user comprehension of each of the key steps in the label. Each of these end points included a prespecified target threshold ranging from 80 to 90% that was evaluated through a comparison of the lower boundary of the 95% exact confidence interval.
Results
The results for performance on six primary end points met or exceeded thresholds, including the steps \"Check for a suspected overdose\" (threshold, 85%; point estimate [PE], 95.8%; 95% confidence interval [CI], 94.0 to 97.1) and \"Give the first dose\" (threshold, 85%; PE, 98.2%; 95% CI, 96.9 to 99.0). The lower boundaries for four other primary end points ranged from 88.8 to 94.0%. One exception was comprehension of \"Call 911 immediately,\" but this instruction closely approximated the target of 90% (PE, 90.3%; 95% CI, 87.9 to 92.4). Another exception was comprehension of the composite step of \"Check, give, and call 911 immediately\" (threshold, 85%; PE, 81.1%; 95% CI, 78.0 to 83.9).
Conclusions
Consumers met thresholds for sufficient understanding of six of eight components of the instructions in the drug facts label for naloxone use and came close on two others. Overall, the FDA found that the model label was adequate for use in the development of a naloxone product intended for over-the-counter sales.

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 27 May 2020; 382:2129-2136
Cohen BR, Mahoney KM, Baro E, Squire C, ... Izem R, Woodcock J
N Engl J Med: 27 May 2020; 382:2129-2136 | PMID: 32459923
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Abstract

Hospitalization and Mortality among Black Patients and White Patients with Covid-19.

Price-Haywood EG, Burton J, Fort D, Seoane L
Background
Many reports on coronavirus disease 2019 (Covid-19) have highlighted age- and sex-related differences in health outcomes. More information is needed about racial and ethnic differences in outcomes from Covid-19.
Methods
In this retrospective cohort study, we analyzed data from patients seen within an integrated-delivery health system (Ochsner Health) in Louisiana between March 1 and April 11, 2020, who tested positive for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, the virus that causes Covid-19) on qualitative polymerase-chain-reaction assay. The Ochsner Health population is 31% black non-Hispanic and 65% white non-Hispanic. The primary outcomes were hospitalization and in-hospital death.
Results
A total of 3626 patients tested positive, of whom 145 were excluded (84 had missing data on race or ethnic group, 9 were Hispanic, and 52 were Asian or of another race or ethnic group). Of the 3481 Covid-19-positive patients included in our analyses, 60.0% were female, 70.4% were black non-Hispanic, and 29.6% were white non-Hispanic. Black patients had higher prevalences of obesity, diabetes, hypertension, and chronic kidney disease than white patients. A total of 39.7% of Covid-19-positive patients (1382 patients) were hospitalized, 76.9% of whom were black. In multivariable analyses, black race, increasing age, a higher score on the Charlson Comorbidity Index (indicating a greater burden of illness), public insurance (Medicare or Medicaid), residence in a low-income area, and obesity were associated with increased odds of hospital admission. Among the 326 patients who died from Covid-19, 70.6% were black. In adjusted time-to-event analyses, variables that were associated with higher in-hospital mortality were increasing age and presentation with an elevated respiratory rate; elevated levels of venous lactate, creatinine, or procalcitonin; or low platelet or lymphocyte counts. However, black race was not independently associated with higher mortality (hazard ratio for death vs. white race, 0.89; 95% confidence interval, 0.68 to 1.17).
Conclusions
In a large cohort in Louisiana, 76.9% of the patients who were hospitalized with Covid-19 and 70.6% of those who died were black, whereas blacks comprise only 31% of the Ochsner Health population. Black race was not associated with higher in-hospital mortality than white race, after adjustment for differences in sociodemographic and clinical characteristics on admission.

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 26 May 2020; epub ahead of print
Price-Haywood EG, Burton J, Fort D, Seoane L
N Engl J Med: 26 May 2020; epub ahead of print | PMID: 32459916
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Abstract

Secukinumab versus adalimumab for treatment of active psoriatic arthritis (EXCEED): a double-blind, parallel-group, randomised, active-controlled, phase 3b trial.

McInnes IB, Behrens F, Mease PJ, Kavanaugh A, ... Pricop L,
Background
Head-to-head trials in psoriatic arthritis are helpful in guiding clinical decision making. The EXCEED study evaluated the efficacy and safety of secukinumab versus adalimumab as first-line biological monotherapy for 52 weeks in patients with active psoriatic arthritis, with a musculoskeletal primary endpoint of American College of Rheumatology (ACR) 20 response.
Methods
This parallel-group, double-blind, active-controlled, phase-3b, multicentre (168 sites in 26 countries) trial enrolled patients aged at least 18 years with active psoriatic arthritis. Eligible patients were randomly assigned (1:1) by means of interactive response technology to receive secukinumab or adalimumab. Patients, investigators, site personnel, and those doing the assessments (except independent study drug administrators) were masked to study assignment. 300 mg secukinumab was administered subcutaneously at baseline, weeks 1, 2, 3, and 4, and then every 4 weeks until week 48 as a pre-filled syringe. Adalimumab was administered every 2 weeks from baseline until week 50 as 40 mg per 0·4 mL citrate free subcutaneous injection. The primary outcome was the proportion of patients with at least 20% improvement in the ACR response criteria (ACR20) at week 52. Patients were analysed according to the treatment to which they were randomly assigned. Safety analyses included all safety data reported up to and including the week 52 visit for each patient who received at least one dose of study drug. The trial is registered at ClinicalTrials.gov, NCT02745080.
Findings
Between April 3, 2017 and Aug 23, 2018, we randomly assigned 853 patients to receive secukinumab (n=426) or adalimumab (n=427). 709 (83%) of 853 patients completed week 52 of the study, of whom 691 (81%) received the last study treatment at week 50. 61 (14%) of 426 patients in the secukinumab group discontinued treatment by week 52 versus 101 (24%) of 427 patients in the adalimumab group. The primary endpoint of superiority of secukinumab versus adalimumab for ACR20 response at week 52 was not met. 67% of patients in the secukinumab group achieved an ACR20 response at week 52 versus 62% of patients in the adalimumab group (OR 1·30, 95% CI 0·98-1·72; p=0·0719). The safety profiles of secukinumab and adalimumab were consistent with previous reports. Seven (2%) of 426 patients in the secukinumab group and six (1%) of 427 patients in the adalimumab group had serious infections. One death was reported in the secukinumab group due to colon cancer and was assessed as not related to the study drug by the investigator.
Interpretation
Secukinumab did not meet statistical significance for superiority versus adalimumab in the primary endpoint of ACR20 response at week 52. However, secukinumab was associated with a higher treatment retention rate than adalimumab. This study provides comparative data on two biological agents with different mechanisms of action, which could help guide clinical decision making in the management of patients with psoriatic arthritis.
Funding
Novartis Pharma.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 08 May 2020; 395:1496-1505
McInnes IB, Behrens F, Mease PJ, Kavanaugh A, ... Pricop L,
Lancet: 08 May 2020; 395:1496-1505 | PMID: 32386593
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Abstract

A Population-Based Registry of Patients With Inherited Cardiac Conditions and Resuscitated Cardiac Arrest.

Rucinski C, Winbo A, Marcondes L, Earle N, ... Martin A, Skinner JR
Background
The relative proportion of each cardiac inherited disease (CID) causing resuscitated sudden cardiac arrest (RSCA) on a population basis is unknown.
Objectives
This study describes the profile of patients with CIDs presenting with RSCA; their data were collected by the national Cardiac Inherited Diseases Registry New Zealand (CIDRNZ).
Methods
Data were collated from CIDRNZ probands presenting with RSCA (2002 to 2018).
Results
CID was identified in 115 (51%) of 225 RSCA cases: long QT syndrome (LQTS) (n = 48 [42%]), hypertrophic cardiomyopathy (HCM) (n = 28 [24%]), Brugada syndrome (BrS) (n = 16 [14%]), catecholaminergic polymorphic ventricular tachycardia (CPVT) (n = 9 [8%]), arrhythmogenic right ventricular cardiomyopathy (ARVC) (n = 9 [8%]), and dilated cardiomyopathy (n = 5 [4%]). Seventy-one (62%) of 115 were male. Of 725 probands from the CIDRNZ with CID, the proportion presenting with RSCA was: CPVT, 9 (53%) of 17; BrS, 16 (33%) of 49; ARVC, 9 (25%) of 36; LQTS, 48 (20%) of 238; dilated cardiomyopathy, 5 (9%) of 58; and HCM, 28 (8%) of 354. Incident activity was: normal everyday activities, 44 (40%); exercising, 33 (30%); concurrent illness, 13 (12%); sleeping, 10 (9%); drugs/medication, 9 (8%); and emotion, 2 (2%). LQTS and CPVT predominated in those <24 years of age, 30 (77%) of 39; cardiomyopathies and BrS predominated in those >24 years of age, 49 (64%) of 76. For those >40 years of age, HCM was the most common (33%) CID. A genetic diagnosis in patients with CID was made in 48 (49%) of 98 tested. Diagnosis by age range was as follows: age 1 to 14 years, 78%; age 15 to 24 years, 53%; age 25 to 39 years, 54%; and age >40 years, 26%.
Conclusions
The commonest CID identified after RSCA was LQTS; the most common CID cause of RSCA for those >40 years of age was HCM. CPVT was the CID most likely to present with RSCA and HCM the least. Genetic yield decreases with age. Only one-third of RSCA cases due to CID occurred while exercising.

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

J Am Coll Cardiol: 01 Jul 2020; 75:2698-2707
Rucinski C, Winbo A, Marcondes L, Earle N, ... Martin A, Skinner JR
J Am Coll Cardiol: 01 Jul 2020; 75:2698-2707 | PMID: 32466885
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Abstract

Suppression of Endothelial AGO1 Promotes Adipose Tissue Browning and Improves Metabolic Dysfunction.

Tang X, Miao Y, Luo Y, Sriram K, ... Zhong S, Chen ZB

Metabolic disorders such as obesity and diabetes can cause dysfunction of endothelial cells (ECs) and vascular rarefaction in adipose tissues. However, the modulatory role of ECs in adipose tissue function is not fully understood. Other than VEGF-VEGFR-mediated angiogenic signaling, little is known about the EC-derived signals in adipose tissue regulation. We previously identified Argonaute 1 (AGO1; a key component of microRNA-induced silencing complex) as a crucial regulator in hypoxia-induced angiogenesis. In this study, we intend to determine the AGO1-mediated EC transcriptome, the functional importance of AGO1-regulated endothelial function , and the relevance to adipose tissue function and obesity.We generated and subjected mice with EC-AGO1 deletion (EC-AGO1-KO) and their wild-type littermates (WT) to a fast-food-mimicking, high-fat high-sucrose diet and profiled the metabolic phenotypes. We employed crosslinking immunoprecipitation (iCLIP)- and RNA-sequencing to identify the AGO1-mediated mechanisms underlying the observed metabolic phenotype of EC-AGO1-KO. We further leveraged cell cultures and mouse models to validate the functional importance of the identified molecular pathway, for which the translational relevance was explored using human endothelium isolated from healthy and obese/Type 2 diabetic donors.We identified an anti-obesity phenotype of EC-AGO1-KO, evident by lower body weight and body fat, improved insulin sensitivity, and enhanced energy expenditure. At the organ level, we observed the most significant phenotype in the subcutaneous and brown adipose tissues of KO mice, with greater vascularity and enhanced browning and thermogenesis. Mechanistically, EC-AGO1 suppression results in inhibition of thrombospondin-1 (/TSP1), an anti-angiogenic and pro-inflammatory cytokine that promotes insulin resistance. In EC-AGO1-KO mice, overexpression of TSP1 substantially attenuated the beneficial phenotype. In human endothelium isolated from obese and/or type 2 diabetic donors, AGO1 and THBS1 are expressed at higher levels than the healthy controls, supporting a pathological role of this pathway.Our study suggests a novel mechanism by which ECs, through AGO1-TSP1 pathway, control vascularization and function of adipose tissues, insulin sensitivity, and whole-body metabolic state.



Circulation: 11 May 2020; epub ahead of print
Tang X, Miao Y, Luo Y, Sriram K, ... Zhong S, Chen ZB
Circulation: 11 May 2020; epub ahead of print | PMID: 32393053
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Abstract

Respiratory disease in rhesus macaques inoculated with SARS-CoV-2.

Munster VJ, Feldmann F, Williamson BN, van Doremalen N, ... Fischer ER, de Wit E

An outbreak of a novel coronavirus, named SARS-CoV-2, causing respiratory disease and a ~2% case fatality rate started in Wuhan, China in December 2019. Following unprecedented global spread, the World Health Organization declared COVID-19 a pandemic on March 11, 2020. Although data on disease in humans are emerging at a steady pace, certain aspects of the pathogenesis of SARS-CoV-2 can only be studied in detail in animal models, where repeated sampling and tissue collection is possible. Here, we show that SARS-CoV-2 causes respiratory disease in infected rhesus macaques, with disease lasting 8-16 days. Pulmonary infiltrates, a hallmark of human disease, were visible in lung radiographs. High viral loads were detected in swabs from the nose and throat of all animals as well as in bronchoalveolar lavages; in one animal we observed prolonged rectal shedding. Taken together, the rhesus macaque recapitulates moderate disease observed in the majority of human cases. The establishment of the rhesus macaque as a model of COVID-19 will increase our understanding of the pathogenesis of this disease and will aid development and testing of medical countermeasures.



Nature: 11 May 2020; epub ahead of print
Munster VJ, Feldmann F, Williamson BN, van Doremalen N, ... Fischer ER, de Wit E
Nature: 11 May 2020; epub ahead of print | PMID: 32396922
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Abstract

Enzalutamide and Survival in Nonmetastatic, Castration-Resistant Prostate Cancer.

Sternberg CN, Fizazi K, Saad F, Shore ND, ... Hussain M,
Background
Preliminary trial results showed that enzalutamide significantly improved metastasis-free survival among men who had nonmetastatic, castration-resistant prostate cancer and rapidly increasing prostate-specific antigen (PSA) levels while taking androgen-deprivation therapy. Results from the final analysis of overall survival have not yet been reported.
Methods
In this double-blind, phase 3 trial, men with nonmetastatic, castration-resistant prostate cancer (defined on the basis of conventional imaging and a PSA doubling time of ≤10 months) who were continuing to receive androgen-deprivation therapy were randomly assigned (in a 2:1 ratio) to receive enzalutamide at a dose of 160 mg or placebo once daily. Overall survival was assessed with a group sequential testing procedure and an O\'Brien-Fleming-type alpha-spending function.
Results
As of October 15, 2019, a total of 288 of 933 patients (31%) in the enzalutamide group and 178 of 468 (38%) in the placebo group had died. Median overall survival was 67.0 months (95% confidence interval [CI], 64.0 to not reached) in the enzalutamide group and 56.3 months (95% CI, 54.4 to 63.0) in the placebo group (hazard ratio for death, 0.73; 95% CI, 0.61 to 0.89; P = 0.001). The exposure-adjusted rate of adverse events of grade 3 or higher was 17 per 100 patient-years in the enzalutamide group and 20 per 100 patient-years in the placebo group. Adverse events in the enzalutamide group were consistent with those previously reported for enzalutamide; the most frequently reported events were fatigue and musculoskeletal events.
Conclusions
Enzalutamide plus androgen-deprivation therapy resulted in longer median overall survival than placebo plus androgen-deprivation therapy among men with nonmetastatic, castration-resistant prostate cancer and a rapidly rising PSA level. The risk of death associated with enzalutamide was 27% lower than with placebo. Adverse events were consistent with the established safety profile of enzalutamide. (Funded by Pfizer and Astellas Pharma; PROSPER ClinicalTrials.gov number, NCT02003924.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 28 May 2020; epub ahead of print
Sternberg CN, Fizazi K, Saad F, Shore ND, ... Hussain M,
N Engl J Med: 28 May 2020; epub ahead of print | PMID: 32469184
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Abstract

Transcriptional and Cellular Diversity of the Human Heart.

Tucker NR, Chaffin M, Fleming SJ, Hall AW, ... Stegmann CM, Ellinor PT

The human heart requires a complex ensemble of specialized cell types to perform its essential function. A greater knowledge of the intricate cellular milieu of the heart is critical to increase our understanding of cardiac homeostasis and pathology. As recent advances in low input RNA-sequencing have allowed definitions of cellular transcriptomes at single cell resolution at scale, here we have applied these approaches to assess the cellular and transcriptional diversity of the non-failing human heart.Microfluidic encapsulation and barcoding was used to perform single nuclear RNA sequencing with samples from seven human donors, selected for their absence of overt cardiac disease. Individual nuclear transcriptomes were then clustered based upon transcriptional profiles of highly variable genes. These clusters were used as the basis for between-chamber and between-sex differential gene expression analyses and intersection with genetic and pharmacologic data.We sequenced the transcriptomes of 287,269 single cardiac nuclei, revealing a total of 9 major cell types and 20 subclusters of cell types within the human heart. Cellular subclasses include two distinct groups of resident macrophages, four endothelial subtypes, and two fibroblasts subsets. Comparisons of cellular transcriptomes by cardiac chamber or sex reveal diversity not only in cardiomyocyte transcriptional programs, but also in subtypes involved in extracellular matrix remodeling and vascularization. Using genetic association data, we identified strong enrichment for the role of cell subtypes in cardiac traits and diseases. Finally, intersection of our dataset with genes on cardiac clinical testing panels and the druggable genome reveals striking patterns of cellular specificity.Using large-scale single nuclei RNA sequencing, we have defined the transcriptional and cellular diversity in the normal human heart. Our identification of discrete cell subtypes and differentially expressed genes within the heart will ultimately facilitate the development of new therapeutics for cardiovascular diseases.



Circulation: 13 May 2020; epub ahead of print
Tucker NR, Chaffin M, Fleming SJ, Hall AW, ... Stegmann CM, Ellinor PT
Circulation: 13 May 2020; epub ahead of print | PMID: 32403949
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Abstract

Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy.

Ho CY, Mealiffe ME, Bach RG, Bhattacharya M, ... Wong TC, Heitner SB
Background
Patients with nonobstructive hypertrophic cardiomyopathy (nHCM) often experience a high burden of symptoms; however, there are no proven pharmacological therapies. By altering the contractile mechanics of the cardiomyocyte, myosin inhibitors have the potential to modify pathophysiology and improve symptoms associated with HCM.
Objectives
MAVERICK-HCM (Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy) explored the safety and efficacy of mavacamten, a first-in-class reversible inhibitor of cardiac-specific myosin, in nHCM.
Methods
The MAVERICK-HCM trial was a multicenter, double-blind, placebo-controlled, dose-ranging phase II study in adults with symptomatic nHCM (New York Heart Association functional class II/III), left ventricular ejection fraction (LVEF) ≥55%, and N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml. Participants were randomized 1:1:1 to mavacamten at a pharmacokinetic-adjusted dose (targeting plasma levels of 200 or 500 ng/ml), or placebo for 16 weeks, followed by an 8-week washout. Initial dose was 5 mg daily with 1 dose titration at week 6.
Results
Fifty-nine participants were randomized (19, 21, 19 patients to 200 ng/ml, 500 ng/ml, placebo, respectively). Their mean age was 54 years, and 58% were women. Serious adverse events occurred in 10% of participants on mavacamten and in 21% participants on placebo. Five participants on mavacamten had reversible reduction in LVEF ≤45%. NT-proBNP geometric mean decreased by 53% in the pooled mavacamten group versus 1% in the placebo group, with geometric mean differences of -435 and -6 pg/ml, respectively (p = 0.0005). Cardiac troponin I (cTnI) geometric mean decreased by 34% in the pooled mavacamten group versus a 4% increase in the placebo group, with geometric mean differences of -0.008 and 0.001 ng/ml, respectively (p = 0.009).
Conclusions
Mavacamten, a novel myosin inhibitor, was well tolerated in most subjects with symptomatic nHCM. Furthermore, treatment was associated with a significant reduction in NT-proBNP and cTnI, suggesting improvement in myocardial wall stress. These results set the stage for future studies of mavacamten in this patient population using clinical parameters, including LVEF, to guide dosing. (A Phase 2 Study of Mavacamten in Adults With Symptomatic Non-Obstructive Hypertrophic Cardiomyopathy [MAVERICK-HCM]; NCT03442764).

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

J Am Coll Cardiol: 01 Jul 2020; 75:2649-2660
Ho CY, Mealiffe ME, Bach RG, Bhattacharya M, ... Wong TC, Heitner SB
J Am Coll Cardiol: 01 Jul 2020; 75:2649-2660 | PMID: 32466879
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Abstract

Tepotinib in Non-Small-Cell Lung Cancer with Exon 14 Skipping Mutations.

Paik PK, Felip E, Veillon R, Sakai H, ... Heymach JV, Le X
Background
A splice-site mutation that results in a loss of transcription of exon 14 in the oncogenic driveroccurs in 3 to 4% of patients with non-small-cell lung cancer (NSCLC). We evaluated the efficacy and safety of tepotinib, a highly selective MET inhibitor, in this patient population.
Methods
In this open-label, phase 2 study, we administered tepotinib (at a dose of 500 mg) once daily in patients with advanced or metastatic NSCLC with a confirmedexon 14 skipping mutation. The primary end point was the objective response by independent review among patients who had undergone at least 9 months of follow-up. The response was also analyzed according to whether the presence of aexon 14 skipping mutation was detected on liquid biopsy or tissue biopsy.
Results
As of January 1, 2020, a total of 152 patients had received tepotinib, and 99 patients had been followed for at least 9 months. The response rate by independent review was 46% (95% confidence interval [CI], 36 to 57), with a median duration of response of 11.1 months (95% CI, 7.2 to could not be estimated) in the combined-biopsy group. The response rate was 48% (95% CI, 36 to 61) among 66 patients in the liquid-biopsy group and 50% (95% CI, 37 to 63) among 60 patients in the tissue-biopsy group; 27 patients had positive results according to both methods. The investigator-assessed response rate was 56% (95% CI, 45 to 66) and was similar regardless of the previous therapy received for advanced or metastatic disease. Adverse events of grade 3 or higher that were considered by investigators to be related to tepotinib therapy were reported in 28% of the patients, including peripheral edema in 7%. Adverse events led to permanent discontinuation of tepotinib in 11% of the patients. A molecular response, as measured in circulating free DNA, was observed in 67% of the patients with matched liquid-biopsy samples at baseline and during treatment.
Conclusions
Among patients with advanced NSCLC with a confirmedexon 14 skipping mutation, the use of tepotinib was associated with a partial response in approximately half the patients. Peripheral edema was the main toxic effect of grade 3 or higher. (Funded by Merck [Darmstadt, Germany]; VISION ClinicalTrials.gov number, NCT02864992.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 28 May 2020; epub ahead of print
Paik PK, Felip E, Veillon R, Sakai H, ... Heymach JV, Le X
N Engl J Med: 28 May 2020; epub ahead of print | PMID: 32469185
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Abstract

Mechanistic Biomarkers Informative of Both Cancer and Cardiovascular Disease: JACC State-of-the-Art Review.

Narayan V, Thompson EW, Demissei B, Ho JE, Januzzi JL, Ky B

Cardiovascular disease (CVD) and cancer are leading causes of morbidity and mortality worldwide. Although conventionally managed as separate disease processes, recent research has lent insight into compelling commonalities between CVD and cancer, including shared mechanisms for disease development and progression. In this review, the authors discuss several pathophysiological processes common to both CVD and cancer, such as inflammation, resistance to cell death, cellular proliferation, neurohormonal stress, angiogenesis, and genomic instability, in an effort to understand common mechanisms of both disease states. In particular, the authors highlight key circulating and genomic biomarkers associated with each of these processes, as well as their associations with risk and prognosis in both cancer and CVD. The purpose of this state-of-the-art review is to further our understanding of the potential mechanisms underlying cancer and CVD by contextualizing pathways and biomarkers common to both diseases.

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

J Am Coll Cardiol: 01 Jul 2020; 75:2726-2737
Narayan V, Thompson EW, Demissei B, Ho JE, Januzzi JL, Ky B
J Am Coll Cardiol: 01 Jul 2020; 75:2726-2737 | PMID: 32466889
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Abstract

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer.

Shitara K, Bang YJ, Iwasa S, Sugimoto N, ... Yamaguchi K,
Background
Trastuzumab deruxtecan (DS-8201) is an antibody-drug conjugate consisting of an anti-HER2 (human epidermal growth factor receptor 2) antibody, a cleavable tetrapeptide-based linker, and a cytotoxic topoisomerase I inhibitor. The drug may have efficacy in patients with HER2-positive advanced gastric cancer.
Methods
In an open-label, randomized, phase 2 trial, we evaluated trastuzumab deruxtecan as compared with chemotherapy in patients with HER2-positive advanced gastric cancer. Patients with centrally confirmed HER2-positive gastric or gastroesophageal junction adenocarcinoma that had progressed while they were receiving at least two previous therapies, including trastuzumab, were randomly assigned in a 2:1 ratio to receive trastuzumab deruxtecan (6.4 mg per kilogram of body weight every 3 weeks) or physician\'s choice of chemotherapy. The primary end point was the objective response, according to independent central review. Secondary end points included overall survival, response duration, progression-free survival, confirmed response (response persisting ≥4 weeks), and safety.
Results
Of 187 treated patients, 125 received trastuzumab deruxtecan and 62 chemotherapy (55 received irinotecan and 7 paclitaxel). An objective response was reported in 51% of the patients in the trastuzumab deruxtecan group, as compared with 14% of those in the physician\'s choice group (P<0.001). Overall survival was longer with trastuzumab deruxtecan than with chemotherapy (median, 12.5 vs. 8.4 months; hazard ratio for death, 0.59; 95% confidence interval, 0.39 to 0.88; P = 0.01, which crossed the prespecified O\'Brien-Fleming boundary [0.0202 on the basis of number of deaths]). The most common adverse events of grade 3 or higher were a decreased neutrophil count (in 51% of the trastuzumab deruxtecan group and 24% of the physician\'s choice group), anemia (38% and 23%, respectively), and decreased white-cell count (21% and 11%). A total of 12 patients had trastuzumab deruxtecan-related interstitial lung disease or pneumonitis (grade 1 or 2 in 9 patients and grade 3 or 4 in 3), as adjudicated by an independent committee. One drug-related death (due to pneumonia) was noted in the trastuzumab deruxtecan group; no drug-related deaths occurred in the physician\'s choice group.
Conclusions
Therapy with trastuzumab deruxtecan led to significant improvements in response and overall survival, as compared with standard therapies, among patients with HER2-positive gastric cancer. Myelosuppression and interstitial lung disease were the notable toxic effects. (Funded by Daiichi Sankyo; DESTINY-Gastric01 ClinicalTrials.gov number, NCT03329690.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 28 May 2020; epub ahead of print
Shitara K, Bang YJ, Iwasa S, Sugimoto N, ... Yamaguchi K,
N Engl J Med: 28 May 2020; epub ahead of print | PMID: 32469182
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Abstract

Drug-Coated Balloon Angioplasty Versus Drug-Eluting Stent Implantation in Patients With Coronary Stent Restenosis.

Giacoppo D, Alfonso F, Xu B, Claessen BEPM, ... Kastrati A, Byrne RA
Background
In patients with coronary in-stent restenosis (ISR) requiring reintervention, it is unclear if the choice of treatment should depend on whether the restenotic stent was a bare-metal stent (BMS) or a drug-eluting stent (DES).
Objectives
This study aimed to assess the comparative efficacy and safety of the 2 most frequently used treatments - angioplasty with drug-coated balloon (DCB) and repeat stenting DES - in patients with BMS-and DES-ISR.
Methods
The DAEDALUS (Difference in Antirestenotic Effectiveness of Drug-Eluting Stent and Drug-Coated Balloon Angioplasty for the Occurrence of Coronary In-Stent Restenosis) study was a pooled analysis of individual patient data from all 10 existing randomized clinical trials comparing DCB angioplasty with repeat DES implantation for the treatment of coronary ISR. In this pre-specified analysis, patients were stratified according to BMS- versus DES-ISR and treatment assigned. The primary efficacy endpoint was target lesion revascularization (TLR) at 3 years. The primary safety endpoint was a composite of all-cause death, myocardial infarction, or target lesion thrombosis at 3 years. Primary analysis was performed by mixed-effects Cox models accounting for the trial of origin. Secondary analyses included nonparsimonious multivariable adjustment accounting also for multiple lesions per patient and 2-stage analyses.
Results
A total of 710 patients with BMS-ISR (722 lesions) and 1,248 with DES-ISR (1,377 lesions) were included. In patients with BMS-ISR, no significant difference between treatments was observed in terms of primary efficacy (9.2% vs. 10.2%; hazard ratio [HR]: 0.83; 95% confidence interval [CI]: 0.51 to 1.37) and safety endpoints (8.7% vs. 7.5%; HR: 1.13; 95% CI: 0.65 to 1.96); results of secondary analyses were consistent. In patients with DES-ISR, the risk of the primary efficacy endpoint was higher with DCB angioplasty than with repeat DES implantation (20.3% vs. 13.4%; HR: 1.58; 95% CI: 1.16 to 2.13), whereas the risk of the primary safety endpoint was numerically lower (9.5% vs. 13.3%; HR: 0.69; 95% CI: 0.47 to 1.00); results of secondary analyses were consistent. Regardless of the treatment used, the risk of TLR was lower in BMS- versus DES-ISR (9.7% vs. 17.0%; HR: 0.56; 95% CI: 0.42 to 0.74), whereas safety was not significantly different between ISR types.
Conclusions
At 3-year follow-up, DCB angioplasty and repeat stenting with DES are similarly effective and safe in the treatment of BMS-ISR, whereas DCB angioplasty is significantly less effective than repeat DES implantation in the treatment DES-ISR, and associated with a nonsignificant reduction in the primary composite safety endpoint. Overall, DES-ISR is associated with higher rates of treatment failure and similar safety compared with BMS-ISR.

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

J Am Coll Cardiol: 01 Jul 2020; 75:2664-2678
Giacoppo D, Alfonso F, Xu B, Claessen BEPM, ... Kastrati A, Byrne RA
J Am Coll Cardiol: 01 Jul 2020; 75:2664-2678 | PMID: 32466881
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Abstract

Validation of the Academic Research Consortium High Bleeding Risk Definition in Contemporary PCI Patients.

Cao D, Mehran R, Dangas G, Baber U, ... Sharma SK, Kini A
Background
Bleeding following percutaneous coronary intervention has important prognostic implications. The Academic Research Consortium (ARC) recently proposed a list of clinical criteria to define patients at high bleeding risk (HBR).
Objectives
This study sought to validate the ARC definition for HBR patients in a contemporary real-world cohort.
Methods
Patients undergoing coronary stenting between 2014 and 2017 at a tertiary-care center were defined as HBR if they met at least 1 major or 2 minor ARC-HBR criteria. To account for the presence of multiple criteria, patients were further stratified by the number of times they fulfilled the ARC-HBR definition. The primary endpoint was a composite of peri-procedural in-hospital or post-discharge bleeding at 1 year. Secondary endpoints included individual components of the primary bleeding endpoint, myocardial infarction, and all-cause mortality.
Results
Among 9,623 patients, 4,278 (44.4%) qualified as HBR. Moderate or severe anemia was the most common major criterion (33.2%); age ≥75 years was the most frequent minor criterion and the most common overall (46.8%). The rate of the primary bleeding endpoint at 1 year was 9.1% in HBR patients compared with 3.2% in non-HBR patients (p < 0.001), with a stepwise increase in bleeding risk corresponding to the number of times the ARC-HBR definition was fulfilled. HBR patients also experienced significantly higher rates of all secondary endpoints.
Conclusions
This study validates the ARC-HBR definition in a contemporary group of patients who underwent percutaneous coronary intervention. The ARC-HBR definition identified patients at increased risk not only for bleeding but also for thrombotic events, including all-cause mortality. Coexistence of multiple ARC-HBR criteria showed additive prognostic value.

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

J Am Coll Cardiol: 01 Jul 2020; 75:2711-2722
Cao D, Mehran R, Dangas G, Baber U, ... Sharma SK, Kini A
J Am Coll Cardiol: 01 Jul 2020; 75:2711-2722 | PMID: 32466887
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Abstract

Oral Relugolix for Androgen-Deprivation Therapy in Advanced Prostate Cancer.

Shore ND, Saad F, Cookson MS, George DJ, ... Tombal B,
Background
Injectable luteinizing hormone-releasing hormone agonists (e.g., leuprolide) are the standard agents for achieving androgen deprivation for prostate cancer despite the initial testosterone surge and delay in therapeutic effect. The efficacy and safety of relugolix, an oral gonadotropin-releasing hormone antagonist, as compared with those of leuprolide are not known.
Methods
In this phase 3 trial, we randomly assigned patients with advanced prostate cancer, in a 2:1 ratio, to receive relugolix (120 mg orally once daily) or leuprolide (injections every 3 months) for 48 weeks. The primary end point was sustained testosterone suppression to castrate levels (<50 ng per deciliter) through 48 weeks. Secondary end points included noninferiority with respect to the primary end point, castrate levels of testosterone on day 4, and profound castrate levels (<20 ng per deciliter) on day 15. Testosterone recovery was evaluated in a subgroup of patients.
Results
A total of 622 patients received relugolix and 308 received leuprolide. Of men who received relugolix, 96.7% (95% confidence interval [CI], 94.9 to 97.9) maintained castration through 48 weeks, as compared with 88.8% (95% CI, 84.6 to 91.8) of men receiving leuprolide. The difference of 7.9 percentage points (95% CI, 4.1 to 11.8) showed noninferiority and superiority of relugolix (P<0.001 for superiority). All other key secondary end points showed superiority of relugolix over leuprolide (P<0.001). The percentage of patients with castrate levels of testosterone on day 4 was 56.0% with relugolix and 0% with leuprolide. In the subgroup of 184 patients followed for testosterone recovery, the mean testosterone levels 90 days after treatment discontinuation were 288.4 ng per deciliter in the relugolix group and 58.6 ng per deciliter in the leuprolide group. Among all the patients, the incidence of major adverse cardiovascular events was 2.9% in the relugolix group and 6.2% in the leuprolide group (hazard ratio, 0.46; 95% CI, 0.24 to 0.88).
Conclusions
In this trial involving men with advanced prostate cancer, relugolix achieved rapid, sustained suppression of testosterone levels that was superior to that with leuprolide, with a 54% lower risk of major adverse cardiovascular events. (Funded by Myovant Sciences; HERO ClinicalTrials.gov number, NCT03085095.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 28 May 2020; epub ahead of print
Shore ND, Saad F, Cookson MS, George DJ, ... Tombal B,
N Engl J Med: 28 May 2020; epub ahead of print | PMID: 32469183
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Abstract

Ascertainment Bias in the Association Between Elevated Lipoprotein(a) and Familial Hypercholesterolemia.

Trinder M, DeCastro ML, Azizi H, Cermakova L, ... Francis GA, Brunham LR
Background
Lipoprotein(a) is an atherogenic low-density lipoprotein-like particle and circulating levels are largely determined by genetics. Patients with familial hypercholesterolemia (FH) have elevated lipoprotein(a); however, it remains unclear why.
Objectives
This study compared the levels of lipoprotein(a) and associated genetic factors between individuals that were ascertained for FH clinically versus genetically.
Methods
We investigated causes of elevated lipoprotein(a) in individuals with clinically diagnosed FH (FH cohort, n = 391) and in individuals with genetically diagnosed FH from the general population (UK Biobank; n = 37,486).
Results
Patients in the FH cohort had significantly greater lipoprotein(a) levels than either the general population or non-FH dyslipidemic patients. This was accounted for by increased frequency of the rs10455872-G LPA risk allele (15.1% vs. 8.8%; p < 0.05). However, within the FH cohort, lipoprotein(a) levels did not differ based on the presence or absence of an FH-causing variant (means = 1.43 log mg/dl vs. 1.42 log mg/dl; p = 0.97). Lipoprotein(a) levels were also not statistically different between individuals with and without an FH-causing variant in the UK Biobank cohort, which represents a population sample not biased to cardiovascular ascertainment (n = 221 vs. 37,486). We performed a phenome-wide association study between LPA genotypes and 19,202 phenotypes to demonstrate that elevated lipoprotein(a) is associated with increased low-density lipoprotein cholesterol, a family history of cardiovascular disease, premature coronary artery disease, and a diagnosis of FH.
Conclusions
These results suggest that FH does not cause elevated lipoprotein(a), but that elevated lipoprotein(a) increases the likelihood that an individual with genetic FH will be clinically recognized.

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

J Am Coll Cardiol: 01 Jul 2020; 75:2682-2693
Trinder M, DeCastro ML, Azizi H, Cermakova L, ... Francis GA, Brunham LR
J Am Coll Cardiol: 01 Jul 2020; 75:2682-2693 | PMID: 32466883
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Abstract

Ramipril in High Risk Patients with COVID-19.

Amat-Santos IJ, Santos-Martinez S, López-Otero D, Nombela-Franco L, ... Ibañez B, San Román JA
Background
The coronavirus disease 2019 (COVID-19) is caused by SARS-CoV2 that interfaces with the renin-angiotensin-aldosterone system (RAAS) through angiotensin-converting enzyme 2 (ACE-2). This interaction has been proposed as a potential risk factor in patients treated with RAAS-inhibitors.
Objectives
To analyze if RAAS-inhibitors modify the risk for COVID-19.
Methods
RASTAVI (NCT03201185) is an ongoing randomized clinical trial randomly allocating Ramipril or control after successful transcatheter aortic valve replacement at 14 centers is Spain. We performed a non-pre-specified interim analysis to evaluate its impact on COVID-19 risk in this vulnerable population.
Results
As in April 1 2020, 102 patients (50 Ramipril and 52 controls) were included in the trial. Mean age was 82.3±6.1 years, 56.9% males. Median time of Ramipril treatment was 6 months [IQR:2.9-11.4]. Eleven patients (10.8%) have been diagnosed with COVID-19 (6 in control group and 5 receiving Ramipril, HR=1.150 [95%CI: 0.351-3.768]). The risk of COVID-19 was increased in older patients (p=0.019), those with atrial fibrillation (p=0.066), lower hematocrit (p=0.084), and more comorbidities according to Society of thoracic surgeons score (p=0.065). Admission and oxygen supply was required in 4.9% (2 patients in the Ramipril and 3 in control), and 4 of them died (two in each randomized group). A higher body mass index was the only factor increasing the mortality rate (p=0.039).
Conclusions
In a high risk population of old patients with cardiovascular disease, randomization to Ramipril had no impact in the incidence or severity of COVID-19. This analysis supports the maintenance of RAAS-inhibitor treatment during COVID-19 crisis.

Copyright © 2020. Published by Elsevier Inc.

J Am Coll Cardiol: 21 May 2020; epub ahead of print
Amat-Santos IJ, Santos-Martinez S, López-Otero D, Nombela-Franco L, ... Ibañez B, San Román JA
J Am Coll Cardiol: 21 May 2020; epub ahead of print | PMID: 32470515
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Abstract

Declines in Hospitalizations for Acute Cardiovascular Conditions During the COVID-19 Pandemic: A Multicenter Tertiary Care Experience.

Bhatt AS, Moscone A, McElrath EE, Varshney AS, ... Solomon SD, Vaduganathan M
Background
While patients with cardiovascular disease face excess risks of severe illness with coronavirus disease-2019 (COVID-19), there may be indirect consequences of the pandemic on this high-risk patient segment.
Objectives
To examine longitudinal trends in hospitalizations for acute cardiovascular conditions across a tertiary care healthcare system.
Methods
We tracked acute cardiovascular hospitalizations between January 1, 2019 and March 31, 2020. We estimated daily hospitalization rates using negative binomial models. Temporal trends in hospitalization rates were compared across the first 3 months of 2020, with the first 3 months of 2019 as a reference.
Results
From January 1, 2019 to March 31, 2020, 6,083 patients experienced 7,187 hospitalizations for primary acute cardiovascular reasons. There was 43.4% (27.4% to 56.0%) fewer estimated daily hospitalizations in March 2020 as compared with March 2019 (P<0.001). The daily rate of hospitalizations did not change throughout 2019 (-0.01% per day [-0.04% to +0.02%], P=0.50), January 2020 (-0.5% per day [-1.6% to +0.5%], P=0.31), or February 2020 (+0.7% per day [-0.6% to +2.0%], P=0.27). There was significant daily decline in hospitalizations in March 2020 (-5.9% per day [-7.6% to -4.3%], P<0.001). Length of stay was shorter (4.8 [2.4,8.3] days vs. 6.0 [3.1,9.6] days; P=0.003) and in-hospital mortality was not significantly different (6.2% vs. 4.4%; P=0.30) in March 2020 compared with March 2019.
Conclusions
During the first phase of the COVID-19 pandemic, there was a marked decline in acute cardiovascular hospitalizations and patients who were admitted had shorter lengths of stay. These data substantiate concerns that acute care of cardiovascular conditions may be delayed, deferred, or abbreviated during the COVID-19 pandemic.

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

J Am Coll Cardiol: 20 May 2020; epub ahead of print
Bhatt AS, Moscone A, McElrath EE, Varshney AS, ... Solomon SD, Vaduganathan M
J Am Coll Cardiol: 20 May 2020; epub ahead of print | PMID: 32470516
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Abstract

Empagliflozin in Heart Failure: Diuretic and Cardio-Renal Effects.

Griffin M, Rao VS, Ivey-Miranda J, Fleming J, ... Inzucchi SE, Testani JM

Sodium-glucose cotransporter-2 inhibitors (SGLT-2i\'s) improve heart failure (HF) related outcomes. The mechanisms underlying these benefits are not well understood, but diuretic properties may contribute. Traditional diuretics, such as furosemide, induce substantial neurohormonal activation contributing to the limited improvement in intravascular volume often seen with these agents. However, the proximal tubular site of action of the SGLT-2i\'s may help circumvent these limitations.20 patients with type-2 diabetes and chronic, stable HF completed a randomized placebo-controlled crossover study of empagliflozin 10mg daily vs. placebo. Patients underwent an intensive 6-hour biospecimen collection and cardio-renal phenotyping at baseline and again after 14 days of study drug. After a 2-week washout, patients crossed over to the alternate therapy with repeat of the above protocol.Oral empagliflozin was rapidly absorbed as evidenced by a 27-fold increase in urinary glucose excretion by 3 hours (p<0.0001). Fractional excretion of sodium (FENa) increased significantly with empagliflozin monotherapy vs. placebo (FENa 1.2 ± 0.7% vs. 0.7 ± 0.4% p=0.001) and there was a synergistic effect in combination with bumetanide (FENa 5.8 ± 2.5% vs. 3.9 ± 1.9%, p=0.001). At 14 days, the natriuretic effect of empagliflozin persisted, resulting in a reduction in blood volume (-208mL, IQR -536 to 153 mL vs -14mL, IQR -282 to 335 mL, p=0.035), and plasma volume (-138mL, IQR -379 to 154mL ± 453 mL, p=0.04). This natriuresis was not, however, associated with evidence of neurohormonal activation as change in norepinephrine was superior (p = 0.02) and all other neurohormones similar (p<0.34) during the empagliflozin vs. placebo period. Furthermore, there was no evidence of potassium wasting (p=0.20), or renal dysfunction (p>0.11 for all biomarkers), whereas both serum magnesium (p<0.001) and uric acid levels (p=0.008) improved. Empagliflozin causes significant natriuresis, particularly when combined with loop diuretics, resulting in an improvement in blood volume. However, off-target electrolyte wasting, renal dysfunction, and neurohormonal activation were not observed. This favorable diuretic profile may offer significant advantage in the management of volume status in HF patients and may represent a mechanism contributing to the superior long-term HF outcomes observed with these agents.URL: https://clinicaltrials.gov Unique Identifier: NCT03029760.



Circulation: 14 May 2020; epub ahead of print
Griffin M, Rao VS, Ivey-Miranda J, Fleming J, ... Inzucchi SE, Testani JM
Circulation: 14 May 2020; epub ahead of print | PMID: 32410463
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Abstract

Evaluation of Risk-Adjusted Home Time After Acute Myocardial Infarction as a Novel Hospital-Level Performance Metric for Medicare Beneficiaries.

Pandey A, Keshvani N, Vaughan-Sarrazin MS, Gao Y, Girotra S

Utility of 30-day risk-standardized readmission rate (RSRR) as a hospital performance metric has been a matter of debate. Home time is a patient-centered outcome measure that accounts for rehospitalization, mortality, and post-discharge care. We aim to characterize risk-adjusted 30-day home time in patients with acute myocardial infarction (AMI) as a hospital-level performance metric and evaluate associations with 30-day RSRR, 30-day risk-standardized mortality rate (RSMR), and 1-year RSMR.The study included 984,612 patients with AMI hospitalization across 2,379 hospitals between 2009 to 2015 derived from 100% Medicare claims data. Home time was defined as the number of days alive and spent outside of a hospital, skilled nursing facility (SNF), or intermediate/long-term acute care facility 30-days after discharge. Correlation between hospital-level risk-adjusted 30-day home time and 30-day RSRR, RSMR, and 1-year RSMR were estimated using Pearson\'s correlation. Reclassification in hospital performance using 30-day home time vs. 30-day RSRR & 30-day RSMR was also evaluated.Median hospital-level risk-adjusted 30-day home time was 24.0 days (range: 15.3-29.0). Hospitals with higher home time were more commonly academic centers, had available cardiac surgery and rehabilitation services, and had higher AMI volume and PCI utilization during the AMI hospitalization. Of the mean 30-day home time days lost, 58% were to intermediate/long-term care or SNF stays (4.7 days), 30% to death (2.5 days), and 12% to readmission (1.0 days). Hospital-level risk adjusted 30-day home time was inversely correlated with 30-day RSMR (r = -0.22, p<0.0001) and 30-day RSRR (r = -0.25, p<0.0001). Patients admitted to hospitals with higher risk-adjusted 30-day home time had lower 30-day readmission (Q1 vs. Q4: 21% vs. 17%), 30-day mortality rate (5% vs. 3%), and 1-year mortality rate (18% vs. 12%). Furthermore, 30-day home time reclassified hospital performance status in approximately 30% of hospitals versus 30-day RSRR and 30-day RSMR.30-day home time for patients with AMI can be assessed as a hospital-level performance metric using Medicare claims data. It varies across hospitals, is associated with post-discharge readmission and mortality outcomes, and meaningfully reclassifies hospital performance compared with the 30-day RSRR and 30-day RSMR metric.



Circulation: 14 May 2020; epub ahead of print
Pandey A, Keshvani N, Vaughan-Sarrazin MS, Gao Y, Girotra S
Circulation: 14 May 2020; epub ahead of print | PMID: 32408764
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Abstract

Incidence, Microbiology and Outcomes in Patient Hospitalized with Infective Endocarditis.

Shah ASV, McAllister DA, Gallacher P, Astengo F, ... Marwick C, Cruden NL

Despite improvements in management, infective endocarditis remains associated with high mortality and morbidity. We describe temporal changes in the incidence, microbiology and outcomes of infective endocarditis and the impact of changes in national antibiotic prophylaxis guidelines on incident infective endocarditis.Using a Scotland-wide, individual-level linkage approach, all patients hospitalized with infective endocarditis from 1990 until 2014 were identified and linked to national microbiology, prescribing and morbidity and mortality datasets. Linked data were used to evaluate trends in the crude and age- and sex-adjusted incidence and outcomes of infective endocarditis hospitalizations. From 2008, microbiology data and associated outcomes adjusted for patient demographics and comorbidity were also analyzed. An interrupted time series analysis was performed to evaluate incidence before and after changes to national antibiotic prophylaxis guidelines.There were 7,638 hospitalizations (65±17 years, 51% females) with infective endocarditis. The estimated crude hospitalization rate increased from 5.3/100,000 (95% confidence interval [CI] 4.8-5.9) to 8.6/100,000 (95% CI 8.1-9.1) between 1990 and 1995 but remained stable thereafter. There was no change in crude incidence following the 2008 change in antibiotic prophylaxis guidelines (relative risk of change 1.06, 95% CI 0.94-1.20). The incidence rate in patients >80 years doubled from 1990 to 2014 (17.7/100,000 [95% CI 13.4-23.3] to 37.9/100,000 [95% CI 31.5-45.5]). The predicted 1 year age- and comorbidity-adjusted case fatality rate for a 65 year-old patient decreased in women (27.3% [95% CI 24.6-30.2] to 23.7% [95% CI 21.1 to 26.6]) and men (30.7% [95% CI 27.7-33.8] to 26.8% [95% CI 24.0-29.7]) from 1990 to 2014. Blood culture data were available from 2008 (n=2,267/7,638, 30%), with positive blood cultures recorded in 42% (950/2,267). Staphylococcus (403/950, 42.4%) and streptococcus (337/950, 35.5%) species were most common.and enterococcus had the highest 1 year mortality (adjusted odds ratio 4.34 [95% CI 3.12-6.05] and 3.41 [95% CI 2.04-5.70], respectively).Despite changes in antibiotic prophylaxis guidelines, the crude incidence of infective endocarditis has remained stable. However, the incidence rate has doubled in the elderly. Positive blood cultures were observed in less than half of patients, withand enterococcus bacteremia associated with worse outcomes.



Circulation: 14 May 2020; epub ahead of print
Shah ASV, McAllister DA, Gallacher P, Astengo F, ... Marwick C, Cruden NL
Circulation: 14 May 2020; epub ahead of print | PMID: 32410460
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Abstract

Proteomics of SARS-CoV-2-infected host cells reveals therapy targets.

Bojkova D, Klann K, Koch B, Widera M, ... Cinatl J, Münch C

A novel coronavirus was recently discovered and termed SARS-CoV-2. Human infection can cause coronavirus disease 2019 (COVID-19), which has been rapidly spreading around the globe. SARS-CoV-2 shows some similarities to other coronaviruses. However, treatment options and a cellular understanding of SARS-CoV-2 infection are lacking. Here we identify the host cell pathways modulated by SARS-CoV-2 infection and show that inhibition of these pathways prevent viral replication in human cells. We established a human cell culture model for infection with SARS-CoV-2 clinical isolate. Employing this system, we determined the SARS-CoV-2 infection profile by translatome and proteome proteomics at different times after infection. These analyses revealed that SARS-CoV-2 reshapes central cellular pathways, such as translation, splicing, carbon metabolism and nucleic acid metabolism. Small molecule inhibitors targeting these pathways prevented viral replication in cells. Our results reveal the cellular infection profile of SARS-CoV-2 and led to the identification of drugs inhibiting viral replication. We anticipate our results to guide efforts to understand the molecular mechanisms underlying host cell modulation upon SARS-CoV-2 infection. Furthermore, our findings provide insight for the development of therapy options for COVID-19.



Nature: 13 May 2020; epub ahead of print
Bojkova D, Klann K, Koch B, Widera M, ... Cinatl J, Münch C
Nature: 13 May 2020; epub ahead of print | PMID: 32408336
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Abstract

A Validated Model for Sudden Cardiac Death Risk Prediction in Pediatric Hypertrophic Cardiomyopathy.

Miron A, Lafreniere-Roula M, Fan CS, Armstrong KR, ... Ho CY, Mital S

Hypertrophic cardiomyopathy (HCM) is the leading cause of sudden cardiac death (SCD) in children and young adults. Our objective was to develop and validate a SCD risk prediction model in pediatric HCM to guide SCD prevention strategies.In an international multi-center observational cohort study, phenotype-positive patients with isolated HCM <18 years at diagnosis were eligible. The primary outcome variable was the time from diagnosis to a composite of SCD events at 5-year follow-up: SCD, resuscitated sudden cardiac arrest (SCA), and aborted SCD, i.e. appropriate shock following primary prevention ICD. Competing risk models with cause-specific hazard regression were used to identify and quantify clinical and genetic factors associated with SCD. The cause-specific regression model was implemented using boosting, and tuned with ten repeated four-fold cross-validations. The final model was fitted using all data with the tuned hyperparameter value that maximizes the c-statistic, and its performance was characterized using c-statistic for competing risk models. The final model was validated in an independent external cohort (SHaRe, n=285).Overall, 572 patients met eligibility criteria with 2855 patient-years of follow-up. The 5-year cumulative proportion of SCD events was 9.1% (14 SCD, 25 resuscitated SCA, 14 aborted SCD). Risk predictors included age at diagnosis, documented non-sustained ventricular tachycardia, unexplained syncope, septal diameter z-score, LV posterior wall diameter z-score, LA diameter z-score, peak LV outflow tract (LVOT) gradient, and presence of a pathogenic variant. Unlike adults, LVOT gradient had an inverse association, and family history of SCD had no association with SCD. Clinical and clinical/genetic models were developed to predict 5-year freedom from SCD. Both models adequately discriminated patients with and without SCD events with a c-statistic of 0.75 and 0.76 respectively and demonstrated good agreement between predicted and observed events in the primary and validation cohorts (validation c-statistic 0.71 and 0.72 respectively). Our study provides a validated SCD risk prediction model with over 70% prediction accuracy and incorporates risk factors that are unique to pediatric HCM. An individualized risk prediction model has the potential to improve the application of clinical practice guidelines and shared decision-making for ICD insertion. URL: https://clinicaltrials.gov Unique Identifier: NCT04036799.



Circulation: 17 May 2020; epub ahead of print
Miron A, Lafreniere-Roula M, Fan CS, Armstrong KR, ... Ho CY, Mital S
Circulation: 17 May 2020; epub ahead of print | PMID: 32418493
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Abstract

An outbreak of severe Kawasaki-like disease at the Italian epicentre of the SARS-CoV-2 epidemic: an observational cohort study.

Verdoni L, Mazza A, Gervasoni A, Martelli L, ... Bonanomi E, D\'Antiga L
Background
The Bergamo province, which is extensively affected by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) epidemic, is a natural observatory of virus manifestations in the general population. In the past month we recorded an outbreak of Kawasaki disease; we aimed to evaluate incidence and features of patients with Kawasaki-like disease diagnosed during the SARS-CoV-2 epidemic.
Methods
All patients diagnosed with a Kawasaki-like disease at our centre in the past 5 years were divided according to symptomatic presentation before (group 1) or after (group 2) the beginning of the SARS-CoV-2 epidemic. Kawasaki- like presentations were managed as Kawasaki disease according to the American Heart Association indications. Kawasaki disease shock syndrome (KDSS) was defined by presence of circulatory dysfunction, and macrophage activation syndrome (MAS) by the Paediatric Rheumatology International Trials Organisation criteria. Current or previous infection was sought by reverse-transcriptase quantitative PCR in nasopharyngeal and oropharyngeal swabs, and by serological qualitative test detecting SARS-CoV-2 IgM and IgG, respectively.
Findings
Group 1 comprised 19 patients (seven boys, 12 girls; aged 3·0 years [SD 2·5]) diagnosed between Jan 1, 2015, and Feb 17, 2020. Group 2 included ten patients (seven boys, three girls; aged 7·5 years [SD 3·5]) diagnosed between Feb 18 and April 20, 2020; eight of ten were positive for IgG or IgM, or both. The two groups differed in disease incidence (group 1group 2, 0·3ten per month), mean age (3·07·5 years), cardiac involvement (two of 19six of ten), KDSS (zero of 19five of ten), MAS (zero of 19five of ten), and need for adjunctive steroid treatment (three of 19eight of ten; all p<0·01).
Interpretation
In the past month we found a 30-fold increased incidence of Kawasaki-like disease. Children diagnosed after the SARS-CoV-2 epidemic began showed evidence of immune response to the virus, were older, had a higher rate of cardiac involvement, and features of MAS. The SARS-CoV-2 epidemic was associated with high incidence of a severe form of Kawasaki disease. A similar outbreak of Kawasaki-like disease is expected in countries involved in the SARS-CoV-2 epidemic.
Funding
None.

© 2020 Elsevier Ltd. All rights reserved.

Lancet: 12 May 2020; epub ahead of print
Verdoni L, Mazza A, Gervasoni A, Martelli L, ... Bonanomi E, D'Antiga L
Lancet: 12 May 2020; epub ahead of print | PMID: 32410760
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Abstract

Pathogenesis and transmission of SARS-CoV-2 in golden hamsters.

Sia SF, Yan LM, Chin AWH, Fung K, ... Peiris M, Yen HL

SARS-CoV-2, a novel coronavirus with high nucleotide identity to SARS-CoV and SARS-related coronaviruses detected in horseshoe bats, has spread across the world and impacted global healthcare systems and economy. A suitable small animal model is needed to support vaccine and therapy development. We report the pathogenesis and transmissibility of the SARS-CoV-2 in golden Syrian hamsters. Immunohistochemistry demonstrated viral antigens in nasal mucosa, bronchial epithelial cells, and in areas of lung consolidation on days 2 and 5 post-inoculation (dpi), followed by rapid viral clearance and pneumocyte hyperplasia on 7 dpi. Viral antigen was also found in the duodenum epithelial cells with viral RNA detected in feces. Notably, SARS-CoV-2 transmitted efficiently from inoculated hamsters to naïve hamsters by direct contact and via aerosols. Transmission via fomites in soiled cages was less efficient. Although viral RNA was continuously detected in the nasal washes of inoculated hamsters for 14 days, the communicable period was short and correlated with the detection of infectious virus but not viral RNA. Inoculated and naturally-infected hamsters showed apparent weight loss, and all animals recovered with the detection of neutralizing antibodies. Our results suggest that SARS-CoV-2 infection in golden Syrian hamsters resemble features found in humans with mild infections.



Nature: 13 May 2020; epub ahead of print
Sia SF, Yan LM, Chin AWH, Fung K, ... Peiris M, Yen HL
Nature: 13 May 2020; epub ahead of print | PMID: 32408338
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Abstract

Infection of dogs with SARS-CoV-2.

Sit THC, Brackman CJ, Ip SM, Tam KWS, ... Poon LLM, Peiris M

SARS-CoV-2 emerged in Wuhan in December 2019 and caused the pandemic respiratory disease, COVID-19. In 2003, the closely related SARS-CoV had been detected in domestic cats and a dog. However, little is known about the susceptibility of domestic pet mammals to SARS-CoV-2. Two out of fifteen dogs from households with confirmed human cases of COVID-19 in Hong Kong SAR were found to be infected using quantitative RT-PCR, serology, sequencing the viral genome, and in one dog, virus isolation. SARS-CoV-2 RNA was detected in a 17-year-old neutered male Pomeranian from five nasal swabs collected over a 13-day period. A 2.5-year-old male German Shepherd dog had SARS CoV-2 RNA on two occasions and virus was isolated from nasal and oral swabs. Both dogs had antibody responses detected using plaque reduction neutralization assays. Viral genetic sequences of viruses from the two dogs were identical to the virus detected in the respective human cases. The animals remained asymptomatic during quarantine. The evidence suggests that these are instances of human-to-animal transmission of SARS-CoV-2. It is unclear whether infected dogs can transmit the virus to other animals or back to humans.



Nature: 13 May 2020; epub ahead of print
Sit THC, Brackman CJ, Ip SM, Tam KWS, ... Poon LLM, Peiris M
Nature: 13 May 2020; epub ahead of print | PMID: 32408337
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Abstract

Artificial intelligence and the future of global health.

Schwalbe N, Wahl B

Concurrent advances in information technology infrastructure and mobile computing power in many low and middle-income countries (LMICs) have raised hopes that artificial intelligence (AI) might help to address challenges unique to the field of global health and accelerate achievement of the health-related sustainable development goals. A series of fundamental questions have been raised about AI-driven health interventions, and whether the tools, methods, and protections traditionally used to make ethical and evidence-based decisions about new technologies can be applied to AI. Deployment of AI has already begun for a broad range of health issues common to LMICs, with interventions focused primarily on communicable diseases, including tuberculosis and malaria. Types of AI vary, but most use some form of machine learning or signal processing. Several types of machine learning methods are frequently used together, as is machine learning with other approaches, most often signal processing. AI-driven health interventions fit into four categories relevant to global health researchers: (1) diagnosis, (2) patient morbidity or mortality risk assessment, (3) disease outbreak prediction and surveillance, and (4) health policy and planning. However, much of the AI-driven intervention research in global health does not describe ethical, regulatory, or practical considerations required for widespread use or deployment at scale. Despite the field remaining nascent, AI-driven health interventions could lead to improved health outcomes in LMICs. Although some challenges of developing and deploying these interventions might not be unique to these settings, the global health community will need to work quickly to establish guidelines for development, testing, and use, and develop a user-driven research agenda to facilitate equitable and ethical use.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 15 May 2020; 395:1579-1586
Schwalbe N, Wahl B
Lancet: 15 May 2020; 395:1579-1586 | PMID: 32416782
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Abstract

Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study.

de Abajo FJ, Rodríguez-Martín S, Lerma V, Mejía-Abril G, ... Rodríguez-Puyol D,
Background
Concerns have been raised about the possibility that inhibitors of the renin-angiotensin-aldosterone system (RAAS) could predispose individuals to severe COVID-19; however, epidemiological evidence is lacking. We report the results of a case-population study done in Madrid, Spain, since the outbreak of COVID-19.
Methods
In this case-population study, we consecutively selected patients aged 18 years or older with a PCR-confirmed diagnosis of COVID-19 requiring admission to hospital from seven hospitals in Madrid, who had been admitted between March 1 and March 24, 2020. As a reference group, we randomly sampled ten patients per case, individually matched for age, sex, region (ie, Madrid), and date of admission to hospital (month and day; index date), from Base de datos para la Investigación Farmacoepidemiológica en Atención Primaria (BIFAP), a Spanish primary health-care database, in its last available year (2018). We extracted information on comorbidities and prescriptions up to the month before index date (ie, current use) from electronic clinical records of both cases and controls. The outcome of interest was admission to hospital of patients with COVID-19. To minimise confounding by indication, the main analysis focused on assessing the association between COVID-19 requiring admission to hospital and use of RAAS inhibitors compared with use of other antihypertensive drugs. We calculated odds ratios (ORs) and 95% CIs, adjusted for age, sex, and cardiovascular comorbidities and risk factors, using conditional logistic regression. The protocol of the study was registered in the EU electronic Register of Post-Authorisation Studies, EUPAS34437.
Findings
We collected data for 1139 cases and 11 390 population controls. Among cases, 444 (39·0%) were female and the mean age was 69·1 years (SD 15·4), and despite being matched on sex and age, a significantly higher proportion of cases had pre-existing cardiovascular disease (OR 1·98, 95% CI 1·62-2·41) and risk factors (1·46, 1·23-1·73) than did controls. Compared with users of other antihypertensive drugs, users of RAAS inhibitors had an adjusted OR for COVID-19 requiring admission to hospital of 0·94 (95% CI 0·77-1·15). No increased risk was observed with either angiotensin-converting enzyme inhibitors (adjusted OR 0·80, 0·64-1·00) or angiotensin-receptor blockers (1·10, 0·88-1·37). Sex, age, and background cardiovascular risk did not modify the adjusted OR between use of RAAS inhibitors and COVID-19 requiring admission to hospital, whereas a decreased risk of COVID-19 requiring admission to hospital was found among patients with diabetes who were users of RAAS inhibitors (adjusted OR 0·53, 95% CI 0·34-0·80). The adjusted ORs were similar across severity degrees of COVID-19.
Interpretation
RAAS inhibitors do not increase the risk of COVID-19 requiring admission to hospital, including fatal cases and those admitted to intensive care units, and should not be discontinued to prevent a severe case of COVID-19.
Funding
Instituto de Salud Carlos III.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 13 May 2020; epub ahead of print
de Abajo FJ, Rodríguez-Martín S, Lerma V, Mejía-Abril G, ... Rodríguez-Puyol D,
Lancet: 13 May 2020; epub ahead of print | PMID: 32416785
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Abstract

Atezolizumab with or without chemotherapy in metastatic urothelial cancer (IMvigor130): a multicentre, randomised, placebo-controlled phase 3 trial.

Galsky MD, Arija JÁA, Bamias A, Davis ID, ... Grande E,
Background
Atezolizumab can induce sustained responses in metastatic urothelial carcinoma. We report the results of IMvigor130, a phase 3 trial that compared atezolizumab with or without platinum-based chemotherapy versus placebo plus platinum-based chemotherapy in first-line metastatic urothelial carcinoma.
Methods
In this multicentre, phase 3, randomised trial, untreated patients aged 18 years or older with locally advanced or metastatic urothelial carcinoma, from 221 sites in 35 countries, were randomly assigned to receive atezolizumab plus platinum-based chemotherapy (group A), atezolizumab monotherapy (group B), or placebo plus platinum-based chemotherapy (group C). Patients received 21-day cycles of gemcitabine (1000 mg/m body surface area, administered intravenously on days 1 and 8 of each cycle), plus either carboplatin (area under the curve of 4·5 mg/mL per min administered intravenously) or cisplatin (70 mg/m body surface area administered intravenously) on day 1 of each cycle with either atezolizumab (1200 mg administered intravenously on day 1 of each cycle) or placebo. Group B patients received 1200 mg atezolizumab, administered intravenously on day 1 of each 21-day cycle. The co-primary efficacy endpoints for the intention-to-treat population were investigator-assessed Response Evaluation Criteria in Solid Tumours 1.1 progression-free survival and overall survival (group A vs group C) and overall survival (group B vs group C), which was to be formally tested only if overall survival was positive for group A versus group C. The trial is registered with ClinicalTrials.gov, NCT02807636.
Findings
Between July 15, 2016, and July 20, 2018, we enrolled 1213 patients. 451 (37%) were randomly assigned to group A, 362 (30%) to group B, and 400 (33%) to group C. Median follow-up for survival was 11·8 months (IQR 6·1-17·2) for all patients. At the time of final progression-free survival analysis and interim overall survival analysis (May 31, 2019), median progression-free survival in the intention-to-treat population was 8·2 months (95% CI 6·5-8·3) in group A and 6·3 months (6·2-7·0) in group C (stratified hazard ratio [HR] 0·82, 95% CI 0·70-0·96; one-sided p=0·007). Median overall survival was 16·0 months (13·9-18·9) in group A and 13·4 months (12·0-15·2) in group C (0·83, 0·69-1·00; one-sided p=0·027). Median overall survival was 15·7 months (13·1-17·8) for group B and 13·1 months (11·7-15·1) for group C (1·02, 0·83-1·24). Adverse events that led to withdrawal of any agent occurred in 156 (34%) patients in group A, 22 (6%) patients in group B, and 132 (34%) patients in group C. 50 (11%) patients in group A, 21 (6%) patients in group B, and 27 (7%) patients in group C had adverse events that led to discontinuation of atezolizumab or placebo.
Interpretation
Addition of atezolizumab to platinum-based chemotherapy as first-line treatment prolonged progression-free survival in patients with metastatic urothelial carcinoma. The safety profile of the combination was consistent with that observed with the individual agents. These results support the use of atezolizumab plus platinum-based chemotherapy as a potential first-line treatment option for metastatic urothelial carcinoma.
Funding
F Hoffmann-La Roche and Genentech.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 15 May 2020; 395:1547-1557
Galsky MD, Arija JÁA, Bamias A, Davis ID, ... Grande E,
Lancet: 15 May 2020; 395:1547-1557 | PMID: 32416780
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Abstract

Estimating excess 1-year mortality associated with the COVID-19 pandemic according to underlying conditions and age: a population-based cohort study.

Banerjee A, Pasea L, Harris S, Gonzalez-Izquierdo A, ... Denaxas S, Hemingway H
Background
The medical, societal, and economic impact of the coronavirus disease 2019 (COVID-19) pandemic has unknown effects on overall population mortality. Previous models of population mortality are based on death over days among infected people, nearly all of whom thus far have underlying conditions. Models have not incorporated information on high-risk conditions or their longer-term baseline (pre-COVID-19) mortality. We estimated the excess number of deaths over 1 year under different COVID-19 incidence scenarios based on varying levels of transmission suppression and differing mortality impacts based on different relative risks for the disease.
Methods
In this population-based cohort study, we used linked primary and secondary care electronic health records from England (Health Data Research UK-CALIBER). We report prevalence of underlying conditions defined by Public Health England guidelines (from March 16, 2020) in individuals aged 30 years or older registered with a practice between 1997 and 2017, using validated, openly available phenotypes for each condition. We estimated 1-year mortality in each condition, developing simple models (and a tool for calculation) of excess COVID-19-related deaths, assuming relative impact (as relative risks [RRs]) of the COVID-19 pandemic (compared with background mortality) of 1·5, 2·0, and 3·0 at differing infection rate scenarios, including full suppression (0·001%), partial suppression (1%), mitigation (10%), and do nothing (80%). We also developed an online, public, prototype risk calculator for excess death estimation.
Findings
We included 3 862 012 individuals (1 957 935 [50·7%] women and 1 904 077 [49·3%] men). We estimated that more than 20% of the study population are in the high-risk category, of whom 13·7% were older than 70 years and 6·3% were aged 70 years or younger with at least one underlying condition. 1-year mortality in the high-risk population was estimated to be 4·46% (95% CI 4·41-4·51). Age and underlying conditions combined to influence background risk, varying markedly across conditions. In a full suppression scenario in the UK population, we estimated that there would be two excess deaths ( baseline deaths) with an RR of 1·5, four with an RR of 2·0, and seven with an RR of 3·0. In a mitigation scenario, we estimated 18 374 excess deaths with an RR of 1·5, 36 749 with an RR of 2·0, and 73 498 with an RR of 3·0. In a do nothing scenario, we estimated 146 996 excess deaths with an RR of 1·5, 293 991 with an RR of 2·0, and 587 982 with an RR of 3·0.
Interpretation
We provide policy makers, researchers, and the public a simple model and an online tool for understanding excess mortality over 1 year from the COVID-19 pandemic, based on age, sex, and underlying condition-specific estimates. These results signal the need for sustained stringent suppression measures as well as sustained efforts to target those at highest risk because of underlying conditions with a range of preventive interventions. Countries should assess the overall (direct and indirect) effects of the pandemic on excess mortality.
Funding
National Institute for Health Research University College London Hospitals Biomedical Research Centre, Health Data Research UK.

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

Lancet: 11 May 2020; epub ahead of print
Banerjee A, Pasea L, Harris S, Gonzalez-Izquierdo A, ... Denaxas S, Hemingway H
Lancet: 11 May 2020; epub ahead of print | PMID: 32405103
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Abstract

Adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus placebo in patients with resected stage IV melanoma with no evidence of disease (IMMUNED): a randomised, double-blind, placebo-controlled, phase 2 trial.

Zimmer L, Livingstone E, Hassel JC, Fluck M, ... Schadendorf D,
Background
Nivolumab and ipilimumab, alone or in combination, are widely used immunotherapeutic treatment options for patients with advanced-ie, unresectable or metastatic-melanoma. This criterion, however, excludes patients with stage IV melanoma with no evidence of disease. We therefore aimed to evaluate the safety and efficacy of adjuvant nivolumab plus ipilimumab or nivolumab monotherapy versus a placebo in this patient population.
Methods
We did a randomised, double-blind, placebo-controlled, phase 2 trial in 20 German academic medical centres. Eligible patients were aged 18-80 years with stage IV melanoma with no evidence of disease after surgery or radiotherapy. Key exclusion criteria included uveal or mucosal melanoma, previous therapy with checkpoint inhibitors, and any previous immunosuppressive therapy within the 30 days before study drug administration. Eligible patients were randomly assigned (1:1:1), using a central, interactive, online system, to the nivolumab plus ipilimumab group (1 mg/kg of intravenous nivolumab every 3 weeks plus 3 mg/kg of intravenous ipilimumab every 3 weeks for four doses, followed by 3 mg/kg of nivolumab every 2 weeks), nivolumab monotherapy group (3 mg/kg of intravenous nivolumab every 2 weeks plus ipilimumab-matching placebo during weeks 1-12), or double-matching placebo group. The primary endpoint was the recurrence-free survival in the intention-to-treat population. The results presented in this report reflect the prespecified interim analysis of recurrence-free survival after 90 events had been reported. This study is registered with ClinicalTrials.gov, NCT02523313, and is ongoing.
Findings
Between Sept 2, 2015, and Nov 20, 2018, 167 patients were randomly assigned to receive nivolumab plus ipilimumab (n=56), nivolumab (n=59), or placebo (n=52). As of July 2, 2019, at a median follow-up of 28·4 months (IQR 17·7-36·8), median recurrence-free survival was not reached in the nivolumab plus ipilimumab group, whereas median recurrence-free survival was 12·4 months (95% CI 5·3-33·3) in the nivolumab group and 6·4 months (3·3-9·6) in the placebo group. The hazard ratio for recurrence for the nivolumab plus ipilimumab group versus placebo group was 0·23 (97·5% CI 0·12-0·45; p<0·0001), and for the nivolumab group versus placebo group was 0·56 (0·33-0·94; p=0·011). In the nivolumab plus ipilimumab group, recurrence-free survival at 1 year was 75% (95% CI 61·0-84·9) and at 2 years was 70% (55·1-81·0); in the nivolumab group, 1-year recurrence-free survival was 52% (38·1-63·9) and at 2 years was 42% (28·6-54·5); and in the placebo group, this rate was 32% (19·8-45·3) at 1 year and 14% (5·9-25·7) at 2 years. Treatment-related grade 3-4 adverse events were reported in 71% (95% CI 57-82) of patients in the nivolumab plus ipilimumab group and in 27% (16-40) of those in the nivolumab group. Treatment-related adverse events of any grade led to treatment discontinuation in 34 (62%) of 55 patients in the nivolumab plus ipilimumab group and seven (13%) of 56 in the nivolumab group. Three deaths from adverse events were reported but were considered unrelated to the study treatment.
Interpretation
Adjuvant therapy with nivolumab alone or in combination with ipilimumab increased recurrence-free survival significantly compared with placebo in patients with stage IV melanoma with no evidence of disease. The rates of grade 3-4 treatment-related adverse events in both active treatment groups were higher than the rates reported in previous pivotal trials done in advanced melanoma with measurable disease.
Funding
Bristol-Myers Squibb.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 15 May 2020; 395:1558-1568
Zimmer L, Livingstone E, Hassel JC, Fluck M, ... Schadendorf D,
Lancet: 15 May 2020; 395:1558-1568 | PMID: 32416781
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Impact:
Abstract

Acute heart failure in multisystem inflammatory syndrome in children (MIS-C) in the context of global SARS-CoV-2 pandemic.

Belhadjer Z, Méot M, Bajolle F, Khraiche D, ... Renolleau S, Bonnet D

Cardiac injury and myocarditis have been described in adults with COVID-19. SARS-CoV-2 infection in children is typically minimally symptomatic. We report a series of febrile pediatric patients with acute heart failure potentially associated with SARS-CoV-2 infection and the multisystem inflammatory syndrome in children (MIS-C) as defined by the US Centers for Disease Control.Over a two-month period contemporary with the SARS-CoV-2 pandemic in France and Switzerland, we retrospectively collected clinical, biological, therapeutic, and early outcomes data in children who were admitted to pediatric intensive care units in 14 centers for cardiogenic shock, left ventricular dysfunction and severe inflammatory state.Thirty-five children were identified and included in the study. Median age at admission was 10 years (range 2-16 years). Co-morbidities were present in 28% including asthma and overweight. Gastrointestinal symptoms were prominent. Left ventricular ejection fraction was <30% in one third; 80% required inotropic support with 28% treated with ECMO. Inflammation markers were suggestive of cytokine storm (interleukin 6 median 135 pg/mL) and macrophage activation (D-dimer median 5284 ng/mL). Mean brain natriuretic peptide was elevated (5743 pg/mL). Thirty-one/35 (88%) patients tested positive for SARS-CoV-2 infection by PCR of nasopharyngeal swab or serology. All patients received intravenous immune globulin, with adjunctive steroid therapy used in one third. Left ventricular function was restored in the 25/35 of those discharged from the intensive care unit. No patient died, and all patients treated with ECMO were successfully weaned.Children may experience an acute cardiac decompensation due to severe inflammatory state following SARS-CoV-2 infection (multisystem inflammatory syndrome in children - MIS-C). Treatment with immune globulin appears to be associated with recovery of left ventricular systolic function.



Circulation: 16 May 2020; epub ahead of print
Belhadjer Z, Méot M, Bajolle F, Khraiche D, ... Renolleau S, Bonnet D
Circulation: 16 May 2020; epub ahead of print | PMID: 32418446
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Impact:
Abstract

Transethnic Genome-Wide Association Study Provides Insights in the Genetic Architecture and Heritability of Long QT Syndrome.

Lahrouchi N, Tadros R, Crotti L, Mizusawa Y, ... Tanck MWT, Bezzina CR

Long QT syndrome (LQTS) is a rare genetic disorder and a major preventable cause of sudden cardiac death in the young. A causal rare genetic variant with large effect size is identified in up to 80% of probands (genotype positive) and cascade family screening shows incomplete penetrance of genetic variants. Furthermore, a proportion of cases meeting diagnostic criteria for LQTS remain genetically elusive despite genetic testing of established genes (genotype negative). These observations raise the possibility that common genetic variants with small effect size contribute to the clinical picture of LQTS. This study aimed to characterize and quantify the contribution of common genetic variation to LQTS disease susceptibility.We conducted genome-wide association studies (GWAS) followed by transethnic meta-analysis in 1,656 unrelated LQTS patients of European or Japanese ancestry and 9,890 controls to identify susceptibility single nucleotide polymorphisms (SNPs). We estimated the SNP heritability () of LQTS and tested the genetic correlation between LQTS susceptibility and other cardiac traits. Furthermore, we tested the aggregate effect of the 68 SNPs previously associated with QTc in the general population using a polygenic risk score (PRS).Genome-wide association analysis identified three loci associated with LQTS at genome-wide statistical significance (P<5x10) near ,and , and one missense variant in(p.Asp85Asn) at the suggestive threshold (P<10). Heritability analyses showed that ~15% of variance in overall LQTS susceptibility was attributable to common genetic variation ( 0.148; standard error [SE] 0.019). LQTS susceptibility showed a strong genome-wide genetic correlation with the QT interval in the general population (r=0.40, P=3.2x10). PRS was greater in LQTS cases compared to controls (P<10), and notably, among LQTS patients PRS was greater in genotype negative compared to genotype positive patients (P<0.005).This work establishes an important role for common genetic variation in susceptibility to LQTS. We demonstrate overlap between genetic control of the QT interval in the general population and genetic factors contributing to LQTS susceptibility. Using polygenic risk score analyses aggregating common genetic variants that modulate the QT interval in the general population, we provide evidence for a polygenic architecture in genotype negative LQTS.



Circulation: 19 May 2020; epub ahead of print
Lahrouchi N, Tadros R, Crotti L, Mizusawa Y, ... Tanck MWT, Bezzina CR
Circulation: 19 May 2020; epub ahead of print | PMID: 32429735
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Impact:
Abstract

Deep Vein Thrombosis in Hospitalized Patients with Coronavirus Disease 2019 (COVID-19) in Wuhan, China: Prevalence, Risk Factors, and Outcome.

Zhang L, Feng X, Zhang D, Jiang C, ... Hu Y, Xie M

To investigate deep vein thrombosis (DVT) in hospitalized patients with coronavirus disease 2019 (COVID-19), we performed a single institutional study to evaluate its prevalence, risk factors, prognosis, and potential thromboprophylaxis strategies in a large referral and treatment center.We studied a total of 143 patients with COVID-19 from January 29 to February 29, 2020. Demographic and clinical data, laboratory data, including ultrasound scans of the lower extremities, and outcome variables were obtained, comparisons were made between DVT and non-DVT groups.Of the 143 patients hospitalized with COVID-19 (aged 63 ± 14 years; 74 [51.7%] man), 66 patients developed lower extremity DVT (46.1%, included 23 [34.8%] with proximal DVT and 43 [65.2%] with distal DVT).Compared with patients who with no DVT, patients with DVT were older and had a lower oxygenation index, a higher rate of cardiac injury, and worse prognosis including an increased proportion of deaths (23 [34.8%] vs 9 [11.7%],= 0.001) and a decreased proportion of patients discharged (32 [48.5%] vs 60 [77.9%],< 0.001). Multivariant analysis only showed an association between CURB-65 score 3-5 (OR = 6.122,= 0.031), Padua prediction score ≥ 4 (OR = 4.016,= 0.04), and D-dimer >1.0 (μg/ml) (OR = 5.818,< 0.014) and DVT in this cohort, respectively. The combination of a CURB-65 score 3-5, a Padua prediction score ≥ 4, and D-dimer > 1.0 (μg/ml) has a sensitivity of 88.52% and a specificity of 61.43% for screening for DVT. In the subgroup of patients with a Padua prediction score ≥ 4 and whose ultrasound scans were performed ˃72 hours after admission, DVT was present in 18 (34.0%) of the subgroup receiving venous thromboembolism prophylaxis vs 35 (63.3%) in the nonprophylaxis group ( = 0.010).The prevalence of DVT is high and is associated with adverse outcomes in hospitalized patients with COVID-19. Prophylaxis for venous thromboembolism may be protective in patients with a Padua protection score ≥ 4 after admission. Our data seem to suggest that COVID-19 is probably an additional risk factor for DVT in the hospitalized patients.



Circulation: 17 May 2020; epub ahead of print
Zhang L, Feng X, Zhang D, Jiang C, ... Hu Y, Xie M
Circulation: 17 May 2020; epub ahead of print | PMID: 32421381
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Abstract

The COMPASS Trial: Net Clinical Benefit of Low-Dose Rivaroxaban Plus Aspirin as Compared to Aspirin in Patients Chronic Vascular Disease.

Steffel J, Eikelboom JW, Anand SS, Shestakovska O, Yusuf S, Fox KAA

Rivaroxaban 2.5mg twice daily plus aspirin 100mg reduced the risk of cardiovascular events as compared to aspirin monotherapy in the COMPASS (Cardiovascular Outcomes for People Using Anticoagulation Strategies) trial but increased the risk of major bleedings. Analysis of net clinical benefit (NCB) is of key clinical relevance and represents an integrated measure of overall patient outcome.The current pre-specified analysis was performed to assess the NCB of adding rivaroxaban 2.5mg twice daily to aspirin monotherapy in patients with chronic vascular disease in the COMPASS study cohort (intention-to treat study population), with a specific focus on high-risk subgroups. The pre-defined NCB outcome was the composite of cardiovascular death, stroke, myocardial infarction, fatal bleeding, or symptomatic bleeding into a critical organ.A lower number of NCB adverse outcomes was observed with rivaroxaban 2.5mg twice daily + ASA vs. ASA alone (Hazard Ratio (HR) 0.80, 95% Confidence Interval (CI) 0.70-0.91), p=0.0005), which became increasingly favorable with longer treatment duration. The main drivers of NCB outcomes were \'efficacy\' events, in particular stroke (0.5%/yr vs. 0.8%/yr, HR 0.58, 95% CI 0.44-0.76, p<0.0001) and cardiovascular death (0.9%/vr vs. 1.2%/yr, HR 0.78, 95% CI 0.64-0.96, p=0.02), while the bleeding components of the NCB, in particular fatal bleeding (0.09%/yr vs. 0.06%/yr, HR 1.49, 95% CI 0.67-3.33, p=0.32), only represented a minority of NCB events. In selected high-risk subgroups, including patients with polyvascular disease (≥2 vascular beds affected with atherosclerosis), impaired renal function, heart failure, and / or diabetes, a larger absolute risk reduction for experiencing a NCB event was observed.Compared to ASA monotherapy the combination of rivaroxaban 2.5mg twice daily+ ASA resulted in fewer NCB events primarily by preventing adverse efficacy events, particularly stroke and cardiovascular mortality, whereas severe bleedings were less frequent and with less clinical impact. The NCB was particularly favorable in high-risk subgroups and those with multiple risk characteristics.URL: https://www.clinicaltrials.gov. Unique identifier: NCT01776424.



Circulation: 20 May 2020; epub ahead of print
Steffel J, Eikelboom JW, Anand SS, Shestakovska O, Yusuf S, Fox KAA
Circulation: 20 May 2020; epub ahead of print | PMID: 32436455
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Abstract

Use of Administrative Claims to Assess Outcomes and Treatment Effect in Randomized Clinical Trials for Transcatheter Aortic Valve Replacement: Findings from the Extending Trial-Based Evaluations of Medical Therapies Using Novel Sources of Data (EXTEND) Study.

Strom JB, Faridi KF, Butala NM, Zhao Y, ... Kazi DS, Yeh RW

Whether passively collected data can substitute for adjudicated outcomes to reproduce the magnitude and direction of treatment effect observed in cardiovascular clinical trials is not well known.We linked adults aged ≥65 in the US CoreValve Pivotal High Risk (HiR) and Surgical or Transcatheter Aortic Valve Replacement in Intermediate-Risk Patients (SURTAVI) Trials to 100% Medicare inpatient claims, 1/1/2003-12/31/2016. Primary (e.g. death and stroke) and secondary trial endpoints, were compared across treatment arms (e.g. TAVR vs. SAVR) using trial-adjudicated outcomes versus outcomes derived from claims at 1-year (HiR) or 2-years (SURTAVI).Among 600 linked CoreValve HiR participants (linkage rate 80.0%), the rate of the trial\'s primary endpoint of all-cause mortality occurred in 13.7% of patients receiving TAVR and 16.4% of patients receiving SAVR at 1-year using both trial data (HR 0.84, 95% CI 0.65-1.09; p= 0.33) and claims data (HR 0.86, 95% CI 0.66-1.11; p = 0.34; interaction p-value = 0.80). Noninferiority of TAVR relative to SAVR was seen using both trial and claims-based outcomes (p < 0.001 for both). Among 1005 linked SURTAVI trial participants (linkage rate 60.5%), the trial\'s primary endpoint was 12.9% for TAVR and 13.1% for SAVR using trial data (HR 1.08, 95% CI 0.79-1.48, p = 0.90), and 11.3% for TAVR and 12.5% for SAVR patients using claims data (HR 1.02, 95% CI 0.73-1.41, p = 0.58; interaction p-value = 0.89). TAVR was noninferior to SAVR when compared using both trial and claims (p < 0.001 for both). Rates of procedural secondary outcomes (e.g. aortic valve reintervention, pacemaker rates) were more closely concordant between trial and claims data than non-procedural outcomes (e.g., stroke, bleeding, cardiogenic shock).In the CoreValve HiR and SURTAVI trials, ascertainment of trial primary endpoints using claims reproduced both the magnitude and direction of treatment effect compared with adjudicated event data, but non-fatal and non-procedural secondary outcomes were not as well reproduced. Use of claims to substitute for adjudicated outcomes in traditional trial treatment comparisons may be valid and feasible for all-cause mortality and certain procedural outcomes, but may be less suitable for other endpoints.



Circulation: 20 May 2020; epub ahead of print
Strom JB, Faridi KF, Butala NM, Zhao Y, ... Kazi DS, Yeh RW
Circulation: 20 May 2020; epub ahead of print | PMID: 32436390
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Abstract

Coexistence and outcome of coronary artery disease in Takotsubo syndrome.

Napp LC, Cammann VL, Jaguszewski M, Szawan KA, ... Ghadri JR, Templin C
Aims
Takotsubo syndrome (TTS) is an acute heart failure syndrome, which shares many features with acute coronary syndrome (ACS). Although TTS was initially described with angiographically normal coronary arteries, smaller studies recently indicated a potential coexistence of coronary artery disease (CAD) in TTS patients. This study aimed to determine the coexistence, features, and prognostic role of CAD in a large cohort of patients with TTS.
Methods and results
Coronary anatomy and CAD were studied in patients diagnosed with TTS. Inclusion criteria were compliance with the International Takotsubo Diagnostic Criteria for TTS, and availability of original coronary angiographies with ventriculography performed during the acute phase. Exclusion criteria were missing views, poor quality of angiography loops, and angiography without ventriculography. A total of 1016 TTS patients were studied. Of those, 23.0% had obstructive CAD, 41.2% had non-obstructive CAD, and 35.7% had angiographically normal coronary arteries. A total of 47 patients (4.6%) underwent percutaneous coronary intervention, and 3 patients had acute and 8 had chronic coronary artery occlusion concomitant with TTS, respectively. The presence of CAD was associated with increased incidence of shock, ventilation, and death from any cause. After adjusting for confounders, the presence of obstructive CAD was associated with mortality at 30 days. Takotsubo syndrome patients with obstructive CAD were at comparable risk for shock and death and nearly at twice the risk for ventilation compared to an age- and sex-matched ACS cohort.
Conclusions
Coronary artery disease frequently coexists in TTS patients, presents with the whole spectrum of coronary pathology including acute coronary occlusion, and is associated with adverse outcome.
Trial registration
ClinicalTrials.gov number: NCT01947621.

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: 01 Jun 2020; epub ahead of print
Napp LC, Cammann VL, Jaguszewski M, Szawan KA, ... Ghadri JR, Templin C
Eur Heart J: 01 Jun 2020; epub ahead of print | PMID: 32484517
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Abstract

Implementing the new European Regulations on medical devices-clinical responsibilities for evidence-based practice: a report from the Regulatory Affairs Committee of the European Society of Cardiology.

Fraser AG, Byrne RA, Kautzner J, Butchart EG, ... Vardas PE, Badimon L

The new European Union (EU) law governing the regulatory approval of medical devices that entered into force in May 2017 will now take effect from 26 May 2021. Here, we consider how it will change daily practice for cardiologists, cardiac surgeons, and healthcare professionals. Clinical evidence for any high-risk device must be reported by the manufacturer in a Summary of Safety and Clinical Performance (SSCP) that will be publicly available in the European Union Database on Medical Devices (Eudamed) maintained by the European Commission; this will facilitate evidence-based choices of which devices to recommend. Hospitals must record all device implantations, and each high-risk device will be trackable by Unique Device Identification (UDI). Important new roles are envisaged for clinicians, scientists, and engineers in EU Expert Panels-in particular to scrutinize clinical data submitted by manufacturers for certain high-risk devices and the evaluations of that data made by notified bodies. They will advise manufacturers on the design of their clinical studies and recommend to regulators when new technical specifications or guidance are needed. Physicians should support post-market surveillance by reporting adverse events and by contributing to comprehensive medical device registries. A second law on In Vitro Diagnostic Medical Devices will take effect from 2022. We encourage all healthcare professionals to contribute proactively to these new systems, in order to enhance the efficacy and safety of high-risk devices and to promote equitable access to effective innovations. The European Society of Cardiology will continue to advise EU regulators on appropriate clinical evaluation of high-risk devices.

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: 01 Jun 2020; epub ahead of print
Fraser AG, Byrne RA, Kautzner J, Butchart EG, ... Vardas PE, Badimon L
Eur Heart J: 01 Jun 2020; epub ahead of print | PMID: 32484542
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Abstract

Single-Cell RNA Sequencing to Dissect the Immunological Network of Autoimmune Myocarditis.

Hua X, Hu G, Hu Q, Chang Y, ... Li M, Song J

Myocarditis can develop into dilated cardiomyopathy (DCM), which may require heart transplantation (HTx). The immunological network of myocarditis phases remains unknown. This study aimed to investigate the immunological network during the transition from myocarditis to cardiomyopathy and to identify the genes contributing to the inflammatory response to myocarditis.Mice were treated with myosin heavy-chain-α peptides to generate an experimental autoimmune myocarditis (EAM) model. We performed single-cell RNA sequencing (scRNA-seq) analysis ofcells extracted from mouse hearts during different EAM phases, including normal control, acute inflammatory, subacute inflammatory and myopathy phases. Human heart tissues were collected from the surgically removed hearts of patients who had undergone HTx.We identified 26 cell subtypes among 34,665 cells. Macrophages constituted the main immune cell population at all disease phases (greater than 60%), and an inflammation-associated macrophage cluster was identified in which the expression of -regulated genes was upregulated. The neutrophil population was increased after the induction of EAM, and neutrophils then releasedto participate in the EAM process. T cells were observed at the highest percentage at the subacute inflammatory phase. Th17 cells, in which the expression of -regulated genes was upregulated, constituted the main T cell population detected at the acute inflammatory phase, while Treg cells were the main T cell population detected at the subacute inflammatory phase, and γδ T cells releasingwere the main T cell population observed at the myopathy phase. Moreover, theexpression level correlated with the extent of inflammation. Additionally, PX-478 could alleviate the inflammatory responses of the different EAM phases. Finally,was expressed at higher levels in acute autoimmune myocarditis patients than in DCM patients and healthy controls.We herein present a comprehensive single-cell landscape of the cardiac immune cells in different EAM phases. In addition, we elucidated the contribution ofto the inflammatory response through the regulation of immune cell activity, particularly of macrophage cluster 2 and Th17 cells. Moreover, ainhibitor alleviated inflammatory cell infiltration of the EAM model and may serve as a potential therapeutic target in the clinic.



Circulation: 19 May 2020; epub ahead of print
Hua X, Hu G, Hu Q, Chang Y, ... Li M, Song J
Circulation: 19 May 2020; epub ahead of print | PMID: 32431172
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Abstract

Randomised Comparison of the Polymer-Free Biolimus-Coated BioFreedom Stent with the Ultrathin Strut Biodegradable Polymer Sirolimus-Eluting Orsiro Stent in an All-Comers Population Treated with Percutaneous Coronary Intervention: The SORT OUT IX Trial.

Jensen LO, Maeng M, Raungaard B, Kahlert J, ... Steen Hansen H, Christiansen EH

In patients with increased bleeding risk, the biolimus A9-coated BioFreedom stent, a stainless steel drug-coated stent free from polymer, has shown superiority compared to a bare-metal stent. The aim of this study was to investigate whether the BioFreedom stent is non-inferior to a modern ultrathin strut biodegradable polymer cobalt-chromium sirolimus-eluting Orsiro stent in an all-comers patient population treated with percutaneous coronary intervention.The Scandinavian Organization for Randomized Trials with Clinical Outcome (SORT OUT) IX trial, was a large-scale, registry-based, randomized, multicenter, single-blind, two-arm, non-inferiority trial. The primary endpoint, major adverse cardiovascular events (MACE), was defined as the composite of cardiac death, myocardial infarction not related to any segment other than the target lesion or target lesion revascularization within 1 year, analyzed by intention-to-treat. The trial was powered to assess non-inferiority for MACE of the BioFreedom stent compared with the Orsiro stent with a predetermined non-inferiority margin of 0.021. The trial is registered with ClinicalTrials.gov, NCT02623140.Between December 14, 2015 and April 21, 2017, 3,151 patients were assigned to treatment with the BioFreedom stent (1,572 patients, 1,966 lesions) or to the Orsiro stent (1,579 patients, 1,985 lesions). Five patients were lost to follow-up because of emigration (99.9% follow-up rate). Mean age was 66.3 {plus minus} 10.9, diabetes was seen in 19.3% of patients and 53% of the patients had acute coronary syndromes. At 1 year, intention-to-treat analysis showed that 79 (5.0%) patients, who were assigned the BioFreedom stent, and 59 (3.7%), who were assigned the Orsiro stent, met the primary endpoint (absolute risk difference 1.29% [upper limit of one-sided 95% CI 2.50%]; p(non-inferiority)=0.14). Significantly more patients in the BioFreedom stent group had target lesion revascularization than those in the Orsiro stent group (55 [3.5%] vs 20 [1.3%], rate ratio 2.77 [95% CI 1.66-4.62]; p<0.0001). The biolimus A9-coated BioFreedom polymer-free stent did not meet criteria for non-inferiority for MACE at 12 months when compared with the ultrathin strut biodegradable polymer sirolimus-eluting Orsiro stent in an all-comers populationURL: https://clinicaltrials.gov Unique Identifier: NCT02623140.



Circulation: 20 May 2020; epub ahead of print
Jensen LO, Maeng M, Raungaard B, Kahlert J, ... Steen Hansen H, Christiansen EH
Circulation: 20 May 2020; epub ahead of print | PMID: 32434381
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Abstract

Cross-neutralization of SARS-CoV-2 by a human monoclonal SARS-CoV antibody.

Pinto D, Park YJ, Beltramello M, Walls AC, ... Veesler D, Corti D

SARS-CoV-2 is a newly emerged coronavirus responsible for the current COVID-19 pandemic that has resulted in more than 3.7 million infections and 260,000 deaths as of 6 May 2020. Vaccine and therapeutic discovery efforts are paramount to curb the pandemic spread of this zoonotic virus. The SARS-CoV-2 spike (S) glycoprotein promotes entry into host cells and is the main target of neutralizing antibodies. Here we describe multiple monoclonal antibodies targeting SARS-CoV-2 S identified from memory B cells of an individual who was infected with SARS-CoV in 2003. One antibody, named S309, potently neutralizes SARS-CoV-2 and SARS-CoV pseudoviruses as well as authentic SARS-CoV-2 by engaging the S receptor-binding domain. Using cryo-electron microscopy and binding assays, we show that S309 recognizes a glycan-containing epitope that is conserved within the sarbecovirus subgenus, without competing with receptor attachment. Antibody cocktails including S309 along with other antibodies identified here further enhanced SARS-CoV-2 neutralization and may limit the emergence of neutralization-escape mutants. These results pave the way for using S309- and S309-containing antibody cocktails for prophylaxis in individuals at high risk of exposure or as a post-exposure therapy to limit or treat severe disease.



Nature: 17 May 2020; epub ahead of print
Pinto D, Park YJ, Beltramello M, Walls AC, ... Veesler D, Corti D
Nature: 17 May 2020; epub ahead of print | PMID: 32422645
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Abstract

Cardiac Energetics in Patients with Aortic Stenosis and Preserved versus Reduced Ejection Fraction.

Peterzan MA, Clarke WT, Lygate CA, Lake HA, ... Rodgers C, Rider OJ

Why some but not all patients with severe AS (SevAS) develop otherwise unexplained reduced systolic function is unclear. We investigate the hypothesis that reduced creatine kinase (CK) capacity and/or flux is associated with this transition.102 participants were recruited to five groups: moderate AS (ModAS, n=13), severe AS, LVEF ≥55% (SevAS-pEF, n=37), severe AS, LVEF<55% (SevAS-rEF, n=15), healthy volunteers with non-hypertrophied hearts with normal systolic function (NHv, n=30), and patients with non-hypertrophied, non-pressure loaded hearts with normal systolic function undergoing cardiac surgery and donating LV biopsy (NHbx, n=7). All underwent CMR imaging and P magnetic resonance spectroscopy (MRS) for myocardial energetics. LV biopsies (AS and NHBx) were analysed for; CK total activity, CK isoforms, citrate synthase (CS) activity and total creatine. Using serial block-face scanning electron microscopy, mitochondria-sarcomere diffusion distances were calculated.In the absence of failure, CK flux was lower in the presence of AS (by 32%, p=0.04), driven primarily by reduction in PCr/ATP (by 17%, p <0.001), with CK k unchanged (p=0.46),and is present in ModAS. Although lowest in the SevAS-rEF group, CK flux was not different to the SevAS-pEF group (p>0.99). Accompanying the fall in CK flux, total CK and CS activities, and absolute activities of MtCK and CK-MM were also lower (p<0.02, all analyses). Median mitochondria-sarcomere diffusion distances correlated well with CK total activity (r=0.86, p=.003).Total CK capacity is reduced in SevAS, with median values lowest in those with systolic failure, consistent with reduced energy supply reserve. Despite this, in vivo MRS measures of resting CK flux suggest that ATP delivery is reduced earlier, at the moderate AS stage, but where LV function remains preserved. These findings show that significant energetic impairment is already established in moderate AS, and suggest a fall in CK flux is not per se the cause of transition to systolic failure. However, as ATP demands increase with AS severity this could increase susceptibility to systolic failure. As such, targeting CK capacity and/or flux may be a therapeutic strategy to prevent/treat systolic failure in AS.



Circulation: 21 May 2020; epub ahead of print
Peterzan MA, Clarke WT, Lygate CA, Lake HA, ... Rodgers C, Rider OJ
Circulation: 21 May 2020; epub ahead of print | PMID: 32438845
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Abstract

Subnational mapping of under-5 and neonatal mortality trends in India: the Global Burden of Disease Study 2000-17.


Background
India has made substantial progress in improving child survival over the past few decades, but a comprehensive understanding of child mortality trends at disaggregated geographical levels is not available. We present a detailed analysis of subnational trends of child mortality to inform efforts aimed at meeting the India National Health Policy (NHP) and Sustainable Development Goal (SDG) targets for child mortality.
Methods
We assessed the under-5 mortality rate (U5MR) and neonatal mortality rate (NMR) from 2000 to 2017 in 5 × 5 km grids across India, and for the districts and states of India, using all accessible data from various sources including surveys with subnational geographical information. The 31 states and groups of union territories were categorised into three groups using their Socio-demographic Index (SDI) level, calculated as part of the Global Burden of Diseases, Injuries, and Risk Factors Study on the basis of per-capita income, mean education, and total fertility rate in women younger than 25 years. Inequality between districts within the states was assessed using the coefficient of variation. We projected U5MR and NMR for the states and districts up to 2025 and 2030 on the basis of the trends from 2000 to 2017 and compared these projections with the NHP 2025 and SDG 2030 targets for U5MR (23 deaths and 25 deaths per 1000 livebirths, respectively) and NMR (16 deaths and 12 deaths per 1000 livebirths, respectively). We assessed the causes of child death and the contribution of risk factors to child deaths at the state level.
Findings
U5MR in India decreased from 83·1 (95% uncertainty interval [UI] 76·7-90·1) in 2000 to 42·4 (36·5-50·0) per 1000 livebirths in 2017, and NMR from 38·0 (34·2-41·6) to 23·5 (20·1-27·8) per 1000 livebirths. U5MR varied 5·7 times between the states of India and 10·5 times between the 723 districts of India in 2017, whereas NMR varied 4·5 times and 8·0 times, respectively. In the low SDI states, 275 (88%) districts had a U5MR of 40 or more per 1000 livebirths and 291 (93%) districts had an NMR of 20 or more per 1000 livebirths in 2017. The annual rate of change from 2010 to 2017 varied among the districts from a 9·02% (95% UI 6·30-11·63) reduction to no significant change for U5MR and from an 8·05% (95% UI 5·34-10·74) reduction to no significant change for NMR. Inequality between districts within the states increased from 2000 to 2017 in 23 of the 31 states for U5MR and in 24 states for NMR, with the largest increases in Odisha and Assam among the low SDI states. If the trends observed up to 2017 were to continue, India would meet the SDG 2030 U5MR target but not the SDG 2030 NMR target or either of the NHP 2025 targets. To reach the SDG 2030 targets individually, 246 (34%) districts for U5MR and 430 (59%) districts for NMR would need a higher rate of improvement than they had up to 2017. For all major causes of under-5 death in India, the death rate decreased between 2000 and 2017, with the highest decline for infectious diseases, intermediate decline for neonatal disorders, and the smallest decline for congenital birth defects, although the magnitude of decline varied widely between the states. Child and maternal malnutrition was the predominant risk factor, to which 68·2% (65·8-70·7) of under-5 deaths and 83·0% (80·6-85·0) of neonatal deaths in India could be attributed in 2017; 10·8% (9·1-12·4) of under-5 deaths could be attributed to unsafe water and sanitation and 8·8% (7·0-10·3) to air pollution.
Interpretation
India has made gains in child survival, but there are substantial variations between the states in the magnitude and rate of decline in mortality, and even higher variations between the districts of India. Inequality between districts within states has increased for the majority of the states. The district-level trends presented here can provide crucial guidance for targeted efforts needed in India to reduce child mortality to meet the Indian and global child survival targets. District-level mortality trends along with state-level trends in causes of under-5 and neonatal death and the risk factors in this Article provide a comprehensive reference for further planning of child mortality reduction in India.
Funding
Bill & Melinda Gates Foundation; and Indian Council of Medical Research, Department of Health Research, Ministry of Health and Family Welfare, Government of India.

© 2020 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY 3.0 IGO license which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. In any use of this article, there should be no suggestion that WHO endorses any specific organisation, products, or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article\'s original URL.

Lancet: 10 May 2020; epub ahead of print
Lancet: 10 May 2020; epub ahead of print | PMID: 32413293
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Abstract

The Environment-Sensing Aryl-Hydrocarbon Receptor Inhibits the Chondrogenic Fate of Modulated Smooth Muscle Cells in Atherosclerotic Lesions.

Kim JB, Zhao Q, Nguyen T, Pjanic M, ... Kundu R, Quertermous T

Smooth muscle cells (SMC) play a critical role in atherosclerosis. The Aryl hydrocarbon receptor (AHR) is an environment-sensing transcription factor that contributes to vascular development, and has been implicated in coronary artery disease (CAD) risk. We hypothesized that AHR can affect atherosclerosis by regulating phenotypic modulation of SMC.We combined RNA-Seq, ChIP-Seq, ATAC-Seq and in-vitro assays in human coronary artery SMC (HCASMC), with single-cell RNA-Seq (scRNA-Seq), histology, and RNAscope in an SMC-specific lineage-tracingknockout mouse model of atherosclerosis to better understand the role ofin vascular disease.Genomic studies coupled with functional assays in cultured HCASMC revealed thatmodulates HCASMC phenotype and suppresses ossification in these cells. Lineage tracing and activity tracing studies in the mouse aortic sinus showed that thepathway is active in modulated SMC in the atherosclerotic lesion cap. Furthermore, scRNA-Seq studies of the SMC-specific Ahr knockout mice showed a significant increase in the proportion of modulated SMC expressing chondrocyte markers such asand , which localized to the lesion neointima. These cells, which we term \"chondromyocytes\" (CMC), were also identified in the neointima of human coronary arteries. In histological analyses, these changes manifested as larger lesion size, increased lineage-traced SMC participation in the lesion, decreased lineage-traced SMC in the lesion cap, and increased alkaline phosphatase activity in lesions in theknockout compared to wild-type mice. We propose thatis likely protective based on these data and inference from human genetic analyses.Overall, we conclude thatpromotes maintenance of lesion cap integrity and diminishes the disease related SMC-to-CMC transition in atherosclerotic tissues.



Circulation: 21 May 2020; epub ahead of print
Kim JB, Zhao Q, Nguyen T, Pjanic M, ... Kundu R, Quertermous T
Circulation: 21 May 2020; epub ahead of print | PMID: 32441123
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Abstract

Extracellular Vesicle-Mediated Delivery of CircSCMH1 Promotes Functional Recovery in Rodent and Nonhuman Primate Ischemic Stroke Models.

Yang L, Han B, Zhang Z, Wang S, ... Wang J, Yao H

Stroke is a leading cause of adult disability that can severely compromise patients\' quality of life, yet no effective medication currently exists to accelerate rehabilitation. A variety of circular RNA (circRNAs) molecules are known to function in ischemic brain injury. Lentivirus-based expression systems have been widely used in basic studies of circRNAs, but safety issues with such delivery systems have limited exploration of potential therapeutic roles for circRNAs.Circular RNA SCMH1 (circSCMH1) was screened from the plasma of acute ischemic stroke (AIS) patients using circRNA microarrays. Engineered RVG-circSCMH1-extracellular vesicles (RVG-circSCMH1-EVs) were generated to selectively deliver circSCMH1 to the brain. Nissl staining was used to examine infarct size. Behavioral tasks were performed to evaluate motor functions in both rodent and nonhuman primate ischemic stroke models. Golgi staining and immunostaining were used to examine neuroplasticity and glial activation. Proteomic assays and RNA-seq data combined with transcriptional profiling were used to identify downstream targets of circSCMH1.CircSCMH1 levels were significantly decreased in plasma of AIS patients, offering significant power in predicting stroke outcomes. The decreased levels of circSCMH1 were further confirmed in the plasma and peri-infarct cortex of photothrombotic (PT) stroke mice. Beyond demonstrating proof-of-concept for an RNA drug delivery technology, we observed that circSCMH1 treatment improved functional recovery post stroke in both mice and monkeys, and discovered that circSCMH1 enhanced the neuronal plasticity and also inhibited glial activation and peripheral immune cell infiltration. Mechanistically, circSCMH1 binds to the transcription factor MeCP2, thereby releasing repression of MeCP2 target gene transcription.RVG-circSCMH1-EVs afford protection by promoting functional recovery in the rodent and the nonhuman primate ischemic stroke models. Our study presents a potentially widely applicable nucleotide drug delivery technology and demonstrates the basic mechanism of how circRNAs can be therapeutically exploited to improve post-stroke outcomes.



Circulation: 21 May 2020; epub ahead of print
Yang L, Han B, Zhang Z, Wang S, ... Wang J, Yao H
Circulation: 21 May 2020; epub ahead of print | PMID: 32441115
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Abstract

A Randomized Trial of Hydroxychloroquine as Postexposure Prophylaxis for Covid-19.

Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, ... Lee TC, Hullsiek KH
Background
Coronavirus disease 2019 (Covid-19) occurs after exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For persons who are exposed, the standard of care is observation and quarantine. Whether hydroxychloroquine can prevent symptomatic infection after SARS-CoV-2 exposure is unknown.
Methods
We conducted a randomized, double-blind, placebo-controlled trial across the United States and parts of Canada testing hydroxychloroquine as postexposure prophylaxis. We enrolled adults who had household or occupational exposure to someone with confirmed Covid-19 at a distance of less than 6 ft for more than 10 minutes while wearing neither a face mask nor an eye shield (high-risk exposure) or while wearing a face mask but no eye shield (moderate-risk exposure). Within 4 days after exposure, we randomly assigned participants to receive either placebo or hydroxychloroquine (800 mg once, followed by 600 mg in 6 to 8 hours, then 600 mg daily for 4 additional days). The primary outcome was the incidence of either laboratory-confirmed Covid-19 or illness compatible with Covid-19 within 14 days.
Results
We enrolled 821 asymptomatic participants. Overall, 87.6% of the participants (719 of 821) reported a high-risk exposure to a confirmed Covid-19 contact. The incidence of new illness compatible with Covid-19 did not differ significantly between participants receiving hydroxychloroquine (49 of 414 [11.8%]) and those receiving placebo (58 of 407 [14.3%]); the absolute difference was -2.4 percentage points (95% confidence interval, -7.0 to 2.2; P = 0.35). Side effects were more common with hydroxychloroquine than with placebo (40.1% vs. 16.8%), but no serious adverse reactions were reported.
Conclusions
After high-risk or moderate-risk exposure to Covid-19, hydroxychloroquine did not prevent illness compatible with Covid-19 or confirmed infection when used as postexposure prophylaxis within 4 days after exposure. (Funded by David Baszucki and Jan Ellison Baszucki and others; ClinicalTrials.gov number, NCT04308668.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 02 Jun 2020; epub ahead of print
Boulware DR, Pullen MF, Bangdiwala AS, Pastick KA, ... Lee TC, Hullsiek KH
N Engl J Med: 02 Jun 2020; epub ahead of print | PMID: 32492293
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