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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

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

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

Copyright © 2020 Massachusetts Medical Society.

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

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

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

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

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

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

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

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

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

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

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

Copyright © 2020. Published by Elsevier Inc.

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

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

He FJ, Tan M, Ma Y, MacGregor GA

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

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

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

Long-Term Evolocumab in Patients With Familial Hypercholesterolemia.

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

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

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

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

Beckman JA, Ansel GM, Lyden SP, Das TS

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

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

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

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

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

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

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

Outbreak of Listeriosis in South Africa Associated with Processed Meat.

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

Copyright © 2020 Massachusetts Medical Society.

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

Plasma Exchange and Glucocorticoids in Severe ANCA-Associated Vasculitis.

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

Copyright © 2020 Massachusetts Medical Society.

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

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

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

Copyright © 2020 Massachusetts Medical Society.

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

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

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

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

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

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

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

Copyright © 2020 Massachusetts Medical Society.

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

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

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

Copyright © 2020 Massachusetts Medical Society.

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

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

Farmakis D, Mueller C, Apple FS

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

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

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

Clinical application of the 4th Universal Definition of Myocardial Infarction.

Hartikainen TS, Sörensen NA, Haller PM, Goßling A, ... Westermann D, Neumann JT
Aims
The recently released 4th version of the Universal Definition of Myocardial Infarction (UDMI) introduces an increased emphasis on the entities of acute and chronic myocardial injury. We applied the 4th UDMI retrospectively in patients presenting to the emergency department with symptoms potentially indicating myocardial infarction (MI) to investigate its effect on diagnosis and prognosis.
Methods and results
We included 2302 patients presenting to the emergency department with symptoms suggestive of MI. The final diagnosis was adjudicated sequentially according to the 3rd and 4th UDMI. Reclassification after readjudication was assessed. Established diagnostic algorithms for patients with suspected MI were applied to compare diagnostic accuracy. All patients were followed to assess mortality, recurrent MI, revascularization, and rehospitalization to investigate the effect of the 4th UDMI on prognosis. After readjudication, 697 patients were reclassified. Most of these patients were reclassified as having acute (n = 78) and chronic myocardial injury (n = 585). Four hundred and thirty-four (18.9%) patients were diagnosed with MI, compared with 501 (21.8%) MIs when adjudication was based on the 3rd UDMI. In the non-MI population, patients with myocardial injury (n = 663) were older, more often female and had worse renal function compared with patients without myocardial injury (n = 1205). Application of diagnostic algorithms for patients with suspected MI revealed a high accuracy after readjudication. Reclassified patients had a substantially higher rate of cardiovascular events compared with not-reclassified patients, particularly patients reclassified to the category of myocardial injury.
Conclusion
By accentuating the categories of acute and chronic myocardial injury the 4th UDMI succeeds to identify patients with higher risk for cardiovascular events and poorer outcome and thus seems to improve risk assessment in patients with suspected MI. Application of established diagnostic algorithms remains safe when using the 4th UDMI.

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

Eur Heart J: 19 Feb 2020; epub ahead of print
Hartikainen TS, Sörensen NA, Haller PM, Goßling A, ... Westermann D, Neumann JT
Eur Heart J: 19 Feb 2020; epub ahead of print | PMID: 32077925
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Abstract

Effects of glucagon-like peptide-1 receptor agonists on major cardiovascular events in patients with Type 2 diabetes mellitus with or without established cardiovascular disease: a meta-analysis of randomized controlled trials.

Marsico F, Paolillo S, Gargiulo P, Bruzzese D, ... Iesu I, Perrone Filardi P
Aims 
Glucose-lowering, glucagon-like peptide-1 (GLP-1) receptor agonists reduce incidence of major cardiovascular (CV) events in patients with Type 2 diabetes mellitus (DM). However, randomized clinical trials reported inconsistent effects on myocardial infarction (MI) and stroke, and limited data in DM patients without established CV disease (CVD). Very recently, new relevant evidence was available from additional CV outcome trials (CVOTs) that also included large subgroups of patients with DM without established CVD. Thus, the aim of this meta-analysis was to investigate the effects of GLP-1 receptor agonists on major CV events and safety in DM patients with and without established CVD.
Methods and results 
In this trial-level meta-analysis, we analysed data from randomized placebo-controlled CVOTs assessing efficacy and safety of GLP-1 receptor agonists in adult patients with Type 2 DM. We searched PubMed, Embase, Cochrane, ISI Web of Science, SCOPUS, and clinicaltrial.gov databases for eligible trials. Of 360 articles identified and screened for eligibility, seven CVOTs were included, with an overall of 56 004 patients included. The difference in efficacy with respect to the major adverse cardiovascular events (MACE) primary endpoint (including CV mortality, non-fatal MI, and non-fatal stroke) between patients with established CVD and patients with CV risk factors only was not significant [pooled interaction effect, expressed as ratio of hazard ratio (HR) 1.06, 95% confidence interval (CI) 0.85-1.34]. In the analysis of the whole population of DM patients, GLP-1 receptor agonists showed a significant 12% reduction in the hazard of the three-point MACE composite endpoint (HR 0.88, 95% CI 0.80-0.96) and a significant reduction in the risk of CV mortality (HR 0.88, 95% CI 0.79-0.98), all-cause mortality (HR 0.89, 95% CI 0.81-0.97), fatal and non-fatal stroke (HR 0.84, 95% CI 0.76-0.94), and heart failure (HF) hospitalization (HR 0.92, 95% CI 0.86-0.97). No significant effect was observed for fatal and non-fatal MI (HR 0.91, 95% CI 0.82-1.02), although in a sensitivity analysis, based on a less conservative statistical approach, the pooled HR become statistically significant (HR 0.91, 95% CI 0.83-1.00; P = 0.039). No excess of hypoglycaemia, pancreatitis, and pancreatic cancer was observed between GLP-1 receptor agonists and placebo.
Conclusion 
Glucagon-like peptide-1 receptor agonists significantly reduce MACE, CV and total mortality stroke, and hospitalization for HF, with a trend for reduction of MI, in patients with Type 2 DM with and without established CVD.

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

Eur Heart J: 19 Feb 2020; epub ahead of print
Marsico F, Paolillo S, Gargiulo P, Bruzzese D, ... Iesu I, Perrone Filardi P
Eur Heart J: 19 Feb 2020; epub ahead of print | PMID: 32077924
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Abstract

Plasma lipids and risk of aortic valve stenosis: a Mendelian randomization study.

Nazarzadeh M, Pinho-Gomes AC, Bidel Z, Dehghan A, ... Otto CM, Rahimi K
Aims
Aortic valve stenosis is commonly considered a degenerative disorder with no recommended preventive intervention, with only valve replacement surgery or catheter intervention as treatment options. We sought to assess the causal association between exposure to lipid levels and risk of aortic stenosis.
Methods and results
Causality of association was assessed using two-sample Mendelian randomization framework through different statistical methods. We retrieved summary estimations of 157 genetic variants that have been shown to be associated with plasma lipid levels in the Global Lipids Genetics Consortium that included 188 577 participants, mostly European ancestry, and genetic association with aortic stenosis as the main outcome from a total of 432 173 participants in the UK Biobank. Secondary negative control outcomes included aortic regurgitation and mitral regurgitation. The odds ratio for developing aortic stenosis per unit increase in lipid parameter was 1.52 [95% confidence interval (CI) 1.22-1.90; per 0.98 mmol/L] for low density lipoprotein (LDL)-cholesterol, 1.03 (95% CI 0.80-1.31; per 0.41 mmol/L) for high density lipoprotein (HDL)-cholesterol, and 1.38 (95% CI 0.92-2.07; per 1 mmol/L) for triglycerides. There was no evidence of a causal association between any of the lipid parameters and aortic or mitral regurgitation.
Conclusion
Lifelong exposure to high LDL-cholesterol increases the risk of symptomatic aortic stenosis, suggesting that LDL-lowering treatment may be effective in its prevention.

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

Eur Heart J: 19 Feb 2020; epub ahead of print
Nazarzadeh M, Pinho-Gomes AC, Bidel Z, Dehghan A, ... Otto CM, Rahimi K
Eur Heart J: 19 Feb 2020; epub ahead of print | PMID: 32076698
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Abstract

Long-Term Exposure to Fine Particulate Matter and Cardiovascular Disease in China.

Liang F, Liu F, Huang K, Yang X, ... Lu X, Gu D
Background
Evidence of the effects of long-term fine particulate matter (PM) exposure on cardiovascular diseases (CVDs) is rare for populations exposed to high levels of PM in China and in other countries with similarly high levels.
Objectives
The aim of this study was to assess the CVD risks associated with long-term exposure to PM in China.
Methods
A nationwide cohort study, China-PAR (Prediction for Atherosclerotic Cardiovascular Disease Risk in China), was used, with 116,972 adults without CVD in 2000 being included. Participants were followed until 2015. Satellite-based PM concentrations at 1-km spatial resolution during the study period were used for exposure assessment. A Cox proportional hazards model with time-varying exposures was used to estimate the CVD risks associated with PM exposure, adjusting for individual risk factors.
Results
Annual mean concentrations of PM at the China-PAR sites ranged from 25.5 to 114.0 μg/m. For each 10 μg/m increase in PM exposures, the multivariate-adjusted hazard ratio was 1.251 (95% confidence interval: 1.220 to 1.283) for CVD incidence and 1.164 (95% confidence interval: 1.117 to 1.213) for CVD mortality. The slopes of concentration-response functions of PM exposure and CVD risks were steeper at high PM levels. In addition, older residents, rural residents, and never smokers were more prone to adverse effects of PM exposure.
Conclusions
This study provides evidence that elevated long-term PM exposures lead to increased CVD risk in China. The effects are more pronounced at higher PM levels. These findings expand the current knowledge on adverse health effects of severe air pollution and highlight the potential cardiovascular benefits of air quality improvement in China and other low- and middle-income countries.

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

J Am Coll Cardiol: 24 Feb 2020; 75:707-717
Liang F, Liu F, Huang K, Yang X, ... Lu X, Gu D
J Am Coll Cardiol: 24 Feb 2020; 75:707-717 | PMID: 32081278
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Abstract

Readmission and Mortality After Hospitalization for Myocardial Infarction and Heart Failure.

Ko DT, Khera R, Lau G, Qiu F, ... Wijeysundera HC, Krumholz HM
Background
Readmission rates after acute myocardial infarction (AMI) and heart failure (HF) hospitalizations have decreased in the United States since the implementation of the Hospital Readmissions Reduction Program.
Objectives
This study was designed to examine the temporal trends of readmission and mortality after AMI and HF in Ontario, Canada, where reducing hospital readmissions has not had a policy incentive.
Methods
The cohort was comprised of AMI or HF patients 65 years of age or older who had been hospitalized from 2006 to 2017. Primary outcomes were 30-day readmission and post-discharge mortality. Secondary outcomes included in-hospital mortality, 30-day mortality from admission, and in-hospital mortality or 30-day mortality post-discharge. Adjusted monthly trends for each outcome were examined over the study period.
Results
Our cohorts included 152,808 AMI and 223,283 HF patients. Age- and sex-standardized AMI hospitalization rates in Ontario declined 32% from 2006 to 2017 while HF hospitalization rates declined slightly (9.1%). For AMI, risk-adjusted 30-day readmission rates declined from 17.4% in 2006 to 14.7% in 2017. All AMI risk-adjusted mortality rates also declined from 2006 to 2017 with 30-day post-discharge mortality from 5.1% to 4.4%. For HF, overall risk-adjusted 30-day readmission was largely unchanged from 2006 to 2014 at 21.9%, followed by a decline to 20.8% in 2017. Risk-adjusted 30-day post-discharge mortality declined from 7.1% in 2006 to 6.6% in 2017.
Conclusions
The patterns of outcomes in Ontario are consistent with the United States for AMI, but diverge for HF. For AMI and HF, admissions, readmissions, and mortality rates declined over this period. The reasons for the country-specific patterns for HF need further exploration.

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

J Am Coll Cardiol: 24 Feb 2020; 75:736-746
Ko DT, Khera R, Lau G, Qiu F, ... Wijeysundera HC, Krumholz HM
J Am Coll Cardiol: 24 Feb 2020; 75:736-746 | PMID: 32081282
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Abstract

Detection of Hypertrophic Cardiomyopathy Using a Convolutional Neural Network-Enabled Electrocardiogram.

Ko WY, Siontis KC, Attia ZI, Carter RE, ... Friedman PA, Noseworthy PA
Background
Hypertrophic cardiomyopathy (HCM) is an uncommon but important cause of sudden cardiac death.
Objectives
This study sought to develop an artificial intelligence approach for the detection of HCM based on 12-lead electrocardiography (ECG).
Methods
A convolutional neural network (CNN) was trained and validated using digital 12-lead ECG from 2,448 patients with a verified HCM diagnosis and 51,153 non-HCM age- and sex-matched control subjects. The ability of the CNN to detect HCM was then tested on a different dataset of 612 HCM and 12,788 control subjects.
Results
In the combined datasets, mean age was 54.8 ± 15.9 years for the HCM group and 57.5 ± 15.5 years for the control group. After training and validation, the area under the curve (AUC) of the CNN in the validation dataset was 0.95 (95% confidence interval [CI]: 0.94 to 0.97) at the optimal probability threshold of 11% for having HCM. When applying this probability threshold to the testing dataset, the CNN\'s AUC was 0.96 (95% CI: 0.95 to 0.96) with sensitivity 87% and specificity 90%. In subgroup analyses, the AUC was 0.95 (95% CI: 0.94 to 0.97) among patients with left ventricular hypertrophy by ECG criteria and 0.95 (95% CI: 0.90 to 1.00) among patients with a normal ECG. The model performed particularly well in younger patients (sensitivity 95%, specificity 92%). In patients with HCM with and without sarcomeric mutations, the model-derived median probabilities for having HCM were 97% and 96%, respectively.
Conclusions
ECG-based detection of HCM by an artificial intelligence algorithm can be achieved with high diagnostic performance, particularly in younger patients. This model requires further refinement and external validation, but it may hold promise for HCM screening.

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

J Am Coll Cardiol: 24 Feb 2020; 75:722-733
Ko WY, Siontis KC, Attia ZI, Carter RE, ... Friedman PA, Noseworthy PA
J Am Coll Cardiol: 24 Feb 2020; 75:722-733 | PMID: 32081280
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Impact:
Abstract

Long-Term Changes in Gut Microbial Metabolite Trimethylamine N-Oxide and Coronary Heart Disease Risk.

Heianza Y, Ma W, DiDonato JA, Sun Q, ... Manson JE, Qi L
Background
A gut-microbial metabolite, trimethylamine N-oxide (TMAO), has been associated with coronary atherosclerotic burden. No previous prospective study has addressed associations of long-term changes in TMAO with coronary heart disease (CHD) incidence.
Objectives
The purpose of this study was to investigate whether 10-year changes in plasma TMAO levels were significantly associated with CHD incidence.
Methods
This prospective nested case-control study included 760 healthy women at baseline. Plasma TMAO levels were measured both at the first (1989 to 1990) and the second (2000 to 2002) blood collections; 10-year changes (Δ) in TMAO were calculated. Incident cases of CHD (n = 380) were identified after the second blood collection through 2016 and were matched to controls (n = 380).
Results
Regardless of the initial TMAO levels, 10-year increases in TMAO from the first to second blood collection were significantly associated with an increased risk of CHD (relative risk [RR] in the top tertile: 1.58 [95% confidence interval (CI): 1.05 to 2.38]; RR per 1-SD increment: 1.33 [95% CI: 1.06 to 1.67]). Participants with elevated TMAO levels (the top tertile) at both time points showed the highest RR of 1.79 (95% CI: 1.08 to 2.96) for CHD as compared with those with consistently low TMAO levels. Further, we found that the ΔTMAO-CHD relationship was strengthened by unhealthy dietary patterns (assessed by the Alternate Healthy Eating Index) and was attenuated by healthy dietary patterns (p interaction = 0.008).
Conclusions
Long-term increases in TMAO were associated with higher CHD risk, and repeated assessment of TMAO over 10 years improved the identification of people with a higher risk of CHD. Diet may modify the associations of ΔTMAO with CHD risk.

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

J Am Coll Cardiol: 24 Feb 2020; 75:763-772
Heianza Y, Ma W, DiDonato JA, Sun Q, ... Manson JE, Qi L
J Am Coll Cardiol: 24 Feb 2020; 75:763-772 | PMID: 32081286
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Abstract

Editor-in-Chief\'s Top Picks From 2019.

Fuster V

Each week, I record audio summaries for every paper in JACC, as well as an issue summary. Although this process is quite time-consuming, I have become familiar with every paper that we publish. Thus, I have personally selected the top 100 papers (both Original Investigations and Review Articles, and an occasional Editorial Comment) from the distinct specialties each year. In addition to my personal choices, I have included papers that have been the most accessed or downloaded on our websites, as well as those selected by the JACC Editorial Board members. In order to present the full breadth of this important research in a consumable fashion, we will present these abstracts in this issue of JACC, as well as most of the central illustrations, with the realization that a magnifying glass will be be needed for appropriate visualization. The highlights comprise the following sections: Basic & Translational Research, Cardiac Failure & Myocarditis, Cardiomyopathies/Congenital & Genetics, Cardio-Oncology, Coronary Disease & Interventions, Hypertension, Imaging, Metabolic & Lipid Disorders, Neurovascular Disease & Dementia, Promoting Health & Prevention, Rhythm Disorders & Thromboembolism, Valvular Heart Disease, and Vascular Medicine (1-100).

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

J Am Coll Cardiol: 24 Feb 2020; 75:776-834
Fuster V
J Am Coll Cardiol: 24 Feb 2020; 75:776-834 | PMID: 32081288
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Impact:
Abstract

Prognostic Value of Left Ventricular Global Longitudinal Strain in Patients With Secondary Mitral Regurgitation.

Namazi F, van der Bijl P, Hirasawa K, Kamperidis V, ... Delgado V, Bax JJ
Background
Left ventricular (LV) systolic function may be overestimated in patients with secondary mitral regurgitation (MR) when using LV ejection fraction (EF). LV global longitudinal strain (GLS) is a less load-dependent measure of LV function. However, the prognostic value of LV GLS in secondary MR has not been evaluated.
Objectives
This study sought to demonstrate the prognostic value of LV GLS over LVEF in patients with secondary MR.
Methods
A total of 650 patients (mean 66 ± 11 years of age, 68% men) with significant secondary MR were included. The study population was subdivided based on the LV GLS value at which the hazard ratio (HR) for all-cause mortality was >1 using a spline curve analysis (LV GLS <7.0%, impaired LV systolic function vs. LV GLS ≥7.0%, preserved LV systolic function). The primary endpoint was all-cause mortality.
Results
During a median follow-up of 56 (interquartile range: 28 to 106 months) months, 334 (51%) patients died. Patients with a more impaired LV GLS showed significantly higher mortality rates at 1-, 2-, and 5-year follow-up (13%, 23%, and 44%, respectively) when compared with patients with more preserved LV systolic function (5%, 14%, and 31%, respectively). On multivariable analysis, LV GLS <7.0% was associated with increased mortality (HR: 1.337; 95% confidence interval: 1.038 to 1.722; p = 0.024), whereas LVEF ≤30% was not (HR: 1.055; 95% confidence interval: 0.794 to 1.403; p = 0.711).
Conclusions
In patients with secondary MR, impaired LV GLS was independently associated with an increased risk for all-cause mortality, whereas LVEF was not. LV GLS may therefore be useful in the risk stratification of patients with secondary MR.

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

J Am Coll Cardiol: 24 Feb 2020; 75:750-758
Namazi F, van der Bijl P, Hirasawa K, Kamperidis V, ... Delgado V, Bax JJ
J Am Coll Cardiol: 24 Feb 2020; 75:750-758 | PMID: 32081284
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Impact:
Abstract

Women\'s Participation in Cardiovascular Clinical Trials From 2010 to 2017.

Jin X, Chandramouli C, Allocco B, Gong E, Lam CSP, Yan LL
Background
Cardiovascular disease is the leading cause of death among women worldwide, yet, women have historically been underrepresented in cardiovascular trials.
Methods
We systematically assessed the participation of women in completed cardiovascular trials registered in ClinicalTrials.gov between 2010 and 2017, and extracted publicly available information including disease type, sponsor type, country, trial size, intervention type, and the demographic characteristics of trial participants. We calculated the female-to-male ratio for each trial and determined the prevalence-adjusted estimates for participation of women by dividing the percentage of women among trial participants by the percentage of women in the disease population (participation prevalence ratio; a ratio of 0.8 to 1.2 suggests comparable prevalence and good representation).
Results
We identified 740 completed cardiovascular trials including a total of 862 652 adults, of whom 38.2% were women. The median female-to-male ratio of each trial was 0.51 (25th quartile, 0.32; 75th quartile, 0.90) overall and varied by age group (1.02 in ≤55 year old group versus 0.40 in the 61- to 65-year-old group), type of intervention (0.44 for procedural trials versus 0.78 for lifestyle intervention trials), disease type (0.34 for acute coronary syndrome versus 3.20 for pulmonary hypertension), region (0.45 for Western Pacific versus 0.55 for the Americas), funding/sponsor type (0.14 for government-funded versus 0.73 for multiple sponsors), and trial size (0.56 for smaller [n≤47] versus 0.49 for larger [n≥399] trials). Relative to their prevalence in the disease population, participation prevalence ratio was higher than 0.8 for hypertension, pulmonary arterial hypertension and lower (participation prevalence ratio 0.48 to 0.78) for arrhythmia, coronary heart disease, acute coronary syndrome, and heart failure trials. The most recent time period (2013 to 2017) saw significant increases in participation prevalence ratios for stroke (=0.007) and heart failure (=0.01) trials compared with previous periods.
Conclusions
Among cardiovascular trials in the current decade, men still predominate overall, but the representation of women varies with disease and trial characteristics, and has improved in stroke and heart failure trials.



Circulation: 17 Feb 2020; 141:540-548
Jin X, Chandramouli C, Allocco B, Gong E, Lam CSP, Yan LL
Circulation: 17 Feb 2020; 141:540-548 | PMID: 32065763
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Impact:
Abstract

Aromatase Inhibitors and the Risk of Cardiovascular Outcomes in Women With Breast Cancer: A Population-Based Cohort Study.

Khosrow-Khavar F, Filion KB, Bouganim N, Suissa S, Azoulay L
Background
The association between aromatase inhibitors and cardiovascular outcomes among women with breast cancer is controversial. Given the discrepant findings from randomized controlled trials and observational studies, additional studies are needed to address this safety concern.
Methods
We conducted a population-based cohort study using the UK Clinical Practice Research Datalink linked to the Hospital Episode Statistics and Office for National Statistics databases. The study population consisted of women newly diagnosed with breast cancer initiating hormonal therapy with aromatase inhibitors or tamoxifen between April 1, 1998, and February 29, 2016. We usedCox proportional hazards models with inverse probability of treatment and censoring weighting to estimate hazard ratios (HRs) with 95% CIs comparing new users of aromatase inhibitors with new users of tamoxifen for each of the study outcomes (myocardial infarction, ischemic stroke, heart failure, and cardiovascular mortality).
Results
The study population consisted of 23 525 patients newly diagnosed with breast cancer, of whom 17 922 initiated treatment with either an aromatase inhibitor or tamoxifen (8139 and 9783, respectively). The use of aromatase inhibitors was associated with a significantly increased risk of heart failure (incidence rate, 5.4 versus 1.8 per 1000 person-years; HR, 1.86 [95% CI, 1.14-3.03]) and cardiovascular mortality (incidence rate, 9.5 versus 4.7 per 1000 person-years; HR, 1.50 [95% CI, 1.11-2.04]) compared with the use of tamoxifen. Aromatase inhibitors were associated with elevated HRs, but with CIs including the null value, for myocardial infarction (incidence rate, 3.9 versus 1.8 per 1000 person-years; HR, 1.37 [95% CI, 0.88-2.13]) and ischemic stroke (incidence rate, 5.6 versus 3.2 per 1000 person-years; HR, 1.19 [95% CI, 0.82-1.72]).
Conclusions
In this population-based study, aromatase inhibitors were associated with increased risks of heart failure and cardiovascular mortality compared with tamoxifen. There were also trends toward increased risks, although nonsignificant, of myocardial infarction and ischemic stroke. The increased risk of cardiovascular events associated with aromatase inhibitors should be balanced with their favorable clinical benefits compared with tamoxifen.



Circulation: 17 Feb 2020; 141:549-559
Khosrow-Khavar F, Filion KB, Bouganim N, Suissa S, Azoulay L
Circulation: 17 Feb 2020; 141:549-559 | PMID: 32065766
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Abstract

Sex Differences in Primary and Secondary Prevention of Cardiovascular Disease in China.

Xia S, Du X, Guo L, Du J, ... Dong J, Ma C
Background
Despite improvements in diagnostic and therapeutic interventions to combat cardiovascular disease (CVD) in recent decades, there are significant ongoing access gaps and sex disparities in prevention that have not been adequately quantified in China.
Methods
A representative, cross-sectional, community-based survey of adults (aged ≥45 years) was conducted in 7 geographic regions of China between 2014 and 2016. Logistic regression models were used to determine sex differences in primary and secondary CVD prevention, and any interaction by age, education level, and area of residence. Data are presented as adjusted odds ratios (ORs) and 95% CIs.
Results
Of 47 841 participants (61.3% women), 5454 (57.2% women) had established CVD and 9532 (70.5% women) had a high estimated 10-year CVD risk (≥10%). Only 48.5% and 48.6% of women and 39.3% and 59.8% of men were on any kind of blood pressure (BP)-lowering medication, lipid-lowering medication, or antiplatelet therapy for primary and secondary prevention, respectively. Women with established CVD were significantly less likely than men to receive BP-lowering medications (OR, 0.79 [95% CI, 0.65-0.95]), lipid-lowering medications (OR, 0.69 [95% CI, 0.56-0.84]), antiplatelets (OR, 0.53 [95% CI, 0.45-0.62]), or any CVD prevention medication (OR, 0.62 [95% CI, 0.52-0.73]). Women with established CVD, however, had better BP control (OR, 1.31 [95% CI, 1.14-1.50]) but less well-controlled low-density lipoprotein cholesterol (OR, 0.66 [95% CI, 0.57-0.76]), and were less likely to smoke (OR, 13.89 [95% CI, 11.24-17.15]) and achieve physical activity targets (OR, 1.92 [95% CI, 1.61-2.29]). Conversely, women with high CVD risk were less likely than men to have their BP, low-density lipoprotein cholesterol, and bodyweight controlled (OR, 0.46 [95% CI, 0.38-0.55]; OR, 0.60 [95% CI, 0.52-0.69]; OR, 0.55 [95% CI, 0.48-0.63], respectively), despite a higher use of BP-lowering medications (OR, 1.21 [95% CI, 1.01-1.45]). Younger patients (<65 years) with established CVD were less likely to be taking CVD preventive medications, but there were no sex differences by area of residence or education level.
Conclusions
Large and variable gaps in primary and secondary CVD prevention exist in China, particularly for women. Effective CVD prevention requires an improved overall nationwide strategy and a special emphasis on women with established CVD, who have the greatest disparity and the most to benefit.



Circulation: 17 Feb 2020; 141:530-539
Xia S, Du X, Guo L, Du J, ... Dong J, Ma C
Circulation: 17 Feb 2020; 141:530-539 | PMID: 32065775
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Abstract

The Use of Sex-Specific Factors in the Assessment of Women\'s Cardiovascular Risk.

Agarwala A, Michos ED, Samad Z, Ballantyne CM, Virani SS

Cardiovascular disease (CVD) is the leading cause of death among women in the United States. As compared with men, women are less likely to be diagnosed appropriately, receive preventive care, or be treated aggressively for CVD. Sex differences between men and women have allowed for the identification of CVD risk factors and risk markers that are unique to women. The 2018 American Heart Association/American College of Cardiology Multi-Society cholesterol guideline and 2019 American College of Cardiology/American Heart Association guideline on the primary prevention of CVD introduced the concept of risk-enhancing factors that are specific to women and are associated with an increased risk of incident atherosclerotic CVD in women. These factors, if present, would favor more intensified lifestyle interventions and consideration of initiation or intensification of statin therapy for primary prevention to mitigate the increased risk. In this primer, we highlight sex-specific CVD risk factors in women, stress the importance of eliciting a thorough obstetrical and gynecological history during cardiovascular risk assessment, and provide a framework for how to initiate appropriate preventive measures when sex-specific risk factors are present.



Circulation: 17 Feb 2020; 141:592-599
Agarwala A, Michos ED, Samad Z, Ballantyne CM, Virani SS
Circulation: 17 Feb 2020; 141:592-599 | PMID: 32065772
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Abstract

Global, regional, and national burden of chronic kidney disease, 1990-2017: a systematic analysis for the Global Burden of Disease Study 2017.


Background
Health system planning requires careful assessment of chronic kidney disease (CKD) epidemiology, but data for morbidity and mortality of this disease are scarce or non-existent in many countries. We estimated the global, regional, and national burden of CKD, as well as the burden of cardiovascular disease and gout attributable to impaired kidney function, for the Global Burden of Diseases, Injuries, and Risk Factors Study 2017. We use the term CKD to refer to the morbidity and mortality that can be directly attributed to all stages of CKD, and we use the term impaired kidney function to refer to the additional risk of CKD from cardiovascular disease and gout.
Methods
The main data sources we used were published literature, vital registration systems, end-stage kidney disease registries, and household surveys. Estimates of CKD burden were produced using a Cause of Death Ensemble model and a Bayesian meta-regression analytical tool, and included incidence, prevalence, years lived with disability, mortality, years of life lost, and disability-adjusted life-years (DALYs). A comparative risk assessment approach was used to estimate the proportion of cardiovascular diseases and gout burden attributable to impaired kidney function.
Findings
Globally, in 2017, 1·2 million (95% uncertainty interval [UI] 1·2 to 1·3) people died from CKD. The global all-age mortality rate from CKD increased 41·5% (95% UI 35·2 to 46·5) between 1990 and 2017, although there was no significant change in the age-standardised mortality rate (2·8%, -1·5 to 6·3). In 2017, 697·5 million (95% UI 649·2 to 752·0) cases of all-stage CKD were recorded, for a global prevalence of 9·1% (8·5 to 9·8). The global all-age prevalence of CKD increased 29·3% (95% UI 26·4 to 32·6) since 1990, whereas the age-standardised prevalence remained stable (1·2%, -1·1 to 3·5). CKD resulted in 35·8 million (95% UI 33·7 to 38·0) DALYs in 2017, with diabetic nephropathy accounting for almost a third of DALYs. Most of the burden of CKD was concentrated in the three lowest quintiles of Socio-demographic Index (SDI). In several regions, particularly Oceania, sub-Saharan Africa, and Latin America, the burden of CKD was much higher than expected for the level of development, whereas the disease burden in western, eastern, and central sub-Saharan Africa, east Asia, south Asia, central and eastern Europe, Australasia, and western Europe was lower than expected. 1·4 million (95% UI 1·2 to 1·6) cardiovascular disease-related deaths and 25·3 million (22·2 to 28·9) cardiovascular disease DALYs were attributable to impaired kidney function.
Interpretation
Kidney disease has a major effect on global health, both as a direct cause of global morbidity and mortality and as an important risk factor for cardiovascular disease. CKD is largely preventable and treatable and deserves greater attention in global health policy decision making, particularly in locations with low and middle SDI.
Funding
Bill & Melinda Gates Foundation.

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

Lancet: 12 Feb 2020; epub ahead of print
Lancet: 12 Feb 2020; epub ahead of print | PMID: 32061315
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Abstract

Body Mass Index in Young Women and Risk of Cardiomyopathy: A Long-Term Follow-Up Study in Sweden.

Robertson J, Lindgren M, Schaufelberger M, Adiels M, ... Rosengren A, Åberg M
Background
Incidence rates of cardiomyopathies, which are a common cause of heart failure in young people, have increased during the last decades. An association between body weight in adolescence and future cardiomyopathy among men was recently identified. Whether or not this holds true also for women is unknown. The aim was therefore to determine whether for young women being overweight or obese is associated with a higher risk of developing cardiomyopathy.
Methods
This was a registry-based national prospective cohort study with data collected from the Swedish Medical Birth Register, 1982 to 2014, with up to 33 years of follow-up. Included women were of childbearing age (18-45 years) during the initial antenatal visit in their first or second pregnancy (n=1 393 346). We obtained baseline data on body mass index (BMI), smoking, education, and previous disorders. After exclusions, mainly because of previous disorders, the final sample was composed of 1 388 571 women. Cardiomyopathy cases were identified by linking the Medical Birth Register to the National Patient and Cause of Death registers.
Results
In total, we identified 1699 cases of cardiomyopathy (mean age at diagnosis, 46.2 [SD 9.1] years) during the follow-up with an incidence rate of 5.9 per 100 000 observation years. Of these, 481 were diagnosed with dilated cardiomyopathy, 246 had hypertrophic cardiomyopathy, 61 had alcohol/drug-induced cardiomyopathy, and 509 had other forms. The lowest risk for being diagnosed with a cardiomyopathy was detected at a BMI of 21 kg/m, with a gradual increase in risk with higher BMI, particularly for dilated cardiomyopathy, where a hazard ratio of 4.71 (95% CI, 2.81-7.89) was found for severely obese subjects (BMI ≥35 kg/m), as compared with BMI 20 to <22.5.
Conclusions
Elevated BMI among young women was associated with an increased risk of being diagnosed with a subsequent cardiomyopathy, especially dilated cardiomyopathy, starting already at mildly elevated body weight, whereas severe obesity entailed an almost 5-fold increase in risk. With the increasing numbers of persons who are overweight or obese, higher rates of cardiomyopathy can be expected in the future, along with an altered disease burden related to adiposity.



Circulation: 17 Feb 2020; 141:520-529
Robertson J, Lindgren M, Schaufelberger M, Adiels M, ... Rosengren A, Åberg M
Circulation: 17 Feb 2020; 141:520-529 | PMID: 32065765
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Abstract

Sex-Specific Trends in Acute Myocardial Infarction Within an Integrated Healthcare Network, 2000 Through 2014.

Mefford MT, Li BH, Qian L, Reading SR, ... Woodward M, Reynolds K
Background
In recent decades, the rates of incident acute myocardial infarction (AMI) have declined in the United States, yet disparities by sex remain. In an integrated healthcare delivery system, we examined temporal trends in incident AMI among women and men.
Methods
We identified hospitalized AMI among members ≥35 years of age in Kaiser Permanente Southern California. The first hospitalization for AMI overall, and for ST-segment-elevation MI and non-ST-segment-elevation MI was identified byprimary discharge diagnosis codes in each calendar year from 2000 through 2014. Age- and sex-standardized incidence rates per 100 000 person-years were calculated by using direct adjustment to the 2010 US Census population. Average annual percent changes (AAPCs) and period percent changes were calculated, and trend tests were conducted using Poisson regression.
Results
We identified 45 331 AMI hospitalizations between 2000 and 2014. Age- and sex-standardized incidence rates of AMI declined from 322.4 (95% CI, 311.0-333.9) in 2000 to 174.6 (95% CI, 168.2-181.0) in 2014, representing an AAPC of -4.4% (95% CI, -4.2 to -4.6) and a period percent change of -46.6%. The AAPC for AMI in women was -4.6% (95% CI, -4.1 to -5.2) between 2000 and 2009 and declined to -2.3% (95% CI, -1.2 to -3.4) between 2010 and 2014. The AAPC for AMI in men was stable over the study period (-4.7% [95% CI, -4.4 to -4.9]). The AAPC for ST-segment-elevation MI hospitalization overall was -8.3% (95% CI, -8.0% to -8.6%).The AAPC in ST-segment-elevation MI changed among women in 2009 (2000-2009: -10.2% [95% CI, -9.3 to -11.1] and in 2010-2014: -5.2% [95% CI, -3.1 to -7.3]) while remaining stable among men (-8.0% [95% CI, -7.6 to -8.4]). The AAPC for non-ST-segment-elevation MI hospitalization was smaller than for ST-segment-elevation MI among both women and men (-1.9% [95% CI, -1.5 to -2.3] and -2.8% [95% CI, -2.5 to -3.2], respectively).
Conclusions
These results suggest that the incidence of hospitalized AMI declined between 2000 and 2014; however, declines in AMI have slowed among women in comparison with men in recent years. Determining unmet care needs among women may reduce these sex-based AMI disparities.



Circulation: 17 Feb 2020; 141:509-519
Mefford MT, Li BH, Qian L, Reading SR, ... Woodward M, Reynolds K
Circulation: 17 Feb 2020; 141:509-519 | PMID: 32065770
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Abstract

Effects of Exercise Therapy Dosing Schedule on Impaired Cardiorespiratory Fitness in Patients With Primary Breast Cancer: A Randomized Controlled Trial.

Scott JM, Thomas SM, Peppercorn JM, Herndon JE, ... Eves ND, Jones LW
Background
Current exercise guidelines for clinical populations recommend an exercise therapy (ET) prescription of fixed intensity (moderate), duration (40-50 minutes per session), and volume (120-160 min/wk). A critical overarching element of exercise programming that has received minimal attention is dose scheduling. We investigated the tolerability and efficacy of 2 exercise training dose regimens on cardiorespiratory fitness and patient-reported outcomes in patients with posttreatment primary breast cancer.
Methods
Using a parallel-group randomized trial, we randomly allocated 174 postmenopausal patients (2.8 years after adjuvant therapy) with impaired peak oxygen consumption (VOpeak) to 1 of 2 supervised exercise training interventions delivered with a standard linear (LET) (fixed dose intensity per session for 160 min/wk) or nonlinear (NLET) (variable dose intensity per session for ≈120 min/wk) schedule compared with a stretching attention control group for 16 consecutive weeks. Stretching was matched to exercise dosing arms on the basis of location, frequency, duration, and treatment length. The primary end point was change in VOpeak (mL O·kg·min) from baseline to after intervention. Secondary end points were patient-reported outcomes, tolerability, and safety.
Results
No serious adverse events were observed. Mean attendance was 64%, 75%, and 80% for attention control, LET, and NLET, respectively. In intention-to-treat analysis, VOpeak increased 0.6±1.7 mL O·kg·min (=0.05) and 0.8±1.8 mL O·kg·min (=0.07) in LET and NLET, respectively, compared with attention control. Change in VOpeak ranged from -2.7 to 4.1 mL O·kg·min and from -3.6 to 5.1 mL O·kg·min in LET and NLET, respectively. Approximately 40% of patients in both exercise dosing regimens were classified as VOpeak responders (ie, Δ ≥1.32 mL O·kg·min). NLET improved all patient-reported outcomes compared with attention control.
Conclusions
Short-term exercise training, independently of dosing schedule, is associated with modest improvements in cardiorespiratory fitness in patients previously treated for early-stage breast cancer.
Clinical trial registration
URL: https://www.clinicaltrials.gov. Unique identifier: NCT01186367.



Circulation: 17 Feb 2020; 141:560-570
Scott JM, Thomas SM, Peppercorn JM, Herndon JE, ... Eves ND, Jones LW
Circulation: 17 Feb 2020; 141:560-570 | PMID: 32065769
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Abstract

Improving the prognosis of health care in the USA.

Galvani AP, Parpia AS, Foster EM, Singer BH, Fitzpatrick MC

Although health care expenditure per capita is higher in the USA than in any other country, more than 37 million Americans do not have health insurance, and 41 million more have inadequate access to care. Efforts are ongoing to repeal the Affordable Care Act which would exacerbate health-care inequities. By contrast, a universal system, such as that proposed in the Medicare for All Act, has the potential to transform the availability and efficiency of American health-care services. Taking into account both the costs of coverage expansion and the savings that would be achieved through the Medicare for All Act, we calculate that a single-payer, universal health-care system is likely to lead to a 13% savings in national health-care expenditure, equivalent to more than US$450 billion annually (based on the value of the US$ in 2017). The entire system could be funded with less financial outlay than is incurred by employers and households paying for health-care premiums combined with existing government allocations. This shift to single-payer health care would provide the greatest relief to lower-income households. Furthermore, we estimate that ensuring health-care access for all Americans would save more than 68 000 lives and 1·73 million life-years every year compared with the status quo.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 14 Feb 2020; 395:524-533
Galvani AP, Parpia AS, Foster EM, Singer BH, Fitzpatrick MC
Lancet: 14 Feb 2020; 395:524-533 | PMID: 32061298
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Abstract

Copper-mediated synthesis of drug-like bicyclopentanes.

Zhang X, Smith RT, Le C, McCarver SJ, ... Carruthers NI, MacMillan DWC

Multicomponent reactions have become a mainstay in both academic and industrial synthetic organic chemistry owing to their step- and atom-economy advantages over traditional synthetic sequences. Recently, bicyclo[1.1.1]pentane (BCP) motifs have come to the fore as valuable pharmaceutical bioisosteres of benzene rings, and, in particular, 1,3-disubstituted BCP moieties have become widely adopted in medicinal chemistry as para-phenyl ring replacements. Often these structures are generated from [1.1.1]propellane via opening of the internal C-C bond, through the addition of either radicals or metal-based nucleophiles. The resulting propellane-addition adducts are subsequently transformed to the requisite polysubstituted BCP compounds via a range of synthetic sequences that traditionally involve multiple chemical steps. While this approach has been effective so far, it is clear that a multicomponent reaction that enables single-step access to complex and diverse polysubstituted BCP products would be synthetically advantageous over the current stepwise approaches. Here we report a one-step three-component radical coupling of [1.1.1]propellane to afford diverse functionalized bicycles using various radical precursors and heteroatom nucleophiles via a metallaphotoredox catalysis protocol. The reaction operates on short timescales (five minutes to one hour) across multiple (>10) nucleophile classes and can accommodate a diverse array of radical precursors, including those which generate alkyl, α-acyl, trifluoromethyl, and sulfonyl radicals. This method has been used to rapidly prepare BCP analogues of known pharmaceuticals, one of which has pharmacokinetic properties substantially different to those of its commercial progenitor.



Nature: 16 Feb 2020; epub ahead of print
Zhang X, Smith RT, Le C, McCarver SJ, ... Carruthers NI, MacMillan DWC
Nature: 16 Feb 2020; epub ahead of print | PMID: 32066140
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Abstract

Power generation from ambient humidity using protein nanowires.

Liu X, Gao H, Ward JE, Liu X, ... Lovley DR, Yao J

Harvesting energy from the environment offers the promise of clean power for self-sustained systems. Known technologies-such as solar cells, thermoelectric devices and mechanical generators-have specific environmental requirements that restrict where they can be deployed and limit their potential for continuous energy production. The ubiquity of atmospheric moisture offers an alternative. However, existing moisture-based energy-harvesting technologies can produce only intermittent, brief (shorter than 50 seconds) bursts of power in the ambient environment, owing to the lack of a sustained conversion mechanism. Here we show that thin-film devices made from nanometre-scale protein wires harvested from the microbe Geobacter sulfurreducens can generate continuous electric power in the ambient environment. The devices produce a sustained voltage of around 0.5 volts across a 7-micrometre-thick film, with a current density of around 17 microamperes per square centimetre. We find the driving force behind this energy generation to be a self-maintained moisture gradient that forms within the film when the film is exposed to the humidity that is naturally present in air. Connecting several devices linearly scales up the voltage and current to power electronics. Our results demonstrate the feasibility of a continuous energy-harvesting strategy that is less restricted by location or environmental conditions than other sustainable approaches.



Nature: 16 Feb 2020; epub ahead of print
Liu X, Gao H, Ward JE, Liu X, ... Lovley DR, Yao J
Nature: 16 Feb 2020; epub ahead of print | PMID: 32066937
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Impact:
Abstract

The Prognostic Significance of Quantitative Myocardial Perfusion: An Artificial Intelligence Based Approach Using Perfusion Mapping.

Knott KD, Seraphim A, Augusto JB, Xue H, ... Kellman P, Moon JC

Myocardial perfusion reflects the macro- and microvascular coronary circulation. Recent quantitation developments using cardiovascular magnetic resonance (CMR) perfusion permit automated measurement clinically. We explored the prognostic significance of stress myocardial blood flow (MBF) and myocardial perfusion reserve (MPR, the ratio of stress to rest MBF).A two center study of patients with both suspected and known coronary artery disease referred clinically for perfusion assessment. Image analysis was performed automatically using a novel artificial intelligence approach deriving global and regional stress and rest MBF and MPR. Cox proportional hazard models adjusting for co-morbidities and CMR parameters sought associations of stress MBF and MPR with death and major adverse cardiovascular events (MACE), including myocardial infarction, stroke, heart failure hospitalization, late (>90 day) revascularization and death.1049 patients were included with median follow-up 605 (interquartile range 464-814) days. There were 42 (4.0%) deaths and 188 MACE in 174 (16.6%) patients. Stress MBF and MPR were independently associated with both death and MACE. For each 1ml/g/min decrease in stress MBF the adjusted hazard ratio (HR) for death and MACE were 1.93 (95% CI 1.08-3.48, P=0.028) and 2.14 (95% CI 1.58-2.90, P<0.0001) respectively, even after adjusting for age and co-morbidity. For each 1 unit decrease in MPR the adjusted HR for death and MACE were 2.45 (95% CI 1.42-4.24, P=0.001) and 1.74 (95% CI 1.36-2.22, P<0.0001) respectively. In patients without regional perfusion defects on clinical read and no known macrovascular coronary artery disease (n=783), MPR remained independently associated with death and MACE, with stress MBF remaining associated with MACE only.In patients with known or suspected coronary artery disease, reduced MBF and MPR measured automatically inline using artificial intelligence quantification of CMR perfusion mapping provides a strong, independent predictor of adverse cardiovascular outcomes.



Circulation: 13 Feb 2020; epub ahead of print
Knott KD, Seraphim A, Augusto JB, Xue H, ... Kellman P, Moon JC
Circulation: 13 Feb 2020; epub ahead of print | PMID: 32078380
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Impact:
Abstract

Gene expression and cell identity controlled by anaphase-promoting complex.

Oh E, Mark KG, Mocciaro A, Watson ER, ... Zhou CY, Rape M

Metazoan development requires the robust proliferation of progenitor cells, the identities of which are established by tightly controlled transcriptional networks. As gene expression is globally inhibited during mitosis, the transcriptional programs that define cell identity must be restarted in each cell cycle but how this is accomplished is poorly understood. Here we identify a ubiquitin-dependent mechanism that integrates gene expression with cell division to preserve cell identity. We found that WDR5 and TBP, which bind active interphase promoters, recruit the anaphase-promoting complex (APC/C) to specific transcription start sites during mitosis. This allows APC/C to decorate histones with ubiquitin chains branched at Lys11 and Lys48 (K11/K48-branched ubiquitin chains) that recruit p97 (also known as VCP) and the proteasome, which ensures the rapid expression of pluripotency genes in the next cell cycle. Mitotic exit and the re-initiation of transcription are thus controlled by a single regulator (APC/C), which provides a robust mechanism for maintaining cell identity throughout cell division.



Nature: 18 Feb 2020; epub ahead of print
Oh E, Mark KG, Mocciaro A, Watson ER, ... Zhou CY, Rape M
Nature: 18 Feb 2020; epub ahead of print | PMID: 32076268
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Impact:
Abstract

Caveolae in CNS arterioles mediate neurovascular coupling.

Chow BW, Nuñez V, Kaplan L, Granger AJ, ... Sabatini BL, Gu C

Proper brain function depends on neurovascular coupling: neural activity rapidly increases local blood flow to meet moment-to-moment changes in regional brain energy demand. Neurovascular coupling is the basis for functional brain imaging, and impaired neurovascular coupling is implicated in neurodegeneration. The underlying molecular and cellular mechanisms of neurovascular coupling remain poorly understood. The conventional view is that neurons or astrocytes release vasodilatory factors that act directly on smooth muscle cells (SMCs) to induce arterial dilation and increase local blood flow. Here, using two-photon microscopy to image neural activity and vascular dynamics simultaneously in the barrel cortex of awake mice under whisker stimulation, we found that arteriolar endothelial cells (aECs) have an active role in mediating neurovascular coupling. We found that aECs, unlike other vascular segments of endothelial cells in the central nervous system, have abundant caveolae. Acute genetic perturbations that eliminated caveolae in aECs, but not in neighbouring SMCs, impaired neurovascular coupling. Notably, caveolae function in aECs is independent of the endothelial NO synthase (eNOS)-mediated NO pathway. Ablation of both caveolae and eNOS completely abolished neurovascular coupling, whereas the single mutants exhibited partial impairment, revealing that the caveolae-mediated pathway in aECs is a major contributor to neurovascular coupling. Our findings indicate that vasodilation is largely mediated by endothelial cells that actively relay signals from the central nervous system to SMCs via a caveolae-dependent pathway.



Nature: 18 Feb 2020; epub ahead of print
Chow BW, Nuñez V, Kaplan L, Granger AJ, ... Sabatini BL, Gu C
Nature: 18 Feb 2020; epub ahead of print | PMID: 32076269
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Impact:
Abstract

ILC2s amplify PD-1 blockade by activating tissue-specific cancer immunity.

Moral JA, Leung J, Rojas LA, Ruan J, ... Merghoub T, Balachandran VP

Group 2 innate lymphoid cells (ILC2s) regulate inflammation and immunity in mammalian tissues. Although ILC2s are found in cancers of these tissues, their roles in cancer immunity and immunotherapy are unclear. Here we show that ILC2s infiltrate pancreatic ductal adenocarcinomas (PDACs) to activate tissue-specific tumour immunity. Interleukin-33 (IL33) activates tumour ILC2s (TILC2s) and CD8 T cells in orthotopic pancreatic tumours but not heterotopic skin tumours in mice to restrict pancreas-specific tumour growth. Resting and activated TILC2s express the inhibitory checkpoint receptor PD-1. Antibody-mediated PD-1 blockade relieves ILC2 cell-intrinsic PD-1 inhibition to expand TILC2s, augment anti-tumour immunity, and enhance tumour control, identifying activated TILC2s as targets of anti-PD-1 immunotherapy. Finally, both PD-1 TILC2s and PD-1 T cells are present in most human PDACs. Our results identify ILC2s as anti-cancer immune cells for PDAC immunotherapy. More broadly, ILC2s emerge as tissue-specific enhancers of cancer immunity that amplify the efficacy of anti-PD-1 immunotherapy. As ILC2s and T cells co-exist in human cancers and share stimulatory and inhibitory pathways, immunotherapeutic strategies to collectively target anti-cancer ILC2s and T cells may be broadly applicable.



Nature: 18 Feb 2020; epub ahead of print
Moral JA, Leung J, Rojas LA, Ruan J, ... Merghoub T, Balachandran VP
Nature: 18 Feb 2020; epub ahead of print | PMID: 32076273
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Impact:
Abstract

Structural basis of energy transfer in Porphyridium purpureum phycobilisome.

Ma J, You X, Sun S, Wang X, Qin S, Sui SF

Photosynthetic organisms have developed various light-harvesting systems to adapt to their environments. Phycobilisomes are large light-harvesting protein complexes found in cyanobacteria and red algae, although how the energies of the chromophores within these complexes are modulated by their environment is unclear. Here we report the cryo-electron microscopy structure of a 14.7-megadalton phycobilisome with a hemiellipsoidal shape from the red alga Porphyridium purpureum. Within this complex we determine the structures of 706 protein subunits, including 528 phycoerythrin, 72 phycocyanin, 46 allophycocyanin and 60 linker proteins. In addition, 1,598 chromophores are resolved comprising 1,430 phycoerythrobilin, 48 phycourobilin and 120 phycocyanobilin molecules. The markedly improved resolution of our structure compared with that of the phycobilisome of Griffithsia pacifica enabled us to build an accurate atomic model of the P. purpureum phycobilisome system. The model reveals how the linker proteins affect the microenvironment of the chromophores, and suggests that interactions of the aromatic amino acids of the linker proteins with the chromophores may be a key factor in fine-tuning the energy states of the chromophores to ensure the efficient unidirectional transfer of energy.



Nature: 18 Feb 2020; epub ahead of print
Ma J, You X, Sun S, Wang X, Qin S, Sui SF
Nature: 18 Feb 2020; epub ahead of print | PMID: 32076272
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Abstract

A simple dynamic model explains the diversity of island birds worldwide.

Valente L, Phillimore AB, Melo M, Warren BH, ... Aschenbach T, Etienne RS

Colonization, speciation and extinction are dynamic processes that influence global patterns of species richness. Island biogeography theory predicts that the contribution of these processes to the accumulation of species diversity depends on the area and isolation of the island. Notably, there has been no robust global test of this prediction for islands where speciation cannot be ignored, because neither the appropriate data nor the analytical tools have been available. Here we address both deficiencies to reveal, for island birds, the empirical shape of the general relationships that determine how colonization, extinction and speciation rates co-vary with the area and isolation of islands. We compiled a global molecular phylogenetic dataset of birds on islands, based on the terrestrial avifaunas of 41 oceanic archipelagos worldwide (including 596 avian taxa), and applied a new analysis method to estimate the sensitivity of island-specific rates of colonization, speciation and extinction to island features (area and isolation). Our model predicts-with high explanatory power-several global relationships. We found a decline in colonization with isolation, a decline in extinction with area and an increase in speciation with area and isolation. Combining the theoretical foundations of island biogeography with the temporal information contained in molecular phylogenies proves a powerful approach to reveal the fundamental relationships that govern variation in biodiversity across the planet.



Nature: 18 Feb 2020; epub ahead of print
Valente L, Phillimore AB, Melo M, Warren BH, ... Aschenbach T, Etienne RS
Nature: 18 Feb 2020; epub ahead of print | PMID: 32076267
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Abstract

γδ T cells and adipocyte IL-17RC control fat innervation and thermogenesis.

Hu B, Jin C, Zeng X, Resch JM, ... Mathis D, Spiegelman BM

The sympathetic nervous system innervates peripheral organs to regulate their function and maintain homeostasis, whereas target cells also produce neurotrophic factors to promote sympathetic innervation. The molecular basis of this bi-directional communication remains to be fully determined. Here we use thermogenic adipose tissue from mice as a model system to show that T cells, specifically γδ T cells, have a crucial role in promoting sympathetic innervation, at least in part by driving the expression of TGFβ1 in parenchymal cells via the IL-17 receptor C (IL-17RC). Ablation of IL-17RC specifically in adipose tissue reduces expression of TGFβ1 in adipocytes, impairs local sympathetic innervation and causes obesity and other metabolic phenotypes that are consistent with defective thermogenesis; innervation can be fully rescued by restoring TGFβ1 expression. Ablating γδ Τ cells and the IL-17RC signalling pathway also impairs sympathetic innervation in other tissues such as salivary glands. These findings demonstrate coordination between T cells and parenchymal cells to regulate sympathetic innervation.



Nature: 18 Feb 2020; epub ahead of print
Hu B, Jin C, Zeng X, Resch JM, ... Mathis D, Spiegelman BM
Nature: 18 Feb 2020; epub ahead of print | PMID: 32076265
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Abstract

Single-cell and spatial transcriptomics reveal somitogenesis in gastruloids.

van den Brink SC, Alemany A, van Batenburg V, Moris N, ... Martinez Arias A, van Oudenaarden A

Gastruloids are three-dimensional aggregates of embryonic stem cells that display key features of mammalian development after implantation, including germ-layer specification and axial organization. To date, the expression pattern of only a small number of genes in gastruloids has been explored with microscopy, and the extent to which genome-wide expression patterns in gastruloids mimic those in embryos is unclear. Here we compare mouse gastruloids with mouse embryos using single-cell RNA sequencing and spatial transcriptomics. We identify various embryonic cell types that were not previously known to be present in gastruloids, and show that key regulators of somitogenesis are expressed similarly between embryos and gastruloids. Using live imaging, we show that the somitogenesis clock is active in gastruloids and has dynamics that resemble those in vivo. Because gastruloids can be grown in large quantities, we performed a small screen that revealed how reduced FGF signalling induces a short-tail phenotype in embryos. Finally, we demonstrate that embedding in Matrigel induces gastruloids to generate somites with the correct rostral-caudal patterning, which appear sequentially in an anterior-to-posterior direction over time. This study thus shows the power of gastruloids as a model system for exploring development and somitogenesis in vitro in a high-throughput manner.



Nature: 18 Feb 2020; epub ahead of print
van den Brink SC, Alemany A, van Batenburg V, Moris N, ... Martinez Arias A, van Oudenaarden A
Nature: 18 Feb 2020; epub ahead of print | PMID: 32076263
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Abstract

Bacterial coexistence driven by motility and spatial competition.

Gude S, Pinçe E, Taute KM, Seinen AB, Shimizu TS, Tans SJ

Elucidating elementary mechanisms that underlie bacterial diversity is central to ecology and microbiome research. Bacteria are known to coexist by metabolic specialization, cooperation and cyclic warfare. Many species are also motile, which is studied in terms of mechanism, benefit, strategy, evolution and ecology. Indeed, bacteria often compete for nutrient patches that become available periodically or by random disturbances. However, the role of bacterial motility in coexistence remains unexplored experimentally. Here we show that-for mixed bacterial populations that colonize nutrient patches-either population outcompetes the other when low in relative abundance. This inversion of the competitive hierarchy is caused by active segregation and spatial exclusion within the patch: a small fast-moving population can outcompete a large fast-growing population by impeding its migration into the patch, while a small fast-growing population can outcompete a large fast-moving population by expelling it from the initial contact area. The resulting spatial segregation is lost for weak growth-migration trade-offs and a lack of virgin space, but is robust to population ratio, density and chemotactic ability, and is observed in both laboratory and wild strains. These findings show that motility differences and their trade-offs with growth are sufficient to promote diversity, and suggest previously undescribed roles for motility in niche formation and collective expulsion-containment strategies beyond individual search and survival.



Nature: 18 Feb 2020; epub ahead of print
Gude S, Pinçe E, Taute KM, Seinen AB, Shimizu TS, Tans SJ
Nature: 18 Feb 2020; epub ahead of print | PMID: 32076271
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Abstract

Hydrogen peroxide sensor HPCA1 is an LRR receptor kinase in Arabidopsis.

Wu F, Chi Y, Jiang Z, Xu Y, ... Chen X, Pei ZM

Hydrogen peroxide (HO) is a major reactive oxygen species in unicellular and multicellular organisms, and is produced extracellularly in response to external stresses and internal cues. HO enters cells through aquaporin membrane proteins and covalently modifies cytoplasmic proteins to regulate signalling and cellular processes. However, whether sensors for HO also exist on the cell surface remains unknown. In plant cells, HO triggers an influx of Ca ions, which is thought to be involved in HO sensing and signalling. Here, by using forward genetic screens based on Ca imaging, we isolated hydrogen-peroxide-induced Ca increases (hpca) mutants in Arabidopsis, and identified HPCA1 as a leucine-rich-repeat receptor kinase belonging to a previously uncharacterized subfamily that features two extra pairs of cysteine residues in the extracellular domain. HPCA1 is localized to the plasma membrane and is activated by HO via covalent modification of extracellular cysteine residues, which leads to autophosphorylation of HPCA1. HPCA1 mediates HO-induced activation of Ca channels in guard cells and is required for stomatal closure. Our findings help to identify how the perception of extracellular HO is integrated with responses to various external stresses and internal cues in plants, and have implications for the design of crops with enhanced fitness.



Nature: 18 Feb 2020; epub ahead of print
Wu F, Chi Y, Jiang Z, Xu Y, ... Chen X, Pei ZM
Nature: 18 Feb 2020; epub ahead of print | PMID: 32076270
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Abstract

On-device lead sequestration for perovskite solar cells.

Li X, Zhang F, He H, Berry JJ, Zhu K, Xu T

Perovskite solar cells, as an emerging high-efficiency and low-cost photovoltaic technology, face obstacles on their way towards commercialization. Substantial improvements have been made to device stability, but potential issues with lead toxicity and leaching from devices remain relatively unexplored. The potential for lead leakage could be perceived as an environmental and public health risk when using perovskite solar cells in building-integrated photovoltaics. Here we present a chemical approach for on-device sequestration of more than 96 per cent of lead leakage caused by severe device damage. A coating of lead-absorbing material is applied to the front and back sides of the device stack. On the glass side of the front transparent conducting electrode, we use a transparent lead-absorbing molecular film containing phosphonic acid groups that bind strongly to lead. On the back (metal) electrode side, we place a polymer film blended with lead-chelating agents between the metal electrode and a standard photovoltaic packing film. The lead-absorbing films on both sides swell to absorb the lead, rather than dissolve, when subjected to water soaking, thus retaining structural integrity for easy collection of lead after damage.



Nature: 18 Feb 2020; epub ahead of print
Li X, Zhang F, He H, Berry JJ, Zhu K, Xu T
Nature: 18 Feb 2020; epub ahead of print | PMID: 32076266
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Abstract

Structural basis of ligand recognition and self-activation of orphan GPR52.

Lin X, Li M, Wang N, Wu Y, ... Lei M, Xu F

GPR52 is a class-A orphan G-protein-coupled receptor that is highly expressed in the brain and represents a promising therapeutic target for the treatment of Huntington\'s disease and several psychiatric disorders. Pathological malfunction of GPR52 signalling occurs primarily through the heterotrimeric G protein, but it is unclear how GPR52 and G couple for signal transduction and whether a native ligand or other activating input is required. Here we present the high-resolution structures of human GPR52 in three states: a ligand-free state, a G-coupled self-activation state and a potential allosteric ligand-bound state. Together, our structures reveal that extracellular loop 2 occupies the orthosteric binding pocket and operates as a built-in agonist, conferring an intrinsically high level of basal activity to GPR52. A fully active state is achieved when G is coupled to GPR52 in the absence of an external agonist. The receptor also features a side pocket for ligand binding. These insights into the structure and function of GPR52 could improve our understanding of other self-activated GPCRs, enable the identification of endogenous and tool ligands, and guide drug discovery efforts that target GPR52.



Nature: 18 Feb 2020; epub ahead of print
Lin X, Li M, Wang N, Wu Y, ... Lei M, Xu F
Nature: 18 Feb 2020; epub ahead of print | PMID: 32076264
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Abstract

Selective loading and processing of prespacers for precise CRISPR adaptation.

Kim S, Loeff L, Colombo S, Jergic S, Brouns SJJ, Joo C

CRISPR-Cas immunity protects prokaryotes against invading genetic elements. It uses the highly conserved Cas1-Cas2 complex to establish inheritable memory (spacers). How Cas1-Cas2 acquires spacers from foreign DNA fragments (prespacers) and integrates them into the CRISPR locus in the correct orientation is unclear. Here, using the high spatiotemporal resolution of single-molecule fluorescence, we show that Cas1-Cas2 selects precursors of prespacers from DNA in various forms-including single-stranded DNA and partial duplexes-in a manner that depends on both the length of the DNA strand and the presence of a protospacer adjacent motif (PAM) sequence. We also identify DnaQ exonucleases as enzymes that process the Cas1-Cas2-loaded prespacer precursors into mature prespacers of a suitable size for integration. Cas1-Cas2 protects the PAM sequence from maturation, which results in the production of asymmetrically trimmed prespacers and the subsequent integration of spacers in the correct orientation. Our results demonstrate the kinetic coordination of prespacer precursor selection and PAM trimming, providing insight into the mechanisms that underlie the integration of functional spacers in the CRISPR loci.



Nature: 18 Feb 2020; epub ahead of print
Kim S, Loeff L, Colombo S, Jergic S, Brouns SJJ, Joo C
Nature: 18 Feb 2020; epub ahead of print | PMID: 32076262
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Abstract

Skin emollient and early complementary feeding to prevent infant atopic dermatitis (PreventADALL): a factorial, multicentre, cluster-randomised trial.

Skjerven HO, Rehbinder EM, Vettukattil R, LeBlanc M, ... Nordlund B, Carlsen KCL
Background
Skin emollients applied during early infancy could prevent atopic dermatitis, and early complementary food introduction might reduce food allergy in high-risk infants. The study aimed to determine if either regular skin emollients applied from 2 weeks of age, or early complementary feeding introduced between 12 and 16 weeks of age, reduced development of atopic dermatitis by age 12 months in the general infant population.
Methods
This population-based 2×2 factorial, randomised clinical trial was done at Oslo University Hospital and Østfold Hospital Trust, Oslo, Norway; and Karolinska University Hospital, Stockholm, Sweden. Infants of women recruited antenatally at the routine ultrasound pregnancy screening at 18 weeks were cluster-randomised at birth from 2015 to 2017 to the following groups: (1) controls with no specific advice on skin care while advised to follow national guidelines on infant nutrition (no intervention group); (2) skin emollients (bath additives and facial cream; skin intervention group); (3) early complementary feeding of peanut, cow\'s milk, wheat, and egg (food intervention group); or (4) combined skin and food interventions (combined intervention group). Participants were randomly assigned (1:1:1:1) using computer- generated cluster randomisation based on 92 geographical living area blocks as well as eight 3-month time blocks. Carers were instructed to apply the interventions on at least 4 days per week. Atopic dermatitis by age 12 months was the primary outcome, based on clinical investigations at 3, 6 and 12 months by investigators masked to group allocation. Atopic dermatitis was assessed after completing the 12-month investigations and diagnosed if either of the UK Working Party and Hanifin and Rajka (12 months only) diagnostic criteria were fulfilled. The primary efficacy analyses was done by intention-to-treat analysis on all randomly assigned participants. Food allergy results will be reported once all investigations at age 3 years are completed in 2020. This was a study performed within ORAACLE (the Oslo Research Group of Asthma and Allergy in Childhood; the Lung and Environment). The study is registered at clinicaltrials.gov, NCT02449850.
Findings
2697 women were recruited between Dec 9, 2014, and Oct 31, 2016, from whom 2397 newborn infants were enrolled from April 14, 2015, to April 11, 2017. Atopic dermatitis was observed in 478 (8%) of 596 infants in the no intervention group, 64 (11%) of 575 in the skin intervention group, 58 (9%) of 642 in the food intervention group, and 31 (5%) of 583 in the combined intervention group. Neither skin emollients nor early complementary feeding reduced development of atopic dermatitis, with a risk difference of 3·1% (95% CI -0·3 to 6·5) for skin intervention and 1·0% (-2·1 to 4·1) for food intervention, in favour of control. No safety concerns with the interventions were identified. Reported skin symptoms and signs (including itching, oedema, exanthema, dry skin, and urticaria) were no more frequent in the skin, food, and combined intervention groups than in the no intervention group.
Interpretation
Neither early skin emollients nor early complementary feeding reduced development of atopic dermatitis by age 12 months. Our study does not support the use of these interventions to prevent atopic dermatitis by 12 months of age in infants.
Funding
The study was funded by several public and private funding bodies: The Regional Health Board South East, The Norwegian Research Council, Health and Rehabilitation Norway, The Foundation for Healthcare and Allergy Research in Sweden-Vårdalstiftelsen, Swedish Asthma and Allergy Association\'s Research Foundation, Swedish Research Council-the Initiative for Clinical Therapy Research, The Swedish Heart-Lung Foundation, SFO-V at the Karolinska Institute, Freemason Child House Foundation in Stockholm, Swedish Research Council for Health, Working Life and Welfare-FORTE, Oslo University Hospital, the University of Oslo, and Østfold Hospital Trust.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 18 Feb 2020; epub ahead of print
Skjerven HO, Rehbinder EM, Vettukattil R, LeBlanc M, ... Nordlund B, Carlsen KCL
Lancet: 18 Feb 2020; epub ahead of print | PMID: 32087121
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Abstract

Antiretroviral therapy alone versus antiretroviral therapy with a kick and kill approach, on measures of the HIV reservoir in participants with recent HIV infection (the RIVER trial): a phase 2, randomised trial.

Fidler S, Stöhr W, Pace M, Dorrell L, ... Frater J,
Background
Antiretroviral therapy (ART) cannot cure HIV infection because of a persistent reservoir of latently infected cells. Approaches that force HIV transcription from these cells, making them susceptible to killing-termed kick and kill regimens-have been explored as a strategy towards an HIV cure. RIVER is the first randomised trial to determine the effect of ART-only versus ART plus kick and kill on markers of the HIV reservoir.
Methods
This phase 2, open-label, multicentre, randomised, controlled trial was undertaken at six clinical sites in the UK. Patients aged 18-60 years who were confirmed as HIV-positive within a maximum of the past 6 months and started ART within 1 month from confirmed diagnosis were randomly assigned by a computer generated randomisation list to receive ART-only (control) or ART plus the histone deacetylase inhibitor vorinostat (the kick) and replication-deficient viral vector T-cell inducing vaccines encoding conserved HIV sequences ChAdV63. HIVconsv-prime and MVA.HIVconsv-boost (the kill; ART + V + V; intervention). The primary endpoint was total HIV DNA isolated from peripheral blood CD4 T-cells at weeks 16 and 18 after randomisation. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, NCT02336074.
Findings
Between June 14, 2015 and Jul 11, 2017, 60 men with HIV were randomly assigned to receive either an ART-only (n=30) or an ART + V + V (n=30) regimen; all 60 participants completed the study, with no loss-to-follow-up. Mean total HIV DNA at weeks 16 and 18 after randomisation was 3·02 log copies HIV DNA per 10 CD4 T-cells in the ART-only group versus 3·06 log copies HIV DNA per 10 CD4 T-cells in ART + V + V group, with no statistically significant difference between the two groups (mean difference of 0·04 log copies HIV DNA per 10 CD4 T-cells [95% CI -0·03 to 0·11; p=0·26]). There were no intervention-related serious adverse events.
Interpretation
This kick and kill approach conferred no significant benefit compared with ART alone on measures of the HIV reservoir. Although this does not disprove the efficacy kick and kill strategy, for future trials enhancement of both kick and kill agents will be required.
Funding
Medical Research Council (MR/L00528X/1).

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 17 Feb 2020; epub ahead of print
Fidler S, Stöhr W, Pace M, Dorrell L, ... Frater J,
Lancet: 17 Feb 2020; epub ahead of print | PMID: 32085823
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Abstract

Daily emollient during infancy for prevention of eczema: the BEEP randomised controlled trial.

Chalmers JR, Haines RH, Bradshaw LE, Montgomery AA, ... Williams HC,
Background
Skin barrier dysfunction precedes eczema development. We tested whether daily use of emollient in the first year could prevent eczema in high-risk children.
Methods
We did a multicentre, pragmatic, parallel-group, randomised controlled trial in 12 hospitals and four primary care sites across the UK. Families were approached via antenatal or postnatal services for recruitment of term infants (at least 37 weeks\' gestation) at high risk of developing eczema (ie, at least one first-degree relative with parent-reported eczema, allergic rhinitis, or asthma, diagnosed by a doctor). Term newborns with a family history of atopic disease were randomly assigned (1:1) to application of emollient daily (either Diprobase cream or DoubleBase gel) for the first year plus standard skin-care advice (emollient group) or standard skin-care advice only (control group). The randomisation schedule was created using computer-generated code (stratified by recruiting centre and number of first-degree relatives with atopic disease) and participants were assigned to groups using an internet-based randomisation system. The primary outcome was eczema at age 2 years (defined by UK working party criteria) with analysis as randomised regardless of adherence to allocation for participants with outcome data collected, and adjusting for stratification variables. This trial is registered with ISRCTN, ISRCTN21528841. Data collection for long-term follow-up is ongoing, but the trial is closed to recruitment.
Findings
1394 newborns were randomly assigned to study groups between Nov 19, 2014, and Nov 18, 2016; 693 were assigned to the emollient group and 701 to the control group. Adherence in the emollient group was 88% (466 of 532) at 3 months, 82% (427 of 519) at 6 months, and 74% (375 of 506) at 12 months in those with complete questionnaire data. At age 2 years, eczema was present in 139 (23%) of 598 infants with outcome data collected in the emollient group and 150 (25%) of 612 infants in the control group (adjusted relative risk 0·95 [95% CI 0·78 to 1·16], p=0·61; adjusted risk difference -1·2% [-5·9 to 3·6]). Other eczema definitions supported the results of the primary analysis. Mean number of skin infections per child in year 1 was 0·23 (SD 0·68) in the emollient group versus 0·15 (0·46) in the control group; adjusted incidence rate ratio 1·55 (95% CI 1·15 to 2·09).
Interpretation
We found no evidence that daily emollient during the first year of life prevents eczema in high-risk children and some evidence to suggest an increased risk of skin infections. Our study shows that families with eczema, asthma, or allergic rhinitis should not use daily emollients to try and prevent eczema in their newborn.
Funding
National Institute for Health Research Health Technology Assessment.

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

Lancet: 18 Feb 2020; epub ahead of print
Chalmers JR, Haines RH, Bradshaw LE, Montgomery AA, ... Williams HC,
Lancet: 18 Feb 2020; epub ahead of print | PMID: 32087126
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Abstract

Efficacy and safety of nerinetide for the treatment of acute ischaemic stroke (ESCAPE-NA1): a multicentre, double-blind, randomised controlled trial.

Hill MD, Goyal M, Menon BK, Nogueira RG, ... Tymianski M,
Background
Nerinetide, an eicosapeptide that interferes with post-synaptic density protein 95, is a neuroprotectant that is effective in preclinical stroke models of ischaemia-reperfusion. In this trial, we assessed the efficacy and safety of nerinetide in human ischaemia-reperfusion that occurs with rapid endovascular thrombectomy in patients who had an acute ischaemic stroke.
Methods
For this multicentre, double-blind, randomised, placebo-controlled study done in 48 acute care hospitals in eight countries, we enrolled patients with acute ischaemic stroke due to large vessel occlusion within a 12 h treatment window. Eligible patients were aged 18 years or older with a disabling ischaemic stroke at the time of randomisation, had been functioning independently in the community before the stroke, had an Alberta Stroke Program Early CT Score (ASPECTS) greater than 4, and vascular imaging showing moderate-to-good collateral filling, as determined by multiphase CT angiography. Patients were randomly assigned (1:1) to receive intravenous nerinetide in a single dose of 2·6 mg/kg, up to a maximum dose of 270 mg, on the basis of estimated or actual weight (if known) or saline placebo by use of a real-time, dynamic, internet-based, stratified randomised minimisation procedure. Patients were stratified by intravenous alteplase treatment and declared endovascular device choice. All trial personnel and patients were masked to sequence and treatment allocation. All patients underwent endovascular thrombectomy and received alteplase in usual care when indicated. The primary outcome was a favourable functional outcome 90 days after randomisation, defined as a modified Rankin Scale (mRS) score of 0-2. Secondary outcomes were measures of neurological disability, functional independence in activities of daily living, excellent functional outcome (mRS 0-1), and mortality. The analysis was done in the intention-to-treat population and adjusted for age, sex, baseline National Institutes of Health Stroke Scale score, ASPECTS, occlusion location, site, alteplase use, and declared first device. The safety population included all patients who received any amount of study drug. This trial is registered with ClinicalTrials.gov, NCT02930018.
Findings
Between March 1, 2017, and Aug 12, 2019, 1105 patients were randomly assigned to receive nerinetide (n=549) or placebo (n=556). 337 (61·4%) of 549 patients with nerinetide and 329 (59·2%) of 556 with placebo achieved an mRS score of 0-2 at 90 days (adjusted risk ratio 1·04, 95% CI 0·96-1·14; p=0·35). Secondary outcomes were similar between groups. We observed evidence of treatment effect modification resulting in inhibition of treatment effect in patients receiving alteplase. Serious adverse events occurred equally between groups.
Interpretation
Nerinetide did not improve the proportion of patients achieving good clinical outcomes after endovascular thrombectomy compared with patients receiving placebo.
Funding
Canadian Institutes for Health Research, Alberta Innovates, and NoNO.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 19 Feb 2020; epub ahead of print
Hill MD, Goyal M, Menon BK, Nogueira RG, ... Tymianski M,
Lancet: 19 Feb 2020; epub ahead of print | PMID: 32087818
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Abstract

Preparedness and vulnerability of African countries against importations of COVID-19: a modelling study.

Gilbert M, Pullano G, Pinotti F, Valdano E, ... Kraemer MUG, Colizza V
Background
The novel coronavirus disease 2019 (COVID-19) epidemic has spread from China to 25 countries. Local cycles of transmission have already occurred in 12 countries after case importation. In Africa, Egypt has so far confirmed one case. The management and control of COVID-19 importations heavily rely on a country\'s health capacity. Here we evaluate the preparedness and vulnerability of African countries against their risk of importation of COVID-19.
Methods
We used data on the volume of air travel departing from airports in the infected provinces in China and directed to Africa to estimate the risk of importation per country. We determined the country\'s capacity to detect and respond to cases with two indicators: preparedness, using the WHO International Health Regulations Monitoring and Evaluation Framework; and vulnerability, using the Infectious Disease Vulnerability Index. Countries were clustered according to the Chinese regions contributing most to their risk.
Findings
Countries with the highest importation risk (ie, Egypt, Algeria, and South Africa) have moderate to high capacity to respond to outbreaks. Countries at moderate risk (ie, Nigeria, Ethiopia, Sudan, Angola, Tanzania, Ghana, and Kenya) have variable capacity and high vulnerability. We identified three clusters of countries that share the same exposure to the risk originating from the provinces of Guangdong, Fujian, and the city of Beijing, respectively.
Interpretation
Many countries in Africa are stepping up their preparedness to detect and cope with COVID-19 importations. Resources, intensified surveillance, and capacity building should be urgently prioritised in countries with moderate risk that might be ill-prepared to detect imported cases and to limit onward transmission.
Funding
EU Framework Programme for Research and Innovation Horizon 2020, Agence Nationale de la Recherche.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 19 Feb 2020; epub ahead of print
Gilbert M, Pullano G, Pinotti F, Valdano E, ... Kraemer MUG, Colizza V
Lancet: 19 Feb 2020; epub ahead of print | PMID: 32087820
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Abstract

Management of acute ischemic stroke.

Phipps MS, Cronin CA

Stroke is the leading cause of long term disability in developed countries and one of the top causes of mortality worldwide. The past decade has seen substantial advances in the diagnostic and treatment options available to minimize the impact of acute ischemic stroke. The key first step in stroke care is early identification of patients with stroke and triage to centers capable of delivering the appropriate treatment, as fast as possible. Here, we review the data supporting pre-hospital and emergency stroke care, including use of emergency medical services protocols for identification of patients with stroke, intravenous thrombolysis in acute ischemic stroke including updates to recommended patient eligibility criteria and treatment time windows, and advanced imaging techniques with automated interpretation to identify patients with large areas of brain at risk but without large completed infarcts who are likely to benefit from endovascular thrombectomy in extended time windows from symptom onset. We also review protocols for management of patient physiologic parameters to minimize infarct volumes and recent updates in secondary prevention recommendations including short term use of dual antiplatelet therapy to prevent recurrent stroke in the high risk period immediately after stroke. Finally, we discuss emerging therapies and questions for future research.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

BMJ: 12 Feb 2020; 368:l6983
Phipps MS, Cronin CA
BMJ: 12 Feb 2020; 368:l6983 | PMID: 32054610
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Abstract

Adverse Effects of Low-Dose Methotrexate: A Randomized Trial.

Solomon DH, Glynn RJ, Karlson EW, Lu F, ... Paynter NP, Ridker PM
Background
Low-dose methotrexate (LD-MTX) is the most commonly used drug for systemic rheumatic diseases worldwide and is the recommended first-line agent for rheumatoid arthritis. Despite extensive clinical use for more than 30 years, few data on adverse event (AE) rates derive from randomized, placebo-controlled trials, where both causality and magnitude of risk can be inferred.
Objective
To investigate AE rates, risk, and risk differences comparing LD-MTX versus placebo.
Design
Prespecified secondary analyses of a double-blind, placebo-controlled, randomized trial. (ClinicalTrials.gov: NCT01594333).
Setting
North America.
Participants
Adults with known cardiovascular disease and diabetes or metabolic syndrome.
Intervention
Random allocation to LD-MTX (≤20 mg/wk) or placebo. All participants received folic acid, 1 mg/d, 6 days per week.
Measurements
Risks for specific AEs of interest, as well as for all AEs, were compared across treatment groups after blinded adjudication.
Results
After an active run-in period, 6158 patients were enrolled and 4786 randomly assigned to a group; median follow-up was 23 months and median dosage 15 mg/wk. Among the randomly assigned participants, 81.2% were male, median age was 65.7 years, and median body mass index was 31.5 kg/m2. Of 2391 participants assigned to LD-MTX, 2080 (87.0%) had an AE of interest, compared with 1951 of 2395 (81.5%) assigned to placebo (hazard ratio [HR], 1.17 [95% CI, 1.10 to 1.25]). The relative hazards of gastrointestinal (HR, 1.91 [CI, 1.75 to 2.10]), pulmonary (HR, 1.52 [CI, 1.16 to 1.98]), infectious (HR, 1.15 [CI, 1.01 to 1.30]), and hematologic (HR, 1.15 [CI, 1.07 to 1.23]) AEs were elevated for LD-MTX versus placebo. With the exception of increased risk for skin cancer (HR, 2.05 [CI, 1.28 to 3.28]), the treatment groups did not differ in risk for other cancer or mucocutaneous, neuropsychiatric, or musculoskeletal AEs. Renal AEs were reduced in the LD-MTX group (HR, 0.85 [CI, 0.78 to 0.93]).
Limitation
The trial was done in patients without rheumatic disease who tolerated LD-MTX during an active run-in period.
Conclusion
Use of LD-MTX was associated with small to moderate elevations in risks for skin cancer and gastrointestinal, infectious, pulmonary, and hematologic AEs, whereas renal AEs were decreased.
Primary funding source
National Institutes of Health.



Ann Intern Med: 17 Feb 2020; epub ahead of print
Solomon DH, Glynn RJ, Karlson EW, Lu F, ... Paynter NP, Ridker PM
Ann Intern Med: 17 Feb 2020; epub ahead of print | PMID: 32066146
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Abstract

The Management of Chronic Insomnia Disorder and Obstructive Sleep Apnea: Synopsis of the 2019 U.S. Department of Veterans Affairs and U.S. Department of Defense Clinical Practice Guidelines.

Mysliwiec V, Martin JL, Ulmer CS, Chowdhuri S, ... Spevak C, Sall J
Description
In September 2019, the U.S. Department of Veterans Affairs (VA) and the U.S. Department of Defense (DoD) approved a new joint clinical practice guideline for assessing and managing patients with chronic insomnia disorder and obstructive sleep apnea (OSA). This guideline is intended to give health care teams a framework by which to screen, evaluate, treat, and manage the individual needs and preferences of VA and DoD patients with either of these conditions.
Methods
In October 2017, the VA/DoD Evidence-Based Practice Work Group initiated a joint VA/DoD guideline development effort that included clinical stakeholders and conformed to the Institute of Medicine\'s tenets for trustworthy clinical practice guidelines. The guideline panel developed key questions, systematically searched and evaluated the literature, created three 1-page algorithms, and advanced 41 recommendations using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) system.
Recommendations
This synopsis summarizes the key recommendations of the guideline in 3 areas: diagnosis and assessment of OSA and chronic insomnia disorder, treatment and management of OSA, and treatment and management of chronic insomnia disorder. Three clinical practice algorithms are also included.



Ann Intern Med: 17 Feb 2020; epub ahead of print
Mysliwiec V, Martin JL, Ulmer CS, Chowdhuri S, ... Spevak C, Sall J
Ann Intern Med: 17 Feb 2020; epub ahead of print | PMID: 32066145
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Abstract

Randomized Dose-Response Study of the New Dual Endothelin Receptor Antagonist Aprocitentan in Hypertension.

Verweij P, Danaietash P, Flamion B, Ménard J, Bellet M

This study examined the dose-response characteristics of aprocitentan, a dual endothelin A/endothelin B receptor antagonist, in patients with essential hypertension. In a randomized, double-blind, parallel study design, eligible patients with a sitting diastolic blood pressure (BP) of 90-109 mm Hg received aprocitentan 5, 10, 25, or 50 mg, placebo, or lisinopril 20 mg as a positive control once daily for 8 weeks. Multiple automated office BP readings were obtained with patients resting unattended (unattended automated office BP) at baseline, weeks 2, 4, and 8. Ambulatory BP was monitored for 24 hours at baseline and week 8. After a single-blind placebo run-in period, 490 eligible patients were randomized to the double-blind phase, with 409 patients completing 8 weeks of therapy per protocol. Aprocitentan 10, 25, and 50 mg decreased sitting systolic/diastolic unattended automated office BP from baseline to week 8 (placebo-corrected decreases: 7.05/4.93, 9.90/6.99, and 7.58/4.95 mm Hg, respectively, ≤0.014 versus placebo), compared with an unattended automated office BP reduction of 4.84/3.81 mm Hg with lisinopril 20 mg. For patients with valid ambulatory BP, aprocitentan 10, 25, and 50 mg significantly decreased placebo-corrected 24-hour BP by 3.99/4.04, 4.83/5.89, and 3.67/4.45 mm Hg, respectively. Incidence of adverse events was similar in the aprocitentan groups (22.0%-40.2%) and the placebo group (36.6%). Aprocitentan produced dose-dependent decreases in hemoglobin, hematocrit, albumin, and uric acid, an increase in estimated plasma volume, but no change in weight versus placebo. These findings support further investigation of aprocitentan at doses of 10 to 25 mg in hypertension. Registration- URL: https://www.clinicaltrials.gov; Unique identifier: NCT02603809.



Hypertension: 16 Feb 2020:HYPERTENSIONAHA11914504; epub ahead of print
Verweij P, Danaietash P, Flamion B, Ménard J, Bellet M
Hypertension: 16 Feb 2020:HYPERTENSIONAHA11914504; epub ahead of print | PMID: 32063059
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Abstract

Report of the National Heart, Lung, and Blood Institute Working Group on Hypertension: Barriers to Translation.

Sigmund CD, Carey RM, Appel LJ, Arnett DK, ... Wright JD, Oh YS

The National Heart, Lung, and Blood Institute convened a multidisciplinary working group of hypertension researchers on December 6 to 7, 2018, in Bethesda, MD, to share current scientific knowledge in hypertension and to identify barriers to translation of basic into clinical science/trials and implementation of clinical science into clinical care of patients with hypertension. The goals of the working group were (1) to provide an overview of recent discoveries that may be ready for testing in preclinical and clinical studies; (2) to identify gaps in knowledge that impede translation; (3) to highlight the most promising scientific areas in which to pursue translation; (4) to identify key challenges and barriers for moving basic science discoveries into translation, clinical studies, and trials; and (5) to identify roadblocks for effective dissemination and implementation of basic and clinical science in real-world settings. The working group addressed issues that were responsive to many of the objectives of the National Heart, Lung, and Blood Institute Strategic Vision. The working group identified major barriers and opportunities for translating research to improved control of hypertension. This review summarizes the discussion and recommendations of the working group.



Hypertension: 16 Feb 2020:HYPERTENSIONAHA11913887; epub ahead of print
Sigmund CD, Carey RM, Appel LJ, Arnett DK, ... Wright JD, Oh YS
Hypertension: 16 Feb 2020:HYPERTENSIONAHA11913887; epub ahead of print | PMID: 32063061
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Abstract

Skeletal Muscle Reflex-Induced Sympathetic Dysregulation and Sensitization of Muscle Afferents in Type 1 Diabetic Rats.

Ishizawa R, Kim HK, Hotta N, Iwamoto GA, ... Smith SA, Mizuno M

The blood pressure response to exercise is exaggerated in the type 1 diabetes mellitus (T1DM). An overactive exercise pressor reflex (EPR) contributes to the potentiated pressor response. However, the mechanism(s) underlying this abnormal EPR activity remains unclear. This study tested the hypothesis that the heightened blood pressure response to exercise in T1DM is mediated by EPR-induced sympathetic overactivity. Additionally, the study examined whether the single muscle afferents are sensitized by PKC (protein kinase C) activation in this disease. Sprague-Dawley rats were intraperitoneally administered either 50 mg/kg streptozotocin (T1DM) or saline (control). At 1 to 3 weeks after administration, renal sympathetic nerve activity and mean arterial pressure responses to activation of the EPR, mechanoreflex, and metaboreflex were measured in decerebrate animals. Action potential responses to mechanical and chemical stimulation were determined in group IV afferents with pPKCα (phosphorylated-PKCα) levels assessed in dorsal root ganglia. Compared with control, EPR (58±18 versus 96±33%; <0.05), mechanoreflex (21±13 versus 51±20%; <0.05), and metaboreflex (40±20 versus 88±39%; <0.01) activation in T1DM rats evoked significant increases in renal sympathetic nerve activity as well as mean arterial pressure. The response of group IV afferents to mechanical (18±24 versus 61±45 spikes; <0.01) and chemical (0.3±0.4 versus 1.6±0.8 Hz; <0.01) stimuli were significantly greater in T1DM than control. T1DM rats showed markedly increased pPKCα levels in dorsal root ganglia compared with control. These data suggest that in T1DM, abnormally muscle reflex-evoked increases in sympathetic activity mediate exaggerations in blood pressure. Further, sensitization of muscle afferents, potentially via PKC activation, may contribute to this abnormal circulatory responsiveness.



Hypertension: 16 Feb 2020:HYPERTENSIONAHA11914118; epub ahead of print
Ishizawa R, Kim HK, Hotta N, Iwamoto GA, ... Smith SA, Mizuno M
Hypertension: 16 Feb 2020:HYPERTENSIONAHA11914118; epub ahead of print | PMID: 32063060
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Abstract

Combining Biomarkers to Predict Pregnancy Complications and Redefine Preeclampsia: The Angiogenic-Placental Syndrome.

Stepan H, Hund M, Andraczek T

Placental dysfunction underlies a spectrum of perinatal pathologies, including preeclampsia and fetal growth restriction. Angiogenesis-related factors, including sFlt-1 (soluble fms-like tyrosine kinase 1) and PlGF (placental growth factor), play an important role in placental dysfunction; altered levels are detectable several weeks before onset of pregnancy complications. In vitro diagnostic tests for these biomarkers can improve early diagnosis and facilitate prediction of maternal and fetal outcomes. We assessed evidence for combining angiogenic biomarkers with other biomarkers or clinical parameters to predict maternal/fetal outcomes in pregnant women with placental dysfunction. Pooled information on placental perfusion (ultrasonography, mean arterial pressure), clinical characteristics, and biomarker levels (PlGF) can improve first-trimester prediction and preeclampsia diagnosis. Angiogenic factors (sFlt-1/PlGF ratio; PlGF alone) with or without clinical characteristics can facilitate second-/third-trimester prediction of early-onset and late-onset preeclampsia. A combination of increased sFlt-1/PlGF ratio and ultrasound can rule out early fetal growth restriction. The sFlt-1/PlGF ratio is also a reliable tool for discriminating between pregnancy-related hypertensive disorders, including superimposed preeclampsia and gestational hypertension. Analysis of angiogenic factors with or without uterine Doppler substantially improves sensitivity and specificity for predicting adverse outcomes and iatrogenic preterm delivery. We propose to extend the American College of Obstetricians and Gynecologists definition of preeclampsia in the future to include the combination of new-onset hypertension and new-onset of altered angiogenic factors (sFlt-1/PlGF ratio or PlGF alone). In summary, altered angiogenic biomarkers indicate placental dysfunction, and their implementation into clinical practice will help reduce the considerable burden of morbidity and mortality associated with adverse pregnancy outcomes as a consequence of angiogenic-placental syndrome.



Hypertension: 16 Feb 2020:HYPERTENSIONAHA11913763; epub ahead of print
Stepan H, Hund M, Andraczek T
Hypertension: 16 Feb 2020:HYPERTENSIONAHA11913763; epub ahead of print | PMID: 32063058
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Abstract

Measuring multimorbidity beyond counting diseases: systematic review of community and population studies and guide to index choice.

Stirland LE, González-Saavedra L, Mullin DS, Ritchie CW, Muniz-Terrera G, Russ TC
Objectives
To identify and summarise existing indices for measuring multimorbidity beyond disease counts, to establish which indices include mental health comorbidities or outcomes, and to develop recommendations based on applicability, performance, and usage.
Design
Systematic review.
Data sources
Seven medical research databases (Medline, Web of Science Core Collection, Cochrane Library, Embase, PsycINFO, Scopus, and CINAHL Plus) from inception to October 2018 and bibliographies and citations of relevant papers. Searches were limited to English language publications.
Eligibility criteria for study selection
Original articles describing a new multimorbidity index including more information than disease counts and not focusing on comorbidity associated with one specific disease. Studies were of adults based in the community or at population level.
Results
Among 7128 search results, 5560 unique titles were identified. After screening against eligibility criteria the review finally included 35 papers. As index components, 25 indices used conditions (weighted or in combination with other parameters), five used diagnostic categories, four used drug use, and one used physiological measures. Predicted outcomes included mortality (18 indices), healthcare use or costs (13), hospital admission (13), and health related quality of life (7). 29 indices considered some aspect of mental health, with most including it as a comorbidity. 12 indices are recommended for use.
Conclusions
35 multimorbidity indices are available, with differing components and outcomes. Researchers and clinicians should examine existing indices for suitability before creating new ones.
Systematic review registration
PROSPERO CRD42017074211.

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BMJ: 17 Feb 2020; 368:m160
Stirland LE, González-Saavedra L, Mullin DS, Ritchie CW, Muniz-Terrera G, Russ TC
BMJ: 17 Feb 2020; 368:m160 | PMID: 32071114
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Abstract

Trends and risk factors of mortality and disability adjusted life years for chronic respiratory diseases from 1990 to 2017: systematic analysis for the Global Burden of Disease Study 2017.

Li X, Cao X, Guo M, Xie M, Liu X
Objective
To describe the temporal and spatial trends of mortality and disability adjusted life years (DALYs) due to chronic respiratory diseases, by age and sex, across the world during 1990-2017 using data from the Global Burden of Disease Study 2017.
Design
Systematic analysis.
Data source
The Global Burden of Diseases, Injuries, and Risk Factors Study 2017.
Methods
Mortality and DALYs from chronic respiratory diseases were estimated from the Global Burden of Disease Study 2017 using DisMod-MR 2.1, a Bayesian meta-regression tool. The estimated annual percentage change of the age standardised mortality rate was calculated using a generalised linear model with a Gaussian distribution. Mortality and DALYs were stratified according to the Socio-demographic index. The strength and direction of the association between the Socio-demographic index and mortality rate were measured using the Spearman rank order correlation. Risk factors for chronic respiratory diseases were analysed from exposure data.
Results
Between 1990 and 2017, the total number of deaths due to chronic respiratorydiseases increased by 18.0%, from 3.32 (95% uncertainty interval 3.01 to 3.43) million in 1990 to 3.91 (3.79 to 4.04) million in 2017. The age standardised mortality rate of chronic respiratory diseases decreased by an average of 2.41% (2.28% to 2.55%) annually. During the 27 years, the annual decline in mortality rates of chronic obstructive pulmonary disease (COPD; 2.36%, uncertainty interval 2.21% to 2.50%) and pneumoconiosis (2.56%, 2.44% to 2.68%) has been slow, whereas the mortality rate for interstitial lung disease and pulmonary sarcoidosis (0.97%, 0.92% to 1.03%) has increased. Reductions in DALYs for asthma and pneumoconiosis have been seen, but DALYs due to COPD, and interstitial lung disease and pulmonary sarcoidosis have increased. Mortality and the annual change in mortality rate due to chronic respiratory diseases varied considerably across 195 countries. Assessment of the factors responsible for regional variations in mortality and DALYs and the unequal distribution of improvements during the 27 years showed negative correlations between the Socio-demographic index and the mortality rates of COPD, pneumoconiosis, and asthma. Regions with a low Socio-demographic index had the highest mortality and DALYs. Smoking remained the major risk factor for mortality due to COPD and asthma. Pollution from particulate matter was the major contributor to deaths from COPD in regions with a low Socio-demographic index. Since 2013, a high body mass index has become the principal risk factor for asthma.
Conclusions
Regions with a low Socio-demographic index had the greatest burden of disease. The estimated contribution of risk factors (such as smoking, environmental pollution, and a high body mass index) to mortality and DALYs supports the need for urgent efforts to reduce exposure to them.

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BMJ: 18 Feb 2020; 368:m234
Li X, Cao X, Guo M, Xie M, Liu X
BMJ: 18 Feb 2020; 368:m234 | PMID: 32075787
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Abstract

HuR (Human Antigen R) Regulates the Contraction of Vascular Smooth Muscle and Maintains Blood Pressure.

Liu S, Jiang X, Lu H, Xing M, ... Zhang C, Zhang W
Objective
HuR (human antigen R)-an RNA-binding protein-is involved in regulating mRNA stability by binding adenylate-uridylate-rich elements. This study explores the role of HuR in the regulation of smooth muscle contraction and blood pressure. Approach and Results: Vascular HuR (smooth muscle-specific HuR knockout) mice were generated by crossbreeding HuR mice with α-SMA (α-smooth muscle actin)-Cre mice. As compared with CTR (control) mice, HuR mice showed hypertension and cardiac hypertrophy. HuR levels were decreased in aortas from hypertensive patients and SHRs (spontaneously hypertensive rats), and overexpression of HuR could lower the blood pressure of SHRs. Contractile response to vasoconstrictors was increased in mesenteric artery segments isolated from HuR mice. The functional abnormalities in HuR mice were attributed to decreased mRNA and protein levels of RGS (regulator of G-protein signaling) protein(s) RGS2, RGS4, and RGS5, which resulted in increased intracellular calcium increase. Consistently, the degree of intracellular calcium ion increase in HuR-deficient smooth muscle cells was reduced by overexpression of RGS2, RGS4, or RGS5. Finally, administration of RGS2 and RGS5 reversed the elevated blood pressure in HuR mice.
Conclusions
Our findings indicate that HuR regulates vascular smooth muscle contraction and maintains blood pressure by modulating RGS expression.



Arterioscler Thromb Vasc Biol: 19 Feb 2020:ATVBAHA119313897; epub ahead of print
Liu S, Jiang X, Lu H, Xing M, ... Zhang C, Zhang W
Arterioscler Thromb Vasc Biol: 19 Feb 2020:ATVBAHA119313897; epub ahead of print | PMID: 32075416
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Abstract

Maternal and fetal outcomes following exposure to duloxetine in pregnancy: cohort study.

Huybrechts KF, Bateman BT, Pawar A, Bessette LG, ... Upadhyaya HP, Hernandez-Diaz S
Objective
To evaluate the risk of adverse maternal and infant outcomes following in utero exposure to duloxetine.
Design
Cohort study nested in the Medicaid Analytic eXtract for 2004-13.
Setting
Publicly insured pregnancies in the United States.
Participants
Pregnant women 18 to 55 years of age and their liveborn infants.
Interventions
Duloxetine exposure during the etiologically relevant time window, compared with no exposure to duloxetine, exposure to selective serotonin reuptake inhibitors, exposure to venlafaxine, and exposure to duloxetine before but not during pregnancy.
Main outcome measures
Congenital malformations overall, cardiac malformations, preterm birth, small for gestational age infant, pre-eclampsia, and postpartum hemorrhage.
Results
Cohort sizes ranged from 1.3 to 4.1 million, depending on the outcome. The number of women exposed to duloxetine varied by cohort and exposure contrast and was around 2500-3000 for early pregnancy exposure and 900-950 for late pregnancy exposure. The base risk per 1000 unexposed women was 36.6 (95% confidence interval 36.3 to 36.9) for congenital malformations overall, 13.7 (13.5 to 13.9) for cardiovascular malformations, 107.8 (107.3 to 108.3) for preterm birth, 20.4 (20.1 to 20.6) for small for gestational age infant, 33.6 (33.3 to 33.9) for pre-eclampsia, and 23.3 (23.1 to 23.4) for postpartum hemorrhage. After adjustment for measured potential confounding variables, all baseline characteristics were well balanced for all exposure contrasts. In propensity score adjusted analyses versus unexposed pregnancies, the relative risk was 1.11 (95% confidence interval 0.93 to 1.33) for congenital malformations overall and 1.29 (0.99 to 1.68) for cardiovascular malformations. For preterm birth, the relative risk was 1.01 (0.92 to 1.10) for early exposure and 1.19 (1.04 to 1.37) for late exposure. For small for gestational age infants the relative risks were 1.14 (0.92 to 1.41) and 1.20 (0.83 to 1.72) for early and late pregnancy exposure, respectively, and for pre-eclampsia they were 1.12 (0.96 to 1.31) and 1.04 (0.80 to 1.35). The relative risk for postpartum hemorrhage was 1.53 (1.08 to 2.18). Results from sensitivity analyses were generally consistent with the findings from the main analyses.
Conclusions
On the basis of the evidence available to date, duloxetine is unlikely to be a major teratogen but may be associated with an increased risk of postpartum hemorrhage and a small increased risk of cardiac malformations. While continuing to monitor the safety of duloxetine as data accumulate over time, these potential small increases in risk of relatively uncommon outcomes must be weighed against the benefits of treating depression and pain during pregnancy in a given patient.
Trial registration
EUPAS 15946.

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BMJ: 18 Feb 2020; 368:m237
Huybrechts KF, Bateman BT, Pawar A, Bessette LG, ... Upadhyaya HP, Hernandez-Diaz S
BMJ: 18 Feb 2020; 368:m237 | PMID: 32075794
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Abstract

Mechanisms of Arterial Stiffening: From Mechanotransduction to Epigenetics.

Lacolley P, Regnault V, Laurent S

Arterial stiffness is a major independent risk factor for cardiovascular complications causing isolated systolic hypertension and increased pulse pressure in the microvasculature of target organs. Stiffening of the arterial wall is determined by common mechanisms including reduced elastin/collagen ratio, production of elastin cross-linking, reactive oxygen species-induced inflammation, calcification, vascular smooth muscle cell stiffness, and endothelial dysfunction. This brief review will discuss current biological mechanisms by which other cardiovascular risk factors (eg. aging, hypertension, diabetes mellitus, and chronic kidney disease) cause arterial stiffness, with a particular focus on recent advances regarding nuclear mechanotransduction, mitochondrial oxidative stress, metabolism and dyslipidemia, genome mutations, and epigenetics. Targeting these different molecular pathways at different time of cardiovascular risk factor exposure may be a novel approach for discovering drugs to reduce arterial stiffening without affecting artery strength and normal remodeling.



Arterioscler Thromb Vasc Biol: 19 Feb 2020:ATVBAHA119313129; epub ahead of print
Lacolley P, Regnault V, Laurent S
Arterioscler Thromb Vasc Biol: 19 Feb 2020:ATVBAHA119313129; epub ahead of print | PMID: 32075419
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Abstract

Microvascular Disease Increases Amputation in Patients With Peripheral Artery Disease.

Behroozian A, Beckman JA

It is estimated that >2 million patients are living with an amputation in the United States. Peripheral artery disease (PAD) and diabetes mellitus account for the majority of nontraumatic amputations. The standard measurement to diagnose PAD is the ankle-brachial index, which integrates all occlusive disease in the limb to create a summary value of limb artery occlusive disease. Despite its accuracy, ankle-brachial index fails to well predict limb outcomes. There is an emerging body of literature that implicates microvascular disease (MVD; ie, retinopathy, nephropathy, neuropathy) as a systemic phenomenon where diagnosis of MVD in one capillary bed implicates microvascular dysfunction systemically. MVD independently associates with lower limb outcomes, regardless of diabetic or PAD status. The presence of PAD and concomitant MVD phenotype reveal a synergistic, rather than simply additive, effect. The higher risk of amputation in patients with MVD, PAD, and concomitant MVD and PAD should prompt aggressive foot surveillance and diagnosis of both conditions to maintain ambulation and prevent amputation in older patients.



Arterioscler Thromb Vasc Biol: 19 Feb 2020:ATVBAHA119312859; epub ahead of print
Behroozian A, Beckman JA
Arterioscler Thromb Vasc Biol: 19 Feb 2020:ATVBAHA119312859; epub ahead of print | PMID: 32075418
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Abstract

Associations between macrolide antibiotics prescribing during pregnancy and adverse child outcomes in the UK: population based cohort study.

Fan H, Gilbert R, O\'Callaghan F, Li L
Objective
To assess the association between macrolide antibiotics prescribing during pregnancy and major malformations, cerebral palsy, epilepsy, attention deficit hyperactivity disorder, and autism spectrum disorder in children.
Design
Population based cohort study.
Setting
The UK Clinical Practice Research Datalink.
Participants
The study cohort included 104 605 children born from 1990 to 2016 whose mothers were prescribed one macrolide monotherapy (erythromycin, clarithromycin, or azithromycin) or one penicillin monotherapy from the fourth gestational week to delivery. Two negative control cohorts consisted of 82 314 children whose mothers were prescribed macrolides or penicillins before conception, and 53 735 children who were siblings of the children in the study cohort.
Main outcome measures
Risks of any major malformations and system specific major malformations (nervous, cardiovascular, gastrointestinal, genital, and urinary) after macrolide or penicillin prescribing during the first trimester (four to 13 gestational weeks), second to third trimester (14 gestational weeks to birth), or any trimester of pregnancy. Additionally, risks of cerebral palsy, epilepsy, attention deficit hyperactivity disorder, and autism spectrum disorder.
Results
Major malformations were recorded in 186 of 8632 children (21.55 per 1000) whose mothers were prescribed macrolides and 1666 of 95 973 children (17.36 per 1000) whose mothers were prescribed penicillins during pregnancy. Macrolide prescribing during the first trimester was associated with an increased risk of any major malformation compared with penicillin (27.6517.65 per 1000, adjusted risk ratio 1.55, 95% confidence interval 1.19 to 2.03) and specifically cardiovascular malformations (10.606.61 per 1000, 1.62, 1.05 to 2.51). Macrolide prescribing in any trimester was associated with an increased risk of genital malformations (4.753.07 per 1000, 1.58, 1.14 to 2.19, mainly hypospadias). Erythromycin in the first trimester was associated with an increased risk of any major malformation (27.3917.65 per 1000, 1.50, 1.13 to 1.99). No statistically significant associations were found for other system specific malformations or for neurodevelopmental disorders. Findings were robust to sensitivity analyses.
Conclusions
Prescribing macrolide antibiotics during the first trimester of pregnancy was associated with an increased risk of any major malformation and specifically cardiovascular malformations compared with penicillin antibiotics. Macrolide prescribing in any trimester was associated with an increased risk of genital malformations. These findings show that macrolides should be used with caution during pregnancy and if feasible alternative antibiotics should be prescribed until further research is available.
Trial registration
ClinicalTrials.gov NCT03948620.

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BMJ: 18 Feb 2020; 368:m331
Fan H, Gilbert R, O'Callaghan F, Li L
BMJ: 18 Feb 2020; 368:m331 | PMID: 32075790
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Abstract

Angiocrine FSTL1 (Follistatin-Like Protein 1) Insufficiency Leads to Atrial and Venous Wall Fibrosis via SMAD3 Activation.

Jiang H, Zhang L, Liu X, Sun W, ... Gao X, He Y
Objective
Angiocrine factors, mediating the endothelial-mural cell interaction in vascular wall construction as well as maintenance, are incompletely characterized. This study aims to investigate the role of endothelial cell-derived FSTL1 (follistatin-like protein 1) in vascular homeostasis. Approach and Results: Using conditional knockout mouse models, we show that loss of FSTL1 in endothelial cells () led to an increase of pulmonary vascular resistance, resulting in the heart regurgitation especially with tricuspid valves. However, this abnormality was not detected in mutant mice withdeletion in smooth muscle cells or hematopoietic cells. We further showed that there was excessive αSMA (α-smooth muscle actin) associated with atrial endocardia, heart valves, veins, and microvessels after the endothelial FSTL1 deletion. There was also an increase in collagen deposition, as demonstrated in livers ofmutants. The SMAD3 phosphorylation was significantly enhanced, and pSMAD3 staining was colocalized with αSMA in vein walls, suggesting the activation of TGFβ (transforming growth factor β) signaling in vascular mural cells ofmice. Consistently, treatment with a TGFβ pathway inhibitor reduced the abnormal association of αSMA with the atria and blood vessels inmutant mice.
Conclusions
The findings imply that endothelial FSTL1 is critical for the homeostasis of vascular walls, and its insufficiency may favor cardiovascular fibrosis leading to heart failure.



Arterioscler Thromb Vasc Biol: 12 Feb 2020:ATVBAHA119313901; epub ahead of print
Jiang H, Zhang L, Liu X, Sun W, ... Gao X, He Y
Arterioscler Thromb Vasc Biol: 12 Feb 2020:ATVBAHA119313901; epub ahead of print | PMID: 32078339
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Abstract

- and -Induced Vascular Progenitor Cells Enhance Functional Recovery in Ischemic Vascular Disease Model.

Park SY, Lee H, Kwon YW, Park MR, Kim JH, Kim JB
Objective
Vascular progenitor cells (VPCs), which are able to differentiate into both endothelial cells and smooth muscle cells, have the potential for treatment of ischemic diseases. Generated by pluripotent stem cells, VPCs carry the risk of tumorigenicity in clinical application. This issue could be resolved by direct lineage conversion, the induction of functional cells from another lineage by using only lineage-restricted transcription factors. Here, we show that induced VPCs (iVPCs) can be generated from fibroblasts by ETS (E-twenty six) transcription factors,and . Approach and Results: Mouse fibroblasts were infected with lentivirus encodingand . Cell colonies appeared in - and -infected groups and were mechanically picked. The identity of cell colonies was confirmed by proliferation assay and reverse-transcription polymerase chain reaction with vascular markers- infected cell colonies were sorted by CD144 (CDH5, VE-cadherin). We defined that CD144-positive iVPCs maintained its own population and expanded stably at multiple passages. iVPCs could differentiate into functional endothelial cells and smooth muscle cells by a defined medium. The functionalities of iVPC-derived endothelial cells and smooth muscle cells were confirmed by analyzing LDL (low-density lipoprotein) uptake, carbachol-induced contraction, and tube formation in vitro. Transplantation of iVPCs into the ischemic hindlimb model enhanced blood flow without tumor formation in vivo. Human iVPCs were generated byand .
Conclusions
We demonstrate that ischemic disease curable iVPCs, which have self-renewal and bipotency, can be generated from mouse fibroblasts by enforced ETS family transcription factors,andexpression. Our simple strategy opens insights into stem cell-based ischemic disease therapy.



Arterioscler Thromb Vasc Biol: 19 Feb 2020:ATVBAHA119313684; epub ahead of print
Park SY, Lee H, Kwon YW, Park MR, Kim JH, Kim JB
Arterioscler Thromb Vasc Biol: 19 Feb 2020:ATVBAHA119313684; epub ahead of print | PMID: 32075417
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Abstract

Clinical findings in a group of patients infected with the 2019 novel coronavirus (SARS-Cov-2) outside of Wuhan, China: retrospective case series.

Xu XW, Wu XX, Jiang XG, Xu KJ, ... Qiu YQ, Li LJ
Objective
To study the clinical characteristics of patients in Zhejiang province, China, infected with the 2019 severe acute respiratory syndrome coronavirus 2 (SARS-Cov-2) responsible for coronavirus disease 2019 (covid-2019).
Design
Retrospective case series.
Setting
Seven hospitals in Zhejiang province, China.
Participants
62 patients admitted to hospital with laboratory confirmed SARS-Cov-2 infection. Data were collected from 10 January 2020 to 26 January 2020.
Main outcome measures
Clinical data, collected using a standardised case report form, such as temperature, history of exposure, incubation period. If information was not clear, the working group in Hangzhou contacted the doctor responsible for treating the patient for clarification.
Results
Of the 62 patients studied (median age 41 years), only one was admitted to an intensive care unit, and no patients died during the study. According to research, none of the infected patients in Zhejiang province were ever exposed to the Huanan seafood market, the original source of the virus; all studied cases were infected by human to human transmission. The most common symptoms at onset of illness were fever in 48 (77%) patients, cough in 50 (81%), expectoration in 35 (56%), headache in 21 (34%), myalgia or fatigue in 32 (52%), diarrhoea in 3 (8%), and haemoptysis in 2 (3%). Only two patients (3%) developed shortness of breath on admission. The median time from exposure to onset of illness was 4 days (interquartile range 3-5 days), and from onset of symptoms to first hospital admission was 2 (1-4) days.
Conclusion
As of early February 2020, compared with patients initially infected with SARS-Cov-2 in Wuhan, the symptoms of patients in Zhejiang province are relatively mild.

Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://group.bmj.com/group/rights-licensing/permissions.

BMJ: 18 Feb 2020; 368:m606
Xu XW, Wu XX, Jiang XG, Xu KJ, ... Qiu YQ, Li LJ
BMJ: 18 Feb 2020; 368:m606 | PMID: 32075786
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Abstract

Novel Long Noncoding RNA, Macrophage Inflammation-Suppressing Transcript (), Regulates Macrophage Activation During Obesity.

Stapleton K, Das S, Reddy MA, Leung A, ... Deiuliis JA, Natarajan R
Objective
Systemic low-grade inflammation associated with obesity and metabolic syndrome is a strong risk factor for the development of diabetes mellitus and associated cardiovascular complications. This inflammatory state is caused by release of proinflammatory cytokines by macrophages, especially in adipose tissue. Long noncoding RNAs regulate macrophage activation and inflammatory gene networks, but their role in macrophage dysfunction during diet-induced obesity has been largely unexplored. Approach and Results: We sequenced total RNA from peritoneal macrophages isolated from mice fed either high-fat diet or standard diet and performed de novo transcriptome assembly to identify novel differentially expressed mRNAs and long noncoding RNAs. A top candidate long noncoding RNA, macrophage inflammation-suppressing transcript (), was downregulated in both peritoneal macrophages and adipose tissue macrophages from high-fat diet-fed mice. GapmeR-mediatedknockdown in vitro and in vivo upregulated expression of genes associated with immune response and inflammation and increased modified LDL (low-density lipoprotein) uptake in macrophages. Conversely,overexpression decreased basal and LPS (lipopolysaccharide)-induced expression of inflammatory response genes and decreased modified LDL uptake. RNA-pull down coupled with mass spectrometry showed thatinteracts with PARP1 (poly [ADP]-ribose polymerase-1). Disruption of this RNA-protein interaction increased PARP1 recruitment and chromatin PARylation at promoters of inflammatory genes, resulting in increased gene expression. Furthermore, human orthologouswas also downregulated by proinflammatory stimuli, and its expression in human adipose tissue macrophages inversely correlated with obesity and insulin resistance.
Conclusions
is a novel protective long noncoding RNA, and its loss during obesity contributes to metabolic dysfunction and proinflammatory phenotype of macrophages via epigenetic mechanisms.



Arterioscler Thromb Vasc Biol: 12 Feb 2020:ATVBAHA119313359; epub ahead of print
Stapleton K, Das S, Reddy MA, Leung A, ... Deiuliis JA, Natarajan R
Arterioscler Thromb Vasc Biol: 12 Feb 2020:ATVBAHA119313359; epub ahead of print | PMID: 32078363
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Abstract

Warfarin Accelerates Medial Arterial Calcification in Humans.

Alappan HR, Kaur G, Manzoor S, Navarrete J, O\'Neill WC
Objective
Warfarin is associated with medial arterial calcification in humans, but the magnitude and specificity of this effect and the role of other risk factors are unknown. Using serial mammograms, progression of arterial calcification was compared in women receiving no anticoagulants, warfarin, or other anticoagulants, and before, during, and after warfarin use. Approach and Results: Warfarin users with mammograms were identified by computerized searches of medical records that included renal function and diabetes mellitus. Lengths of calcified arterial segments were measured, with progression expressed as millimeters per breast per year and presented as medians and interquartile range (IQR). In women with normal renal function (estimated glomerular filtration rate >60 mL/minute per 1.73 m), progression was 3.9-fold greater in warfarin users: 9.9 (3.8-16) versus 2.5 (0.7-6.7) in controls, =0.0003, but not increased in users of other anticoagulants. In longitudinal analyses, progression increased from 2.1 (IQR, 0.3-3.9) to 13.8 (IQR, 7.8-38.7; =0.011) after starting warfarin (n=11) and decreased from 8.8 (IQR, 1.1-10) to 1.9 (IQR, -10 to 6.7; =0.024) after discontinuation of warfarin (n=13). Progression of calcification was similar in warfarin users with chronic kidney disease (7.3 [IQR, 3.6-17], n=29) but markedly accelerated in warfarin users with end-stage renal disease (47 [IQR, 31-183], n=11; =0.0002). Progression was similar in diabetic and nondiabetic warfarin users (10.1 [IQR, 3.8-24] versus 7.8 [IQR, 3.6-15]) and did not correlate with age (=0.09) or duration of warfarin therapy (=0.12).
Conclusions
Warfarin significantly accelerates medial arterial calcification in humans. This effect is markedly augmented in end-stage renal disease.



Arterioscler Thromb Vasc Biol: 12 Feb 2020:ATVBAHA119313879; epub ahead of print
Alappan HR, Kaur G, Manzoor S, Navarrete J, O'Neill WC
Arterioscler Thromb Vasc Biol: 12 Feb 2020:ATVBAHA119313879; epub ahead of print | PMID: 32078340
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Abstract

The Impact of Patient Sex on the Response to Intramyocardial Mesenchymal Stem Cell Administration in Patients with Non-Ischemic Dilated Cardiomyopathy.

Florea V, Rieger AC, Natsumeda M, Tompkins BA, ... Mitrani RD, Hare JM
Aims
Sex differences impact the occurrence, presentation, prognosis, and response to therapy in heart disease. Particularly, the phenotypic presentation of patients with non-ischemic dilated cardiomyopathy (NIDCM) differs between men and women. However, whether the response to mesenchymal stem cell (MSC) therapy is influenced by sex remains unknown. We hypothesize that males and females with NIDCM respond similarly to MSC therapy.
Methods and results
Male (n = 24) and female (n = 10) patients from the POSEIDON-DCM trial who received MSCs via transendocardial injections were evaluated over 12 months. Endothelial function was measured at baseline and 3 months post-TESI. At baseline, EF was lower (p = 0.004) and end diastolic volume (EDV; p = 0.0002) and end systolic volume (ESV; p = 0.0002) were higher in males vs. females. In contrast, baseline demographic characteristics, Minnesota Living with Heart Failure Questionnaire (MLHFQ), and 6-minute walk test (6MWT) were similar between groups. EF improved in males by 6.2 units (p = 0.04) and in females by 8.6 units (p = 0.04; males vs. females, p = 0.57). EDV and ESV were unchanged over time. The MLHFQ score, New York Heart Association (NYHA) class, endothelial progenitor cell-colony forming units (EPC-CFUs), and serum TNF-α improved similarly in both groups.
Conclusions
Despite major differences in phenotypic presentation of NIDCM in males and females, this study is the first of its kind to demonstrate that MSC therapy improves a variety of parameters in NIDCM irrespective of patient sex. These findings have important clinical and pathophysiologic implications regarding the impact of sex on responses to cell-based therapy for NIDCM.
Translational perspective
Important patient sex differences exist in NIDCM clinical phenotype and gene expression profiles. The effectiveness of pharmacological treatment relative to patient sex requires evaluation due to the paucity of sex-specific data in clinical trials. Herein, we report that despite baseline phenotypic differences in left ventricular remodeling, MSC treatment improves the NIDCM phenotype irrespective of patient sex. Importantly, MSC administration to female patients may lead to an increased rate of heart failure with recovered EF, which carries an improved mortality, transplant rate, and hospitalization rate. This hypothesis-generating study encourages the design of future trials that evaluate patient sex differences in response to cell-based therapy.

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

Cardiovasc Res: 12 Feb 2020; epub ahead of print
Florea V, Rieger AC, Natsumeda M, Tompkins BA, ... Mitrani RD, Hare JM
Cardiovasc Res: 12 Feb 2020; epub ahead of print | PMID: 32053144
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Abstract

Secondary mitral regurgitation: pathophysiology, proportionality and prognosis.

Chehab O, Roberts-Thomson R, Ng Yin Ling C, Marber M, ... Rajani R, Redwood SR

Secondary mitral regurgitation (SMR) occurs as a result of multifactorial left atrioventricular dysfunction and maleficent remodelling. It is the most common and undertreated form of mitral regurgitation (MR) and is associated with a very poor prognosis. Whether SMR is a bystander reflecting the severity of the cardiomyopathy disease process has long been the subject of debate. Studies suggest that SMR is an independent driver of prognosis in patients with an intermediate heart failure (HF) phenotype and not those with advanced HF. There is also no universal agreement regarding the quantitative thresholds defining severe SMR and indeed there are challenges with echocardiographic quantification. Until recently, no surgical or transcatheter intervention for SMR had demonstrated prognostic benefit, in contrast with HF medical therapy and cardiac resynchronisation therapy. In 2018, the first two randomised controlled trials (RCTs) of edge-to-edge transcatheter mitral valve repair versus guideline-directed medical therapy in HF (Percutaneous Repair with the MitraClip Device for Severe (MITRA-FR), Transcather mitral valve repair in patients with heart failure (COAPT)) reported contrasting yet complimentary results. Unlike in MITRA-FR, COAPT demonstrated significant prognostic benefit, largely attributed to the selection of patients with disproportionately severe MR relative to their HF phenotype. Consequently, quantifying the degree of SMR in relation to left ventricular volume may be a useful discriminator in predicting the success of transcatheter intervention. The challenge going forward is the identification and validation of such parameters while in parallel maintaining a heart-team guided holistic approach.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 12 Feb 2020; epub ahead of print
Chehab O, Roberts-Thomson R, Ng Yin Ling C, Marber M, ... Rajani R, Redwood SR
Heart: 12 Feb 2020; epub ahead of print | PMID: 32054671
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Abstract

Junctophilin-2 tethers T-tubules and recruits functional L-type calcium channels to lipid rafts in adult cardiomyocytes.

Poulet C, Sanchez-Alonso J, Swiatlowska P, Mouy F, ... Houser S, Gorelik J
Aim
In cardiomyocytes, transverse tubules (T-tubules) associate with the sarcoplasmic reticulum (SR), forming junctional membrane complexes (JMCs) where L-type calcium channels (LTCCs) are juxtaposed to Ryanodine receptors (RyR). Junctophilin-2 (JPH2) supports the assembly of JMCs by tethering T-tubules to the SR membrane. T-tubule remodeling in cardiac diseases is associated with down-regulation of JPH2 expression suggesting that JPH2 plays a crucial role in T-tubule stability. Furthermore, increasing evidence indicate that JPH2 might additionally act as a modulator of calcium signaling by directly regulating RyR and LTCCs. This study aimed at determining whether JPH2 overexpression restores normal T-tubule structure and LTCC function in cultured cardiomyocytes.
Methods and results
Rat ventricular myocytes kept in culture for 4 days showed extensive T-tubule remodeling with impaired JPH2 localization and relocation of the scaffolding protein Caveolin3 (Cav3) from the T-tubules to the outer membrane. Overexpression of JPH2 restored T-tubule structure and Cav3 relocation. Depletion of membrane cholesterol by chronic treatment with Methyl-β-cyclodextrin (MβCD) countered the stabilizing effect of JPH2 overexpression on T-tubules and Cav3. Super-resolution scanning patch-clamp showed that JPH2 overexpression greatly increased the number of functional LTCCs at the plasma membrane. Treatment with MβCD reduced LTCC open probability and activity. Proximity ligation assays showed that MβCD did not affect JPH2 interaction with RyR and the pore-forming LTCC subunit Cav1.2, but strongly impaired JPH2 association with Cav3 and the accessory LTCC subunit Cavβ2.
Conclusions
JPH2 promotes T-tubule structural stability and recruits functional LTCCs to the membrane, most likely by directly binding to the channel. Cholesterol is involved in the binding of JPH2 to T-tubules as well as in the modulation of LTCC activity. We propose a model where cholesterol and Cav3 support the assembly of lipid rafts which provide an anchor for JPH2 to form JMCs and a platform for signaling complexes to regulate LTCC activity.
Translational perspective
By tethering T-tubules to the sarcoplasmic reticulum, junctophilin-2 (JPH2) supports the assembly of junctional membrane complexes (JMCs), major sites of excitation-contraction coupling in cardiomyocytes. JPH2 downregulation underlies the disruption of JMCs and T-tubules in cardiomyopathies and enhancing JPH2 expression is a promising therapeutic approach for the treatment of heart failure. Our study demonstrates a new role for JPH2 in the recruitment of calcium channels to the membrane and provides innovative insights into the formation and organization of JMCs as well as into the regulation of excitation-contraction coupling. Our results are of significant importance when considering JPH2 as a therapeutic target.

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

Cardiovasc Res: 12 Feb 2020; epub ahead of print
Poulet C, Sanchez-Alonso J, Swiatlowska P, Mouy F, ... Houser S, Gorelik J
Cardiovasc Res: 12 Feb 2020; epub ahead of print | PMID: 32053184
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Abstract

Light Sheet Fluorescence Microscopy as a New Method for Unbiased Three-Dimensional Analysis of Vascular Injury.

Buglak NE, Lucitti J, Ariel P, Maiocchi S, Miller FJ, Bahnson ESM
Aims
Assessment of preclinical models of vascular disease are paramount in the successful translation of novel treatments. The results of these models have traditionally relied on 2-D histological methodologies. Light sheet fluorescence microscopy (LSFM) is an imaging platform that allows for 3-D visualization of whole organs and tissues. In this study, we describe an improved methodological approach utilizing LSFM for imaging of preclinical vascular injury models while minimizing analysis bias.
Methods and results
The rat carotid artery segmental pressure-controlled balloon injury and mouse carotid artery ligation injury were performed. Arteries were harvested and processed for LSFM imaging and 3-D analysis, as well as for 2-D area histological analysis. Artery processing for LSFM imaging did not induce vessel shrinkage or expansion, and was reversible by rehydrating the artery, allowing for subsequent sectioning and histological staining a posteriori. By generating a volumetric visualization along the length of the arteries, LSFM imaging provided different analysis modalities including volumetric, area, and radial parameters. Thus, LSFM-imaged arteries provided more precise measurements compared to classic histological analysis. Furthermore, LSFM provided additional information as compared to 2-D analysis in demonstrating remodeling of the arterial media in regions of hyperplasia and periadventitial neovascularization around the ligated mouse artery.
Conclusions
LSFM provides a novel and robust 3-D imaging platform for visualizing and quantifying arterial injury in preclinical models. When compared with classic histology, LSFM outperformed traditional methods in precision and quantitative capabilities. LSFM allows for more comprehensive quantitation as compared to traditional histological methodologies, while minimizing user bias associated with area analysis of alternating, 2-D histological artery cross-sections.
Translational perspective
A more reproducible and robust quantitation of vascular pathology in preclinical models is necessary to accelerate translational discovery. Current methodology to assess vascular disease has significant limitations. The methodology described herein employs a modern imaging modality, light sheet fluorescence microscopy (LSFM), to improve assessment of established preclinical vascular injury models. LSFM provides more comprehensive and precise analysis capabilities than classical histological approaches. Hence, LSFM applied to vascular research has the potential to drive new basic discoveries, and ultimately translation of novel therapies.

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

Cardiovasc Res: 12 Feb 2020; epub ahead of print
Buglak NE, Lucitti J, Ariel P, Maiocchi S, Miller FJ, Bahnson ESM
Cardiovasc Res: 12 Feb 2020; epub ahead of print | PMID: 32053173
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Abstract

ApoCIII-Lp(a) complexes in conjunction with Lp(a)-OxPL predict rapid progression of aortic stenosis.

Capoulade R, Torzewski M, Mayr M, Chan KL, ... Pibarot P, Tsimikas S
Objective
This study assessed whether apolipoprotein CIII-lipoprotein(a) complexes (ApoCIII-Lp(a)) associate with progression of calcific aortic valve stenosis (AS).
Methods
Immunostaining for ApoC-III was performed in explanted aortic valve leaflets in 68 patients with leaflet pathological grades of 1-4. Assays measuring circulating levels of ApoCIII-Lp(a) complexes were measured in 218 patients with mild-moderate AS from the AS Progression Observation: Measuring Effects of Rosuvastatin (ASTRONOMER) trial. The progression rate of AS, measured as annualised changes in peak aortic jet velocity (V), and combined rates of aortic valve replacement (AVR) and cardiac death were determined. For further confirmation of the assay data, a proteomic analysis of purified Lp(a) was performed to confirm the presence of apoC-III on Lp(a).
Results
Immunohistochemically detected ApoC-III was prominent in all grades of leaflet lesion severity. Significant interactions were present between ApoCIII-Lp(a) and Lp(a), oxidised phospholipids on apolipoprotein B-100 (OxPL-apoB) or on apolipoprotein (a) (OxPL-apo(a)) with annualised V (all p<0.05). After multivariable adjustment, patients in the top tertile of both apoCIII-Lp(a) and Lp(a) had significantly higher annualised V (p<0.001) and risk of AVR/cardiac death (p=0.03). Similar results were noted with OxPL-apoB and OxPL-apo(a). There was no association between autotaxin (ATX) on ApoB and ATX on Lp(a) with faster progression of AS. Proteomic analysis of purified Lp(a) showed that apoC-III was prominently present on Lp(a).
Conclusion
ApoC-III is present on Lp(a) and in aortic valve leaflets. Elevated levels of ApoCIII-Lp(a) complexes in conjunction with Lp(a), OxPL-apoB or OxPL-apo(a) identify patients with pre-existing mild-moderate AS who display rapid progression of AS and higher rates of AVR/cardiac death.
Trial registration
NCT00800800.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 12 Feb 2020; epub ahead of print
Capoulade R, Torzewski M, Mayr M, Chan KL, ... Pibarot P, Tsimikas S
Heart: 12 Feb 2020; epub ahead of print | PMID: 32054669
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Abstract

Pregnancy outcomes in women with significant valve disease: a systematic review and meta-analysis.

Ducas RA, Javier DA, D\'Souza R, Silversides CK, Tsang W
Objective
To perform a systematic review and meta-analysis of maternal/fetal outcomes in pregnant women with moderate/severe native valvular heart disease (VHD) from medium/higher Human Development Index (HDI) countries.
Methods
OvidSP platform databases were searched (1985-January 2019) to identify studies reporting pregnancy outcomes in women with moderate/severe VHD. The primary maternal outcome was maternal mortality. The primary fetal/neonatal outcome was stillbirth and neonatal death. Pooled incidences and 95% confidence intervals (CI) of maternal/fetal outcomes could only be calculated from studies involving mitral stenosis (MS) or aortic stenosis (AS).
Results
Twelve studies on 646 pregnancies were included. Pregnant women with severe MS had mortality rates of 3% (95% CI, 0% to 6%), pulmonary oedema 37% (23%-51%) and new/recurrent arrhythmias 16% (1%-25%). Their stillbirth, neonatal death and preterm birth rates were 4% (1%-7%), 2% (0%-4%), and 18% (7%-29%), respectively. Women with moderate MS had mortality rates of 1%(0%-2%), pulmonary oedema 18% (2%-33%), new/recurrent arrhythmias 5% (1%-9%), stillbirth 2% (1%-4%) and preterm birth 10%(2%-17%).Pregnant women with severe AS had a risk of mortality of 2% (0%-5%), pulmonary oedema 9% (2%-15%), and new/recurrent arrhythmias 4% (0%-7%). Their stillbirth, neonatal death and preterm birth rates were 2% (0%-5%), 3% (0%-6%) and 14%(4%-24%), respectively. No maternal/neonatal deaths were reported in moderate AS, however women experienced pulmonary oedema (8%; 0%-20%), new/recurrent arrhythmias (2%; 0%-5%), and preterm birth (13%; 6%-20%).
Conclusions
Women with moderate/severe MS and AS are at risk for adverse maternal and fetal/neonatal outcomes. They should receive preconception counseling and pregnancy care by teams with pregnancy and heart disease experience.

© Author(s) (or their employer(s)) 2020. No commercial re-use. See rights and permissions. Published by BMJ.

Heart: 12 Feb 2020; epub ahead of print
Ducas RA, Javier DA, D'Souza R, Silversides CK, Tsang W
Heart: 12 Feb 2020; epub ahead of print | PMID: 32054673
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Abstract

Tetra positive thrombotic Antiphospholipid syndrome: major contribution of anti phosphatidyl-serine/prothrombin antibodies to Lupus anticoagulant activity.

Cattini MG, Bison E, Pontara E, Cheng C, Denas G, Pengo V
Background
The concurrent presence of lupus anticoagulant, anti-cardiolipin and anti β2-glycoprotein I antibodies (triple positive profile) identifies patients at high-risk of thromboembolic events. These patients are also positive for anti phosphatidyl-serine/prothrombin antibodies (tetra positive profile).
Objective
Understand which antibody among anti β2-glycoprotein I and anti phosphatidyl-serine/prothrombin is responsible for lupus anticoagulant activity is not defined.
Patients/methods
Affinity purified anti β2-glycoprotein I antibodies from plasma of 14 tetra positive patients spiked into normal pooled plasma were tested.
Results and conclusions
Anti β2-glycoprotein I antibodies did not prolong the diluted Russell Viper Venom Time and Silica Clotting Time (median ratio 0.98, IQR 0.9-1.06 and 1.0, IQR 0.91-1.03, respectively). Anticoagulant activity remained in the flow through that was deprived of anti β2 glycoprotein I antibodies (median ratio 1.88, IQR 1.58-2.77, and 1.75, IQR 1.17-2.9, respectively). This material was loaded on size-exclusion chromatography Sephacryl S-300 column and showed that anticoagulant activity and anti phosphatidyl-serine/prothrombin antibodies co-eluted in the same fractions. Besides, the flow through was poured into a prothrombin affinity column. Protein yield in three patients ranged from 54 to 91 μg/mL and showed strong positivity in phosphatidyl-serine/prothrombin ELISA. The affinity purified material prolonged the coagulation time of normal pooled plasma: the diluted Russell Viper Venom ratio in the three patients was 2.09, 1.21, 1.35 and that of Silica Clotting Time was 2.05, 1.5, 2.13. In conclusion, under the assay conditions used, anticoagulant activity in tetra positive antiphospholipid syndrome patients may largely be attributable to anti phosphatidyl-serine/prothrombin antibodies.

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J Thromb Haemost: 12 Feb 2020; epub ahead of print
Cattini MG, Bison E, Pontara E, Cheng C, Denas G, Pengo V
J Thromb Haemost: 12 Feb 2020; epub ahead of print | PMID: 32052568
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Abstract

Anti-Platelet Antibodies in Childhood Immune Thrombocytopenia: Prevalence and Prognostic Implications.

Schmidt DE, Heitink-Polle KMJ, Porcelijn L, van der Schoot CE, ... Bruin MCA, de Haas M
Background
Anti-platelet antibody testing may be useful for the diagnosis and management of childhood immune thrombocytopenia (ITP).
Objectives
Here we aimed to assess the prevalence and prognostic significance of anti-platelet glycoprotein-specific IgM and IgG antibodies.
Methods
Children with newly diagnosed ITP were included at diagnosis and randomized to an intravenous immunoglobulins (IVIg) or careful observation group (TIKI trial). In this well-defined and longitudinally followed cohort (N = 179), anti-platelet glycoprotein-specific IgM and IgG antibodies were determined by MAIPA.
Results
The dominant circulating anti-platelet antibody class in childhood ITP was IgM (62% of patients); but IgG antibodies were also found (10%). Children without IgM platelet antibodies were older and more often female. There was weak evidence for an association between IgM anti-GP IIb/IIIa antibodies and an increased bleeding severity (P=0.03). The IgM and IgG anti-platelet responses partially overlapped, and reactivity was frequently directed against multiple glycoproteins. During one year follow-up, children with IgM antibodies in the observation group displayed a faster platelet recovery compared to children without IgM, also after adjustment for age and preceding infections (P=7.1x10 ). The small group of patients with detectable IgG anti-platelet antibodies exhibited an almost complete response to IVIg treatment (N=12; P=0.02), suggesting that IVIg was particularly efficacious in these children.
Conclusions
Testing for circulating anti-platelet antibodies may be helpful for the clinical prognostication and the guidance of treatment decisions in newly diagnosed childhood ITP. Our data suggest that the development of even more sensitive tests may further improve the clinical value of antibody testing.

This article is protected by copyright. All rights reserved.

J Thromb Haemost: 12 Feb 2020; epub ahead of print
Schmidt DE, Heitink-Polle KMJ, Porcelijn L, van der Schoot CE, ... Bruin MCA, de Haas M
J Thromb Haemost: 12 Feb 2020; epub ahead of print | PMID: 32053276
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Abstract

Remote ischemic preconditioning inhibits platelet α β activation in coronary artery disease patients receiving dual antiplatelet therapy - A randomized trial.

Lau JK, Pennings GJ, Reddel CJ, Campbell H, ... Chen VM, Kritharides L
Objectives
We investigated whether remote ischemic preconditioning (RIPC) inhibits agonist-induced conformational activation of platelet α β in patients with coronary artery disease already receiving conventional antiplatelet therapy.
Patients/methods
Consecutive patients with angiographically confirmed coronary artery disease were randomized to RIPC or sham treatment. Venous blood was collected before and immediately after RIPC/sham. Platelet aggregometry (adenosine diphosphate (ADP), arachidonic acid) and whole blood platelet flow cytometry was performed for CD62P, CD63, active α β (PAC-1 binding) before and after stimulation with ADP, thrombin +/- collagen, or PAR-1 thrombin receptor agonist.
Results
Patients (25 RIPC, 23 sham) were well matched, 83% male, age (mean ± SD) 63.3 ± 13.2 y, 95% aspirin, 81% P2Y inhibitor. RIPC did not affect platelet aggregation, nor agonist-induced expression of CD62P, but selectively and significantly decreased α β activation after stimulation with either PAR-1 agonist peptide (SFLLRN) or the combination of thrombin + collagen, but not after ADP nor thrombin alone. The effect of RIPC on platelet α β activation was evident in patients receiving both aspirin and P2Y inhibitor, and was not associated with an increase in vasodilator stimulated phosphoprotein (VASP) phosphorylation.
Conclusions
RIPC inhibits conformational activation of platelet α β in response to exposure to thrombin and collagen in patients with coronary artery disease receiving dual antiplatelet therapy. These findings indicate agonist-specific inhibition of platelet activation by RIPC in coronary artery disease which is not obviated by the prior use of P2Y inhibitors.

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J Thromb Haemost: 12 Feb 2020; epub ahead of print
Lau JK, Pennings GJ, Reddel CJ, Campbell H, ... Chen VM, Kritharides L
J Thromb Haemost: 12 Feb 2020; epub ahead of print | PMID: 32056358
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Abstract

Vps34 derived phosphatidylinositol 3-monophosphate modulates megakaryocyte maturation and proplatelet production through late endosomes/lysosomes.

Bertović I, Kurelić R, Milošević I, Bender M, ... Haucke V, Jurak Begonja A
Background
Development of platelet precursors cells, megakaryocytes (MKs), implies an increase in their size, formation of the elaborate demarcation membrane system (DMS) and extension of branched cytoplasmic structures, proplatelets, that will release platelets. The membrane source(s) for MK expansion and proplatelet formation have remained elusive.
Objective
We hypothesized that traffic of membranes regulated by phosphatidylinositol 3-monophosphate (PI3P) contributes to MK maturation and proplatelet formation.
Results
In immature MKs, PI3P produced by the lipid kinase Vps34 is confined to perinuclear early endosomes (EE), while in mature MKs PI3P shifts to late endosomes and lysosomes (LE/Lys). PI3P partially colocalized with the plasma membrane marker phosphatidylinositol 4,5-bisphosphate (PI(4,5)P ) and with LE/Lys in mature MKs, suggesting that PI3P-containing LE/Lys membranes contribute to MK expansion and proplatelet formation. Consistently, we found that sequestration of PI3P, specific pharmacological inhibition of Vps34-mediated PI3P production, or depletion of PI3P by PI3-phosphatase (MTM1)-mediated hydrolysis potently blocked proplatelet formation. Moreover, Vps34 inhibition led to the intracellular accumulation of enlarged LE/Lys, and decreased expression of surface LE/Lys markers. Inhibiting Vps34 at earlier MK stages caused aberrant DMS development. Finally, inhibition of LE/Lys membrane fusion by a dominant negative mutant of the small GTPase Rab7 or pharmacological inhibition of PI3P conversion into PI(3,5)P led to enlarged LE/Lys, reduced surface levels of LE/Lys markers, and decreased proplatelet formation.
Conclusion
Our results suggest that PI3P-positive LE/Lys contribute to the membrane growth and proplatelet formation in MKs by their translocation to the cell periphery and fusion with the plasma membrane.

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J Thromb Haemost: 12 Feb 2020; epub ahead of print
Bertović I, Kurelić R, Milošević I, Bender M, ... Haucke V, Jurak Begonja A
J Thromb Haemost: 12 Feb 2020; epub ahead of print | PMID: 32056354
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Abstract

NOS1AP polymorphisms reduce NOS1 activity and interact with prolonged repolarization in arrhythmogenesis.

Ronchi C, Bernardi J, Mura M, Stefanello M, ... Gnecchi M, Zaza A

NOS1AP SNPs correlate with QT prolongation and cardiac sudden death in patients affected by long QT syndrome type 1 (LQT1). NOS1AP targets NOS1 to intracellular effectors. We hypothesize that NOS1AP SNPs cause NOS1 dysfunction and this may converge with prolonged action potential duration (APD) to facilitate arrhythmias.
Aims
To test 1) the effects of NOS1 inhibition and their interaction with prolonged APD in a guinea pig cardiomyocyte (GP-CMs) LQT1 model; 2) whether pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) from LQT1 patients differing for NOS1AP variants and mutation penetrance display a phenotype compatible with NOS1 deficiency.
Methods and results
In GP-CMs NOS1 was inhibited by SMTC (or L-VNIO); LQT1 was mimicked by IKs blockade (JNJ203) and β-adrenergic stimulation (isoproterenol). hiPSC-CMs were obtained from symptomatic (S) and asymptomatic (AS) KCNQ1-A341V carriers, harboring the minor and major alleles of NOS1AP SNPs (rs16847548 and rs4657139) respectively. In GP-CMs: NOS1 inhibition prolonged APD, enhanced ICaL and INaL, slowed Ca2+ decay and induced delayed afterdepolarizations. Under action-potential clamp, switching to shorter APD suppressed \"transient inward current\" events induced by NOS1 inhibition and reduced cytosolic Ca2+. In S (vs AS) hiPSC-CMs: APD was longer and ICaL larger; NOS1AP and NOS1 expression and colocalization were decreased.
Conclusions
the minor NOS1AP alleles are associated with NOS1 loss of function. The latter likely contributes to APD prolongation in LQT1 and converges with it to perturb Ca2+ handling. This establishes a mechanistic link between NOS1AP SNPs and aggravation of the arrhythmia phenotype in prolonged repolarization syndromes.

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

Cardiovasc Res: 14 Feb 2020; epub ahead of print
Ronchi C, Bernardi J, Mura M, Stefanello M, ... Gnecchi M, Zaza A
Cardiovasc Res: 14 Feb 2020; epub ahead of print | PMID: 32061134
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Abstract

High miR-133a levels in the circulation anticipates presentation of clinical events in familial hypercholesterolemia patients.

Escate R, Padró T, Suades R, Camino S, ... Mata P, Badimon L
Aims
Presentation of acute events in patients with atherosclerosis remains unpredictable even after controlling for classical risk factors. MicroRNAs (miRNAs) measured in liquid biopsies could be good candidate biomarkers to improve risk prediction. Here, we hypothesized that miRNAs could predict atherosclerotic plaque progression and clinical event presentation in familial hypercholesterolemia (FH) patients.
Methods and results
Circulating miRNAs (plasma, exosomes, microvesicles) were investigated by TaqMan Array and RT-qPCR assays. Patients with genetic diagnosis of FH and healthy relatives from the SAFEHEART cohort were included. A differential signature of 10 miRNA was obtained by comparing two extreme phenotypes consisting of FH-patients suffering a cardiovascular event (CVE) within a 8-year follow-up period (FH-CVE, N=42) and non-FH hypercholesterolemic relatives from the same cohort, matched for age and treatment, without CVE during the same period (nFH-nCVE, N=30). The validation studies included two independent groups of patients with FH-background (Discovery-Group, N=89, Validation-Group N=196), developing a future CVE (FH-CVE) or not (FH-nCVE) within the same time period of follow-up. Of the 10 miRNAs initially selected, miR-133a was significantly higher in FH-CVE than in FH-nCVE patients. ROC-analysis confirmed miR-133a as the best microRNA for predicting CVE in FH-patients (0.76±0.054; P<0.001). Furthermore, Kaplan-Meier and COX-analysis showed that high plasma miR-133a levels associated to the higher risk of presenting a CVE within the next 8 years (HR: 3.89 [95%CI: 1.88-8.07], P<0.001). In silico analysis of curate biological interactions related miR-133a with target genes involved in regulation of the cell-membrane lipid-receptor LRP6 and inflammatory cytokines (CXCL8, IL6, TNF). These predictions were experimentally proven in human macrophages and endothelial cells transfected with agomiR-133a.
Conclusion
Elevated levels of miR-133a in the circulation anticipate those FH-patients that are going to present a clinical CVE within the next 2 years (average). Mechanistically, miR-133a is directly related with lipid- and inflammatory-signalling in key cells for atherosclerosis progression.
Translational perspective
The present study in patients with familial hypercholesterolemia shows that epigenetic markers can allow the identification of those patients that are going to present an acute clinical event within the next two years (average). There are currently few prognostic biomarkers able to identify subjects at risk of developing major acute cardiovascular events. Here, by using a non-targeted approach of miRNA-discovery, we show for first time that plasma levels of miR-133a have prognostic value to predict incident cardiovascular events in patients with familial hypercholesterolemia treated as per guidelines. Future studies with larger independent cohorts are needed to validate the prognostic value of miR-133a in the general population.

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

Cardiovasc Res: 14 Feb 2020; epub ahead of print
Escate R, Padró T, Suades R, Camino S, ... Mata P, Badimon L
Cardiovasc Res: 14 Feb 2020; epub ahead of print | PMID: 32061123
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Abstract

Effect of a Machine Learning-Derived Early Warning System for Intraoperative Hypotension vs Standard Care on Depth and Duration of Intraoperative Hypotension During Elective Noncardiac Surgery: The HYPE Randomized Clinical Trial.

Wijnberge M, Geerts BF, Hol L, Lemmers N, ... Vlaar AP, Veelo DP
Importance
Intraoperative hypotension is associated with increased morbidity and mortality. A machine learning-derived early warning system to predict hypotension shortly before it occurs has been developed and validated.
Objective
To test whether the clinical application of the early warning system in combination with a hemodynamic diagnostic guidance and treatment protocol reduces intraoperative hypotension.
Design, setting, and participants
Preliminary unblinded randomized clinical trial performed in a tertiary center in Amsterdam, the Netherlands, among adult patients scheduled for elective noncardiac surgery under general anesthesia and an indication for continuous invasive blood pressure monitoring, who were enrolled between May 2018 and March 2019. Hypotension was defined as a mean arterial pressure (MAP) below 65 mm Hg for at least 1 minute.
Interventions
Patients were randomly assigned to receive either the early warning system (n = 34) or standard care (n = 34), with a goal MAP of at least 65 mm Hg in both groups.
Main outcomes and measures
The primary outcome was time-weighted average of hypotension during surgery, with a unit of measure of millimeters of mercury. This was calculated as the depth of hypotension below a MAP of 65 mm Hg (in millimeters of mercury) × time spent below a MAP of 65 mm Hg (in minutes) divided by total duration of operation (in minutes).
Results
Among 68 randomized patients, 60 (88%) completed the trial (median age, 64 [interquartile range {IQR}, 57-70] years; 26 [43%] women). The median length of surgery was 256 minutes (IQR, 213-430 minutes). The median time-weighted average of hypotension was 0.10 mm Hg (IQR, 0.01-0.43 mm Hg) in the intervention group vs 0.44 mm Hg (IQR, 0.23-0.72 mm Hg) in the control group, for a median difference of 0.38 mm Hg (95% CI, 0.14-0.43 mm Hg; P = .001). The median time of hypotension per patient was 8.0 minutes (IQR, 1.33-26.00 minutes) in the intervention group vs 32.7 minutes (IQR, 11.5-59.7 minutes) in the control group, for a median difference of 16.7 minutes (95% CI, 7.7-31.0 minutes; P < .001). In the intervention group, 0 serious adverse events resulting in death occurred vs 2 (7%) in the control group.
Conclusions and relevance
In this single-center preliminary study of patients undergoing elective noncardiac surgery, the use of a machine learning-derived early warning system compared with standard care resulted in less intraoperative hypotension. Further research with larger study populations in diverse settings is needed to understand the effect on additional patient outcomes and to fully assess safety and generalizability.
Trial registration
ClinicalTrials.gov Identifier: NCT03376347.



JAMA: 16 Feb 2020; epub ahead of print
Wijnberge M, Geerts BF, Hol L, Lemmers N, ... Vlaar AP, Veelo DP
JAMA: 16 Feb 2020; epub ahead of print | PMID: 32065827
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Abstract

Effect of Intravenous Interferon β-1a on Death and Days Free From Mechanical Ventilation Among Patients With Moderate to Severe Acute Respiratory Distress Syndrome: A Randomized Clinical Trial.

Ranieri VM, Pettilä V, Karvonen MK, Jalkanen J, ... Bellingan G,
Importance
Acute respiratory distress syndrome (ARDS) is associated with high mortality. Interferon (IFN) β-1a may prevent the underlying event of vascular leakage.
Objective
To determine the efficacy and adverse events of IFN-β-1a in patients with moderate to severe ARDS.
Design, setting, and participants
Multicenter, randomized, double-blind, parallel-group trial conducted at 74 intensive care units in 8 European countries (December 2015-December 2017) that included 301 adults with moderate to severe ARDS according to the Berlin definition. The radiological and partial pressure of oxygen, arterial (Pao2)/fraction of inspired oxygen (Fio2) criteria for ARDS had to be met within a 24-hour period, and the administration of the first dose of the study drug had to occur within 48 hours of the diagnosis of ARDS. The last patient visit was on March 6, 2018.
Interventions
Patients were randomized to receive an intravenous injection of 10 μg of IFN-β-1a (144 patients) or placebo (152 patients) once daily for 6 days.
Main outcomes and measures
The primary outcome was a score combining death and number of ventilator-free days at day 28 (score ranged from -1 for death to 27 if the patient was off ventilator on the first day). There were 16 secondary outcomes, including 28-day mortality, which were tested hierarchically to control type I error.
Results
Among 301 patients who were randomized (mean age, 58 years; 103 women [34.2%]), 296 (98.3%) completed the trial and were included in the primary analysis. At 28 days, the median composite score of death and number of ventilator-free days at day 28 was 10 days (interquartile range, -1 to 20) in the IFN-β-1a group and 8.5 days (interquartile range, 0 to 20) in the placebo group (P = .82). There was no significant difference in 28-day mortality between the IFN-β-1a vs placebo groups (26.4% vs 23.0%; difference, 3.4% [95% CI, -8.1% to 14.8%]; P = .53). Seventy-four patients (25.0%) experienced adverse events considered to be related to treatment during the study (41 patients [28.5%] in the IFN-β-1a group and 33 [21.7%] in the placebo group).
Conclusions and relevance
Among adults with moderate or severe ARDS, intravenous IFN-β-1a administered for 6 days, compared with placebo, resulted in no significant difference in a composite score that included death and number of ventilator-free days over 28 days. These results do not support the use of IFN-β-1a in the management of ARDS.
Trial registration
ClinicalTrials.gov Identifier: NCT02622724.



JAMA: 16 Feb 2020; epub ahead of print
Ranieri VM, Pettilä V, Karvonen MK, Jalkanen J, ... Bellingan G,
JAMA: 16 Feb 2020; epub ahead of print | PMID: 32065831
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Abstract

Vascular effects of serelaxin in patients with stable coronary artery disease: a randomized placebo-controlled trial.

Corcoran D, Radjenovic A, Mordi IR, Nazir SA, ... Squire I, Berry C
Aims
The effects of serelaxin, a recombinant form of human relaxin-2 peptide, on vascular function in the coronary microvascular and systemic macrovascular circulation remain largely unknown. This mechanistic, clinical study assessed the effects of serelaxin on myocardial perfusion, aortic stiffness, and safety in patients with stable coronary artery disease (CAD).
Methods and results
In this multicentre, double-blind, parallel-group, placebo-controlled study, 58 patients were randomized 1:1 to 48 h intravenous infusion of serelaxin (30 µg/kg/day) or matching placebo. The primary endpoints were change from baseline to 47 h post-initiation of the infusion in global myocardial perfusion reserve (MPR) assessed using adenosine stress perfusion cardiac magnetic resonance imaging, and applanation tonometry-derived augmentation index (AIx). Secondary endpoints were: change from baseline in AIx and pulse wave velocity, assessed at 47 h, Day 30, and Day 180; aortic distensibility at 47 h; pharmacokinetics and safety. Exploratory endpoints were the effect on cardiorenal biomarkers [N-terminal pro-brain natriuretic peptide (NT-proBNP), high-sensitivity troponin T (hsTnT), endothelin-1, and cystatin C]. Of 58 patients, 51 were included in the primary analysis (serelaxin, n = 25; placebo, n = 26). After 2 and 6 h of serelaxin infusion, mean placebo-corrected blood pressure reductions of -9.6 mmHg (P = 0.01) and -13.5 mmHg (P = 0.0003) for systolic blood pressure and -5.2 mmHg (P = 0.02) and -8.4 mmHg (P = 0.001) for diastolic blood pressure occurred. There were no between-group differences from baseline to 47 h in global MPR (-0.24 vs. -0.13, P = 0.44) or AIx (3.49% vs. 0.04%, P = 0.21) with serelaxin compared with placebo. Endothelin-1 and cystatin C levels decreased from baseline in the serelaxin group, and there were no clinically relevant changes observed with serelaxin for NT-proBNP or hsTnT. Similar numbers of serious adverse events were observed in both groups (serelaxin, n = 5; placebo, n = 7) to 180-day follow-up.
Conclusion
In patients with stable CAD, 48 h intravenous serelaxin reduced blood pressure but did not alter myocardial perfusion.

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

Cardiovasc Res: 16 Feb 2020; epub ahead of print
Corcoran D, Radjenovic A, Mordi IR, Nazir SA, ... Squire I, Berry C
Cardiovasc Res: 16 Feb 2020; epub ahead of print | PMID: 32065620
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Abstract

Association of Physician Orders for Life-Sustaining Treatment With ICU Admission Among Patients Hospitalized Near the End of Life.

Lee RY, Brumback LC, Sathitratanacheewin S, Lober WB, ... Curtis JR, Kross EK
Importance
Patients with chronic illness frequently use Physician Orders for Life-Sustaining Treatment (POLST) to document treatment limitations.
Objectives
To evaluate the association between POLST order for medical interventions and intensive care unit (ICU) admission for patients hospitalized near the end of life.
Design, setting, and participants
Retrospective cohort study of patients with POLSTs and with chronic illness who died between January 1, 2010, and December 31, 2017, and were hospitalized 6 months or less before death in a 2-hospital academic health care system.
Exposures
POLST order for medical interventions (\"comfort measures only\" vs \"limited additional interventions\" vs \"full treatment\"), age, race/ethnicity, education, days from POLST completion to admission, histories of cancer or dementia, and admission for traumatic injury.
Main outcomes and measures
The primary outcome was the association between POLST order and ICU admission during the last hospitalization of life; the secondary outcome was receipt of a composite of 4 life-sustaining treatments: mechanical ventilation, vasopressors, dialysis, and cardiopulmonary resuscitation. For evaluating factors associated with POLST-discordant care, the outcome was ICU admission contrary to POLST order for medical interventions during the last hospitalization of life.
Results
Among 1818 decedents (mean age, 70.8 [SD, 14.7] years; 41% women), 401 (22%) had POLST orders for comfort measures only, 761 (42%) had orders for limited additional interventions, and 656 (36%) had orders for full treatment. ICU admissions occurred in 31% (95% CI, 26%-35%) of patients with comfort-only orders, 46% (95% CI, 42%-49%) with limited-interventions orders, and 62% (95% CI, 58%-66%) with full-treatment orders. One or more life-sustaining treatments were delivered to 14% (95% CI, 11%-17%) of patients with comfort-only orders and to 20% (95% CI, 17%-23%) of patients with limited-interventions orders. Compared with patients with full-treatment POLSTs, those with comfort-only and limited-interventions orders were significantly less likely to receive ICU admission (comfort only: 123/401 [31%] vs 406/656 [62%], aRR, 0.53 [95% CI, 0.45-0.62]; limited interventions: 349/761 [46%] vs 406/656 [62%], aRR, 0.79 [95% CI, 0.71-0.87]). Across patients with comfort-only and limited-interventions POLSTs, 38% (95% CI, 35%-40%) received POLST-discordant care. Patients with cancer were significantly less likely to receive POLST-discordant care than those without cancer (comfort only: 41/181 [23%] vs 80/220 [36%], aRR, 0.60 [95% CI, 0.43-0.85]; limited interventions: 100/321 [31%] vs 215/440 [49%], aRR, 0.63 [95% CI, 0.51-0.78]). Patients with dementia and comfort-only orders were significantly less likely to receive POLST-discordant care than those without dementia (23/111 [21%] vs 98/290 [34%], aRR, 0.44 [95% CI, 0.29-0.67]). Patients admitted for traumatic injury were significantly more likely to receive POLST-discordant care (comfort only: 29/64 [45%] vs 92/337 [27%], aRR, 1.52 [95% CI, 1.08-2.14]; limited interventions: 51/91 [56%] vs 264/670 [39%], aRR, 1.36 [95% CI, 1.09-1.68]). In patients with limited-interventions orders, older age was significantly associated with less POLST-discordant care (aRR, 0.93 per 10 years [95% CI, 0.88-1.00]).
Conclusions and relevance
Among patients with POLSTs and with chronic life-limiting illness who were hospitalized within 6 months of death, treatment-limiting POLSTs were significantly associated with lower rates of ICU admission compared with full-treatment POLSTs. However, 38% of patients with treatment-limiting POLSTs received intensive care that was potentially discordant with their POLST.



JAMA: 15 Feb 2020; epub ahead of print
Lee RY, Brumback LC, Sathitratanacheewin S, Lober WB, ... Curtis JR, Kross EK
JAMA: 15 Feb 2020; epub ahead of print | PMID: 32062674
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Abstract

T Cell-Derived miRNA-214 Mediates Perivascular Fibrosis in Hypertension.

Nosalski R, Siedlinski M, Denby L, McGinnigle E, ... Baker AH, Guzik TJ

Despite increasing understanding of the prognostic importance of vascular stiffening linked to perivascular fibrosis in hypertension, the molecular and cellular regulation of this process is poorly understood.To study the functional role of microRNA-214 (miR-214) in the induction of perivascular fibrosis and endothelial dysfunction driving vascular stiffening.Out of 381 miRs screened in the perivascular tissues (PVAT) in response to angiotensin II (Ang II)-mediated hypertension, miR-214 showed the highest induction (8-fold, p=0.0001). MiR-214 induction was pronounced in perivascular and circulating T cells, but not in PVAT adipocytes. Global deletion of miR-214 prevented Ang II-induced periaortic fibrosisandexpression, hydroxyproline accumulation and vascular stiffening, without difference in blood pressure. Mechanistic studies revealed that miR-214 mice were protected against endothelial dysfunction, oxidative stress and increased Nox2, all of which were induced by Ang II in WT mice. Ang II-induced recruitment of T cells into PVAT was abolished in miR-214 mice. Adoptive transfer of miR-214 T cells into RAG1 mice resulted in reduced perivascular fibrosis compared to the effect of WT T cells. Ang II induced hypertension caused significant change in the expression of 1380 T cell genes in WT, but only 51 in miR-214. T cell activation, proliferation and chemotaxis pathways were differentially affected. miR-214-/- prevented Ang II-induction of pro-fibrotic T cell cytokines (IL-17, TNF-alpha, IL-9 and IFN-ý)and chemokine receptors (CCR1, CCR2, CCR4, CCR5, CCR6 and CXCR3). This manifested in reduced in vitro and in vivo T cell chemotaxis resulting in attenuation of profibrotic perivascular inflammation. Translationally, we show that miR-214 is increased in plasma of hypertensive patients and is directly correlated to pulse wave velocity as a measure of vascular stiffness.T cell-derived miR-214 controls pathological perivascular fibrosis in hypertension mediated by T cell recruitment and local profibrotic cytokine release.



Circ Res: 16 Feb 2020; epub ahead of print
Nosalski R, Siedlinski M, Denby L, McGinnigle E, ... Baker AH, Guzik TJ
Circ Res: 16 Feb 2020; epub ahead of print | PMID: 32065054
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