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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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

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

Copyright © 2020. Published by Elsevier Inc.

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

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

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

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

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

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

Packer M

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

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

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

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

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

Copyright © 2020 Massachusetts Medical Society.

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

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

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

Copyright © 2020 Massachusetts Medical Society.

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

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

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

Copyright © 2020 Massachusetts Medical Society.

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

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

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

Copyright © 2020 Massachusetts Medical Society.

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

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

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

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

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

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

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

Copyright © 2020 Massachusetts Medical Society.

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

Evaluation of Mavacamten in Symptomatic Patients With Nonobstructive Hypertrophic Cardiomyopathy.

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

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

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

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

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

Copyright © 2020 Massachusetts Medical Society.

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

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

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

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

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

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

Trastuzumab Deruxtecan in Previously Treated HER2-Positive Gastric Cancer.

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

Copyright © 2020 Massachusetts Medical Society.

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

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

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

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

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

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

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

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

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

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

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

Copyright © 2020 Massachusetts Medical Society.

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

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

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

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

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

Coexistence and outcome of coronary artery disease in Takotsubo syndrome.

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

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

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

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

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

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

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

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

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

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

Copyright © 2020 Massachusetts Medical Society.

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

Handgun Ownership and Suicide in California.

Studdert DM, Zhang Y, Swanson SA, Prince L, ... Wintemute GJ, Miller M
Background
Research has consistently identified firearm availability as a risk factor for suicide. However, existing studies are relatively small in scale, estimates vary widely, and no study appears to have tracked risks from commencement of firearm ownership.
Methods
We identified handgun acquisitions and deaths in a cohort of 26.3 million male and female residents of California, 21 years old or older, who had not previously acquired handguns. Cohort members were followed for up to 12 years 2 months (from October 18, 2004, to December 31, 2016). We used survival analysis to estimate the relationship between handgun ownership and both all-cause mortality and suicide (by firearm and by other methods) among men and women. The analysis allowed the baseline hazard to vary according to neighborhood and was adjusted for age, race and ethnic group, and ownership of long guns (i.e., rifles or shotguns).
Results
A total of 676,425 cohort members acquired one or more handguns, and 1,457,981 died; 17,894 died by suicide, of which 6691 were suicides by firearm. Rates of suicide by any method were higher among handgun owners, with an adjusted hazard ratio of 3.34 for all male owners as compared with male nonowners (95% confidence interval [CI], 3.13 to 3.56) and 7.16 for female owners as compared with female nonowners (95% CI, 6.22 to 8.24). These rates were driven by much higher rates of suicide by firearm among both male and female handgun owners, with a hazard ratio of 7.82 for men (95% CI, 7.26 to 8.43) and 35.15 for women (95% CI, 29.56 to 41.79). Handgun owners did not have higher rates of suicide by other methods or higher all-cause mortality. The risk of suicide by firearm among handgun owners peaked immediately after the first acquisition, but 52% of all suicides by firearm among handgun owners occurred more than 1 year after acquisition.
Conclusions
Handgun ownership is associated with a greatly elevated and enduring risk of suicide by firearm. (Funded by the Fund for a Safer Future and others.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 03 Jun 2020; 382:2220-2229
Studdert DM, Zhang Y, Swanson SA, Prince L, ... Wintemute GJ, Miller M
N Engl J Med: 03 Jun 2020; 382:2220-2229 | PMID: 32492303
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Abstract

Rituximab for High-Risk, Mature B-Cell Non-Hodgkin\'s Lymphoma in Children.

Minard-Colin V, Aupérin A, Pillon M, Burke GAA, ... Gross TG,
Background
Rituximab added to chemotherapy prolongs survival among adults with B-cell cancer. Data on its efficacy and safety in children with high-grade, mature B-cell non-Hodgkin\'s lymphoma are limited.
Methods
We conducted an open-label, international, randomized, phase 3 trial involving patients younger than 18 years of age with high-risk, mature B-cell non-Hodgkin\'s lymphoma (stage III with an elevated lactate dehydrogenase level or stage IV) or acute leukemia to compare the addition of six doses of rituximab to standard lymphomes malins B (LMB) chemotherapy with standard LMB chemotherapy alone. The primary end point was event-free survival. Overall survival and toxic effects were also assessed.
Results
Analyses were based on 328 patients who underwent randomization (164 patients per group); 85.7% of the patients had Burkitt\'s lymphoma. The median follow-up was 39.9 months. Events were observed in 10 patients in the rituximab-chemotherapy group and in 28 in the chemotherapy group. Event-free survival at 3 years was 93.9% (95% confidence interval [CI], 89.1 to 96.7) in the rituximab-chemotherapy group and 82.3% (95% CI, 75.7 to 87.5) in the chemotherapy group (hazard ratio for primary refractory disease or first occurrence of progression, relapse after response, death from any cause, or second cancer, 0.32; 95% CI, 0.15 to 0.66; one-sided P = 0.00096, which reached the significance level required for this analysis). Eight patients in the rituximab-chemotherapy group died (4 deaths were disease-related, 3 were treatment-related, and 1 was from a second cancer), as did 20 in the chemotherapy group (17 deaths were disease-related, and 3 were treatment-related) (hazard ratio, 0.36; 95% CI, 0.16 to 0.82). The incidence of acute adverse events of grade 4 or higher after prephase treatment was 33.3% in the rituximab-chemotherapy group and 24.2% in the chemotherapy group (P = 0.07); events were related mainly to febrile neutropenia and infection. Approximately twice as many patients in the rituximab-chemotherapy group as in the chemotherapy group had a low IgG level 1 year after trial inclusion.
Conclusions
Rituximab added to standard LMB chemotherapy markedly prolonged event-free survival and overall survival among children and adolescents with high-grade, high-risk, mature B-cell non-Hodgkin\'s lymphoma and was associated with a higher incidence of hypogammaglobulinemia and, potentially, more episodes of infection. (Funded by the Clinical Research Hospital Program of the French Ministry of Health and others; ClinicalTrials.gov number, NCT01516580.).

Copyright © 2020 Massachusetts Medical Society.

N Engl J Med: 03 Jun 2020; 382:2207-2219
Minard-Colin V, Aupérin A, Pillon M, Burke GAA, ... Gross TG,
N Engl J Med: 03 Jun 2020; 382:2207-2219 | PMID: 32492302
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Abstract

A human neutralizing antibody targets the receptor binding site of SARS-CoV-2.

Shi R, Shan C, Duan X, Chen Z, ... Yuan Z, Yan J

An outbreak of the coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spread globally. Countermeasures are needed to treat and prevent further dissemination of the virus. In this study, we report the isolation of 2 specific human monoclonal antibodies (MAbs) from a convalescent COVID-19 patient. CA1 and CB6 demonstrated potent SARS-CoV-2-specific neutralization activity in vitro against SARS-CoV-2. In addition, CB6 inhibited SARS-CoV-2 infection in rhesus monkeys at both prophylactic and treatment settings. Further structural studies revealed that CB6 recognizes an epitope that overlaps with angiotensin converting enzyme 2 (ACE2)-binding sites in SARS-CoV-2 receptor binding domain (RBD), thereby interfering with the virus/receptor interactions by both steric hindrance and direct interface-residue competition. Our results suggest CB6 deserves further clinical translation.



Nature: 25 May 2020; epub ahead of print
Shi R, Shan C, Duan X, Chen Z, ... Yuan Z, Yan J
Nature: 25 May 2020; epub ahead of print | PMID: 32454512
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Impact:
Abstract

Human neutralizing antibodies elicited by SARS-CoV-2 infection.

Ju B, Zhang Q, Ge J, Wang R, ... Zhang Z, Zhang L

The emerging coronavirus SARS-CoV-2 pandemic presents a global health emergency in urgent need of interventions. SARS-CoV-2 entry into the target cells depends on binding between the receptor-binding domain (RBD) of the viral Spike protein and the ACE2 cell receptor. Here, we report the isolation and characterization of 206 RBD-specific monoclonal antibodies derived from single B cells of eight SARS-CoV-2 infected individuals. We identified antibodies with potent anti-SARS-CoV-2 neutralization activity that correlates with their competitive capacity with ACE2 for RBD binding. Surprisingly, neither the anti-SARS-CoV-2 antibodies nor the infected plasma cross-reacted with SARS-CoV or MERS-CoV RBDs, although substantial plasma cross-reactivity to their trimeric Spike proteins was found. Crystal structure analysis of RBD-bound antibody revealed steric hindrance that inhibits viral engagement with ACE2 and thereby blocks viral entry. These findings suggest that anti-RBD antibodies are viral species-specific inhibitors. The antibodies identified here may be candidates for the development of SARS-CoV-2 clinical interventions.



Nature: 25 May 2020; epub ahead of print
Ju B, Zhang Q, Ge J, Wang R, ... Zhang Z, Zhang L
Nature: 25 May 2020; epub ahead of print | PMID: 32454513
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Abstract

Mapping and characterization of structural variation in 17,795 human genomes.

Abel HJ, Larson DE, Regier AA, Chiang C, ... Stitziel NO, Hall IM

A key goal of whole-genome sequencing (WGS) for human genetics studies is to interrogate all forms of variation, including single nucleotide variants (SNV), small insertion/deletion (indel) variants and structural variants (SV). However, tools and resources for the study of SV have lagged behind those for smaller variants. Here, we used a scalable pipeline to map and characterize SV in 17,795 deeply sequenced human genomes. We publicly release site-frequency data to create the largest WGS-based SV resource to date. On average, individuals carry 2.9 rare SVs that alter coding regions, affecting the dosage or structure of 4.2 genes and accounting for 4.0-11.2% of rare high-impact coding alleles. Based on a computational model, we estimate that SVs account for 17.2% of rare alleles genome-wide with predicted deleterious effects equivalent to loss-of-function coding alleles; approximately 90% of such SVs are non-coding deletions (mean 19.1 per genome). We report 158,991 ultra-rare SVs and show that around 2% of individuals carry ultra-rare megabase-scale SVs, nearly half of which are balanced or complex rearrangements. Finally, we infer the dosage sensitivity of genes and non-coding elements, revealing trends related to element class and conservation. This work will help guide SV analysis and interpretation in the era of WGS.



Nature: 26 May 2020; epub ahead of print
Abel HJ, Larson DE, Regier AA, Chiang C, ... Stitziel NO, Hall IM
Nature: 26 May 2020; epub ahead of print | PMID: 32460305
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Abstract

Cardiovascular Health in American Indians and Alaska Natives: A Scientific Statement From the American Heart Association.

Breathett K, Sims M, Gross M, Jackson EA, ... Howard BV,
Background
Cardiovascular disease (CVD) is the leading cause of death among American Indians and Alaska Natives. Over the past 50 years, the prevalence of CVD has been rising among American Indians and Alaska Natives. The objective of this statement is to summarize population-level risk factors and management techniques tailored for the American Indian and Alaska Native populations.
Methods
PubMed/MEDLINE, the Centers for Disease Control and Prevention, and the annual Heart Disease and Stroke Statistics report from the American Heart Association were used to identify risk factors and interventions specific to American Indians and Alaska Natives.
Results
Diabetes mellitus is a major contributor to disproportionately higher rates of coronary heart disease among American Indians and Alaska Natives compared with other racial and ethnic groups. Additional risk factors for CVD include low-density lipoprotein cholesterol levels, hypertension, renal disease, age, and sex. Smoking and exposure to toxic metals are risk factors for some subpopulations. A quarter of American Indians live below the federal poverty line, and thus, low socioeconomic status is an important social determinant of cardiovascular health. Community-based interventions have reduced CVD risk in American Indians and Alaska Natives. Underreporting of American Indian and Alaska Native race could underestimate the extent of CVD in this population.
Conclusions
Prevention and treatment of CVD in American Indians and Alaska Natives should focus on control of risk factors and community-based interventions that address social determinants of health, particularly among individuals with diabetes mellitus. Accurate reporting of race/ethnicity is encouraged to address race-specific risk factors.



Circulation: 27 May 2020:CIR0000000000000773; epub ahead of print
Breathett K, Sims M, Gross M, Jackson EA, ... Howard BV,
Circulation: 27 May 2020:CIR0000000000000773; epub ahead of print | PMID: 32460555
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Abstract

Hepatic NADH reductive stress underlies common variation in metabolic traits.

Goodman RP, Markhard AL, Shah H, Sharma R, ... Kim JK, Mootha VK

The cellular NADH/NAD ratio is fundamental to biochemistry, but the extent to which it reflects versus drives metabolic physiology in vivo is poorly understood. Here we report the in vivo application of Lactobacillus brevis (Lb)NOX, a bacterial water-forming NADH oxidase, to assess the metabolic consequences of directly lowering the hepatic cytosolic NADH/NAD ratio in mice. By combining this genetic tool with metabolomics, we identify circulating α-hydroxybutyrate levels as a robust marker of an elevated hepatic cytosolic NADH/NAD ratio, also known as reductive stress. In humans, elevations in circulating α-hydroxybutyrate levels have previously been associated with impaired glucose tolerance, insulin resistance and mitochondrial disease, and are associated with a common genetic variant in GCKR, which has previously been associated with many seemingly disparate metabolic traits. Using LbNOX, we demonstrate that NADH reductive stress mediates the effects of GCKR variation on many metabolic traits, including circulating triglyceride levels, glucose tolerance and FGF21 levels. Our work identifies an elevated hepatic NADH/NAD ratio as a latent metabolic parameter that is shaped by human genetic variation and contributes causally to key metabolic traits and diseases. Moreover, it underscores the utility of genetic tools such as LbNOX to empower studies of \'causal metabolism\'.



Nature: 26 May 2020; epub ahead of print
Goodman RP, Markhard AL, Shah H, Sharma R, ... Kim JK, Mootha VK
Nature: 26 May 2020; epub ahead of print | PMID: 32461692
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Abstract

Phase and context shape the function of composite oncogenic mutations.

Gorelick AN, Sánchez-Rivera FJ, Cai Y, Bielski CM, ... Reznik E, Taylor BS

Cancers develop as a result of driver mutations that lead to clonal outgrowth and the evolution of disease. The discovery and functional characterization of individual driver mutations are central aims of cancer research, and have elucidated myriad phenotypes and therapeutic vulnerabilities. However, the serial genetic evolution of mutant cancer genes and the allelic context in which they arise is poorly understood in both common and rare cancer genes and tumour types. Here we find that nearly one in four human tumours contains a composite mutation of a cancer-associated gene, defined as two or more nonsynonymous somatic mutations in the same gene and tumour. Composite mutations are enriched in specific genes, have an elevated rate of use of less-common hotspot mutations acquired in a chronology driven in part by oncogenic fitness, and arise in an allelic configuration that reflects context-specific selective pressures. cis-acting composite mutations are hypermorphic in some genes in which dosage effects predominate (such as TERT), whereas they lead to selection of function in other genes (such as TP53). Collectively, composite mutations are driver alterations that arise from context- and allele-specific selective pressures that are dependent in part on gene and mutation function, and which lead to complex-often neomorphic-functions of biological and therapeutic importance.



Nature: 26 May 2020; epub ahead of print
Gorelick AN, Sánchez-Rivera FJ, Cai Y, Bielski CM, ... Reznik E, Taylor BS
Nature: 26 May 2020; epub ahead of print | PMID: 32461694
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Abstract

Structures of α-synuclein filaments from multiple system atrophy.

Schweighauser M, Shi Y, Tarutani A, Kametani F, ... Scheres SHW, Goedert M

Synucleinopathies, which include multiple system atrophy (MSA), Parkinson\'s disease, Parkinson\'s disease with dementia and dementia with Lewy bodies (DLB), are human neurodegenerative diseases. Existing treatments are at best symptomatic. These diseases are characterized by the presence of, and believed to be caused by the formation of, filamentous inclusions of α-synuclein in brain cells. However, the structures of α-synuclein filaments from the human brain are unknown. Here, using cryo-electron microscopy, we show that α-synuclein inclusions from the brains of individuals with MSA are made of two types of filament, each of which consists of two different protofilaments. In each type of filament, non-proteinaceous molecules are present at the interface of the two protofilaments. Using two-dimensional class averaging, we show that α-synuclein filaments from the brains of individuals with MSA differ from those of individuals with DLB, which suggests that distinct conformers or strains characterize specific synucleinopathies. As is the case with tau assemblies, the structures of α-synuclein filaments extracted from the brains of individuals with MSA differ from those formed in vitro using recombinant proteins, which has implications for understanding the mechanisms of aggregate propagation and neurodegeneration in the human brain. These findings have diagnostic and potential therapeutic relevance, especially because of the unmet clinical need to be able to image filamentous α-synuclein inclusions in the human brain.



Nature: 26 May 2020; epub ahead of print
Schweighauser M, Shi Y, Tarutani A, Kametani F, ... Scheres SHW, Goedert M
Nature: 26 May 2020; epub ahead of print | PMID: 32461689
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Abstract

Electromechanical coupling in the hyperpolarization-activated K channel KAT1.

Clark MD, Contreras GF, Shen R, Perozo E

Voltage-gated potassium (K) channels coordinate electrical signalling and control cell volume by gating in response to membrane depolarization or hyperpolarization. However, although voltage-sensing domains transduce transmembrane electric field changes by a common mechanism involving the outward or inward translocation of gating charges, the general determinants of channel gating polarity remain poorly understood. Here we suggest a molecular mechanism for electromechanical coupling and gating polarity in non-domain-swapped K channels on the basis of the cryo-electron microscopy structure of KAT1, the hyperpolarization-activated K channel from Arabidopsis thaliana. KAT1 displays a depolarized voltage sensor, which interacts with a closed pore domain directly via two interfaces and indirectly via an intercalated phospholipid. Functional evaluation of KAT1 structure-guided mutants at the sensor-pore interfaces suggests a mechanism in which direct interaction between the sensor and the C-linker hairpin in the adjacent pore subunit is the primary determinant of gating polarity. We suggest that an inward motion of the S4 sensor helix of approximately 5-7 Å can underlie a direct-coupling mechanism, driving a conformational reorientation of the C-linker and ultimately opening the activation gate formed by the S6 intracellular bundle. This direct-coupling mechanism contrasts with allosteric mechanisms proposed for hyperpolarization-activated cyclic nucleotide-gated channels, and may represent an unexpected link between depolarization- and hyperpolarization-activated channels.



Nature: 26 May 2020; epub ahead of print
Clark MD, Contreras GF, Shen R, Perozo E
Nature: 26 May 2020; epub ahead of print | PMID: 32461693
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Abstract

Ensuring meiotic DNA break formation in the mouse pseudoautosomal region.

Acquaviva L, Boekhout M, Karasu ME, Brick K, ... Jasin M, Keeney S

Sex chromosomes in males of most eutherian mammals share only a small homologous segment, the pseudoautosomal region (PAR), in which the formation of double-strand breaks (DSBs), pairing and crossing over must occur for correct meiotic segregation. How cells ensure that recombination occurs in the PAR is unknown. Here we present a dynamic ultrastructure of the PAR and identify controlling cis- and trans-acting factors that make the PAR the hottest segment for DSB formation in the male mouse genome. Before break formation, multiple DSB-promoting factors hyperaccumulate in the PAR, its chromosome axes elongate and the sister chromatids separate. These processes are linked to heterochromatic mo-2 minisatellite arrays, and require MEI4 and ANKRD31 proteins but not the axis components REC8 or HORMAD1. We propose that the repetitive DNA sequence of the PAR confers unique chromatin and higher-order structures that are crucial for recombination. Chromosome synapsis triggers collapse of the elongated PAR structure and, notably, oocytes can be reprogrammed to exhibit spermatocyte-like levels of DSBs in the PAR simply by delaying or preventing synapsis. Thus, the sexually dimorphic behaviour of the PAR is in part a result of kinetic differences between the sexes in a race between the maturation of the PAR structure, formation of DSBs and completion of pairing and synapsis. Our findings establish a mechanistic paradigm for the recombination of sex chromosomes during meiosis.



Nature: 26 May 2020; epub ahead of print
Acquaviva L, Boekhout M, Karasu ME, Brick K, ... Jasin M, Keeney S
Nature: 26 May 2020; epub ahead of print | PMID: 32461690
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Abstract

Base-pair conformational switch modulates miR-34a targeting of Sirt1 mRNA.

Baronti L, Guzzetti I, Ebrahimi P, Friebe Sandoz S, ... Chen AA, Petzold K

MicroRNAs (miRNAs) regulate the levels of translation of messenger RNAs (mRNAs). At present, the major parameter that can explain the selection of the target mRNA and the efficiency of translation repression is the base pairing between the \'seed\' region of the miRNA and its counterpart mRNA. Here we use R relaxation-dispersion nuclear magnetic resonance and molecular simulations to reveal a dynamic switch-based on the rearrangement of a single base pair in the miRNA-mRNA duplex-that elongates a weak five-base-pair seed to a complete seven-base-pair seed. This switch also causes coaxial stacking of the seed and supplementary helix fitting into human Argonaute 2 protein (Ago2), reminiscent of an active state in prokaryotic Ago. Stabilizing this transient state leads to enhanced repression of the target mRNA in cells, revealing the importance of this miRNA-mRNA structure. Our observations tie together previous findings regarding the stepwise miRNA targeting process from an initial \'screening\' state to an \'active\' state, and unveil the role of the RNA duplex beyond the seed in Ago2.



Nature: 26 May 2020; epub ahead of print
Baronti L, Guzzetti I, Ebrahimi P, Friebe Sandoz S, ... Chen AA, Petzold K
Nature: 26 May 2020; epub ahead of print | PMID: 32461691
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Abstract

Structural transitions in influenza haemagglutinin at membrane fusion pH.

Benton DJ, Gamblin SJ, Rosenthal PB, Skehel JJ

Infection by enveloped viruses involves fusion of their lipid envelopes with cellular membranes to release the viral genome into cells. For HIV, Ebola, influenza and numerous other viruses, envelope glycoproteins bind the infecting virion to cell-surface receptors and mediate membrane fusion. In the case of influenza, the receptor-binding glycoprotein is the haemagglutinin (HA), and following receptor-mediated uptake of the bound virus by endocytosis, it is the HA that mediates fusion of the virus envelope with the membrane of the endosome. Each subunit of the trimeric HA consists of two disulfide-linked polypeptides, HA1 and HA2. The larger, virus-membrane-distal, HA1 mediates receptor binding; the smaller, membrane-proximal, HA2 anchors HA in the envelope and contains the fusion peptide, a region that is directly involved in membrane interaction. The low pH of endosomes activates fusion by facilitating irreversible conformational changes in the glycoprotein. The structures of the initial HA at neutral pH and the final HA at fusion pH have been investigated by electron microscopy and X-ray crystallography. Here, to further study the process of fusion, we incubate HA for different times at pH 5.0 and directly image structural changes using single-particle cryo-electron microscopy. We describe three distinct, previously undescribed forms of HA, most notably a 150 Å-long triple-helical coil of HA2, which may bridge between the viral and endosomal membranes. Comparison of these structures reveals concerted conformational rearrangements through which the HA mediates membrane fusion.



Nature: 26 May 2020; epub ahead of print
Benton DJ, Gamblin SJ, Rosenthal PB, Skehel JJ
Nature: 26 May 2020; epub ahead of print | PMID: 32461688
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Abstract

Comparative Efficacy and Safety of Oral P2Y12 Inhibitors in Acute Coronary Syndrome: Network Meta-Analysis of 52,816 Patients from 12 Randomized Trials.

Navarese EP, Khan SU, Kołodziejczak M, Kubica J, ... Roe MT, James S

New randomized controlled trials (RCTs) have become available on oral P2Y inhibitors in acute coronary syndrome (ACS). We aimed to evaluate current evidence comparing the efficacy and safety profile of prasugrel, ticagrelor and clopidogrel in ACS by a meta-analysis of RCTs.We performed a network meta-analysis and direct pairwise comparison analysis of efficacy and safety outcomes from twelve RCTs including a total of 52,816 patients with ACS.Compared with clopidogrel, ticagrelor significantly reduced cardiovascular mortality (hazard ratio(HR), 0.82 [95% confidence interval(CI), 0.72-0.92]) and all-cause mortality (HR, 0.83 [95% CI, 0.75-0.92]), whereas there was no statistically significant mortality reduction with prasugrel (HR, 0.90 [95% CI, 0.80-1.01] and HR, 0.92 [95% CI, 0.84-1.02], respectively). Compared with each other there were no significant differences in mortality (HR prasugrel vs ticagrelor, 1.10 [95% CI, 0.94-1.29] and 1.12 [95% CI, 0.98-1.28]). Compared with clopidogrel, prasugrel reduced myocardial infarction (HR, 0.81 [95% CI, 0.67-0.98]), whereas ticagrelor showed no risk reduction (HR, 0.97 [95% CI, 0.78-1.22]). Differences between prasugrel and ticagrelor were not statistically significant. Stent thrombosis risk was significantly reduced by both ticagrelor and prasugrel vs clopidogrel (28-50% range of reduction). Compared with clopidogrel, both prasugrel (HR, 1.26 [95% CI, 1.01-1.56]) and ticagrelor (HR, 1.27 [95% CI, 1.04-1.55]) significantly increased major bleeding. There were no significant differences between prasugrel and ticagrelor for all outcomes explored. Prasugrel and ticagrelor reduced ischemic events and increased bleeding in comparison to clopidogrel. A significant mortality reduction was observed with ticagrelor only. There was no efficacy and safety difference between prasugrel and ticagrelor.CRD42019155648.



Circulation: 28 May 2020; epub ahead of print
Navarese EP, Khan SU, Kołodziejczak M, Kubica J, ... Roe MT, James S
Circulation: 28 May 2020; epub ahead of print | PMID: 32468837
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Abstract

The Spectrum of Cardiac Manifestations in Coronavirus Disease 2019 (COVID-19) - a Systematic Echocardiographic Study.

Szekely Y, Lichter Y, Taieb P, Banai A, ... Arbel Y, Topilsky Y

Information regarding the cardiac manifestations of COVID-19 is scarce. We performed a systematic and comprehensive echocardiographic evaluation of consecutive patients hospitalized with COVID-19 infection.100 consecutive patients diagnosed with COVID-19 infection underwent complete echocardiographic evaluation within 24 hours of admission and were compared to reference values. Echocardiographic studies included left ventricular (LV) systolic and diastolic function, valve hemodynamics and right ventricular (RV) assessment, as well as lung ultrasound. A second exam was performed in case of clinical deterioration.Thirty two patients (32%) had a normal echocardiogram at baseline. The most common cardiac pathology was RV dilatation and dysfunction (observed in 39% of patients), followed by LV diastolic dysfunction (16%) and LV systolic dysfunction (10%). Patients with elevated troponin (20%) or worse clinical condition did not demonstrate any significant difference in LV systolic function compared to patients with normal troponin or better clinical condition, but had worse RV function. Clinical deterioration occurred in 20% of patients. In these patients, the most common echocardiographic abnormality at follow-up was RV function deterioration (12 patients), followed by LV systolic and diastolic deterioration (in 5 patients). Femoral vein thrombosis (DVT) was diagnosed in 5 of 12 patients with RV failure. In COVID-19 infection, LV systolic function is preserved in the majority of patients, but LV diastolic and RV function are impaired. Elevated troponin and poorer clinical grade are associated with worse RV function. In patients presenting with clinical deterioration at follow-up, acute RV dysfunction, with or without DVT, is more common, but acute LV systolic dysfunction was noted in ≈20%.



Circulation: 28 May 2020; epub ahead of print
Szekely Y, Lichter Y, Taieb P, Banai A, ... Arbel Y, Topilsky Y
Circulation: 28 May 2020; epub ahead of print | PMID: 32469253
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Impact:
Abstract

PI3Kβ-Regulated Pericyte Maturation Governs Vascular Remodeling.

Figueiredo AM, Villacampa P, Diéguez-Hurtado R, Lozano JJ, ... Carracedo A, Graupera M

Pericytes regulate vessel stabilization and function and their loss is associated with diseases such as diabetic retinopathy or cancer. Despite their physiological importance, pericyte function and molecular regulation during angiogenesis remain poorly understood.To decipher the transcriptomic programs of pericytes during angiogenesis, we crossed theinto the RiboTag mice. Pericyte morphological changes were assessed in mural cell-specific R26-mTmG reporter mice, in which low doses of tamoxifen allowed labeling of single cell pericytes at high resolution. To study the role of phosphoinositide 3-kinase (PI3K) signaling in pericyte biology during angiogenesis, we used genetic mouse models which allow selective inactivation of PI3Kα and PI3Kβ isoforms and their negative regulator PTEN (phosphate and tensin homologue deleted on chromosome ten, PTEN) in mural cells.At the onset of angiogenesis, pericytes exhibit molecular traits of cell proliferation and activated PI3K signaling, whereas during vascular remodeling pericytes upregulate genes involved in mature pericyte cell function, together with a remarkable decrease in PI3K signaling. Immature pericytes showed stellate shape and high proliferation, and mature pericytes were quiescent and elongated. Unexpectedly, we demonstrate that the PI3Kβ, but not PI3Kα, regulates pericyte proliferation and maturation during vessel formation. Genetic PI3Kβ inactivation in pericytes triggered early pericyte maturation. Conversely, unleashing PI3K signaling by means of PTEN deletion delayed pericyte maturation. Pericyte maturation was necessary to undergo vessel remodeling during angiogenesis.Our results identify new molecular and morphological traits associated to pericyte maturation and uncover PI3Kβ activity as a checkpoint to ensure appropriate vessel formation. In turn, our results may open new therapeutic opportunities to regulate angiogenesis in pathological processes through the manipulation of pericyte PI3Kβ activity.



Circulation: 28 May 2020; epub ahead of print
Figueiredo AM, Villacampa P, Diéguez-Hurtado R, Lozano JJ, ... Carracedo A, Graupera M
Circulation: 28 May 2020; epub ahead of print | PMID: 32466671
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Impact:
Abstract

COVID-19 mortality in patients with cancer on chemotherapy or other anticancer treatments: a prospective cohort study.

Lee LYW, Cazier JB, Starkey T, Turnbull CD, ... Kerr R, Middleton G
Background
Individuals with cancer, particularly those who are receiving systemic anticancer treatments, have been postulated to be at increased risk of mortality from COVID-19. This conjecture has considerable effect on the treatment of patients with cancer and data from large, multicentre studies to support this assumption are scarce because of the contingencies of the pandemic. We aimed to describe the clinical and demographic characteristics and COVID-19 outcomes in patients with cancer.
Methods
In this prospective observational study, all patients with active cancer and presenting to our network of cancer centres were eligible for enrolment into the UK Coronavirus Cancer Monitoring Project (UKCCMP). The UKCCMP is the first COVID-19 clinical registry that enables near real-time reports to frontline doctors about the effects of COVID-19 on patients with cancer. Eligible patients tested positive for severe acute respiratory syndrome coronavirus 2 on RT-PCR assay from a nose or throat swab. We excluded patients with a radiological or clinical diagnosis of COVID-19, without a positive RT-PCR test. The primary endpoint was all-cause mortality, or discharge from hospital, as assessed by the reporting sites during the patient hospital admission.
Findings
From March 18, to April 26, 2020, we analysed 800 patients with a diagnosis of cancer and symptomatic COVID-19. 412 (52%) patients had a mild COVID-19 disease course. 226 (28%) patients died and risk of death was significantly associated with advancing patient age (odds ratio 9·42 [95% CI 6·56-10·02]; p<0·0001), being male (1·67 [1·19-2·34]; p=0·003), and the presence of other comorbidities such as hypertension (1·95 [1·36-2·80]; p<0·001) and cardiovascular disease (2·32 [1·47-3·64]). 281 (35%) patients had received cytotoxic chemotherapy within 4 weeks before testing positive for COVID-19. After adjusting for age, gender, and comorbidities, chemotherapy in the past 4 weeks had no significant effect on mortality from COVID-19 disease, when compared with patients with cancer who had not received recent chemotherapy (1·18 [0·81-1·72]; p=0·380). We found no significant effect on mortality for patients with immunotherapy, hormonal therapy, targeted therapy, radiotherapy use within the past 4 weeks.
Interpretation
Mortality from COVID-19 in cancer patients appears to be principally driven by age, gender, and comorbidities. We are not able to identify evidence that cancer patients on cytotoxic chemotherapy or other anticancer treatment are at an increased risk of mortality from COVID-19 disease compared with those not on active treatment.
Funding
University of Birmingham, University of Oxford.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 27 May 2020; epub ahead of print
Lee LYW, Cazier JB, Starkey T, Turnbull CD, ... Kerr R, Middleton G
Lancet: 27 May 2020; epub ahead of print | PMID: 32473682
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Impact:
Abstract

Clinical impact of COVID-19 on patients with cancer (CCC19): a cohort study.

Kuderer NM, Choueiri TK, Shah DP, Shyr Y, ... Warner JL,
Background
Data on patients with COVID-19 who have cancer are lacking. Here we characterise the outcomes of a cohort of patients with cancer and COVID-19 and identify potential prognostic factors for mortality and severe illness.
Methods
In this cohort study, we collected de-identified data on patients with active or previous malignancy, aged 18 years and older, with confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection from the USA, Canada, and Spain from the COVID-19 and Cancer Consortium (CCC19) database for whom baseline data were added between March 17 and April 16, 2020. We collected data on baseline clinical conditions, medications, cancer diagnosis and treatment, and COVID-19 disease course. The primary endpoint was all-cause mortality within 30 days of diagnosis of COVID-19. We assessed the association between the outcome and potential prognostic variables using logistic regression analyses, partially adjusted for age, sex, smoking status, and obesity. This study is registered with ClinicalTrials.gov, NCT04354701, and is ongoing.
Findings
Of 1035 records entered into the CCC19 database during the study period, 928 patients met inclusion criteria for our analysis. Median age was 66 years (IQR 57-76), 279 (30%) were aged 75 years or older, and 468 (50%) patients were male. The most prevalent malignancies were breast (191 [21%]) and prostate (152 [16%]). 366 (39%) patients were on active anticancer treatment, and 396 (43%) had active (measurable) cancer. At analysis (May 7, 2020), 121 (13%) patients had died. In logistic regression analysis, independent factors associated with increased 30-day mortality, after partial adjustment, were: increased age (per 10 years; partially adjusted odds ratio 1·84, 95% CI 1·53-2·21), male sex (1·63, 1·07-2·48), smoking status (former smoker vs never smoked: 1·60, 1·03-2·47), number of comorbidities (two vs none: 4·50, 1·33-15·28), Eastern Cooperative Oncology Group performance status of 2 or higher (status of 2 vs 0 or 1: 3·89, 2·11-7·18), active cancer (progressing vs remission: 5·20, 2·77-9·77), and receipt of azithromycin plus hydroxychloroquine (vs treatment with neither: 2·93, 1·79-4·79; confounding by indication cannot be excluded). Compared with residence in the US-Northeast, residence in Canada (0·24, 0·07-0·84) or the US-Midwest (0·50, 0·28-0·90) were associated with decreased 30-day all-cause mortality. Race and ethnicity, obesity status, cancer type, type of anticancer therapy, and recent surgery were not associated with mortality.
Interpretation
Among patients with cancer and COVID-19, 30-day all-cause mortality was high and associated with general risk factors and risk factors unique to patients with cancer. Longer follow-up is needed to better understand the effect of COVID-19 on outcomes in patients with cancer, including the ability to continue specific cancer treatments.
Funding
American Cancer Society, National Institutes of Health, and Hope Foundation for Cancer Research.

Copyright © 2020 Elsevier Ltd. All rights reserved.

Lancet: 27 May 2020; epub ahead of print
Kuderer NM, Choueiri TK, Shah DP, Shyr Y, ... Warner JL,
Lancet: 27 May 2020; epub ahead of print | PMID: 32473681
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Abstract

Cardiovascular Risk of Isolated Systolic or Diastolic Hypertension in Young Adults.

Lee H, Yano Y, Cho SMJ, Park JH, ... Lloyd-Jones DM, Kim HC
Background
Little is known regarding health outcomes associated with isolated systolic hypertension (ISH), isolated diastolic hypertension (IDH), or systolic and diastolic hypertension (SDH) among young adults with stage 1 hypertension, defined using the 2017 American College of Cardiology/American Heart Association blood pressure (BP) guideline.
Methods
From a nationwide health screening database, we included 6 424 090 participants, aged 20 to 39 years, who were not taking antihypertensive medication at the baseline examination in 2003 to 2007. Participants were categorized as having normal BP (untreated systolic BP [SBP] <120/diastolic BP [DBP] <80 mm Hg; n=2 665 310); elevated BP (SBP 120-129/DBP <80 mm Hg; n=705 344); stage 1 IDH (SBP <130/DBP 80-89 mm Hg; n=1 271 505); stage 1 ISH (SBP 130-139/DBP <80 mm Hg; n=255 588); stage 1 SDH (SBP 130-139/DBP 80-89 mm Hg; n=711 503); and stage 2 hypertension (SBP ≥140, DBP ≥90 mm Hg; n=814 840). The primary outcome was composite cardiovascular disease (CVD) events, including myocardial infarction, stroke, heart failure, and CVD-related death.
Results
The median age of the participants was 30 years and 60.9% were male. Over a median follow-up of 13.2 years, 44 070 new CVD events occurred. With normal BP as the reference, multivariable-adjusted hazard ratios (95% CIs) for CVD events were 1.14 (1.09-1.18) for elevated BP, 1.32 (1.28-1.36) for stage 1 IDH, 1.36 (1.29-1.43) for stage 1 ISH, 1.67 (1.61-1.72) for stage 1 SDH, and 2.40 (2.33-2.47) for stage 2 hypertension.
Conclusions
Among young adults, stage 1 ISH, IDH, and SDH were all associated with higher CVD risks than normal BP. The CVD risks of stage 1 ISH and IDH were similar to each other but lower than the risk of stage 1 SDH. Categorizing young adults with stage 1 hypertension further into stage 1 ISH, IDH, and SDH may improve risk stratification for identifying high-risk individuals.



Circulation: 01 Jun 2020; 141:1778-1786
Lee H, Yano Y, Cho SMJ, Park JH, ... Lloyd-Jones DM, Kim HC
Circulation: 01 Jun 2020; 141:1778-1786 | PMID: 32479205
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Abstract

Implications of Altered Ketone Metabolism and Therapeutic Ketosis in Heart Failure.

Selvaraj S, Kelly DP, Margulies KB

Despite existing therapy, patients with heart failure (HF) experience substantial morbidity and mortality, highlighting the urgent need to identify novel pathophysiological mechanisms and therapies, as well. Traditional models for pharmacological intervention have targeted neurohormonal axes and hemodynamic disturbances in HF. However, several studies have now highlighted the potential for ketone metabolic modulation as a promising treatment paradigm. During the pathophysiological progression of HF, the failing heart reduces fatty acid and glucose oxidation, with associated increases in ketone metabolism. Recent studies indicate that enhanced myocardial ketone use is adaptive in HF, and limited data demonstrate beneficial effects of exogenous ketone therapy in studies of animal models and humans with HF. This review will summarize current evidence supporting a salutary role for ketones in HF including (1) normal myocardial ketone use, (2) alterations in ketone metabolism in the failing heart, (3) effects of therapeutic ketosis in animals and humans with HF, and (4) the potential significance of ketosis associated with sodium-glucose cotransporter 2 inhibitors. Although a number of important questions remain regarding the use of therapeutic ketosis and mechanism of action in HF, current evidence suggests potential benefit, in particular, in HF with reduced ejection fraction, with theoretical rationale for its use in HF with preserved ejection fraction. Although it is early in its study and development, therapeutic ketosis across the spectrum of HF holds significant promise.



Circulation: 01 Jun 2020; 141:1800-1812
Selvaraj S, Kelly DP, Margulies KB
Circulation: 01 Jun 2020; 141:1800-1812 | PMID: 32479196
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Abstract

Cardiac Amyloidosis: Evolving Diagnosis and Management: A Scientific Statement From the American Heart Association.

Kittleson MM, Maurer MS, Ambardekar AV, Bullock-Palmer RP, ... Ruberg FL,

Transthyretin amyloid cardiomyopathy (ATTR-CM) results in a restrictive cardiomyopathy caused by extracellular deposition of transthyretin, normally involved in the transportation of the hormone thyroxine and retinol-binding protein, in the myocardium. Enthusiasm about ATTR-CM has grown as a result of 3 simultaneous areas of advancement: Imaging techniques allow accurate noninvasive diagnosis of ATTR-CM without the need for confirmatory endomyocardial biopsies; observational studies indicate that the diagnosis of ATTR-CM may be underrecognized in a significant proportion of patients with heart failure; and on the basis of elucidation of the mechanisms of amyloid formation, therapies are now approved for treatment of ATTR-CM. Because therapy for ATTR-CM may be most effective when administered before significant cardiac dysfunction, early identification of affected individuals with readily available noninvasive tests is essential. This scientific statement is intended to guide clinical practice and to facilitate management conformity by covering current diagnostic and treatment strategies, as well as unmet needs and areas of active investigation in ATTR-CM.



Circulation: 31 May 2020:CIR0000000000000792; epub ahead of print
Kittleson MM, Maurer MS, Ambardekar AV, Bullock-Palmer RP, ... Ruberg FL,
Circulation: 31 May 2020:CIR0000000000000792; epub ahead of print | PMID: 32476490
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Abstract

Early Cardiac Remodeling Promotes Tumor Growth and Metastasis.

Avraham S, Abu-Sharki S, Shofti R, Haas T, ... Shaked Y, Aronheim A

Recent evidence suggests that cancer and cardiovascular diseases are associated. Chemotherapy drugs are known to result in cardiotoxicity, and studies have shown that heart failure (HF) and stress correlate with poor cancer prognosis. Yet, whether cardiac remodeling in the absence of HF is sufficient to promote cancer is unknown.To investigate the effect of early cardiac remodeling on tumor growth and metastasis colonization, we used transverse aortic constriction (TAC), a model for pressure overload-induced cardiac hypertrophy, and followed it by cancer cell implantation.TAC-operated mice developed larger primary tumors with higher proliferation rate and displayed more metastatic lesions compared with controls. Serum derived from TAC-operated mice potentiated cancer cell proliferation , suggesting the existence of secreted tumor-promoting factors. Using RNA-seq data, we identified elevated mRNA levels ofin the hearts of TAC-operated mice. Periostin levels were also found high in the serum following TAC. Interestingly, depletion of Periostin from the serum abrogated the proliferation of cancer cells, conversely, the addition of Periostin enhanced cancer cell proliferation . Collectively, this is the first study to show that early cardiac remodeling nurtures tumor growth and metastasis, and therefore promotes cancer progression.Our study highlights the importance of early diagnosis and treatment of cardiac remodeling as it may attenuate cancer progression and improve cancer outcome.



Circulation: 31 May 2020; epub ahead of print
Avraham S, Abu-Sharki S, Shofti R, Haas T, ... Shaked Y, Aronheim A
Circulation: 31 May 2020; epub ahead of print | PMID: 32475164
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Abstract

Mortality and pulmonary complications in patients undergoing surgery with perioperative SARS-CoV-2 infection: an international cohort study.


Background
The impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on postoperative recovery needs to be understood to inform clinical decision making during and after the COVID-19 pandemic. This study reports 30-day mortality and pulmonary complication rates in patients with perioperative SARS-CoV-2 infection.
Methods
This international, multicentre, cohort study at 235 hospitals in 24 countries included all patients undergoing surgery who had SARS-CoV-2 infection confirmed within 7 days before or 30 days after surgery. The primary outcome measure was 30-day postoperative mortality and was assessed in all enrolled patients. The main secondary outcome measure was pulmonary complications, defined as pneumonia, acute respiratory distress syndrome, or unexpected postoperative ventilation.
Findings
This analysis includes 1128 patients who had surgery between Jan 1 and March 31, 2020, of whom 835 (74·0%) had emergency surgery and 280 (24·8%) had elective surgery. SARS-CoV-2 infection was confirmed preoperatively in 294 (26·1%) patients. 30-day mortality was 23·8% (268 of 1128). Pulmonary complications occurred in 577 (51·2%) of 1128 patients; 30-day mortality in these patients was 38·0% (219 of 577), accounting for 82·6% (219 of 265) of all deaths. In adjusted analyses, 30-day mortality was associated with male sex (odds ratio 1·75 [95% CI 1·28-2·40], p<0·0001), age 70 years or older versus younger than 70 years (2·30 [1·65-3·22], p<0·0001), American Society of Anesthesiologists grades 3-5 versus grades 1-2 (2·35 [1·57-3·53], p<0·0001), malignant versus benign or obstetric diagnosis (1·55 [1·01-2·39], p=0·046), emergency versus elective surgery (1·67 [1·06-2·63], p=0·026), and major versus minor surgery (1·52 [1·01-2·31], p=0·047).
Interpretation
Postoperative pulmonary complications occur in half of patients with perioperative SARS-CoV-2 infection and are associated with high mortality. Thresholds for surgery during the COVID-19 pandemic should be higher than during normal practice, particularly in men aged 70 years and older. Consideration should be given for postponing non-urgent procedures and promoting non-operative treatment to delay or avoid the need for surgery.
Funding
National Institute for Health Research (NIHR), Association of Coloproctology of Great Britain and Ireland, Bowel and Cancer Research, Bowel Disease Research Foundation, Association of Upper Gastrointestinal Surgeons, British Association of Surgical Oncology, British Gynaecological Cancer Society, European Society of Coloproctology, NIHR Academy, Sarcoma UK, Vascular Society for Great Britain and Ireland, and Yorkshire Cancer Research.

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

Lancet: 28 May 2020; epub ahead of print
Lancet: 28 May 2020; epub ahead of print | PMID: 32479829
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Abstract

Desymmetrization of difluoromethylene groups by C-F bond activation.

Butcher TW, Yang JL, Amberg WM, Watkins NB, Wilkinson ND, Hartwig JF

Tertiary stereogenic centers containing a fluorine atom are valuable for medicinal chemistry because they mimic common tertiary stereogenic centers containing one hydrogen, but possess distinct charge distribution, lipophilicity, conformation, and metabolic stability. Although tertiary stereogenic centers containing one hydrogen atom are often set by enantioselective reactions at one of two methylene carbon-hydrogen (C-H) bonds, tertiary stereocenters containing fluorine have not been constructed by the analogous reaction at one of two difluoromethylene carbon-fluorine (C-F) bonds. Fluorine atoms are close in size to hydrogen atoms, but distinct in electronic properties, causing C-F bonds to be exceptionally strong and geminal C-F bonds to strengthen one another. Thus, exhaustive defluorination typically dominates over selective replacement of a single C-F bond, making the more valuable enantioselective substitution of one fluorine atom to form a stereogenic center enantioselectively unknown. We report the catalytic, enantioselective activation of a single C-F bond in an allylic difluoromethylene group to provide a broad range of products containing a monofluorinated-tertiary stereogenic center. By combining a tailored, chiral iridium phosphoramidite catalyst that controls regioselectivity, chemoselectivity, and enantioselectivity with a fluorophilic activator that assists oxidative addition of the C-F bond, these reactions occur in high yield and selectivity. The design principles outlined in this work extend to palladium-catalyzed benzylic substitution, demonstrating the generality of the approach.



Nature: 31 May 2020; epub ahead of print
Butcher TW, Yang JL, Amberg WM, Watkins NB, Wilkinson ND, Hartwig JF
Nature: 31 May 2020; epub ahead of print | PMID: 32480398
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Abstract

Loss of Protease-Activated Receptor 4 Prevents Inflammation Resolution and Predisposes the Heart to Cardiac Rupture after Myocardial Infarction.

Kolpakov MA, Guo X, Rafiq K, Vlasenko L, ... Houser SR, Sabri A

Cardiac rupture is a major lethal complication of acute myocardial infarction (MI). Despite significant advances in reperfusion strategies, mortality from cardiac rupture remains high. Studies suggest that cardiac rupture can be accelerated by thrombolytic therapy, but the relevance of this risk factor remains controversial.We analyzed protease activated receptor (Par)4 expression in mouse hearts with MI and investigated the effects of Par4 deletion on cardiac remodeling and function post-MI by echocardiography, quantitative immunohistochemistry and flow cytometry.Par4 mRNA and protein levels were increased in mouse hearts after MI and in isolated cardiomyocytes in response to hypertrophic and inflammatory stimuli. Par4-deficient mice showed less myocyte apoptosis, reduced infarct size and improved functional recovery after acute MI relative to wild-type (WT). Conversely, Par4 mice showed impaired cardiac function, greater rates of myocardial rupture and increased mortality after chronic MI relative to WT. Pathological evaluation of hearts from Par4 mice demonstrated a greater infarct expansion, increased cardiac hemorrhage and delayed neutrophil accumulation, which resulted in impaired post-MI healing compared to WT. Par4 deficiency also attenuated neutrophil apoptosisand after MIand impaired inflammation resolution in infarcted myocardium. Transfer of Par4 neutrophils, but not of Par4 platelets, in WT recipient mice delayed inflammation resolution, increased cardiac hemorrhage and enhanced cardiac dysfunction. In parallel, adoptive transfer of WT neutrophils into Par4 mice restored inflammation resolution, reduced cardiac rupture incidence and improved cardiac function post-MI.These findings reveal essential roles of Par4 in neutrophil apoptosis and inflammation resolution during myocardial healing and point to Par4 inhibition as potential therapy that should be limited to the acute phases of ischemic insult and to be avoided for chronic treatment post-MI.



Circulation: 02 Jun 2020; epub ahead of print
Kolpakov MA, Guo X, Rafiq K, Vlasenko L, ... Houser SR, Sabri A
Circulation: 02 Jun 2020; epub ahead of print | PMID: 32489148
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Abstract

Impact of Left Atrial Appendage Exclusion on Short Term Outcomes In Isolated Coronary Artery Bypass Graft Surgery.

Mahmood E, Matyal R, Mahmood F, Xu X, ... Karani S, Khabbaz KR

The objective of this study was to evaluate the impact of LAA exclusion on short term outcomes in patients with atrial fibrillation undergoing isolated coronary artery bypass graft (CABG) surgery.We queried the 2010-2014 National Readmissions Database (NRD) for patients who underwent coronary artery bypass graft repair with and without left atrial appendage ligation using ICD-9 procedure codes (ICD-9: 36.1xx). Only patients with a history of atrial fibrillation were included in our analysis. The primary outcome of our study was 30-day readmissions following discharge. Secondary outcomes were in hospital mortality and stroke. To assess the postoperative outcomes, we utilized multivariate logistic regression models to adjust for clinical and demographic covariates.In total we analyzed 253,287 CABG patients, 7.0% of whom received LAA closure. LAA exclusion was associated with a greater risk of postoperative respiratory failure (8.2% vs. 6.2%, p <.0001), acute kidney injury (21.8% vs. 18.5%, p <.0001), but did not significantly change the rate of blood transfusions or occurrence of cardiac tamponade. LAA exclusion was associated with a non-significant reduction in stroke (7.9% vs. 8.6%, p = .12), no difference in in-hospital mortality (2.2% vs. 2.2% p = .99), and a greater risk of 30-day readmission (16.0% vs. 9.6%, p < .0001) After covariate adjustment, LAA ligation remained a significant predictor of 30-day readmission (OR: 1.640, 95% CI: 1.603 - 1.677, p <.0001).LAA exclusion during isolated CABG in patients with AF is associated with a higher rate of 30-day readmission. Post-operative measures to mitigate the loss of the hormonal and hemodynamic effects of the LAA may increase the therapeutic benefit of this procedure.



Circulation: 02 Jun 2020; epub ahead of print
Mahmood E, Matyal R, Mahmood F, Xu X, ... Karani S, Khabbaz KR
Circulation: 02 Jun 2020; epub ahead of print | PMID: 32489114
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Abstract

Temporal Trends in Prevalence & Prognostic Implications of Comorbidities Among Patients with Acute Decompensated Heart Failure: The ARIC Study Community Surveillance.

Pandey A, Vaduganathan M, Arora S, Qamar A, ... Rosamond WD, Caughey MC

Patients with heart failure (HF) have multiple co-existing comorbidities. The temporal trends in the burden of comorbidities and associated risk of mortality among patients with HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF) are not well-established.HF related hospitalizations were sampled by stratified design from four US areas in 2005 to 2014 by the community surveillance component of the ARIC (Atherosclerosis Risk in Communities) study. Acute decompensated HF was classified by standardized physician review and a previously validated algorithm. An ejection fraction <50% was considered HFrEF. A total of 15 co-morbidities were abstracted from the medical record. Mortality outcomes were ascertained for up to 1-year post-admission, by linking hospital records with death files.A total of 5,460 hospitalizations (24,937 weighted hospitalizations) classified as acute decompensated HF had available ejection fraction data (53% female, 68% white, 53% HFrEF, 47% HFpEF). The average number of comorbidities was higher for patients with HFpEF vs. HFrEF, both for women (5.53 vs. 4.94, <0.0001) and men (5.20 vs. 4.82, <0.0001). There was a significant temporal increase in the overall burden of co-morbidities, both for patients with HFpEF (Women: 5.17 in 2005-2009 to 5.87 in 2010-2013; Men: 4.94 in 2005-2009 and 5.45 in 2010-2013) and HFrEF (Women: 4.78 in 2005-2009 to 5.14 in 2010-2013; Men: 4.62 in 2005-2009 and 5.06 in 2010-2013, -trend<0.0001 for all). Higher comorbidity burden was significantly associated with higher adjusted risk of 1-year mortality, with a stronger association noted for HFpEF [HR (95% CI) per 1-higher co-morbidity:1.19(1.14-1.25) vs. HFrEF [HR (95%CI): 1.10(1.05-1.14); -interaction by HF type = 0.02]. The associated mortality risk per 1-higher co-morbidity also increased significantly over time for patients with HFpEF as well HFrEF (P-for interaction with time =0.002 and 0.02 respectively).The burden of comorbidities among hospitalized patients with acute decompensated HFpEF and HFrEF has increased over time, as has its associated mortality risk. Higher burden of comorbidities is associated with higher risk of mortality, with a stronger association noted among patients with HFpEF vs. HFrEF.



Circulation: 02 Jun 2020; epub ahead of print
Pandey A, Vaduganathan M, Arora S, Qamar A, ... Rosamond WD, Caughey MC
Circulation: 02 Jun 2020; epub ahead of print | PMID: 32486833
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Abstract

Diurnal Timing Dependent Alterations in Gut Microbial Composition Are Synchronously Linked to Salt-Sensitive Hypertension and Renal Damage.

Chakraborty S, Mandal J, Cheng X, Galla S, ... Yang T, Joe B

Alterations of diurnal rhythms of blood pressure (BP) and reshaping of gut microbiota are both independently associated with hypertension. However, the relationships between biorhythms of BP and gut microbial composition are unknown. We hypothesized that diurnal timing-associated alterations of microbial compositions are synchronous with diurnal rhythmicity, dip in BP, and renal function. To test this hypothesis, Dahl salt-sensitive (S) rats on low- and high-salt diets were examined for time of day effects on gut microbiota, BP, and indicators of renal damage. Major shifts in night and day patterns of specific groups of microbiota were observed between the dark (active) and light (rest) phases, which correlated with diurnal rhythmicity of BP. The diurnal abundance of Firmicutes, Bacteroidetes, and Actinobacteria were independently associated with BP. Discrete bacterial taxa were observed to correlate independently or interactively with one or more of the following 3 factors: (1) BP rhythm, (2) dietary salt, and (3) dip in BP. Phylogenetic Investigation of Communities revealed diurnal timing effects on microbial pathways, characterized by upregulated biosynthetic processes during the active phase of host, and upregulated degradation pathways of metabolites in the resting phase. Additional metagenomics functional pathways with rhythm variations were noted for aromatic amino acid metabolism and taurine metabolism. These diurnal timing dependent changes in microbiota, their functional pathways, and BP dip were associated with concerted effects of the levels of renal lipocalin 2 and kidney injury molecule-1 expression. These data provide evidence for a firm and concerted diurnal timing effects of BP, renal damage, and select microbial communities.



Hypertension: 25 May 2020:HYPERTENSIONAHA12014830; epub ahead of print
Chakraborty S, Mandal J, Cheng X, Galla S, ... Yang T, Joe B
Hypertension: 25 May 2020:HYPERTENSIONAHA12014830; epub ahead of print | PMID: 32450738
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Abstract

Maternal and Perinatal Outcomes of White Coat Hypertension During Pregnancy: A Systematic Review and Meta-Analysis.

Johnson S, Liu B, Kalafat E, Thilaganathan B, Khalil A

The aim of this meta-analysis is to investigate whether white-coat hypertension (WCH) has an adverse effect on maternal, fetal, and neonatal outcomes. Medline, EMBASE, www.Clinicaltrials.gov, and Cochrane Library databases were searched electronically in December 2019. The outcomes were compared between pregnant women with WCH and normotensive controls, women with chronic hypertension, gestational hypertension or any hypertensive disorder of pregnancy. Twelve studies were eligible for inclusion in the systematic review. Women with WCH enrolled below 20 weeks had a significantly increased risk of preeclampsia (pooled risk ratio [RR], 5.43 [95% CI, 2.00-14.71]). Furthermore, women with WCH had increased risk of delivering a small-for-gestational-age newborn (RR, 2.47 [95% CI, 1.21-5.05], =0.013) and preterm birth (RR, 2.86 [95% CI, 1.44-5.68], =0.002). The risk of preeclampsia (risk ratio, 0.43 [95% CI, 0.23-0.78], =0.005), small-for-gestational-age (RR, 0.46 [95% CI, 0.26-0.82], =0.008), preterm birth (RR, 0.47 [95% CI, 0.31-0.71], <0.001) were significantly lower with WCH compared with women with gestational hypertension. Women with WCH delivered ≈1 week later compared with women with chronic hypertension (mean difference, 1.06 weeks [95% CI, 0.44-1.67 weeks]; <0.001). WCH is associated with a worse perinatal and maternal outcome than normotension, but better outcomes than gestational hypertension and chronic hypertension. Therefore, diagnosis of WCH should be ascertained in pregnant women presenting with hypertension. When the diagnosis is confirmed, these women require monitoring for developing preeclampsia, small-for-gestational-age and preterm birth.



Hypertension: 25 May 2020:HYPERTENSIONAHA11914627; epub ahead of print
Johnson S, Liu B, Kalafat E, Thilaganathan B, Khalil A
Hypertension: 25 May 2020:HYPERTENSIONAHA11914627; epub ahead of print | PMID: 32450741
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Abstract

Blood Pressure and Risks of Cognitive Impairment and Dementia: A Systematic Review and Meta-Analysis of 209 Prospective Studies.

Ou YN, Tan CC, Shen XN, Xu W, ... Tan L, Yu JT

Controversies persist regarding the association between blood pressure (BP) and the risks of cognitive impairment and dementia due to inconsistent definitions of BP exposure and varying population characteristics. Here, we searched PubMed and performed a meta-analysis of the influence of BP exposure on the risks of cognitive disorders in prospective studies. Dose-response analyses were performed to illustrate the existence of linear/nonlinear relationships. The credibility of each meta-analysis was evaluated according to the risk of bias, inconsistency, and imprecision. Of the 31 628 citations, 209 were included in our systematic review, among which 136 were eligible for the meta-analysis. Overall, stronger associations were found in midlife than late-life. Moderate-quality evidence indicated that midlife hypertension was related to a 1.19- to 1.55-fold excess risk of cognitive disorders. Dose-response analyses of 5 studies indicated that midlife systolic BP >130 mm Hg was associated with an increased risk of cognitive disorders. With regard to BP exposure in late-life, high systolic BP, low diastolic BP, excessive BP variability, and orthostatic hypotension were all associated with an increased dementia risk. Encouragingly, the use of antihypertensive medications exhibited a 21% reduction in dementia risk. The U-shaped dose-response curve indicated that the protective window of diastolic BP level was between 90 and 100 mm Hg for low risk of Alzheimer disease. The relationships between BP variables and cognitive disorders are age- and BP type-dependent. Antihypertensive medications were associated with a reduced risk of dementia. However, the optimal dose, duration, and type for preventing cognitive disorders warrant further investigation.



Hypertension: 25 May 2020:HYPERTENSIONAHA12014993; epub ahead of print
Ou YN, Tan CC, Shen XN, Xu W, ... Tan L, Yu JT
Hypertension: 25 May 2020:HYPERTENSIONAHA12014993; epub ahead of print | PMID: 32450739
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Abstract

The Prognostic Value of Angiogenic Markers in Twin Pregnancies to Predict Delivery Due to Maternal Complications of Preeclampsia.

Binder J, Palmrich P, Pateisky P, Kalafat E, ... Thilaganathan B, Khalil A

The sFlt-1 (soluble fms-like tyrosine kinase-1), PlGF (placental growth factor), and their ratio are useful for predicting delivery because of preeclampsia in singleton pregnancies. Evidence on the utility of sFlt-1/PlGF ratio in twin pregnancies is lacking. We aimed to evaluate the predictive value of sFlt-1/PlGF ratio for delivery because of preeclampsia in twins. A retrospective data analysis of 164 twin pregnancies with suspected preeclampsia was performed. The sFlt-1/PlGF ratio, which was known to clinicians, was significantly higher in women who delivered within 1 and 2 weeks compared with those who did not (median: 98.9 and 84.2 versus 23.5 pg/mL, respectively; <0.001). The area under the curve values sFlt-1/PlGF ratio levels were 0.88 (95% CI, 0.83-0.84) and 0.88 (95% CI, 0.83-0.93) for predicting delivery because of preeclampsia within 1 and 2 weeks of blood sampling, respectively. The predictive accuracy of sFlt-1/PlGF was independent of gestational age at sampling and chorionicity (>0.100 for interaction). The area under the curve values of sFlt-1/PlGF were significantly higher than for PlGF alone (mean 0.88 and 0.88 versus 0.81 and 0.80) for predicting delivery because of preeclampsia within 1 and 2 weeks of blood sampling (=0.055 and 0.001, respectively). sFlt-1/PlGF ratio lower than 38 was able to rule-out delivery within 1 and 2 weeks with a negative predictive value of 98.8% and 96.4% for delivery because of preeclampsia within 1 and 2 weeks, respectively. A cutoff of 38 is applicable for ruling out delivery because of preeclampsia in twin pregnancies.



Hypertension: 25 May 2020:HYPERTENSIONAHA12014957; epub ahead of print
Binder J, Palmrich P, Pateisky P, Kalafat E, ... Thilaganathan B, Khalil A
Hypertension: 25 May 2020:HYPERTENSIONAHA12014957; epub ahead of print | PMID: 32450740
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Abstract

Vascular Endothelial Cells and Innate Immunity.

Shao Y, Saredy J, Yang WY, Sun Y, ... Wang H, Yang X

In addition to the roles of endothelial cells (ECs) in physiological processes, ECs actively participate in both innate and adaptive immune responses. We previously reported that, in comparison to macrophages, a prototypic innate immune cell type, ECs have many innate immune functions that macrophages carry out, including cytokine secretion, phagocytic function, antigen presentation, pathogen-associated molecular patterns-, and danger-associated molecular patterns-sensing, proinflammatory, immune-enhancing, anti-inflammatory, immunosuppression, migration, heterogeneity, and plasticity. In this highlight, we introduce recent advances published in bothand many other journals: (1) several significant characters classify ECs as novel immune cells not only in infections and allograft transplantation but also in metabolic diseases; (2) several new receptor systems including conditional danger-associated molecular pattern receptors, nonpattern receptors, and homeostasis associated molecular patterns receptors contribute to innate immune functions of ECs; (3) immunometabolism and innate immune memory determine the innate immune functions of ECs; (4) a great induction of the immune checkpoint receptors in ECs during inflammations suggests the immune tolerogenic functions of ECs; and (5) association of immune checkpoint inhibitors with cardiovascular adverse events and cardio-oncology indicates the potential contributions of ECs as innate immune cells.



Arterioscler Thromb Vasc Biol: 30 May 2020; 40:e138-e152
Shao Y, Saredy J, Yang WY, Sun Y, ... Wang H, Yang X
Arterioscler Thromb Vasc Biol: 30 May 2020; 40:e138-e152 | PMID: 32459541
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Impact:
Abstract

Lyme borreliosis: diagnosis and management.

Kullberg BJ, Vrijmoeth HD, van de Schoor F, Hovius JW

Lyme borreliosis is the most common vectorborne disease in the northern hemisphere. It usually begins with erythema migrans; early disseminated infection particularly causes multiple erythema migrans or neurologic disease, and late manifestations predominantly include arthritis in North America, and acrodermatitis chronica atrophicans (ACA) in Europe. Diagnosis of Lyme borreliosis is based on characteristic clinical signs and symptoms, complemented by serological confirmation of infection once an antibody response has been mounted. Manifestations usually respond to appropriate antibiotic regimens, but the disease can be followed by sequelae, such as immune arthritis or residual damage to affected tissues. A subset of individuals reports persistent symptoms, including fatigue, pain, arthralgia, and neurocognitive symptoms, which in some people are severe enough to fulfil the criteria for post-treatment Lyme disease syndrome. The reported prevalence of such persistent symptoms following antimicrobial treatment varies considerably, and its pathophysiology is unclear. Persistent active infection in humans has not been identified as a cause of this syndrome, and randomized treatment trials have invariably failed to show any benefit of prolonged antibiotic treatment. For prevention of Lyme borreliosis, post-exposure prophylaxis may be indicated in specific cases, and novel vaccine strategies are under development.

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: 25 May 2020; 369:m1041
Kullberg BJ, Vrijmoeth HD, van de Schoor F, Hovius JW
BMJ: 25 May 2020; 369:m1041 | PMID: 32457042
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Abstract

.

Guo X, Zhu Y, Hong Y

The coronavirus disease 2019 (COVID-19) is caused by the infection of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), having gradually developed into a pandemic and endangered global health. The continued use of angiotensin converting enzyme inhibitor (ACEIs) and angiotensin II receptor blockers (ARBs) which are part of renin-angiotensin-aldosterone system (RAAS) inhibitors in COVID-19 patients with hypertension has become controversial. We conducted a meta-analysis by searching Pubmed, Web of Science, Scopus and Embase up to 13 May 2020. Data analyses were performed by the Cochrane Collaboration\'s Review Manager 5.3 software. Finally, we included 9 studies comprising 3936 patients with hypertension and COVID-19 infection. Compared with non-ACEI/ARB treatment, ACEI/ARB treatment was not associated with disease severity (OR 0.71, 95 % CI 0.46-1.08, P 0.11, I 59%) but was related to lower mortality of COVID-19 in patients with hypertension (OR 0.57, 95 % CI 0.38-0.84, P 0.004, I 0). In summary, ACEI/ARB therapy did not aggravate disease severity of COVID-19. Besides, ACEI/ARB therapy can decrease the mortality of COVID-19. Current evidence suggested that RAAS inhibitors should be continued in COVID-19 patients with hypertension. Future well-designed randomized controlled trials are needed to confirm these findings.



Hypertension: 26 May 2020; epub ahead of print
Guo X, Zhu Y, Hong Y
Hypertension: 26 May 2020; epub ahead of print | PMID: 32458694
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Abstract

Global Plasma Metabolomics to Identify Potential Biomarkers of Blood Pressure Progression.

Lin YT, Salihovic S, Fall T, Hammar U, ... Lind L, Sundström J
Objective
The pathophysiology of hypertension remains incompletely understood. We investigated associations of circulating metabolites with longitudinal blood pressure (BP) changes in the Prospective Investigation of the Vasculature in Uppsala Seniors cohort and validated the findings in the Uppsala Longitudinal Study of Adult Men cohort. Approach and Results: Circulating metabolite levels were assessed with liquid- and gas-chromatography coupled to mass spectrometry among persons without BP-lowering medication at baseline. We studied associations of baseline levels of metabolites with changes in BP levels and the clinical BP stage between baseline and a follow-up examination 5 years later. In the discovery cohort, we investigated 504 individuals that contributed with 757 observations of paired BP measurements. The mean baseline systolic and diastolic BPs were 144 (19.7)/76 (9.7) mm Hg, and change in systolic and diastolic BPs were 3.7 (15.8)/-0.5 (8.6) mm Hg over 5 years. The metabolites associated with diastolic BP change were ceramide, triacylglycerol, total glycerolipids, oleic acid, and cholesterylester. No associations with longitudinal changes in systolic BP or BP stage were observed. Metabolites with similar structures to the 5 top findings in the discovery cohort were investigated in the validation cohort. Diacylglycerol (36:2) and monoacylglycerol (18:0), 2 glycerolipids, were associated with diastolic BP change in the validation cohort.
Conclusions
Circulating baseline levels of ceramide, triacylglycerol, total glycerolipids, and oleic acid were positively associated with longitudinal diastolic BP change, whereas cholesterylester levels were inversely associated with longitudinal diastolic BP change. Two glycerolipids were validated in an independent cohort. These metabolites may point towards pathophysiological pathways of hypertension.



Arterioscler Thromb Vasc Biol: 27 May 2020:ATVBAHA120314356; epub ahead of print
Lin YT, Salihovic S, Fall T, Hammar U, ... Lind L, Sundström J
Arterioscler Thromb Vasc Biol: 27 May 2020:ATVBAHA120314356; epub ahead of print | PMID: 32460578
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Abstract

Hydroxychloroquine or Chloroquine for Treatment or Prophylaxis of COVID-19: A Living Systematic Review.

Hernandez AV, Roman YM, Pasupuleti V, Barboza JJ, White CM
Background
Hydroxychloroquine and chloroquine have antiviral effects in vitro against severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2).
Purpose
To summarize evidence about the benefits and harms of hydroxychloroquine or chloroquine for the treatment or prophylaxis of coronavirus disease 2019 (COVID-19).
Data sources
PubMed (via MEDLINE), EMBASE (via Ovid), Scopus, Web of Science, Cochrane Library, bioRxiv, Preprints, ClinicalTrials.gov, World Health Organization International Clinical Trials Registry Platform, and the Chinese Clinical Trials Registry from 1 December 2019 until 8 May 2020.
Study selection
Studies in any language reporting efficacy or safety outcomes from hydroxychloroquine or chloroquine use in any setting in adults or children with suspected COVID-19 or at risk for SARS-CoV-2 infection.
Data extraction
Independent, dually performed data extraction and quality assessments.
Data synthesis
Four randomized controlled trials, 10 cohort studies, and 9 case series assessed treatment effects of the medications, but no studies evaluated prophylaxis. Evidence was conflicting and insufficient regarding the effect of hydroxychloroquine on such outcomes as all-cause mortality, progression to severe disease, clinical symptoms, and upper respiratory virologic clearance with antigen testing. Several studies found that patients receiving hydroxychloroquine developed a QTc interval of 500 ms or greater, but the proportion of patients with this finding varied among the studies. Two studies assessed the efficacy of chloroquine; 1 trial, which compared higher-dose (600 mg twice daily for 10 days) with lower-dose (450 mg twice daily on day 1 and once daily for 4 days) therapy, was stopped owing to concern that the higher dose therapy increased lethality and QTc interval prolongation. An observational study that compared adults with COVID-19 receiving chloroquine phosphate 500 mg once or twice daily with patients not receiving chloroquine found minor fever resolution and virologic clearance benefits with chloroquine.
Limitation
There were few controlled studies, and control for confounding was inadequate in observational studies.
Conclusion
Evidence on the benefits and harms of using hydroxychloroquine or chloroquine to treat COVID-19 is very weak and conflicting.
Primary funding source
Agency for Healthcare Research and Quality.



Ann Intern Med: 26 May 2020; epub ahead of print
Hernandez AV, Roman YM, Pasupuleti V, Barboza JJ, White CM
Ann Intern Med: 26 May 2020; epub ahead of print | PMID: 32459529
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Abstract

Sex-Specific Regulation of Inflammation and Metabolic Syndrome in Obesity.

Ter Horst R, van den Munckhof ICL, Schraa K, Aguirre-Gamboa R, ... Netea MG, Riksen NP
Objective
Metabolic dysregulation and inflammation are important consequences of obesity and impact susceptibility to cardiovascular disease. Anti-inflammatory therapy in cardiovascular disease is being developed under the assumption that inflammatory pathways are identical in women and men, but it is not known if this is indeed the case. In this study, we assessed the sex-specific relation between inflammation and metabolic dysregulation in obesity. Approach and Results: Three hundred two individuals were included, half with a BMI 27 to 30 kg/m and half with a BMI>30 kg/m, 45% were women. The presence of metabolic syndrome was assessed according to the National Cholesterol Education Program-ATPIII criteria, and inflammation was studied using circulating markers of inflammation, cell counts, and ex vivo cytokine production capacity of isolated immune cells. Additionally, lipidomic and metabolomic data were gathered, and subcutaneous fat biopsies were histologically assessed. Metabolic syndrome is associated with an increased inflammatory profile that profoundly differs between women and men: women with metabolic syndrome show a lower concentration of the anti-inflammatory adiponectin, whereas men show increased levels of several pro-inflammatory markers such as IL (interleukin)-6 and leptin. Adipose tissue inflammation showed similar sex-specific associations with these markers. Peripheral blood mononuclear cells isolated from men, but not women, with metabolic syndrome display enhanced cytokine production capacity.
Conclusions
We identified sex-specific pathways that influence inflammation in obesity. Excessive production of proinflammatory cytokines was observed in men with metabolic syndrome. In contrast, women typically showed reduced levels of the anti-inflammatory adipokine adiponectin. These different mechanisms of inflammatory dysregulation between women and men with obesity argue for sex-specific therapeutic strategies.



Arterioscler Thromb Vasc Biol: 27 May 2020:ATVBAHA120314508; epub ahead of print
Ter Horst R, van den Munckhof ICL, Schraa K, Aguirre-Gamboa R, ... Netea MG, Riksen NP
Arterioscler Thromb Vasc Biol: 27 May 2020:ATVBAHA120314508; epub ahead of print | PMID: 32460579
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Abstract

S100A9-RAGE Axis Accelerates Formation of Macrophage-Mediated Extracellular Vesicle Microcalcification in Diabetes Mellitus.

Kawakami R, Katsuki S, Travers R, Romero DC, ... Croce K, Aikawa E
Objective
Vascular calcification is a cardiovascular risk factor and accelerated in diabetes mellitus. Previous work has established a role for calcification-prone extracellular vesicles in promoting vascular calcification. However, the mechanisms by which diabetes mellitus provokes cardiovascular events remain incompletely understood. Our goal was to identify that increased S100A9 promotes the release of calcification-prone extracellular vesicles from human macrophages in diabetes mellitus. Approach and Results: Human primary macrophages exposed to high glucose (25 mmol/L) increased S100A9 secretion and the expression of receptor for advanced glycation end products (RAGE) protein. Recombinant S100A9 induced the expression of proinflammatory and osteogenic factors, as well as the number of extracellular vesicles with high calcific potential (alkaline phosphatase activity, <0.001) in macrophages. Treatment with a RAGE antagonist or silencing with S100A9 siRNA in macrophages abolished these responses, suggesting that stimulation of the S100A9-RAGE axis by hyperglycemia favors a procalcific environment. We further showed that an imbalance between Nrf-2 (nuclear factor 2 erythroid related factor 2) and NF-κB (nuclear factor-κB) pathways contributes to macrophage activation and promotes a procalcific environment. In addition, streptozotocin-induced diabetic ApoeS100a9 mice and mice treated with S100a9 siRNA encapsulated in macrophage-targeted lipid nanoparticles showed decreased inflammation and microcalcification in atherosclerotic plaques, as gauged by molecular imaging and comprehensive histological analysis. In human carotid plaques, comparative proteomics in patients with diabetes mellitus and histological analysis showed that the S100A9-RAGE axis associates with osteogenic activity and the formation of microcalcification.
Conclusions
Under hyperglycemic conditions, macrophages release calcific extracellular vesicles through mechanisms involving the S100A9-RAGE axis, thus contributing to the formation of microcalcification within plaques.



Arterioscler Thromb Vasc Biol: 27 May 2020:ATVBAHA118314087; epub ahead of print
Kawakami R, Katsuki S, Travers R, Romero DC, ... Croce K, Aikawa E
Arterioscler Thromb Vasc Biol: 27 May 2020:ATVBAHA118314087; epub ahead of print | PMID: 32460581
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Abstract

TGFβ (Transforming Growth Factor-Beta)-Activated Kinase 1 Regulates Arteriovenous Fistula Maturation.

Hu H, Lee SR, Bai H, Guo J, ... Yatsula B, Dardik A
Objective
Arteriovenous fistulae (AVF) are the optimal conduit for hemodialysis access but have high rates of primary maturation failure. Successful AVF maturation requires deposition of ECM (extracellular matrix) including collagen and fibronectin, as well as orderly temporal regulation of ECM components. TAK1 (TGFβ [transforming growth factor-beta]-activated kinase 1) is a mediator of noncanonical TGFβ signaling and plays crucial roles in regulation of ECM production and deposition; therefore, we hypothesized that TAK1 regulates wall thickening during AVF maturation by alteration of expression of components of the ECM. Approach and Results: In both human and mouse AVF, immunoreactivity of TAK1, JNK (c-Jun N-terminal kinase), p38, collagen 1, and fibronectin was significantly increased compared with control veins. Manipulation of TAK1 in vivo altered AVF wall thickening and luminal diameter; reduced TAK1 function was associated with reduced thickness and smaller diameter, whereas activation of TAK1 function was associated with increased thickness and larger diameter. Arterial magnitudes of laminar shear stress (20 dyne/cm) activated noncanonical TGFβ signaling including TAK1 phosphorylation in mouse endothelial cells.
Conclusions
TAK1 is increased in AVF, and TAK1 manipulation in a mouse AVF model regulates AVF thickness and diameter. Targeting noncanonical TGFβ signaling such as TAK1 might be a novel therapeutic approach to improve AVF maturation.



Arterioscler Thromb Vasc Biol: 27 May 2020:ATVBAHA119313848; epub ahead of print
Hu H, Lee SR, Bai H, Guo J, ... Yatsula B, Dardik A
Arterioscler Thromb Vasc Biol: 27 May 2020:ATVBAHA119313848; epub ahead of print | PMID: 32460580
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Abstract

Association of TIM-1 (T-Cell Immunoglobulin and Mucin Domain 1) With Incidence of Stroke.

Song L, Sun J, Söderholm M, Melander O, ... Borné Y, Engström G
Objective
The aim of this study was to investigate if there is a causal relationship between circulating levels of TIM-1 (T-cell immunoglobulin and mucin domain 1) and incidence of stroke. Approach and Results: Plasma TIM-1 was analyzed in 4591 subjects (40% men; mean age, 57.5 years) attending the Malmö Diet and Cancer Study. Incidence of stroke was studied in relation to TIM-1 levels during a mean of 19.5 years follow-up. Genetic variants associated with TIM-1 (pQTLs [protein quantitative trait loci]) were examined, and a 2-sample Mendelian randomization analysis was performed to explore the role of TIM-1 in stroke using summary statistics from our pQTLs and the MEGASTROKE consortium. A total of 416 stroke events occurred during follow-up, of which 338 were ischemic strokes. After risk factor adjustment, TIM-1 was associated with increased incidence of all-cause stroke (hazards ratio for third versus first tertile, 1.44 [95% CI, 1.10-1.87];for trend, 0.004), and ischemic stroke (hazards ratio, 1.42 [95% CI, 1.06-1.90];for trend, 0.011). Nineteen independent lead SNPs, located in three genomic risk loci showed significant associations with TIM-1 (<5×10). A 2-sample Mendelian Randomization analysis suggested a causal effect of TIM-1 on stroke (β=0.083, =0.0004) and ischemic stroke (β=0.102, =7.7×10).
Conclusions
Plasma level of TIM-1 is associated with incidence of stroke. The genetic analyses suggest that this could be a causal relationship.



Arterioscler Thromb Vasc Biol: 27 May 2020:ATVBAHA120314269; epub ahead of print
Song L, Sun J, Söderholm M, Melander O, ... Borné Y, Engström G
Arterioscler Thromb Vasc Biol: 27 May 2020:ATVBAHA120314269; epub ahead of print | PMID: 32460577
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Abstract

National, regional, and worldwide epidemiology of psoriasis: systematic analysis and modelling study.

Parisi R, Iskandar IYK, Kontopantelis E, Augustin M, ... Ashcroft DM,
Objective
To systematically review and provide information on the incidence of psoriasis and quantify global, regional, and country specific estimates of its prevalence.
Design
Systematic review and meta-analysis.
Data sources
Medline, Embase, Web of Science, SciELO, Korean Journal Databases, Russian Science Citation Index, WPRIM, SaudiMedLit, Informit, IndMed, and HERDIN were searched systematically from their inception dates to October 2019.
Methods
Studies were included if they reported on the incidence or prevalence of psoriasis in the general population. Incidence data were summarised descriptively, whereas bayesian hierarchical models were fitted to estimate the global, regional, and country specific prevalence of psoriasis.
Results
41 164 records were identified and 168 studies met the inclusion criteria. In adults, the incidence of psoriasis varied from 30.3 per 100 000 person years (95% confidence interval 26.6 to 34.1) in Taiwan to 321.0 per 100 000 person years in Italy. The prevalence of psoriasis varied from 0.14% (95% uncertainty interval 0.05% to 0.40%) in east Asia to 1.99% (0.64% to 6.60%) in Australasia. The prevalence of psoriasis was also high in western Europe (1.92%, 1.07% to 3.46%), central Europe (1.83%, 0.62% to 5.32%), North America (1.50%, 0.63% to 3.60%), and high income southern Latin America (1.10%, 0.36% to 2.96%).
Conclusions
Eighty one per cent of the countries of the world lack information on the epidemiology of psoriasis. The disease occurs more frequently in adults than in children. Psoriasis is unequally distributed across geographical regions; it is more frequent in high income countries and in regions with older populations. The estimates provided can help guide countries and the international community when making public health decisions on the appropriate management of psoriasis and assessing its natural history over time.
Systematic review registration
PROSPERO CRD42019160817.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 27 May 2020; 369:m1590
Parisi R, Iskandar IYK, Kontopantelis E, Augustin M, ... Ashcroft DM,
BMJ: 27 May 2020; 369:m1590 | PMID: 32467098
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Abstract

Characterization and clinical course of 1000 patients with coronavirus disease 2019 in New York: retrospective case series.

Argenziano MG, Bruce SL, Slater CL, Tiao JR, ... Hripcsak G, Chen R
Objective
To characterize patients with coronavirus disease 2019 (covid-19) in a large New York City medical center and describe their clinical course across the emergency department, hospital wards, and intensive care units.
Design
Retrospective manual medical record review.
Setting
NewYork-Presbyterian/Columbia University Irving Medical Center, a quaternary care academic medical center in New York City.
Participants
The first 1000 consecutive patients with a positive result on the reverse transcriptase polymerase chain reaction assay for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) who presented to the emergency department or were admitted to hospital between 1 March and 5 April 2020. Patient data were manually abstracted from electronic medical records.
Main outcome measures
Characterization of patients, including demographics, presenting symptoms, comorbidities on presentation, hospital course, time to intubation, complications, mortality, and disposition.
Results
Of the first 1000 patients, 150 presented to the emergency department, 614 were admitted to hospital (not intensive care units), and 236 were admitted or transferred to intensive care units. The most common presenting symptoms were cough (732/1000), fever (728/1000), and dyspnea (631/1000). Patients in hospital, particularly those treated in intensive care units, often had baseline comorbidities including hypertension, diabetes, and obesity. Patients admitted to intensive care units were older, predominantly male (158/236, 66.9%), and had long lengths of stay (median 23 days, interquartile range 12-32 days); 78.0% (184/236) developed acute kidney injury and 35.2% (83/236) needed dialysis. Only 4.4% (6/136) of patients who required mechanical ventilation were first intubated more than 14 days after symptom onset. Time to intubation from symptom onset had a bimodal distribution, with modes at three to four days, and at nine days. As of 30 April, 90 patients remained in hospital and 211 had died in hospital.
Conclusions
Patients admitted to hospital with covid-19 at this medical center faced major morbidity and mortality, with high rates of acute kidney injury and inpatient dialysis, prolonged intubations, and a bimodal distribution of time to intubation from symptom onset.

© Author(s) (or their employer(s)) 2019. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.

BMJ: 28 May 2020; 369:m1996
Argenziano MG, Bruce SL, Slater CL, Tiao JR, ... Hripcsak G, Chen R
BMJ: 28 May 2020; 369:m1996 | PMID: 32471884
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Abstract

Multi-Fetal Pregnancy, Preeclampsia, and Long-Term Cardiovascular Disease.

Bergman L, Nordlöf-Callbo P, Wikström AK, Snowden JM, ... Edstedt Bonamy AK, Sandström A

This Swedish register-based cohort study determined the separate and joint contribution of preeclampsia and multi-fetal pregnancy on a woman\'s risk of cardiovascular disease (CVD) later in life. The study included 892 425 first deliveries between 1973 and 2010 of women born 1950 until 1971, identified in the Swedish Medical Birth Register. A composite outcome of CVD was retrieved through linkage with the National Patient and Cause of Death Registers. Cox proportional hazard regression was used to assess the risk of CVD in women who had preeclampsia in a singleton or multi-fetal pregnancy, adjusting for potential confounders, and presented as adjusted hazard ratios. Compared with women who had a singleton pregnancy without preeclampsia (the referent group), women with preeclampsia in a singleton pregnancy had an increased risk of CVD (adjusted hazard ratio 1.75 [95% CI, 1.64-1.86]). Women who had a multi-fetal pregnancy without or with preeclampsia did not have an increased risk of future CVD (adjusted hazard ratios 0.94 [95% CI, 0.79-1.10] and 1.25 [95% CI, 0.83-1.86], respectively). As opposed to preeclampsia in a first singleton pregnancy, preeclampsia in a first multi-fetal pregnancy was not associated with increased risk of future CVD. This may support the theory that preeclampsia in multi-fetal pregnancies more often occurs as a result of the larger pregnancy-related burden on the maternal cardiovascular system and excessive placenta-shed inflammatory factors, rather than the woman\'s underlying cardiovascular phenotype.



Hypertension: 31 May 2020:HYPERTENSIONAHA12014860; epub ahead of print
Bergman L, Nordlöf-Callbo P, Wikström AK, Snowden JM, ... Edstedt Bonamy AK, Sandström A
Hypertension: 31 May 2020:HYPERTENSIONAHA12014860; epub ahead of print | PMID: 32475315
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Abstract

COVID-19: ACE2centric infective disease?

Verdecchia P, Cavallini C, Spanevello A, Angeli F

Diffuse pulmonary inflammation, endothelial inflammation and enhanced thrombosis are cardinal features of COVID-19, the disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). These features are reminiscent of several adverse reactions triggered by angiotensin II, and opposed by angiotensin, in many experimental models. SARS-CoV-2 binds to ACE2 receptors and entries into the cell through the fusion of its membrane with that of the cell. Hence, it down-regulates these receptors. The loss of ACE2 receptor activity from the external site of the membrane will lead to less angiotensin II inactivation and less generation of antiotensin. In various experimental models of lung injury, the imbalance between angiotensin II over-activity and of antiotensin deficiency triggered inflammation, thrombosis and other adverse reactions. In COVID-19, such imbalance could play an important role in influencing the clinical picture and outcome of the disease. According to this line of thinking, some therapeutic approaches including recombinant ACE2, exogenous angiotensin and angiotensin receptor blockers appear particularly promising and are being actively tested.



Hypertension: 31 May 2020; epub ahead of print
Verdecchia P, Cavallini C, Spanevello A, Angeli F
Hypertension: 31 May 2020; epub ahead of print | PMID: 32476472
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Abstract

NOX4/HO/mTORC1 Pathway in Salt-Induced Hypertension and Kidney Injury.

Kumar V, Kurth T, Zheleznova NN, Yang C, Cowley AW

We have reported that a high-salt (4.0% NaCl) dietary intake activates mTORC1 and inhibition of this pathway with rapamycin blunts the chronic phase of salt-induced hypertension and renal injury in Dahl salt-sensitive (SS) rats. In SS rats, high-salt intake is known to increase the renal production of HO by NOX4, the most abundant NOX isoform in the kidney, and the global knockout of NOX4 blunts salt-sensitivity in these rats. Here, we explored the hypothesis that elevations of HO by NOX4 in high-salt fed SS rat stimulate mTORC1 for the full development of salt-induced hypertension and renal injury. Our in vitro studies found that HO activates mTORC1 independent of PI3K/AKT and AMPK pathways. To determine the in vivo relevance of NOX4/HO/mTORC1 in the salt-induced hypertension, SS- knockout (SS) rats were daily administrated with vehicle/rapamycin fed a high-salt diet for 21 days. Rapamycin treatment of SS rats had shown no augmented effect on the salt-induced hypertension nor upon indices of renal injury. Significant reductions of renal T lymphocyte and macrophage together with inhibition of cell proliferation were observed in rapamycin treated rats suggesting a role of mTORC1 independent of NOX4 in the proliferation of immune cell. Given the direct activation of mTORC1 by HO and absence of any further protection from salt-induced hypertension in rapamycin-treated SS rats, we conclude that NOX4-HO is a major upstream activator of mTORC1 that contributes importantly to salt-induced hypertension and renal injury in the SS rat model.



Hypertension: 31 May 2020:HYPERTENSIONAHA12015058; epub ahead of print
Kumar V, Kurth T, Zheleznova NN, Yang C, Cowley AW
Hypertension: 31 May 2020:HYPERTENSIONAHA12015058; epub ahead of print | PMID: 32475313
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Abstract

Modest Sodium Reduction Increases Circulating Short-Chain Fatty Acids in Untreated Hypertensives: A Randomized, Double-Blind, Placebo-Controlled Trial.

Chen L, He FJ, Dong Y, Huang Y, ... Harshfield GA, Zhu H

High-sodium diet may modulate the gut microbiome. Given the circulating short-chain fatty acids (SCFAs) are microbial in origin, we tested the hypothesis that the modest sodium reduction would alter circulating SCFA concentrations among untreated hypertensives, and the changes would be associated with reduced blood pressure and improved cardiovascular phenotypes. A total of 145 participants (42% blacks, 19% Asian, and 34% females) were included from a randomized, double-blind, placebo-controlled cross-over trial of sodium reduction with slow sodium or placebo tablets, each for 6 weeks. Targeted circulating SCFA profiling was performed in paired serum samples, which were collected at the end of each period, so as all outcome measures. Sodium reduction increased all 8 SCFAs, among which the increases in 2-methylbutyrate, butyrate, hexanoate, isobutyrate, and valerate were statistically significant (s<0.05). Also, increased SCFAs were associated with decreased blood pressure and improved arterial compliance. There were significant sex differences of SCFAs in response to sodium reduction (s<0.05). When stratified by sex, the increases in butyrate, hexanoate, isobutyrate, isovalerate, and valerate were significant in females only (s<0.05), not in males (s>0.05). In females, changes in isobutyrate, isovalerate, and 2-methylbutyrate were inversely associated with reduced blood pressures (s<0.05). Increased valerate was associated with decreased carotid-femoral pulse wave velocity (=0.040). Our results show that dietary sodium reduction increases circulating SCFAs, supporting that dietary sodium may influence the gut microbiome in humans. There is a sex difference in SCFA response to sodium reduction. Moreover, increased SCFAs are associated with decreased blood pressures and improved arterial compliance. Registration- URL: https://www.clinicaltrials.gov. Unique identifier: NCT00152074.



Hypertension: 31 May 2020:HYPERTENSIONAHA12014800; epub ahead of print
Chen L, He FJ, Dong Y, Huang Y, ... Harshfield GA, Zhu H
Hypertension: 31 May 2020:HYPERTENSIONAHA12014800; epub ahead of print | PMID: 32475312
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Impact:
Abstract

A Sociotechnical Framework for Safety-Related Electronic Health Record Research Reporting: The SAFER Reporting Framework.

Singh H, Sittig DF

Electronic health record (EHR)-based interventions to improve patient safety are complex and sensitive to who, what, where, why, when, and how they are delivered. Success or failure depends not only on the characteristics and behaviors of individuals who are targeted by an intervention, but also on the technical characteristics of the intervention and the culture and environment of the health system that implements it. Current reporting guidelines do not capture the complexity of sociotechnical factors (technical and nontechnical factors, such as workflow and organizational issues) that confound or influence these interventions. This article proposes a methodological reporting framework for EHR interventions targeting patient safety and builds on an 8-dimension sociotechnical model previously developed by the authors for design, development, implementation, use, and evaluation of health information technology. The Safety-related EHR Research (SAFER) Reporting Framework enables reporting of patient safety-focused EHR-based interventions while accounting for the multifaceted, dynamic sociotechnical context affecting intervention implementation, effectiveness, and generalizability. As an example, an EHR-based intervention to improve communication and timely follow-up of subcritical abnormal test results to operationalize the framework is presented. For each dimension, reporting should include what sociotechnical changes were made to implement an EHR-related intervention to improve patient safety, why the intervention did or did not lead to safety improvements, and how this intervention can be applied or exported to other health care organizations. A foundational list of research and reporting recommendations to address implementation, effectiveness, and generalizability of EHR-based interventions needed to effectively reduce preventable patient harm is provided. The SAFER Reporting Framework is not meant to replace previous research reporting guidelines, but rather provides a sociotechnical adjunct that complements their use.



Ann Intern Med: 01 Jun 2020; 172:S92-S100
Singh H, Sittig DF
Ann Intern Med: 01 Jun 2020; 172:S92-S100 | PMID: 32479184
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Impact:
Abstract

Evidence for a Physiological Mitochondrial Angiotensin II System in the Kidney Proximal Tubules: Novel Roles of Mitochondrial Ang II/AT/O and Ang II/AT/NO Signaling.

Li XC, Zhou X, Zhuo JL

The present study tested the hypotheses that overexpression of an intracellular Ang II (angiotensin II) fusion protein, mito-ECFP/Ang II, selectively in the mitochondria of mouse proximal tubule cells induces mitochondrial oxidative and glycolytic responses and elevates blood pressure via the Ang II/AT receptor/superoxide/NHE3 (the Na/H exchanger 3)-dependent mechanisms. A PT-selective, mitochondria-targeting adenoviral construct encoding Ad-sglt2-mito-ECFP/Ang II was used to test the hypotheses. The expression of mito-ECFP/Ang II was colocalized primarily with Mito-Tracker Red FM in mouse PT cells or with TMRM in kidney PTs. Mito-ECFP/Ang II markedly increased oxygen consumption rate as an index of mitochondrial oxidative response (69.5%; <0.01) and extracellular acidification rate as an index of mitochondrial glycolytic response (34%; <0.01). The mito-ECFP/Ang II-induced oxygen consumption rate and extracellular acidification rate responses were blocked by AT blocker losartan (<0.01) and a mitochondria-targeting superoxide scavenger mito-TEMPO (<0.01). By contrast, the nonselective NO inhibitor L-NAME alone increased, whereas the mitochondria-targeting expression of AT receptors (mito-AT/GFP) attenuated the effects of mito-ECFP/Ang II (<0.01). In the kidney, overexpression of mito-ECFP/Ang II in the mitochondria of the PTs increased systolic blood pressure 12±3 mm Hg (<0.01), and the response was attenuated in PT-specific PT- and PT- mice (<0.01). Conversely, overexpression of AT receptors selectively in the mitochondria of the PTs induced natriuretic responses in PT- and PT- mice (<0.01). Taken together, these results provide new evidence for a physiological role of PT mitochondrial Ang II/AT/superoxide/NHE3 and Ang II/AT/NO/NHE3 signaling pathways in maintaining blood pressure homeostasis.



Hypertension: 31 May 2020:HYPERTENSIONAHA11913942; epub ahead of print
Li XC, Zhou X, Zhuo JL
Hypertension: 31 May 2020:HYPERTENSIONAHA11913942; epub ahead of print | PMID: 32475319
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Abstract

Validation Study to Determine the Accuracy of Central Blood Pressure Measurement Using the Sphygmocor Xcel Cuff Device.

Schultz MG, Picone DS, Armstrong MK, Black JA, ... Roberts-Thomson P, Sharman JE

Numerous devices purport to measure central (aortic) blood pressure (BP) as distinct from conventional brachial BP. This validation study aimed to determine the accuracy of the Sphygmocor Xcel cuff device (AtCor Medical, CardieX, Sydney, Australia) for measuring central BP. 296 patients (mean age 61±12 years) undergoing coronary angiography had simultaneous measurement of invasive central BP and noninvasive cuff-derived central BP using the Xcel cuff device (total n=558 individual comparisons). A subsample (n=151) also had invasive brachial BP measured. Methods were undertaken according to the Artery Society recommendations, and several calibration techniques to derive central systolic BP (SBP) were examined. Minimum acceptable error was ≤5±≤8 mm Hg. Central SBP was significantly underestimated, and with wide variability, when using the default calibration of brachial-cuff SBP and diastolic BP (DBP; mean difference±SD, -7.7±11.0 mm Hg). Similar variability was observed using other calibration methods (cuff 33% form-factor mean arterial pressure and DBP, -4.4±11.5 mm Hg; cuff 40% form-factor mean arterial pressure and DBP, 4.7±11.9 mm Hg; cuff oscillometric mean arterial pressure and DBP, -18.2±12.1 mm Hg). Only calibration with invasive central integrated mean arterial pressure and DBP was within minimal acceptable error (3.3±7.5 mm Hg). The difference between brachial-cuff SBP and invasive central SBP was 3.3±10.7 mm Hg. A subsample analysis to determine the accuracy of central-to-brachial SBP amplification showed this to be overestimated by the Xcel cuff device (mean difference 4.3±9.1 mm Hg, =0.02). Irrespective of cuff calibration technique, the Sphygmocor Xcel cuff device does not meet the Artery Society accuracy criteria for noninvasive measurement of central BP.



Hypertension: 31 May 2020:HYPERTENSIONAHA12014916; epub ahead of print
Schultz MG, Picone DS, Armstrong MK, Black JA, ... Roberts-Thomson P, Sharman JE
Hypertension: 31 May 2020:HYPERTENSIONAHA12014916; epub ahead of print | PMID: 32475318
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Abstract

Effects of Home Particulate Air Filtration on Blood Pressure: A Systematic Review.

Walzer D, Gordon T, Thorpe L, Thurston G, ... Hochman JS, Newman JD

Air pollution is a major contributor to cardiovascular morbidity and mortality. Fine particulate matter <2.5 µm in diameter may be a modifiable risk factor for hypertension. The benefits of in-home air filtration on systolic blood pressure (BP) and diastolic BP are unclear. To examine the effects of in-home personal air cleaner use on fine particulate exposure and BP, we queried PubMed, Web of Science, Cochrane Central Register, Inspec, and EBSCO GreenFILE databases for relevant clinical trials. Included studies were limited to nonsmoking participants in smoke-free homes with active or sham filtration on indoor fine particulate concentrations and changes in systolic and diastolic BP. Of 330 articles identified, 10 trials enrolling 604 participants who met inclusion criteria were considered. Over a median 13.5 days, there was a significant reduction of mean systolic BP by ≈4 mm Hg (-3.94 mm Hg [95% CI, -7.00 to -0.89]; =0.01) but a nonsignificant difference in mean diastolic BP (-0.95 mm Hg [95% CI, -2.81 to 0.91]; =0.32). Subgroup analyses indicated no heterogeneity of effect by age, level of particulate exposure, or study duration. Given the variation in study design, additional study is warranted to confirm and better quantify the observed benefits in systolic BP found with personal air cleaner use.



Hypertension: 31 May 2020:HYPERTENSIONAHA11914456; epub ahead of print
Walzer D, Gordon T, Thorpe L, Thurston G, ... Hochman JS, Newman JD
Hypertension: 31 May 2020:HYPERTENSIONAHA11914456; epub ahead of print | PMID: 32475316
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Abstract

Epoxy Fatty Acids: From Salt Regulation to Kidney and Cardiovascular Therapeutics: 2019 Lewis K. Dahl Memorial Lecture.

Imig JD, Jankiewicz WK, Khan AH

Epoxyeicosatrienoic acids (EETs) are epoxy fatty acids that have biological actions that are essential for maintaining water and electrolyte homeostasis. An inability to increase EETs in response to a high-salt diet results in salt-sensitive hypertension. Vasodilation, inhibition of epithelial sodium channel, and inhibition of inflammation are the major EET actions that are beneficial to the heart, resistance arteries, and kidneys. Genetic and pharmacological means to elevate EETs demonstrated antihypertensive, anti-inflammatory, and organ protective actions. Therapeutic approaches to increase EETs were then developed for cardiovascular diseases. sEH (soluble epoxide hydrolase) inhibitors were developed and progressed to clinical trials for hypertension, diabetes mellitus, and other diseases. EET analogs were another therapeutic approach taken and these drugs are entering the early phases of clinical development. Even with the promise for these therapeutic approaches, there are still several challenges, unexplored areas, and opportunities for epoxy fatty acids.



Hypertension: 31 May 2020:HYPERTENSIONAHA12013898; epub ahead of print
Imig JD, Jankiewicz WK, Khan AH
Hypertension: 31 May 2020:HYPERTENSIONAHA12013898; epub ahead of print | PMID: 32475311
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Abstract

Reduced Nhe1 (Na-H Exchanger-1) Function Protects ApoE-Deficient Mice From Ang II (Angiotensin II)-Induced Abdominal Aortic Aneurysms.

Liu CL, Liu X, Wang Y, Deng Z, ... Wang X, Shi GP

IgE-mediated activation of Nhe1 (Na-H exchanger-1) induces aortic cell extracellular acidification and promotes cell apoptosis. A pH-sensitive probe pHrodo identified acidic regions at positions of macrophage accumulation, IgE expression, and cell apoptosis in human and mouse abdominal aortic aneurysm (AAA) lesions. Ang II (angiotensin II)-induced AAA in Nhe1-insufficientmice andlittermates tested Nhe1 activity in experimental AAA, becausemice develop ataxia and epileptic-like seizures and die early. Nhe1 insufficiency reduced AAA incidence and size, lesion macrophage and T-cell accumulation, collagen deposition, elastin fragmentation, cell apoptosis, smooth muscle cell loss, and MMP (matrix metalloproteinase) activity. Nhe1 insufficiency also reduced blood pressure and the plasma apoptosis marker TCTP (translationally controlled tumor protein) but did not affect plasma IgE. While pHrodo localized the acidic regions to macrophage clusters, IgE expression, and cell apoptosis in AAA lesions frommice, such acidic areas were much smaller in lesions frommice. Nhe1-FcεR1 colocalization in macrophages from AAA lesions support a role of IgE-mediated Nhe1 activation. Gelatin zymography, immunoblot, and real-time polymerase chain reaction analyses demonstrated that Nhe1 insufficiency reduced the MMP activity, cysteinyl cathepsin expression, IgE-induced apoptosis, and NF-κB activation in macrophages and blocked IgE-induced adhesion molecule expression in endothelial cells. A near-infrared fluorescent probe (LS662) together with fluorescence reflectance imaging of intact aortas showed reduced acidity in AAA lesions from Nhe-1-insufficient mice. This study revealed extracellular acidity at regions rich in macrophages, IgE expression, and cell apoptosis in human and mouse AAA lesions and established a direct role of Nhe1 in AAA pathogenesis.



Hypertension: 31 May 2020:HYPERTENSIONAHA11914485; epub ahead of print
Liu CL, Liu X, Wang Y, Deng Z, ... Wang X, Shi GP
Hypertension: 31 May 2020:HYPERTENSIONAHA11914485; epub ahead of print | PMID: 32475310
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Abstract

Reporting and Implementing Interventions Involving Machine Learning and Artificial Intelligence.

Bates DW, Auerbach A, Schulam P, Wright A, Saria S

Increasingly, interventions aimed at improving care are likely to use such technologies as machine learning and artificial intelligence. However, health care has been relatively late to adopt them. This article provides clinical examples in which machine learning and artificial intelligence are already in use in health care and appear to deliver benefit. Three key bottlenecks toward increasing the pace of diffusion and adoption are methodological issues in evaluation of artificial intelligence-based interventions, reporting standards to enable assessment of model performance, and issues that need to be addressed for an institution to adopt these interventions. Methodological best practices will include external validation, ideally at a different site; use of proactive learning algorithms to correct for site-specific biases and increase robustness as algorithms are deployed across multiple sites; addressing subgroup performance; and communicating to providers the uncertainty of predictions. Regarding reporting, especially important issues are the extent to which implementing standardized approaches for introducing clinical decision support has been followed, describing the data sources, reporting on data assumptions, and addressing biases. Although most health care organizations in the United States have adopted electronic health records, they may be ill prepared to adopt machine learning and artificial intelligence. Several steps can enable this: preparing data, developing tools to get suggestions to clinicians in useful ways, and getting clinicians engaged in the process. Open challenges and the role of regulation in this area are briefly discussed. Although these techniques have enormous potential to improve care and personalize recommendations for individuals, the hype regarding them is tremendous. Organizations will need to approach this domain carefully with knowledgeable partners to obtain the hoped-for benefits and avoid failures.



Ann Intern Med: 01 Jun 2020; 172:S137-S144
Bates DW, Auerbach A, Schulam P, Wright A, Saria S
Ann Intern Med: 01 Jun 2020; 172:S137-S144 | PMID: 32479180
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Abstract

Recommendations for the Conduct and Reporting of Research Involving Flexible Electronic Health Record-Based Interventions.

Wright A, McCoy AB, Choudhry NK

In the past 2 decades, the United States has seen widespread adoption of electronic health records (EHRs) and a transition from mostly locally developed EHRs to commercial systems. However, most research on quality improvement and safety interventions in EHRs is still conducted at a single site, in a single EHR. Although single-site studies are important early in the innovation lifecycle, multisite studies of EHR interventions are critical for generalizability. Because EHR software, configuration, and local context differ considerably across health care organizations, it can be difficult to implement a single, standardized intervention across multiple sites in a study. This article outlines key strengths, weaknesses, challenges, and opportunities for standardization of EHR interventions in multisite studies and describes flexible trial designs suitable for studying complex interventions, including EHR interventions. It also outlines key considerations for reporting on flexible trials of EHR interventions, including sharing details of the process for designing interventions and their content, details of outcomes being studied and approaches for pooling, and the importance of sharing code and configuration whenever possible.



Ann Intern Med: 01 Jun 2020; 172:S110-S115
Wright A, McCoy AB, Choudhry NK
Ann Intern Med: 01 Jun 2020; 172:S110-S115 | PMID: 32479179
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Abstract

Studying Workflow and Workarounds in Electronic Health Record-Supported Work to Improve Health System Performance.

Zheng K, Ratwani RM, Adler-Milstein J

Clinical workflow is the enactment of a series of steps to perform a clinical activity. The transition from paper to electronic health records (EHRs) over the past decade has been characterized by profound challenges supporting clinical workflow, impeding frontline clinicians\' ability to deliver safe, efficient, and effective care. In response, there has been substantial effort to study clinical workflow as well as workarounds-exceptions to routine workflow-in order to identify opportunities for improvement. This article describes predominant methods of studying workflow and workarounds and provides examples of the applications of these methods along with the resulting insights. Challenges to studying workflow and workarounds are described, and recommendations for how to approach such studies are given. Although there is not yet a set of standard approaches, this article helps advance workflow research that ultimately serves to inform how to coevolve the design of EHR systems and organizational decisions about processes, roles, and responsibilities in order to support clinical workflow that more consistently delivers on the potential benefits of a digitized health care system.



Ann Intern Med: 01 Jun 2020; 172:S116-S122
Zheng K, Ratwani RM, Adler-Milstein J
Ann Intern Med: 01 Jun 2020; 172:S116-S122 | PMID: 32479181
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Abstract

l-Tryptophan-Induced Vasodilation Is Enhanced in Preeclampsia: Studies on Its Uptake and Metabolism in the Human Placenta.

Broekhuizen M, Klein T, Hitzerd E, de Rijke YB, ... Merkus D, Reiss IKM

l-tryptophan induces IDO (indoleamine 2,3-dioxygenase) 1-dependent vasodilation. IDO1 is expressed in placental endothelial cells and downregulated in preeclampsia. Hypothesizing that this may contribute to diminished placental perfusion, we studied l-tryptophan-induced vasodilation in healthy and early-onset preeclampsia placental arteries, focusing on placental kynurenine pathway alterations. Despite IDO1 downregulation, kynurenine pathway metabolite concentrations (measured with ultra-performance liquid chromatography-tandem mass spectrometry) were unaltered in preeclamptic versus healthy placentas. Most likely, this is due to enhanced l-tryptophan uptake, evidenced by increased l-tryptophan levels in preeclamptic placentas. Ex vivo perfused cotyledons from healthy and preeclamptic placentas released similar amounts of l-tryptophan and kynurenine pathway metabolites into the circulations. This release was not altered by adding l-tryptophan in the maternal circulation, suggesting that l-tryptophan metabolites act intracellularly. Maternally applied l-tryptophan did appear in the fetal circulation, confirming placental passage of this essential amino acid. After in vitro incubation of placental arteries with IDO1-upregulating cytokines interferon-γ and tumor necrosis factor-α, l-tryptophan induced vasodilation. This vasodilation was attenuated by both IDO1 and nitric oxide (NO) synthase inhibitors. Despite IDO1 downregulation, l-tryptophan-induced relaxation was enhanced in preeclamptic versus healthy placental arteries. However, cytokine stimulation additionally upregulated the LAT (l-type amino acid transporter) 1 in preeclamptic placental arteries only. Vasodilation to the lipophilic, transporter independent ethyl ester of l-tryptophan was reduced in preeclamptic versus healthy placental arteries, in agreement with reduced IDO1 expression. In conclusion, l-tryptophan induces IDO1- and NO-dependent relaxation in placental arteries, which is determined by l-tryptophan uptake rather than IDO1 expression. Increased l-tryptophan uptake might compensate for reduced IDO1 expression in preeclamptic placentas.



Hypertension: 31 May 2020:HYPERTENSIONAHA12014970; epub ahead of print
Broekhuizen M, Klein T, Hitzerd E, de Rijke YB, ... Merkus D, Reiss IKM
Hypertension: 31 May 2020:HYPERTENSIONAHA12014970; epub ahead of print | PMID: 32475317
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Abstract

Randomized Controlled Trials of Electronic Health Record Interventions: Design, Conduct, and Reporting Considerations.

Pletcher MJ, Flaherman V, Najafi N, Patel S, ... Gonzales R, Auerbach A

Electronic health record (EHR) systems can be configured to deliver novel EHR interventions that influence clinical decision making and to support efficient randomized controlled trials (RCTs) designed to evaluate the effectiveness, safety, and costs of those interventions. In designing RCTs of EHR interventions, one should carefully consider the unit of randomization (for example, patient, encounter, clinician, or clinical unit), balancing concerns about contamination of an intervention across randomization units within clusters (for example, patients within clinical units) against the superior control of measured and unmeasured confounders that comes with randomizing a larger number of units. One should also consider whether the key computational assessment components of the EHR intervention, such as a predictive algorithm used to target a subgroup for decision support, should occur before randomization (so that only 1 subgroup is randomized) or after randomization (including all subgroups). When these components are applied after randomization, one must consider expected heterogeneity in the effect of the differential decision support across subgroups, which has implications for overall impact potential, analytic approach, and sample size planning. Trials of EHR interventions should be reviewed by an institutional review board, but may not require patient-level informed consent when the interventions being tested can be considered minimal risk or quality improvement, and when clinical decision making is supported, rather than controlled, by an EHR intervention. Data and safety monitoring for RCTs of EHR interventions should be conducted to guide institutional pragmatic decision making about implementation and ensure that continuing randomization remains justified. Reporting should follow the CONSORT (Consolidated Standards of Reporting Trials) Statement, with extensions for pragmatic trials and cluster RCTs when applicable, and should include detailed materials to enhance reproducibility.



Ann Intern Med: 01 Jun 2020; 172:S85-S91
Pletcher MJ, Flaherman V, Najafi N, Patel S, ... Gonzales R, Auerbach A
Ann Intern Med: 01 Jun 2020; 172:S85-S91 | PMID: 32479183
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Abstract

Getting Value From Electronic Health Records: Research Needed to Improve Practice.

Rudin RS, Friedberg MW, Shekelle P, Shah N, Bates DW

Electronic health records (EHRs) are now widely adopted in the United States, but health systems have barely begun using them to deliver high-value care. More directed and rigorous research is needed to fulfill the promise of EHRs to not only store information but also support the delivery of better care. This article describes 4 potential benefits of EHR-based research: improving clinical decisions, supporting triage decisions, enabling collaboration among the care team (including patients), and increasing productivity via automation of tasks. Six recommendations are made for conducting and reporting research to catalyze value creation: develop interventions systematically by using user-centered design and a building-block approach; assess value in terms of cost, quality, outcomes, and work required of providers and patients; consider the time horizon for the intervention; test best practices for implementation in a range of real-world contexts; assess subtleties of behavior change tools used to improve high-value behaviors; and report the intervention in enough detail that it can be replicated, including context. Just as research played a critical role in developing early EHR prototypes and demonstrating their value to justify dissemination, research will continue to be essential in the next phase: expanding EHR-based interventions and maximizing their role in creating value.



Ann Intern Med: 01 Jun 2020; 172:S130-S136
Rudin RS, Friedberg MW, Shekelle P, Shah N, Bates DW
Ann Intern Med: 01 Jun 2020; 172:S130-S136 | PMID: 32479182
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Abstract

Should You Recommend Inhaled Corticosteroids for This Patient With Chronic Obstructive Pulmonary Disease?: Grand Rounds Discussion From Beth Israel Deaconess Medical Center.

Burns RB, Anandaiah A, Rice MB, Smetana GW

Approximately 12 million adults in the United States receive a diagnosis of chronic obstructive pulmonary disease (COPD) each year, and it is the fourth leading cause of death.refers to a group of diseases that cause airflow obstruction and a constellation of symptoms, including cough, sputum production, and shortness of breath. The main risk factor for COPD is tobacco smoke, but other environmental exposures also may contribute. The GOLD (Global Initiative for Chronic Obstructive Lung Disease) 2020 Report aims to provide a nonbiased review of the current evidence for the assessment, diagnosis, and treatment of patients with COPD. To date, no conclusive evidence exists that any existing medications for COPD modify mortality. The mainstay of treatment for COPD is inhaled bronchodilators, whereas the role of inhaled corticosteroids is less clear. Inhaled corticosteroids have substantial risks, including an increased risk for pneumonia. Here, 2 experts, both pulmonologists, reflect on the care of a woman with severe COPD, a 50-pack-year smoking history, frequent COPD exacerbations, and recurrent pneumonia. They consider the indications for inhaled corticosteroids in COPD, when inhaled corticosteroids should be withdrawn, and what other treatments are available.



Ann Intern Med: 01 Jun 2020; 172:735-742
Burns RB, Anandaiah A, Rice MB, Smetana GW
Ann Intern Med: 01 Jun 2020; 172:735-742 | PMID: 32479149
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Abstract

Studying individual risk factors for self-harm in the UK Biobank: A polygenic scoring and Mendelian randomisation study.

Lim KX, Rijsdijk F, Hagenaars SP, Socrates A, ... Lewis CM, Pingault JB
Background
Identifying causal risk factors for self-harm is essential to inform preventive interventions. Epidemiological studies have identified risk factors associated with self-harm, but these associations can be subject to confounding. By implementing genetically informed methods to better account for confounding, this study aimed to better identify plausible causal risk factors for self-harm.
Methods and findings
Using summary statistics from 24 genome-wide association studies (GWASs) comprising 16,067 to 322,154 individuals, polygenic scores (PSs) were generated to index 24 possible individual risk factors for self-harm (i.e., mental health vulnerabilities, substance use, cognitive traits, personality traits, and physical traits) among a subset of UK Biobank participants (N = 125,925, 56.2% female) who completed an online mental health questionnaire in the period from 13 July 2016 to 27 July 2017. In total, 5,520 (4.4%) of these participants reported having self-harmed in their lifetime. In binomial regression models, PSs indexing 6 risk factors (major depressive disorder [MDD], attention deficit/hyperactivity disorder [ADHD], bipolar disorder, schizophrenia, alcohol dependence disorder, and lifetime cannabis use) predicted self-harm, with effect sizes ranging from odds ratio (OR) = 1.05 (95% CI 1.02 to 1.07, q = 0.008) for lifetime cannabis use to OR = 1.20 (95% CI 1.16 to 1.23, q = 1.33 × 10-35) for MDD. No systematic differences emerged between suicidal and non-suicidal self-harm. To further probe causal relationships, two-sample Mendelian randomisation (MR) analyses were conducted, with MDD, ADHD, and schizophrenia emerging as the most plausible causal risk factors for self-harm. The genetic liabilities for MDD and schizophrenia were associated with self-harm independently of diagnosis and medication. Main limitations include the lack of representativeness of the UK Biobank sample, that self-harm was self-reported, and the limited power of some of the included GWASs, potentially leading to possible type II error.
Conclusions
In addition to confirming the role of MDD, we demonstrate that ADHD and schizophrenia likely play a role in the aetiology of self-harm using multivariate genetic designs for causal inference. Among the many individual risk factors we simultaneously considered, our findings suggest that systematic detection and treatment of core psychiatric symptoms, including psychotic and impulsivity symptoms, may be beneficial among people at risk for self-harm.



PLoS Med: 30 May 2020; 17:e1003137
Lim KX, Rijsdijk F, Hagenaars SP, Socrates A, ... Lewis CM, Pingault JB
PLoS Med: 30 May 2020; 17:e1003137 | PMID: 32479557
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Abstract

Factors Influencing Physician Practices\' Adoption of Behavioral Health Integration in the United States: A Qualitative Study.

Malâtre-Lansac A, Engel CC, Xenakis L, Carlasare L, ... Chen PG, Friedberg MW
Background
Behavioral health integration is uncommon among U.S. physician practices despite recent policy changes that may encourage its adoption.
Objective
To describe factors influencing physician practices\' implementation of behavioral health integration.
Design
Semistructured interviews with leaders and clinicians from physician practices that adopted behavioral health integration, supplemented by contextual interviews with experts and vendors in behavioral health integration.
Setting
30 physician practices, sampled for diversity on specialty, size, affiliation with parent organizations, geographic location, and behavioral health integration model (collaborative or co-located).
Participants
47 physician practice leaders and clinicians, 20 experts, and 5 vendors.
Measurements
Qualitative analysis (cyclical coding) of interview transcripts.
Results
Four overarching factors affecting physician practices\' implementation of behavioral health integration were identified. First, practices\' motivations for integrating behavioral health care included expanding access to behavioral health services, improving other clinicians\' abilities to respond to patients\' behavioral health needs, and enhancing practice reputation. Second, practices tailored their implementation of behavioral health integration to local resources, financial incentives, and patient populations. Third, barriers to behavioral health integration included cultural differences and incomplete information flow between behavioral and nonbehavioral health clinicians and billing difficulties. Fourth, practices described the advantages and disadvantages of both fee-for-service and alternative payment models, and few reported positive financial returns.
Limitation
The practice sample was not nationally representative and excluded practices that did not implement or sustain behavioral health integration, potentially limiting generalizability.
Conclusion
Practices currently using behavioral health integration face cultural, informational, and financial barriers to implementing and sustaining behavioral health integration. Tailored, context-specific technical support to guide practices\' implementation and payment models that improve the business case for practices may enhance the dissemination and long-term sustainability of behavioral health integration.
Primary funding source
American Medical Association and The Commonwealth Fund.



Ann Intern Med: 01 Jun 2020; epub ahead of print
Malâtre-Lansac A, Engel CC, Xenakis L, Carlasare L, ... Chen PG, Friedberg MW
Ann Intern Med: 01 Jun 2020; epub ahead of print | PMID: 32479169
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Abstract

Research and Reporting Considerations for Observational Studies Using Electronic Health Record Data.

Callahan A, Shah NH, Chen JH

Electronic health records (EHRs) are an increasingly important source of real-world health care data for observational research. Analyses of data collected for purposes other than research require careful consideration of data quality as well as the general research and reporting principles relevant to observational studies. The core principles for observational research in general also apply to observational research using EHR data, and these are well addressed in prior literature and guidelines. This article provides additional recommendations for EHR-based research. Considerations unique to EHR-based studies include assessment of the accuracy of computer-executable cohort definitions that can incorporate unstructured data from clinical notes and management of data challenges, such as irregular sampling, missingness, and variation across time and place. Principled application of existing research and reporting guidelines alongside these additional considerations will improve the quality of EHR-based observational studies.



Ann Intern Med: 01 Jun 2020; 172:S79-S84
Callahan A, Shah NH, Chen JH
Ann Intern Med: 01 Jun 2020; 172:S79-S84 | PMID: 32479175
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Abstract

Using Electronic Health Record Portals to Improve Patient Engagement: Research Priorities and Best Practices.

Lyles CR, Nelson EC, Frampton S, Dykes PC, Cemballi AG, Sarkar U

Ninety percent of health care systems now offer patient portals to access electronic health records (EHRs) in the United States, but only 15% to 30% of patients use these platforms. Using PubMed, the authors identified 53 studies published from September 2013 to June 2019 that informed best practices and priorities for future research on patient engagement with EHR data through patient portals, These studies mostly involved outpatient settings and fell into 3 major categories: interventions to increase use of patient portals, usability testing of portal interfaces, and documentation of patient and clinician barriers to portal use. Interventions that used one-on-one patient training were associated with the highest portal use. Patients with limited health or digital literacy faced challenges to portal use. Clinicians reported a lack of workflows to support patient use of portals in routine practice. These studies suggest that achieving higher rates of patient engagement through EHR portals will require paying more attention to the needs of diverse patients and systematically measuring usability as well as scope of content. Future work should incorporate implementation science approaches and directly address the key role of clinicians and staff in promoting portal use.



Ann Intern Med: 01 Jun 2020; 172:S123-S129
Lyles CR, Nelson EC, Frampton S, Dykes PC, Cemballi AG, Sarkar U
Ann Intern Med: 01 Jun 2020; 172:S123-S129 | PMID: 32479176
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Abstract

Context and Approach in Reporting Evaluations of Electronic Health Record-Based Implementation Projects.

Haynes RB, Del Fiol G, Michelson M, Iorio A

Electronic health records (EHRs) are ubiquitous yet still evolving, resulting in a moving target for determining the effects of context (features of the work environment, such as organization, payment systems, user training, and roles) on EHR implementation projects. Electronic health records have become instrumental in effecting quality improvement innovations and providing data to evaluate them. However, reports of studies typically fail to provide adequate descriptions of contextual details to permit readers to apply the findings. As for any evaluation, the quality of reporting is essential to learning from, and disseminating, the results. Extensive guidelines exist for reporting of virtually all types of applied health research, but they are not tailored to capture some contextual factors that may affect the outcomes of EHR implementations, such as attitudes toward implementation, format and amount of training, post go-live support, amount of local customization, and time diverted from direct interaction with patients to computers. Nevertheless, evaluators of EHR-based innovations can choose reporting guidelines that match the general purpose of their evaluation and the stage of their investigation (planning, protocol, execution, and analysis) and should report relevant contextual details (including, if pertinent, any pressures to help justify the huge investments and many years required for some implementations). Reporting guidelines are based on the scientific principles and practices that underlie sound research and should be consulted from the earliest stages of planning evaluations and onward, serving as guides for how evaluations should be conducted as well as reported.



Ann Intern Med: 01 Jun 2020; 172:S73-S78
Haynes RB, Del Fiol G, Michelson M, Iorio A
Ann Intern Med: 01 Jun 2020; 172:S73-S78 | PMID: 32479174
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Abstract

Long-Term Rituximab Use to Maintain Remission of Antineutrophil Cytoplasmic Antibody-Associated Vasculitis: A Randomized Trial.

Charles P, Perrodeau É, Samson M, Bonnotte B, ... Mouthon L, Guillevin L
Background
Biannual rituximab infusions over 18 months effectively maintain remission after a \"standard\" remission induction regimen for patients with antineutrophil cytoplasmic antibody-associated vasculitis (AAV).
Objective
To evaluate the efficacy of prolonged rituximab therapy in preventing AAV relapses in patients with granulomatosis with polyangiitis (GPA) or microscopic polyangiitis (MPA) who have achieved complete remission after completing an 18-month maintenance regimen.
Design
Randomized controlled trial. (ClinicalTrials.gov: NCT02433522).
Setting
39 clinical centers in France.
Patients
68 patients with GPA and 29 with MPA who achieved complete remission after the first phase of maintenance therapy.
Intervention
Rituximab or placebo infusion every 6 months for 18 months (4 infusions).
Measurements
The primary end point was relapse-free survival at month 28. Relapse was defined as new or reappearing symptoms or worsening disease, with a Birmingham Vasculitis Activity Score greater than 0.
Results
From March 2015 to April 2016, 97 patients (mean age, 63.9 years; 35% women) were randomly assigned, 50 to the rituximab and 47 to the placebo group. Relapse-free survival estimates at month 28 were 96% (95% CI, 91% to 100%) and 74% (CI, 63% to 88%) in the rituximab and placebo groups, respectively, an absolute difference of 22% (CI, 9% to 36%) with a hazard ratio of 7.5 (CI, 1.67 to 33.7) ( = 0.008). Major relapse-free survival estimates at month 28 were 100% (CI, 93% to 100%) versus 87% (CI, 78% to 97%) ( = 0.009), respectively. At least 1 serious adverse event developed in 12 patients (24%) in the rituximab group (with 9 infectious serious adverse events occurring among 6 patients [12%]) versus 14 patients (30%) in the placebo group (with 6 infectious serious adverse events developing among 4 patients [9%]). No deaths occurred in either group.
Limitation
Potential selection bias based on previous rituximab response and tolerance.
Conclusion
Extended therapy with biannual rituximab infusions over 18 months was associated with a lower incidence of AAV relapse compared with standard maintenance therapy.
Primary funding source
French Ministry of Health and Hoffmann-La Roche.



Ann Intern Med: 01 Jun 2020; epub ahead of print
Charles P, Perrodeau É, Samson M, Bonnotte B, ... Mouthon L, Guillevin L
Ann Intern Med: 01 Jun 2020; epub ahead of print | PMID: 32479166
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Abstract

Transparent Reporting of Multivariable Prediction Models in Journal and Conference Abstracts: TRIPOD for Abstracts.

Heus P, Reitsma JB, Collins GS, Damen JAAG, ... Moons KGM, Hooft L

Clear and informative reporting in titles and abstracts is essential to help readers and reviewers identify potentially relevant studies and decide whether to read the full text. Although the TRIPOD (Transparent Reporting of a multivariable prediction model for Individual Prognosis Or Diagnosis) statement provides general recommendations for reporting titles and abstracts, more detailed guidance seems to be desirable. The authors present TRIPOD for Abstracts, a checklist and corresponding guidance for reporting prediction model studies in abstracts. A list of 32 potentially relevant items was the starting point for a modified Delphi procedure involving 110 experts, of whom 71 (65%) participated in the web-based survey. After 2 Delphi rounds, the experts agreed on 21 items as being essential to report in abstracts of prediction model studies. This number was reduced by merging some of the items. In a third round, participants provided feedback on a draft version of TRIPOD for Abstracts. The final checklist contains 12 items and applies to journal and conference abstracts that describe the development or external validation of a diagnostic or prognostic prediction model, or the added value of predictors to an existing model, regardless of the clinical domain or statistical approach used.



Ann Intern Med: 01 Jun 2020; epub ahead of print
Heus P, Reitsma JB, Collins GS, Damen JAAG, ... Moons KGM, Hooft L
Ann Intern Med: 01 Jun 2020; epub ahead of print | PMID: 32479165
Go to: DOI | PubMed | PDF | Google Scholar |
Impact:
Older ...

This program is still in alpha version.