bluuebunny/crossref_metadata_2025_split huggingface dataset:
BCL10 Mutations Define Distinct Dependencies Guiding Precision Therapy for DLBCL
Authors: Xia Min , David Liron , Teater Matt , Gutierrez Johana , Wang Xiang , Meydan Cem , Lytle Andrew , Slack Graham W. , Scott David W. , Morin Ryan D. , Onder Ozlem , Elenitoba-Johnson Kojo S.J. , Zamponi Nahuel , Cerchietti Leandro , Lu Tianbao , Philippar Ulrike , Fontan Lorena , Wu Hao , Melnick Ari M. 
Published: June 2022

Abstract

Activated B cell–like diffuse large B-cell lymphomas (ABC-DLBCL) have unfavorable outcomes and chronic activation of CARD11–BCL10–MALT1 (CBM) signal amplification complexes that form due to polymerization of BCL10 subunits, which is affected by recurrent somatic mutations in ABC-DLBCLs. Herein, we show that BCL10 mutants fall into at least two functionally distinct classes: missense mutations of the BCL10 CARD domain and truncation of its C-terminal tail. Truncating mutations abrogated a motif through which MALT1 inhibits BCL10 polymerization, trapping MALT1 in its activated filament-bound state. CARD missense mutations enhanced BCL10 filament formation, forming glutamine network structures that stabilize BCL10 filaments. Mutant forms of BCL10 were less dependent on upstream CARD11 activation and thus manifested resistance to BTK inhibitors, whereas BCL10 truncating but not CARD mutants were hypersensitive to MALT1 inhibitors. Therefore, BCL10 mutations are potential biomarkers for BTK inhibitor resistance in ABC-DLBCL, and further precision can be achieved by selecting therapy based on specific biochemical effects of distinct mutation classes.

Significance:
ABC-DLBCLs feature frequent mutations of signaling mediators that converge on the CBM complex. We use structure–function approaches to reveal that BCL10 mutations fall into two distinct biochemical classes. Both classes confer resistance to BTK inhibitors, whereas BCL10 truncations confer hyperresponsiveness to MALT1 inhibitors, providing a road map for precision therapies in ABC-DLBCLs.
Os animais do novo mundo figurados na “Arca de Noé sobre o Monte Ararat” de Simon de Myle (1570): um estudo das fontes iconográficas
Authors: Teixeira Dante Martins 
Published: June 2022

Ativo no terceiro quartel do século XVI, Simon de Myle constitui um verdadeiro enigma, pois sua vida e carreira permanecem totalmente desconhecidas até os dias de hoje. A “Arca de Noé sobre o Monte Ararat” é seu único quadro assinado e datado ("Simone de Myle inventor et fecit 1570"), figurando o desembarque dos animais após o dilúvio. Levando em conta mesmo as representações demasiado precárias, essa composição inclui nada menos de 228 monstros, voláteis e quadrúpedes, isso sem considerar as carcaças e as espécies aquáticas deixadas para trás com o recuo das águas. Entre as fontes iconográficas utilizadas destacam-se vários tomos da “Historia Animalium” de Conrad Gesner, além da “Warachtighe Fabulen der Dieren” de Marcus Gheeraerts. Ao contrário de outras pinturas quinhentistas acerca do mesmo tema, essa “Arca de Noé” retrata um número inesperado de animais do Novo Mundo, elenco composto por dois mamíferos, pelo menos três aves e dois “seres prodígiosos”. Nesse particular, o quadro de Simon de Myle inadvertidamente evoca as dúvidas sobre a verossimilhança da passagem bíblica relativa à Arca de Noé, reflexo da descoberta de um número cada vez maior de espécies zoológicas em terras distantes. Colocada já em 1502 por Amerigo Vespucci, essa questão atravessaria os séculos XVI e XVII, levando autores como Joseph de Acosta (1590) e Athanasius Kircher (1675) a buscar uma improvável conciliação entre a realidade factual observada no outro lado do oceano e a verdade revelada contida no livro do Gênesis.
Myocardial Iron Deficiency and Mitochondrial Dysfunction in Advanced Heart Failure in Humans
Authors: Zhang Hao , Jamieson K. Lockhart , Grenier Justin , Nikhanj Anish , Tang Zeyu , Wang Faqi , Wang Shaohua , Seidman Jonathan G. , Seidman Christine E. , Thompson Richard , Seubert John M. , Oudit Gavin Y. 
Published: June 2022

Background
Myocardial iron deficiency (MID) in heart failure (HF) remains largely unexplored. We aim to establish defining criterion for MID, evaluate its pathophysiological role, and evaluate the applicability of monitoring it non‐invasively in human explanted hearts.

Methods and Results
Biventricular tissue iron levels were measured in both failing (n=138) and non‐failing control (NFC, n=46) explanted human hearts. Clinical phenotyping was complemented with comprehensive assessment of myocardial remodeling and mitochondrial functional profiles, including metabolic and oxidative stress. Myocardial iron status was further investigated by cardiac magnetic resonance imaging. Myocardial iron content in the left ventricle was lower in HF versus NFC (121.4 [88.1–150.3] versus 137.4 [109.2–165.9] μg/g dry weight), which was absent in the right ventricle. With a priori cutoff of 86.1 μg/g d.w. in left ventricle, we identified 23% of HF patients with MID (HF‐MID) associated with higher NYHA class and worsened left ventricle function. Respiratory chain and Krebs cycle enzymatic activities were suppressed and strongly correlated with depleted iron stores in HF‐MID hearts. Defenses against oxidative stress were severely impaired in association with worsened adverse remodeling in iron‐deficient hearts. Mechanistically, iron uptake pathways were impeded in HF‐MID including decreased translocation to the sarcolemma, while transmembrane fraction of ferroportin positively correlated with MID. Cardiac magnetic resonance with T2* effectively captured myocardial iron levels in failing hearts.

Conclusions
MID is highly prevalent in advanced human HF and exacerbates pathological remodeling in HF driven primarily by dysfunctional mitochondria and increased oxidative stress in the left ventricle. Cardiac magnetic resonance demonstrates clinical potential to non‐invasively monitor MID.
Amiodarone Use and All‐Cause Mortality in Patients With a Continuous‐Flow Left Ventricular Assist Device
Authors: Gopinathannair Rakesh , Pothineni Naga Venkata K. , Trivedi Jaimin R. , Roukoz Henri , Cowger Jennifer , Ahmed Mustafa M. , Bhan Adarsh , K. Ravichandran Ashwin , Bhat Geetha , Al Ahmad Amin , Natale Andrea , Di Biase Luigi , Slaughter Mark S. , Lakkireddy Dhanunjaya 
Published: June 2022

Background
Atrial and ventricular arrhythmias are commonly encountered in patients with advanced heart failure, with amiodarone being the most commonly used antiarrhythmic drug in continuous‐flow left ventricular assist device (CF‐LVAD) recipients. The purpose of this study was to assess the impact of amiodarone use on long‐term all‐cause mortality in ptients with a CF‐LVAD.

Methods and Results

A retrospective multicenter study of CF‐LVAD was conducted at 5 centers including all CF‐LVAD implants from 2007 to 2015. Patients were stratified based on pre–CF‐LVAD implant amiodarone use. Additional use of amiodarone after CF‐LVAD implantation was also evaluated. Primary outcome was all‐cause mortality during long‐term follow‐up. Kaplan‐Meier curves were used to assess survival outcomes. Multivariable Cox regression was used to identify predictors of outcomes. Propensity matching was done to address baseline differences. A total of 480 patients with a CF‐LVAD (aged 58±13 years, 81% men) were included. Of these, 170 (35.4%) were on chronic amiodarone therapy at the time of CF‐LVAD implant, and 310 (64.6%) were not on amiodarone. Rate of all‐cause mortality over the follow‐up period was 32.9% in the amiodarone group compared with 29.6% in those not on amiodarone (
P
=0.008). Similar results were noted in the propensity‐matched group (log‐rank,
P
=0.04). On multivariable Cox regression analysis, amiodarone use at baseline was independently associated with all‐cause mortality (hazard ratio, 1.68 [95% CI, 1.1–2.5];
P
=0.01).

Conclusions
Amiodarone use was associated with significantly increased rates of all‐cause mortality in CF‐LVAD recipients. Earlier interventions for arrhythmias to avoid long‐term amiodarone exposure may improve long‐term outcomes in CF‐LVAD recipients and needs further study.
Neutrophil‐to‐Lymphocyte Ratios in Patients Undergoing Aortic Valve Replacement: The PARTNER Trials and Registries
Authors: Shahim Bahira , Redfors Björn , Lindman Brian R. , Chen Shmuel , Dahlen Torsten , Nazif Tamim , Kapadia Samir , Gertz Zachary M. , Crowley Aaron C. , Li Ditian , Thourani Vinod H. , Kodali Susheel K. , Zajarias Alan , Babaliaros Vasilis C. , Guyton Robert A. , Elmariah Sammy , Herrmann Howard C. , Cohen David J. , Mack Michael J. , Smith Craig R. , Leon Martin B. , George Isaac 
Published: June 2022

Background
The neutrophil‐to‐lymphocyte ratio (NLR) as a marker of systemic inflammation has been associated with worse prognosis in several chronic disease states, including heart failure. However, few data exist on the prognostic impact of elevated baseline NLR or change in NLR levels during follow‐up in patients undergoing transcatheter or surgical aortic valve replacement (TAVR or SAVR) for aortic stenosis.

Methods and Results

NLR was available in 5881 patients with severe aortic stenosis receiving TAVR or SAVR in PARTNER (Placement of Aortic Transcatheter Valves) I, II, and S3 trials/registries (median [Q1, Q3] NLR, 3.30 [2.40, 4.90]); mean NLR, 4.10; range, 0.5–24.9) and was evaluated as continuous variable and categorical tertiles (low: NLR ≤2.70, n=1963; intermediate: NLR 2.70–4.20, n=1958; high: NLR ≥4.20, n=1960). No patients had known baseline infection. High baseline NLR was associated with increased risk of death or rehospitalization at 3 years (58.4% versus 41.0%; adjusted hazard ratio [aHR], 1.39; 95% CI, 1.18–1.63;
P
<0.0001) compared with those with low NLR, irrespective of treatment modality. In both patients treated with TAVR and patients treated with SAVR, NLR decreased between baseline and 2 years. A 1‐unit observed decrease in NLR between baseline and 1 year was associated with lower risk of death or rehospitalization between 1 year and 3 years (aHR, 0.86; 95% CI, 0.82–0.89;
P
<0.0001).

Conclusions
Elevated baseline NLR was independently associated with increased subsequent mortality and rehospitalization after TAVR or SAVR. The observed decrease in NLR after TAVR or SAVR was associated with improved outcomes.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT00530894, NCT0134313, NCT02184442, NCT03225001, NCT0322141.
Potential Impact of 2017 American College of Cardiology/American Heart Association Hypertension Guideline on Contemporary Practice: A Cross‐Sectional Analysis From NCDR PINNACLE Registry
Authors: Hussain Aliza , Virani Salim S. , Zheng Luke , Gluckman Ty J. , Borden William B. , Masoudi Frederick A. , Maddox Thomas M. 
Published: June 2022

Background
Clinical implications of change in the 2017 American College of Cardiology (ACC)/American Heart Association (AHA) guideline on the diagnosis and management of hypertension, compared with recommendations by 2014 expert panel and Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC7), are not known.

Methods and Results
Using data from the NCDR (National Cardiovascular Data Registry) PINNACLE (Practice Innovation and Clinical Excellence) Registry (January 2013‐Decemver 2016), we compared the proportion and clinical characteristics of patients seen in cardiology practices diagnosed with hypertension, recommended antihypertensive treatment, and achieving blood pressure (BP) goals per each guideline document. In addition, we evaluated the proportion of patients at the level of practices meeting BP targets defined by each guideline. Of 6 042 630 patients evaluated, 5 027 961 (83.2%) were diagnosed with hypertension per the 2017 ACC/AHA guideline, compared with 4 521 272 (74.8%) per the 2014 panel and 4 545 976 (75.2%) per JNC7. The largest increase in hypertension prevalence was seen in younger ages, women, and those with lower cardiovascular risk. Antihypertensive medication was recommended to 70.6% of patients per the ACC/AHA guideline compared with 61.8% and 65.9% per the 2014 panel and JNC7, respectively. Among those on antihypertensive agents, 41.2% achieved BP targets per the ACC/AHA guideline, compared with 79.4% per the 2014 panel and 64.3% per JNC7. Lower proportions of women, non‐White (Black and "other") races, and those at higher cardiovascular risk achieved BP goals. Median practice‐level proportion of patients meeting BP targets per the 2014 panel but not the ACC/AHA guideline was 37.8% (interquartile range, 34.8%–40.7%) and per JNC7 but not the ACC/AHA guideline was 22.9% (interquartile range, 19.8%–25.9%).

Conclusions
Following publication of the 2017 guideline, significantly more people, particularly younger people and those with lower cardiovascular risk, will be diagnosed with hypertension and need antihypertensive treatment compared with previous recommendations. Significant practice‐level variation in BP control also exists. Efforts are needed to improve guideline‐concordant hypertension management in an effort to improve outcomes.
Lipoprotein(a) and Subclinical Vascular and Valvular Calcification on Cardiac Computed Tomography: The Atherosclerosis Risk in Communities Study
Authors: Obisesan Olufunmilayo H. , Kou Minghao , Wang Frances M. , Boakye Ellen , Honda Yasuyuki , Uddin S. M. Iftekhar , Dzaye Omar , Osei Albert D. , Orimoloye Olusola A. , Howard‐Claudio Candace M. , Coresh Josef , Blumenthal Roger S. , Hoogeveen Ron C. , Budoff Matthew J. , Matsushita Kunihiro , Ballantyne Christie M. , Blaha Michael J. 
Published: June 2022

Background
Lipoprotein(a) (Lp(a)) is a potent causal risk factor for cardiovascular events and mortality. However, its relationship with subclinical atherosclerosis, as defined by arterial calcification, remains unclear. This study uses the ARIC (Atherosclerosis Risk in Communities Study) to evaluate the relationship between Lp(a) in middle age and measures of vascular and valvular calcification in older age.

Methods and Results
Lp(a) was measured at ARIC visit 4 (1996–1998), and coronary artery calcium (CAC), together with extracoronary calcification (including aortic valve calcium, aortic valve ring calcium, mitral valve calcification, and thoracic aortic calcification), was measured at visit 7 (2018–2019). Lp(a) was defined as elevated if >50 mg/dL and CAC/extracoronary calcification were defined as elevated if >100. Logistic and linear regression models were used to evaluate the association between Lp(a) and CAC/extracoronary calcification, with further stratification by race. The mean age of participants at visit 4 was 59.2 (SD 4.3) years, with 62.2% women. In multivariable adjusted analyses, elevated Lp(a) was associated with higher odds of elevated aortic valve calcium (adjusted odds ratio [aOR], 1.82; 95% CI, 1.34–2.47), CAC (aOR, 1.40; 95% CI, 1.08–1.81), aortic valve ring calcium (aOR, 1.36; 95% CI, 1.07–1.73), mitral valve calcification (aOR, 1.37; 95% CI, 1.06–1.78), and thoracic aortic calcification (aOR, 1.36; 95% CI, 1.05–1.77). Similar results were obtained when Lp(a) and CAC/extracoronary calcification were examined on continuous logarithmic scales. There was no significant difference in the association between Lp(a) and each measure of calcification by race or sex.

Conclusions
Elevated Lp(a) at middle age is significantly associated with vascular and valvular calcification in older age, represented by elevated CAC, aortic valve calcium, aortic valve ring calcium, mitral valve calcification, thoracic aortic calcification. Our findings encourage assessing Lp(a) levels in individuals with increased cardiovascular disease risk, with subsequent comprehensive vascular and valvular assessment where elevated.
Prognostic Implications of Prestent Pullback Pressure Gradient and Poststent Quantitative Flow Ratio in Patients Undergoing Percutaneous Coronary Intervention
Authors: Dai Neng , Yuan Sheng , Dou Kefei , Zhang Rui , Hu Nan , He Jining , Guan Changdong , Zou Tongqiang , Qiao Zheng , Duan Shaofeng , Xie Lihua , Yu Yongfu , Zhang Yingmei , Xu Bo , Ge Junbo 
Published: June 2022

Background
Coronary diffuse disease associates with poor outcomes, but little is known about its role after percutaneous coronary intervention (PCI). We aimed to investigate the prognostic implication of pre‐PCI focal or diffuse disease patterns combined with post‐PCI quantitative flow ratio (QFR).

Methods and Results

Pre‐PCI QFR derived pullback pressure gradient (PPG) (QFR‐PPG) was measured to assess physiological disease patterns for 1685 included vessels; the vessels were classified according to dichotomous pre‐PCI QFR‐PPG and post‐PCI QFR. Vessel‐oriented composite outcome, a composite of vessel‐related ischemia‐driven revascularization, vessel‐related myocardial infarction, or cardiac death at 2 years was compared among these groups. Vessels with low pre‐PCI PPG (3.9% versus 2.0%, hazard ratio [HR], 1.93; 95% CI, 1.08–3.44;
P
=0.02) or low post‐PCI QFR (9.8% versus 2.7%, HR, 3.78; 95% CI, 1.61–8.87;
P
=0.001) demonstrated higher vessel‐oriented composite outcome risk after stent implantation. Of note, despite high post‐PCI QFR achieved, vessels with low pre‐PCI QFR‐PPG presented higher risk of vessel‐oriented composite outcome than those with high pre‐PCI QFR‐PPG (3.7% versus 1.8%, HR, 2.03; 95% CI, 1.09–3.76;
P
=0.03) and pre‐PCI QFR‐PPG demonstrated direct prognostic effect not mediated by post‐PCI QFR. Integration of groups classified by pre‐PCI QFR‐PPG and post‐PCI QFR showed significantly higher discriminant and reclassification abilities than clinical factors (C‐index 0.77 versus 0.72,
P
=0.03; integrated discrimination improvement 0.93%,
P
=0.04; net reclassification index 0.33,
P
=0.02).

Conclusions
Prognostic value of pre‐PCI focal or diffuse disease patterns assessed by QFR‐PPG index was retained even after successful PCI, which is mostly explained by its direct effect that was not mediated by post‐PCI QFR. Integration of both pre‐PCI and post‐PCI physiological information can provide better risk stratification in vessels with stent implantation.
Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT05104580.
Workers’ Activity Profiles Associated With Predicted 10‐Year Cardiovascular Disease Risk
Authors: Biswas Aviroop , Chen Cynthia , Prince Stephanie A. , Smith Peter M. , Mustard Cameron A. 
Published: June 2022

Background
There is a need to explore common activity patterns undertaken by workers and the association between these activity profiles and cardiovascular disease (CVD). This study explored the number and type of distinct profiles of activity patterns among workers and the association between these profiles and predicted 10‐year risk for a first atherosclerotic CVD event.

Methods and Results
Distinct activity patterns from a cross‐section of workers’ accelerometer data were sampled from Canadian Health Measures Survey participants (5 cycles, 2007–2017) and identified using hierarchical cluster analysis techniques. Covariates included accelerometer wear time, work factors, sociodemographic factors, clinical markers, and lifestyle variables. Associations between activity profiles and high atherosclerotic CVD risk >10% were estimated using robust Poisson regression models. Six distinct activity profiles were identified from 8909 workers. Compared with the “lowest activity” profile, individuals in the “highest activity” and “moderate evening activity” profiles were at 42% lower risk (relative risk [RR], 0.58; 95% CI, 0.47, 0.70) and 33% lower risk (RR, 0.67; 95% CI, 0.44, 0.87) of predicted 10‐year atherosclerotic CVD risk of >10%, respectively. “Moderate activity” and “fluctuations of moderate activity” profiles were also associated with lower risk estimates, whereas the “high daytime activity” profile was not statistically different to the reference profile.

Conclusions
Workers accumulating physical activity throughout the day and during recreational hours were found to have optimal CVD risk profiles. Workers accumulating physical activity only during daytime work hours were not associated with reduced CVD risk. Findings can inform alternative strategies to conferring the cardiovascular benefits of physical activity among workers. Large prospective studies are needed to confirm these findings.
Clinician Responses to a Clinical Decision Support Advisory for High Risk of Torsades de Pointes
Authors: Gallo Tyler , Heise C. William , Woosley Raymond L. , Tisdale James E. , Tan Malinda S. , Gephart Sheila M. , Antonescu Corneliu C. , Malone Daniel C. 
Published: June 2022

Background
Torsade de pointes (TdP) is a potentially fatal cardiac arrhythmia that is often drug induced. Clinical decision support (CDS) may help minimize TdP risk by guiding decision making in patients at risk. CDS has been shown to decrease prescribing of high‐risk medications in patients at risk of TdP, but alerts are often ignored. Other risk‐management options can potentially be incorporated in TdP risk CDS. Our goal was to evaluate actions clinicians take in response to a CDS advisory that uses a modified Tisdale QT risk score and presents management options that are easily selected (eg, single click).

Methods and Results

We implemented an inpatient TdP risk advisory systemwide across a large health care system comprising 30 hospitals. This CDS was programmed to appear when prescribers attempted ordering medications with a known risk of TdP in a patient with a QT risk score ≥12. The CDS displayed patient‐specific information and offered relevant management options including canceling offending medications and ordering electrolyte replacement protocols or ECGs. We retrospectively studied the actions clinicians took within the advisory and separated by drug class. During an 8‐month period, 7794 TdP risk advisories were issued. Antibiotics were the most frequent trigger of the advisory (n=2578, 33.1%). At least 1 action was taken within the advisory window for 2700 (34.6%) of the advisories. The most frequent action taken was ordering an ECG (n=1584, 20.3%). Incoming medication orders were canceled in 793 (10.2%) of the advisories. The frequency of each action taken varied by drug class (
P
<0.05 for all actions).

Conclusions
A modified Tisdale QT risk score–based CDS that offered relevant single‐click management options yielded a high action/response rate. Actions taken by clinicians varied depending on the class of the medication that evoked the TdP risk advisory, but the most frequent was ordering an ECG.