bluuebunny/crossref_metadata_2025_split huggingface dataset:
Impact of High Deductible Health Plans on Cardiovascular Medication Adherence and Health Disparities
Authors: Lewey Jennifer , Gagne Joshua J. , Franklin Jessica , Lauffenburger Julie C. , Brill Gregory , Choudhry Niteesh K. 
Published: January 2019

Background:
High deductible health plans (HDHP) are associated with high levels of patient cost-sharing and are becoming increasingly used in the United Status as a means of reducing healthcare utilization and spending. Our objective is to determine whether HDHP enrollment is associated with a change in adherence to evidence-based medications to treat cardiovascular risk factors and whether such changes vary based on race/ethnicity or socioeconomic status.

Methods and Results:

We conducted a retrospective cohort study using an interrupted time series with concurrent control group design among beneficiaries of Aetna—a national commercial insurer. We included 14 866 patients who filled prescriptions for medications to treat hypertension, high cholesterol, or diabetes mellitus between 2009 and 2014 and who switched from a traditional plan into an HDHP and 14 866 controls who did not switch to an HDHP matched based on calendar time, medication class, race/ethnicity, socioeconomic status, and propensity score. We were specifically interested in evaluating 4 prespecified subgroups based on race/ethnicity (white versus nonwhite) and socioeconomic status (higher versus lower). The main outcome was medication adherence as measured by proportion of days covered. The overall cohort had an average age of 53 years, and 44% were women. Baseline adherence was the lowest in the nonwhite patient group. Switching to an HDHP was associated with a decrease in the level of adherence of 5 percentage points across all 4 subgroups (change in level, −5.0%; 95% CI, −5.9% to −4.0%;
P
<0.0001).

Conclusions:
HDHP enrollment was associated with a reduction in adherence to medications to treat cardiovascular risk factors. The magnitude of this effect did not vary based on race/ethnicity or socioeconomic status. Because racial/ethnic minorities have lower rates of medication adherence, future studies should evaluate whether HDHP-associated changes in adherence have greater clinical consequences for these patients.
Collaborative Quality Improvement Reduces Postoperative Pneumonia After Isolated Coronary Artery Bypass Grafting Surgery
Authors: Likosky Donald S. , Harrington Steven D. , Cabrera Lourdes , DeLucia Alphonse , Chenoweth Carol E. , Krein Sarah L. , Thibault Dylan , Zhang Min , Matsouaka Roland A. , Strobel Raymond J. , Prager Richard L. 
Published: January 2019

Background:
To date, studies evaluating outcome improvements associated with participation in physician-led collaboratives have been limited by the absence of a contemporaneous control group. We examined post cardiac surgery pneumonia rates associated with participation in a statewide, quality improvement collaborative relative to a national physician reporting program.

Methods and Results:

We evaluated 911 754 coronary artery bypass operations (July 1, 2011, to June 30, 2017) performed across 1198 hospitals participating in a voluntary national physician reporting program (Society of Thoracic Surgeons [STS]), including 33 that participated in a Michigan-based collaborative (MI-Collaborative). Unlike STS hospitals not participating in the MI-Collaborative (i.e., STSnonMI) that solely received blinded reports, MI-Collaborative hospitals received a multi-faceted intervention starting November 2012 (quarterly in-person meetings showcasing unblinded data, webinars, site visits). Eighteen of the MI-Collaborative hospitals received additional support to implement recommended pneumonia prevention practices (“MI-CollaborativePlus”), whereas 15 did not (“MI-CollaborativeOnly”). We evaluated rates of postoperative pneumonia, adjusting for patient mix and hospital effects. Baseline patient characteristics were qualitatively similar between groups and time. During the pre-intervention period (Q3/2011 through Q3/2012), there was no statistically significant difference in the adjusted odds of pneumonia for STS hospitals participating in the MI-Collaborative compared to the STS non-MI hospitals. However, during the intervention period (Q4/2012 through Q2/2017), there was a significant 2% reduction per quarter in the adjusted odds of pneumonia for MI-Collaborative hospitals (
n
=33) relative to the STS non-MI hospitals. There was a significant 3% per quarter reduction in the adjusted odds of pneumonia for the MI-Collaborative Only (
n
=15) hospitals relative to the STS non-MI hospitals. Over the course of the overall study period, the STS non-MI hospitals had a 1.96% reduction in risk-adjusted pneumonia (pre- vs. intervention periods), which was less than the MI-Collaborative (3.23%,
P
=0.011). Over the same time period, the MI-Collaborative Plus (
n
=18) reduced adjusted pneumonia rates by 10.29%,
P
=0.001.

Conclusions:
Participation in a physician-led collaborative was associated with significant reductions in pneumonia relative to a national quality reporting program. Interventions including collaborative learning may yield superior outcomes relative to solely using physician feedback reporting.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT02068716.
Hospital Variation in the Utilization and Implementation of Targeted Temperature Management in Out-of-Hospital Cardiac Arrest
Authors: Khera Rohan , Humbert Andrew , Leroux Brian , Nichol Graham , Kudenchuk Peter , Scales Damon , Baker Andrew , Austin Mike , Newgard Craig D. , Radecki Ryan , Vilke Gary M. , Sawyer Kelly N. , Sopko George , Idris Ahamed H. , Wang Henry , Chan Paul S. , Kurz Michael C. ,   for the Resuscitation Outcomes Consortium Investigators
Published: January 2019

Background
Targeted temperature management (TTM) for out-of-hospital cardiac arrest is associated with improved functional survival and is a class I recommendation in resuscitation guidelines. However, patterns of utilization of TTM and adherence to recommended TTM guidelines in contemporary practice are unknown.

Methods and Results

In a multicenter, prospective cohort of consecutive adults with non-traumatic out-of-hospital cardiac arrest in the Resuscitation Outcomes Consortium in 2012 to 2015, we identified all adults (≥18 years) who were potential candidates for TTM. Of 37 898 out-of-hospital cardiac arrest patients at 186 hospitals across 10 Resuscitation Outcomes Consortium sites, 8313 survived for ≥4 hours after hospital arrival, of which, 2878 (34.6%) received TTM. Mean age was 61.5 years and 36.3% were women. Median hospital rate of TTM use was 27% (interquartile range [IQR]: 14%, 45%), with an over 2-fold difference across sites after accounting for differences in presentation characteristics (median odds ratio, 2.10 [1.83–2.26]). Notably, TTM utilization decreased during the study period (57.5% [2012] to 26.5% [2015],
P
<0.001) including among shockable out-of-hospital cardiac arrest (73.4% to 46.3%,
P
<0.001). When administered, the median rate of deviation from one or more recommended practices was 60% (IQR: 40%, 78%). The median rate for delayed onset of TTM was 13% (IQR: 0%, 25%), varying by 70% for identical patients across 2 randomly chosen hospitals (median odds ratio 1.70 [1.39–1.97]). Similarly, the median rate for TTM <24 hours was 20% (IQR: 0%, 34%) and for achieved temperature <32°C was 18% (IQR: 0%, 39%), with marked variation across sites (median odds ratios of 1.44 [1.18–1.64] and 1.98 [1.62–2.31], respectively).

Conclusions
There has been a substantial decline in the utilization of TTM with significant variation in its real-world implementation. Further standardization of contemporary post-resuscitation practices, like TTM, is critical to ensure that their potential survival benefit is realized.
A Phase 2 Randomized, Sham-Controlled Trial of Internal Carotid Artery Infusion of Autologous Bone Marrow–Derived ALD-401 Cells in Patients With Recent Stable Ischemic Stroke (RECOVER-Stroke)
Authors: Savitz Sean I. , Yavagal Dileep , Rappard George , Likosky William , Rutledge Neal , Graffagnino Carmelo , Alderazi Yazan , Elder Jennifer A. , Chen Peng R. , Budzik Ronald F. , Tarrel Ronald , Huang David Y. , Hinson James M. ,   On behalf of the ALD-401 Trial Group
Published: January 2019

Background:
Ischemic stroke has no approved treatments to enhance recovery. ALD-401 is an enriched population of aldehyde dehydrogenase-bright stem cells, capable of reducing neurological deficits in animal models. The primary objective of this trial was to determine the safety of internal carotid artery, intra-arterially delivered autologous bone marrow–derived ALD-401 in patients with disabling middle cerebral artery stroke in comparison with sham harvest with sham infusion. Secondary objectives were to determine feasibility and efficacy.

Methods:
This was a prospective phase 2, industry-funded, randomized, sham-controlled, parallel-group, multicenter study with blinded assessments. One hundred subjects were planned, aged 30 to 83 years, with confirmed first-time middle cerebral artery ischemic stroke with modified Rankin scale ≥3. Study patients were randomly assigned 3:2 to bone marrow harvest at 11 to 17 days after stroke followed 2 days later by intracarotid infusion of ALD-401 versus sham harvest and then sham infusion in the same timeframe. The primary study outcome was safety based on the incidence of a 4-point National Institutes of Health Stroke Scale worsening and the proportion of serious adverse events. Efficacy was based on modified Rankin scale change at 90 days. Other secondary outcomes were the proportions of patients experiencing adverse events, disability by Barthel Index, quality of life using EQ-5D, rehabilitation utilization, disability at 1 year, and MRI evidence of complications.

Results:

There were no infusional or allergic reactions and no difference in treatment emergent adverse events. Four patients had small areas of asymptomatic restricted diffusion on MRI in the treatment group. There was no significant difference between the ALD-401 and placebo groups on the modified Rankin scale for the intent-to-treat population at day 90 (mean difference, 0.3; 95% CI, –0.3 to 0.8;
P
=0.330). There were no significant differences between the groups on any of the secondary efficacy measures.

Conclusions:
Intracarotid infusion of ALD-401 does not lead to clinical adverse events in patients with subacute ischemic stroke, although there was a higher incidence of small lesions on MRI in the treatment group. There was no difference in the primary efficacy end point between the groups. The study provides a framework for the design and conduct of future intra-arterial cell therapy trials in stroke.

Clinical Trial Registration:

URL:
https://www.clinicaltrials.gov
. Unique identifier: NCT01273337.
Bacteroides vulgatus
and
Bacteroides dorei
Reduce Gut Microbial Lipopolysaccharide Production and Inhibit Atherosclerosis
Authors: Yoshida Naofumi , Emoto Takuo , Yamashita Tomoya , Watanabe Hikaru , Hayashi Tomohiro , Tabata Tokiko , Hoshi Namiko , Hatano Naoya , Ozawa Genki , Sasaki Naoto , Mizoguchi Taiji , Amin Hilman Zulkifli , Hirota Yushi , Ogawa Wataru , Yamada Takuji , Hirata Ken-ichi 
Published: January 2019

Background:

It is increasingly recognized that gut microbiota play a pivotal role in the development of atherosclerotic cardiovascular disease. Previously, we have reported that the abundance of genus
Bacteroides
is lower in patients with coronary artery disease (CAD) than in patients without CAD with coronary risk factors or in healthy volunteers. However, it remains unclear which and how specific gut bacteria contribute to the progression of atherosclerosis.

Methods:
We recruited patients with CAD patients and controls without CAD with coronary risk factors. We then compared gut microbial composition using 16S ribosomal RNA gene sequencing in fecal samples to detect species with differential abundance between 2 groups. Subsequently, we used atherosclerosis-prone mice to study the mechanisms underlying the relationship between such species and atherosclerosis.

Results:

Human fecal 16S ribosomal RNA gene sequencing revealed a significantly lower abundance of
Bacteroides vulgatus
and
Bacteroides dorei
in patients with CAD. This significant differential abundance was confirmed by quantitative polymerase chain reaction. Gavage with live
B. vulgatus
and
B. dorei
attenuated atherosclerotic lesion formation in atherosclerosis-prone mice, markedly ameliorating endotoxemia followed by decreasing gut microbial lipopolysaccharide production, effectively suppressing proinflammatory immune responses. Furthermore, fecal lipopolysaccharide levels in patients with CAD were significantly higher and negatively correlated with the abundance of
B. vulgatus
and
B. dorei
.

Conclusions:

Our translational research findings identify a previously unknown link between specific gut bacteria and atherosclerosis. Treatment with live
B. vulgatus
and
B. dorei
may help prevent CAD.

Clinical Trial Registration:

URL:
https://upload.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000018051
. Unique identifier: UMIN000015703.
Bcl2-Like Protein 12 Is Required for the Aberrant T Helper-2 Polarization in the Heart by Enhancing Interleukin-4 Expression and Compromising Apoptotic Machinery in CD4+ T Cells
Authors: Chen Xiao , Zeng Xian-Hai , Wang Mangyuan , Chen Liang , Zhang Ningning , Rao Man , Yang Ping-Chang , Song Jiangping 
Published: January 2019

Background:
The biased T helper-2 (Th2) response plays a critical role in myocarditis. Bcl2-like protein 12 (Bcl2L12) is associated with the Th2 pattern of inflammation. This study aims to elucidate the role of Bcl2L12 in the pathogenesis of Th2-biased inflammation in the heart.

Methods:
Mice were treated with the myosin heavy-chain-α peptides to induce inflammation in the heart. Human hearts were collected from the surgically removed hearts of patients who had undergone heart transplantation.

Results:

The expression of Bcl2L12 was detected in CD4
+
T cells of the hearts, which was markedly higher in the hearts with myocarditis at the advanced stage of heart failure compared with the control (dilated cardiomyopathy) hearts without myocarditis. Mice with Bcl2L12-deficient CD4
+
T cells failed to induce the Th2-biased inflammation in the heart. CD4
+
T cells with a higher expression of Bcl2L12 were prone to differentiate into Th2 cells. Bcl2L12 formed a complex with GATA3 in CD4
+
T cells to enhance the binding between GATA3 and the
Il4
promoter, which promoted the
Il4
gene transcription. Bcl2L12 compromised the apoptotic machinery by inhibiting the expression of p53 in CD4
+
T cells to reduce the activation-induced CD4
+
T cell death.

Conclusions:

CD4
+
T cells isolated from hearts with myocarditis at the end stage of heart failure express high levels of Bcl2L12, and the latter is required for the development of aberrant Th2 polarization in the heart. The Bcl2L12 may be a novel target in the treatment of myocarditis as well as other Th2-biased inflammation.
Long-Term Association of Low-Density Lipoprotein Cholesterol With Cardiovascular Mortality in Individuals at Low 10-Year Risk of Atherosclerotic Cardiovascular Disease
Authors: Abdullah Shuaib M. , Defina Laura F. , Leonard David , Barlow Carolyn E. , Radford Nina B. , Willis Benjamin L. , Rohatgi Anand , McGuire Darren K. , de Lemos James A. , Grundy Scott M. , Berry Jarett D. , Khera Amit 
Published: January 2019

Background:
The associations of low-density lipoprotein cholesterol (LDL-C) with cardiovascular disease (CVD) and coronary heart disease mortality in an exclusively low estimated 10-year risk group are not well delineated. We sought to determine the long-term associations of various LDL-C and non–high-density lipoprotein cholesterol (HDL-C) thresholds and CVD and coronary heart disease mortality in a large, low 10-year risk cohort.

Methods:
The study sample included participants of the CCLS (Cooper Center Longitudinal Study) without a history of CVD or diabetes mellitus and defined as low risk (<7.5%) for 10-year atherosclerotic CVD events at baseline based on Pooled Cohort Risk Assessment Equations. The associations of fasting LDL-C and non–HDL-C with CVD mortality were tested with Cox proportional hazards models.

Results:
In 36 375 participants (72% men, median age 42) followed for a median of 26.8 years, 1086 CVD and 598 coronary heart disease deaths occurred. Compared with LDL-C <100 mg/dL, LDL-C categories 100 to 129 mg/dL, 130 to 159 mg/dL, 160 to 189.9 mg/dL, and ≥190 mg/dL were associated with a significantly higher risk of CVD death, with hazard ratios of 1.4 (95% CI, 1.1–1.7), 1.3 (95% CI, 1.1–1.6), 1.9 (95% CI, 1.5–2.4), and 1.7 (95% CI, 1.3–2.3), and mean reductions in years free of CVD death of 1.8, 1.1, 4.3, and 3.9, respectively. After adjustment for atherosclerotic CVD risk factors, LDL-C categories 160 to 189 mg/dL and ≥190 mg/dL remained independently associated with CVD mortality, with hazard ratios of 1.7 (95% CI, 1.4–2.2) and 1.5 (95% CI, 1.2–2.1), respectively. In multivariable-adjusted models using non–HDL-C <130 mg/dL as the reference, non–HDL-C 160 to 189 mg/dL, 190 to 219 mg/dL, and ≥220 mg/dL were significantly associated with CVD death, with hazard ratios of 1.3 (95% CI, 1.1–1.6), 1.8 (95% CI, 1.4–2.2), and 1.5 (95% CI, 1.2–2.0), respectively. Restricting the cohort to those with 10-year risk <5% did not diminish the associations of LDL-C and non–HDL-C with CVD mortality.

Conclusions:
In a low 10-year risk cohort with long-term follow-up, LDL-C and non–HDL-C ≥160 mg/dL were independently associated with a 50% to 80% increased relative risk of CVD mortality. These findings may have implications for future cholesterol treatment paradigms.
Oxidized Low-Density Lipoprotein Receptor in Lymphocytes Prevents Atherosclerosis and Predicts Subclinical Disease
Authors: Tsilingiri Katerina , de la Fuente Hortensia , Relaño Marta , Sánchez-Díaz Raquel , Rodríguez Cristina , Crespo Javier , Sánchez-Cabo Fátima , Dopazo Ana , Alonso-Lebrero José L. , Vara Alicia , Vázquez Jesús , Casasnovas José M. , Alfonso Fernando , Ibáñez Borja , Fuster Valentín , Martínez-González José , Martín Pilar , Sánchez-Madrid Francisco 
Published: January 2019

Background:
Although the role of Th17 and regulatory T cells in the progression of atherosclerosis has been highlighted in recent years, their molecular mediators remain elusive. We aimed to evaluate the association between the CD69 receptor, a regulator of Th17/regulatory T cell immunity, and atherosclerosis development in animal models and in patients with subclinical disease.

Methods:
Low-density lipoprotein receptor–deficient chimeric mice expressing or not expressing CD69 on either myeloid or lymphoid cells were subjected to a high fat diet. In vitro functional assays with human T cells were performed to decipher the mechanism of the observed phenotypes. Expression of CD69 and NR4A nuclear receptors was evaluated by reverse transcription–polymerase chain reaction in 305 male participants of the PESA study (Progression of Early Subclinical Atherosclerosis) with extensive (n=128) or focal (n=55) subclinical atherosclerosis and without disease (n=122).

Results:

After a high fat diet, mice lacking CD69 on lymphoid cells developed large atheroma plaque along with an increased Th17/regulatory T cell ratio in blood. Oxidized low-density lipoprotein was shown to bind specifically and functionally to CD69 on human T lymphocytes, inhibiting the development of Th17 cells through the activation of NR4A nuclear receptors. Participants of the PESA study with evidence of subclinical atherosclerosis displayed a significant CD69 and NR4A1 mRNA downregulation in peripheral blood leukocytes compared with participants without disease. The expression of CD69 remained associated with the risk of subclinical atherosclerosis in an adjusted multivariable logistic regression model (odds ratio, 0.62; 95% CI, 0.40–0.94;
P
=0.006) after adjustment for traditional risk factors, the expression of NR4A1, the level of oxidized low-density lipoprotein, and the counts of different leucocyte subsets.

Conclusions:
CD69 depletion from the lymphoid compartment promotes a Th17/regulatory T cell imbalance and exacerbates the development of atherosclerosis. CD69 binding to oxidized low-density lipoprotein on T cells induces the expression of anti-inflammatory transcription factors. Data from a cohort of the PESA study with subclinical atherosclerosis indicate that CD69 expression in PBLs inversely correlates with the presence of disease. The expression of CD69 remained an independent predictor of subclinical atherosclerosis after adjustment for traditional risk factors.
Genetically Determined Levels of Circulating Cytokines and Risk of Stroke
Authors: Georgakis Marios K. , Gill Dipender , Rannikmäe Kristiina , Traylor Matthew , Anderson Christopher D. ,   MEGASTROKE consortium of the International Stroke Genetics Consortium (ISGC), Lee Jin-Moo , Kamatani Yoichiro , Hopewell Jemma C. , Worrall Bradford B. , Bernhagen Jürgen , Sudlow Cathie L. M. , Malik Rainer , Dichgans Martin 
Published: January 2019

Background:
Cytokines and growth factors have been implicated in the initiation and propagation of vascular disease. Observational studies have shown associations of their circulating levels with stroke. Our objective was to explore whether genetically determined circulating levels of cytokines and growth factors are associated with stroke and its etiologic subtypes by conducting a 2-sample Mendelian randomization (MR) study.

Methods:
Genetic instruments for 41 cytokines and growth factors were obtained from a genome-wide association study of 8293 healthy adults. Their associations with stroke and stroke subtypes were evaluated in the MEGASTROKE genome-wide association study data set (67 162 cases; 454 450 controls) applying inverse variance–weighted meta-analysis, weighted-median analysis, Mendelian randomization–Egger regression, and multivariable Mendelian randomization. The UK Biobank cohort was used as an independent validation sample (4985 cases; 364 434 controls). Genetic instruments for monocyte chemoattractant protein-1 (MCP-1/CCL2) were further tested for association with etiologically related vascular traits by using publicly available genome-wide association study data.

Results:

Genetic predisposition to higher MCP-1 levels was associated with higher risk of any stroke (odds ratio [OR] per 1 SD increase, 1.06; 95% CI, 1.02–1.09;
P
=0.0009), any ischemic stroke (OR, 1.06; 95% CI, 1.02–1.10;
P
=0.002), large-artery stroke (OR, 1.19; 95% CI, 1.09–1.30;
P
=0.0002), and cardioembolic stroke (OR, 1.14; 95% CI, 1.06–1.23;
P
=0.0004), but not with small-vessel stroke or intracerebral hemorrhage. The results were stable in sensitivity analyses and remained significant after adjustment for cardiovascular risk factors. Analyses in the UK Biobank showed similar associations for available phenotypes (any stroke: OR, 1.08; 95% CI, 0.99–1.17;
P
=0.09; any ischemic stroke: OR, 1.07; 95% CI, 0.97–1.18;
P
=0.17). Genetically determined higher MCP-1 levels were further associated with coronary artery disease (OR, 1.04; 95% CI, 1.00–1.08;
P
=0.04) and myocardial infarction (OR, 1.05; 95% CI, 1.01–1.09;
P
=0.02), but not with atrial fibrillation. A meta-analysis of observational studies showed higher circulating MCP-1 levels in patients with stroke in comparison with controls.

Conclusions:
Genetic predisposition to elevated circulating levels of MCP-1 is associated with higher risk of stroke, in particular with large-artery stroke and cardioembolic stroke. Whether targeting MCP-1 or its receptors can lower stroke incidence requires further study.