bluuebunny/crossref_metadata_2025_split huggingface dataset:
Viewpoint: Central adjudication of myocardial infarction in outcome-driven clinical trials – Common patterns in TRITON, RECORD, and PLATO?
Authors: Atar Dan , Serebruany Victor L. 
Published: July 2012

SummaryCentral adjudication in randomised controlled outcome-driven trials represents a traditional approach to maintain data integrity by applying uniformed rules for assessment of clinical events. It was the purpose of this investigation to determine the patterns of myocardial infarction (MI) adjudication in the TRITON, RECORD, and PLATO trials. We were matching centrally-adjudicated MI’s (CAMI’s) from the official trial publication with the site-reported MI (SRMI’s) count from the Food and Drug Administration’s secondary analyses for the investigational compounds prasugrel (TRITON), rosiglitazone (RECORD), and ticagrelor (PLATO). CAMI numbers showed a remarkable discrepancy to SRMI’s by more than a doubling of the difference: from 72 to 145 events in TRITON favoring prasugrel (from a hazard ratio [HR]=0.76, p=0.08; to a HR=0.76, p<0.001), and from 44 to 89 events in favour of ticagrelor in PLATO (from a HR=0.94, p=0.095; to a HR=0.84, p<0.001). In contrast, in the RECORD trial, the CAMI count was less than the SRMI count (from 24 to 8 events, from a HR=1.42, p=0.93; to a HR=1.14, p=0.96), in this case diminishing cardiovascular hazards in favour of rosiglitazone. In conclusion, central adjudication in the TRITON, the RECORD, and the PLATO trial turned out to have a critical impact on study outcomes. Trial publications should in the future include site-reported major efficacy and safety endpoints to preserve data integrity. The regulatory authorities should consider independent audits when there is a major disagreement between centrally adjudicated and site reported events influencing the results of a major clinical trial.
Fibrinogen gene regulation
Authors: Fish Richard J. , Neerman-Arbez Marguerite 
Published: July 2012

SummaryThe Aα, Bβ and γ polypeptide chains of fibrinogen are encoded by a three gene cluster on human chromosome four. The fibrinogen genes (FGB-FGA-FGG) are expressed almost exclusively in hepatocytes where their output is coordinated to ensure a sufficient mRNA pool for each chain and maintain an abundant plasma fibrinogen protein level. Fibrinogen gene expression is controlled by the activity of proximal promoters which contain binding sites for hepatocyte transcription factors, including proteins which influence fibrinogen transcription in response to acute-phase inflammatory stimuli. The fibrinogen gene cluster also contains cis regulatory elements; enhancer sequences with liver activities identified by sequence conservation and functional genomics. While the transcriptional control of this gene cluster is fascinating biology, the medical impetus to understand fibrinogen gene regulation stems from the association of cardiovascular disease risk with high level circulating fibrinogen. In the general population this level varies from about 1.5 to 3.5 g/l. This variation between individuals is influenced by genotype, suggesting there are genetic variants contributing to fibrinogen levels which reside in fibrinogen regulatory loci. A complete picture of how fibrinogen genes are regulated will therefore point towards novel sources of regulatory variants. In this review we discuss regulation of the fibrinogen genes from proximal promoters and enhancers, the influence of acute-phase stimulation, post-transcriptional regulation by miRNAs and functional regulatory variants identified in genetic studies. Finally, we discuss the fibrinogen locus in light of recent advances in understanding chromosomal architecture and suggest future directions for researching the mechanisms that control fibrinogen expression.
Dysregulated coagulation associated with hypofibrinogenaemia and plasma hypercoagulability: Implications for identifying coagulopathic mechanisms in humans
Authors: Marchi Rita , Walton Bethany L. , McGary Colleen S. , Lin Feng-Chang , Ma Alice D. , Pawlinski Rafal , Mackman Nigel , Campbell Robert A. , Di Paola Jorge , Wolberg Alisa S. 
Published: July 2012

SummaryIdentifying coagulation abnormalities in patients with combined bleeding and thrombosis history is clinically challenging. Our goal was to probe the complexity of dysregulated coagulation in humans by characterizing pathophysiologic mechanisms in a patient with both bleeding and thrombosis. The patient is a 56-year-old female with a history of haematomas, poor wound healing, and thrombosis (retinal artery occlusion and transient cerebral ischaemia). She had a normal activated partial thromboplastin time, prolonged thrombin and reptilase times, and decreased functional and antigenic fibrinogen levels, and was initially diagnosed with hypodysfibrinogenaemia. This diagnosis was supported by DNA analysis revealing a novel FGB mutation (c.656A>G) predicting a Q189R mutation in the mature chain that was present in the heterozygote state. However, turbidity analysis showed that purified fibrinogen polymerisation and degradation were indistinguishable from normal, and Bβ chain subpopulations appeared normal by two-dimensional difference in-gel electrophoresis, indicating the mutated chain was not secreted. Interestingly, plasma thrombin generation testing revealed the patient’s thrombin generation was higher than normal and could be attributed to elevated levels of factor VIII (FVIII, 163–225%). Accordingly, in an arterial injury model, hypofibrinogenaemic mice (Fgn+/−) infused with factor VIII demonstrated significantly shorter vessel occlusion times than saline-infused Fgn+/− mice. Together, these data associate the complex bleeding and thrombotic presentation with combined hypofibrinogenaemia plus plasma hypercoagulability. These findings suggest previous cases in which fibrinogen abnormalities have been associated with thrombosis may also be complicated by co-existing plasma hypercoagulability and illustrate the importance of “global” coagulation testing in patients with compound presentations.
Ferritin Is Independently Associated With the Presence of Coronary Artery Calcium in 12 033 Men
Authors: Sung Ki-Chul , Kang Seok-Min , Cho Eun-Joo , Park Jeong Bae , Wild Sarah H. , Byrne Christopher D. 
Published: July 2012

Objective—
Ferritin concentrations are often increased in patients with metabolic syndrome and type 2 diabetes mellitus, but few reports have examined the associations between ferritin and atherosclerosis. We investigated whether any relationship between ferritin and coronary artery calcium score (CACS) >0 (as a marker of atherosclerosis) was independent of potential confounders, such as iron-binding capacity (transferrin), low-grade inflammation, and cardiovascular risk factors.

Methods and Results—

Data were analyzed from a South Korean occupational cohort of 12 033 men who underwent a cardiac computed tomography estimation of CACS and measurements of multiple cardiovascular risk factors. One-thousand three- hundred-fifteen of 12 033 (11.2%) subjects had a CACS >0. For people with a CACS >0, median (interquartile range) ferritin concentration was 196.8 (136.3–291.9) compared with 182.2 (128.1–253.6) in people with a CACS=0;
P
<0.001. In the highest ferritin quartile, 14.7% (442/3008) of subjects had a CACS >0 compared with 9.7% (292/3010) in the lowest quartile (
P
<0.0001). With increasing ferritin quartiles, there were also higher proportions of people with diabetes mellitus (
P
<0.0001), hypertension (
P
<0.0001), coronary heart disease (
P
=0.003), and a Framingham Risk Score >10% (
P
<0.0001). In logistic regression modeling with CACS >0 as the outcome, ferritin but not transferrin was independently associated with CACS >0 (odds ratio for highest quartile versus lowest quartile, 1.66 [95% CI, 1.3–1.98];
P
=0.0001).

Conclusion—
Increased ferritin concentrations are associated with the presence of a marker of early coronary artery atherosclerosis, independently of traditional cardiovascular risk factors including Framingham risk score, transferrin, preexisting vascular disease, diabetes mellitus, metabolic syndrome factors, and low-grade inflammation.
Immunization With a Combination of 2 Peptides Derived From the C5a Receptor Significantly Reduces Early Atherosclerotic Lesion in
Ldlr

tm1Her

Apob

tm2Sgy

J Mice
Authors: Lu Xinjie , Xia Min , Endresz Valeria , Faludi Ildiko , Mundkur Lakshmi , Gonczol Eva , Chen Daxin , Kakkar Vijay V. 
Published: July 2012

Objective—

The goal of this study was to assess whether immunization of
Ldlr

tm1Her

Apob

tm2Sgy

J mice with 2 peptides located at the N-terminus of the C5a receptor (C5aR), either alone or in combination, is effective in reducing atherosclerotic lesions.

Methods and Results—

Five- to 6-week-old female
Ldlr

tm1Her

Apob

tm2Sgy

J mice were immunized using a repetitive immunization multiple sites strategy with keyhole limpet hemocyanin-conjugated peptides derived from the C5aR, either alone (designated as C5aR-P1 [aa 1–21] and C5aR-P2 [aa 19–31]) or in combination (designated as C5aR-P1+C5aR-P2). Mice were fed a high-fat diet for 10 weeks. Lesions were evaluated histologically; local and systemic immune responses were analyzed by immunohistochemistry of aorta samples and cytokine measurements in plasma samples and splenocyte supernatants. Immunization of
Ldlr

tm1Her

Apob

tm2Sgy

J mice with these peptides elicited high concentrations of antibodies against each peptide. Immunization with the single peptide inhibited plaque development. Combined inoculation with C5aR-P1+C5aR-P2 had an additive effect on reducing the lesion in the aorta sinus and descending aortas when compared with controls. This effect correlated with cellular infiltration and cytokine/chemokine secretion in the serum or in stimulated spleen cells as well as specific cellular immune responses when compared with controls.

Conclusion—
Immunization of mice with C5aR-P1 and C5aR-P2, either alone or in combination, was effective in reducing early atherosclerotic lesion development. The combined peptide is more potential than either epitope alone to reduce atherosclerotic lesion formation through the induction of a specific Treg cell response as well as blockage of monocyte differentiation into macrophages.
Two Types of Procoagulant Platelets Are Formed Upon Physiological Activation and Are Controlled by Integrin α
IIb
β
3
Authors: Topalov Nikolay N. , Yakimenko Alena O. , Canault Matthias , Artemenko Elena O. , Zakharova Natalia V. , Abaeva Anastasia A. , Loosveld Marie , Ataullakhanov Fazoil I. , Nurden Alan T. , Alessi Marie-Christine , Panteleev Mikhail A. 
Published: July 2012

Objective—
Phosphatidylserine (PS) externalization by platelets upon activation is a key event in hemostasis and thrombosis. It is currently believed that strong stimulation of platelets forms 2 subpopulations, only 1 of which expresses PS.

Methods and Results—

Here, we demonstrate that physiological stimulation leads to the formation of not 1 but 2 types of PS-expressing activated platelets, with dramatically different properties. One subpopulation sustained increased calcium level after activation, whereas another returned to the basal low-calcium state. High-calcium PS-positive platelets had smaller size, high surface density of fibrin(ogen), no active integrin α
IIb
β
3
, depolarized mitochondrial membranes, gradually lost cytoplasmic membrane integrity, and were poorly aggregated. In contrast, the low-calcium PS-positive platelets had normal size, retained mitochondrial membrane potential and cytoplasmic membrane integrity, and combined retention of fibrin(ogen) with active α
IIb
β
3
and high proaggregatory function. Formation of low-calcium PS-positive platelets was promoted by platelet concentration increase or shaking and was decreased by integrin α
IIb
β
3
antagonists, platelet dilution, or in platelets from kindlin-3–deficient and Glanzmann thrombasthenia patients.

Conclusion—

Identification of a novel PS-expressing platelet subpopulation with low calcium regulated by integrin α
IIb
β
3
can be important for understanding the mechanisms of PS exposure and thrombus formation.
Platelets Derived From the Bone Marrow of Diabetic Animals Show Dysregulated Endoplasmic Reticulum Stress Proteins That Contribute to Increased Thrombosis
Authors: Hernández Vera Rodrigo , Vilahur Gemma , Ferrer-Lorente Raquel , Peña Esther , Badimon Lina 
Published: July 2012

Objective—
Patients with diabetes mellitus have an increased risk of suffering atherothrombotic syndromes and are prone to clustering cardiovascular risk factors. However, despite their dysregulated glucose metabolism, intensive glycemic control has proven insufficient to reduce thrombotic complications. Therefore, we aimed to elucidate the determinants of thrombosis in a model of type 2 diabetes mellitus with cardiovascular risk factors clustering.

Methods and Results—
Intravital microscopy was used to analyze thrombosis in vivo in Zucker diabetic fatty rats (ZD) and lean normoglycemic controls. Bone marrow (BM) transplants were performed to test the contribution of each compartment (blood or vessel wall) to thrombogenicity. ZD showed significantly increased thrombosis compared with lean normoglycemic controls. BM transplants demonstrated the key contribution of the hematopoietic compartment to increased thrombogenicity. Indeed, lean normoglycemic controls transplanted with ZD-BM showed increased thrombosis with normal glucose levels, whereas ZD transplanted with lean normoglycemic controls–BM showed reduced thrombosis despite presenting hyperglycemia. Significant alterations in megakaryopoiesis and platelet–endoplasmic reticulum stress proteins, protein disulfide isomerase and 78-kDa glucose-regulated protein, were detected in ZD, and increased tissue factor procoagulant activity was detected in plasma and whole blood of ZD.

Conclusion—
Our results indicate that diabetes mellitus with cardiovascular risk factor clustering favors BM production of hyperreactive platelets with altered protein disulfide isomerase and 78-kDa glucose-regulated protein expression that can contribute to increase thrombotic risk independently of blood glucose levels.
Differences in Health Status Affect Susceptibility and Mapping of Genetic Loci for Atherosclerosis (Fatty Streak) in Inbred Mice
Authors: Srivastava Ujala , Paigen Beverly J. , Korstanje Ron 
Published: July 2012

Objective—
We observed differences in atherosclerosis susceptibility in mouse inbred strains over the years as the health status of our animal rooms increased. Therefore, we investigated the effect of animal room health status on atherosclerosis susceptibility in different strains. As these data can also be used for genome-wide association mapping, we performed a mapping study and compared our results with previously found quantitative trait loci for atherosclerosis in mouse and humans.

Methods and Results—
Males and females from 48 inbred strains were housed in 2 animal rooms with different health status and given an atherogenic diet. We compared atherosclerosis susceptibility between animal rooms and between sexes and found that susceptibility is dependent on both health status and sex. Subsequently, the data were used for associations with loci on the mouse genome using 63 222 single nucleotide polymorphism. Three loci in males and 4 loci in females were identified using the data from the low-health status room. No significant associations were identified using the data from the high-health status room.

Conclusion—
Health status influences susceptibility to atherosclerosis and suggests that microbiological pressure plays an important role in the development of atherosclerosis in many strains. As we were only able to map susceptibility loci using the data from the lower health status room, we argue that susceptibility under these conditions is determined by a few key loci, whereas in the higher health status room different mechanisms might play a role in the differences in atherosclerosis susceptibility between strains and we did not have enough power to map the loci that are involved.
Cardiac Dysfunction and Prolonged Hemodynamic Deterioration After Implantable Cardioverter-Defibrillator Shock in Patients With Systolic Heart Failure
Authors: Toh Norihisa , Nishii Nobuhiro , Nakamura Kazufumi , Tada Takeshi , Oe Hiroki , Nagase Satoshi , Kohno Kunihisa , Morita Hiroshi , Kusano Kengo F. , Ito Hiroshi 
Published: July 2012

Background—
We investigated the acute effects of implantable cardioverter-defibrillator shock on myocardium, cardiac function, and hemodynamics in relation to left ventricular systolic function.

Methods and Results—

We studied 50 patients who underwent implantable cardioverter-defibrillator implantation and defibrillation threshold (DFT) testing: 25 patients with left ventricular ejection fraction (LVEF) ≥45% and 25 patients with LVEF <45%. We measured cardiac biomarkers (creatine kinase, creatine kinase-MB, myoglobin, cardiac troponin T and I, and N-terminal probrain natriuretic peptide). Left ventricular relaxation was assessed by global longitudinal strain rate during the isovolumetric relaxation period using speckle-tracking echocardiography. Blood sampling and echocardiography were performed before, immediately after, and 5 minutes and 4 hours after DFT testing. Mean arterial pressure was measured directly during DFT testing. Cardiac biomarkers showed no significant changes in either group. LVEF was decreased until 5 minutes after DFT testing and had recovered to the baseline at 4 hours in the group with reduced LVEF (
P
<0.001), whereas LVEF reduction was not observed in the group with preserved LVEF (
P
=0.637). Global isovolumetric relaxation period was decreased until 5 minutes after DFT testing and had recovered to the baseline at 4 hours in both groups (preserved LVEF: 0.39±0.14 versus 0.23±0.13* versus 0.23±0.13* versus 0.40±0.13 s
−1
, *
P
<0.001 versus baseline; reduced LVEF: 0.15±0.05 versus 0.08±0.04† versus 0.09±0.04† versus 0.15±0.05 s
−1
, †
P
<0.001 versus baseline, repeated-measures ANOVA). Time to recovery of mean arterial pressure to the baseline was prolonged in the group with reduced LVEF (
P
<0.001).

Conclusions—
Implantable cardioverter-defibrillator shock transiently impairs cardiac function and hemodynamics especially in patients with systolic dysfunction, although significant tissue injury is not observed.
Community Care in England
Authors: Hawkins Nathaniel M. , Scholes Shaun , Bajekal Madhavi , Love Hande , O'Flaherty Martin , Raine Rosalind , Capewell Simon 
Published: July 2012

Background—
Socioeconomic deprivation is associated with increased heart failure (HF) incidence, hospitalization rates, and mortality. However, whether the delivery of survival-enhancing medical therapy is equitable remains uncertain. We examined secular trends in the uptake of key medical therapies (angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, β-blockers, spironolactone) stratified by socioeconomic circumstances in patients with HF. Secondary analyses examined trends in HF incidence, prevalence, and survival.

Methods and Results—
This study was a cross-sectional observational analysis of nationally representative primary care data from England. Treatments for patients with HF in 1999 and 2007 (n=13 330) were extracted from the General Practice Research Database. Socioeconomic circumstances were defined with the Index of Multiple Deprivation 2007, a weighted composite of 7 area-level deprivation domains. Treatment uptake estimates were age standardized. The incidence and prevalence of HF decreased year to year. Although clear socioeconomic gradients in both the incidence and prevalence of HF were apparent, the absolute difference between most and least deprived reduced over time. Uptake of therapies improved over time in both men and women. Angiotensin-converting enzyme inhibitor/angiotensin receptor blocker uptake increased from 46% to 64%, β-blocker uptake from 12% to 41%, and spironolactone uptake from 3% to 20%. Modest age and sex inequalities were apparent. However, no consistent socioeconomic gradients were observed in either treatment or case fatality.

Conclusions—
Socioeconomic gradients in the incidence and prevalence of HF are reducing. Treatment is generally equitable and independent of socioeconomic circumstances. Most important, no significant inequality in outcomes was apparent. Future strategies should continue to address inequalities in the underlying causes of HF and to increase overall treatment levels further.
Cerecyte Coil Trial
Authors: Molyneux Andrew J. , Clarke Alison , Sneade Mary , Mehta Ziyah , Coley Stuart , Roy Daniel , Kallmes David F. , Fox Allan J. 
Published: July 2012

Background and Purpose—
We report the primary outcome of the Cerecyte Coil Trial, a randomized trial to determine whether polymer-loaded Cerecyte coils compared with Micrus bare platinum coils improved the proportion of patients with angiographic occlusion of the aneurysm at 6 months when assessed by a core laboratory. The secondary objectives were to compare the clinical outcomes and retreatment rates in the 2 groups.

Methods—
Five hundred patients between 18 and 70 years of age with a ruptured or unruptured target aneurysm were randomized to be treated with either Cerecyte or bare platinum coils in 23 centers worldwide. Two hundred forty-nine patients were assigned to Cerecyte coils and 251 to bare platinum coils. Analysis was by intention to treat.

Results—

Four hundred ninety-four patients were eligible for analysis. Four hundred eighty-one patients underwent coil treatment of their aneurysm, 227 patients with recently ruptured aneurysms and 254 with unruptured aneurysms. Four hundred thirty-three follow-up angiograms were assessed by the core laboratory; 127 of 215 (59%) and 118 of 218 (54%) in the Cerecyte and bare platinum groups, respectively, fulfilled the trial prespecified definition of success, namely that the treated aneurysm showed complete angiographic occlusion, had stable neck remnant, or improved in angiographic appearance compared with the end-of-treatment angiogram (
P
=0.17). Late retreatment was performed in 25 of 452 (5.5%) patients, 17 (7.7%) Cerecyte versus 8 (3.5%) bare platinum (
P
=0.064; range, 4–34 months). The clinical outcomes did not differ between the groups.

Conclusion—
There was no significant difference at 6 months in the angiographic outcomes between Cerecyte coils and bare platinum coils when assessed by the core laboratory.

Clinical Trial Registration Information—

URL:
www.controlled-trials.com
. Unique Identifier: ISRCTN82461286.