bluuebunny/crossref_metadata_2025_split huggingface dataset:
Diastolic Left Ventricular Function in Relation to Circulating Metabolic Biomarkers in a General Population
Authors: Zhang Zhen‐Yu , Marrachelli Vannina G. , Thijs Lutgarde , Yang Wen‐Yi , Wei Fang‐Fei , Monleon Daniel , Jacobs Lotte , Nawrot Tim , Verhamme Peter , Voigt Jens‐Uwe , Kuznetsova Tatiana , Redón Josep , Staessen Jan A. 
Published: March 2016

Background

The metabolic signature associated with subclinical diastolic left ventricular (
LV
) dysfunction in the population remains ill defined.

Methods and Results

In 711 randomly recruited Flemish (50.8% women; mean age, 50.8 years), we assessed echocardiographic Doppler indexes of diastolic
LV
function in relation to 44 circulating metabolites determined by nuclear magnetic resonance spectroscopy. In multivariable‐adjusted regression analysis with Bonferroni correction of significance levels applied, peak a’ decreased (
P
≤0.048) and e’/a’ increased (
P
≤0.044) with circulating tyrosine, high‐density lipoprotein apolipoproteins, glucose+glutamine, and an unidentified molecule. Effect sizes expressed per 1‐
SD
increment in the metabolite ranged from −0.277 to −0.203 cm/s for peak a’ and from +0.047 to +0.054 for e’/a’. In addition, peak a’ decreased (
P
≤0.031) with glucose+2‐aminobutyrate (−0.261 cm/s) and glucose+2‐phosphoglycerate (−0.209 cm/s). In partial least square discriminant analysis (
PLS
‐
DA
), metabolites associated with normal diastolic
LV
function (n=538) included glucose+glutamine, glucose+2‐aminobutyrate, and glucose+2‐phosphoglycerate, whereas those siding with abnormal function encompassed 4‐aminobutyrate, 4‐hydroxybutyrate, creatinine, and phosphocholine. In receiver operating characteristics plots, adding 3 latent factors identified by
PLS
‐
DA
to prohormone brain natriuretic peptide increased (
P
<0.0001) the area under the curve from 0.64 (95%
CI
, 0.58–0.68) to 0.73 (0.68–0.78).

Conclusions

In a general population, circulating metabolites indicative of energy substrate utilization and protection against oxidative stress differentiated normal from abnormal diastolic
LV
function. These findings improve our understanding of the pathophysiology underlying deterioration of diastolic
LV
function and potentially point to new targets for prevention and treatment of this condition.
Comparative Effectiveness of Personalized Lifestyle Management Strategies for Cardiovascular Disease Risk Reduction
Authors: Chu Paula , Pandya Ankur , Salomon Joshua A. , Goldie Sue J. , Hunink M. G. Myriam 
Published: March 2016

Background
Evidence shows that healthy diet, exercise, smoking interventions, and stress reduction reduce cardiovascular disease risk. We aimed to compare the effectiveness of these lifestyle interventions for individual risk profiles and determine their rank order in reducing 10‐year cardiovascular disease risk.

Methods and Results
We computed risks using the American College of Cardiology/American Heart Association Pooled Cohort Equations for a variety of individual profiles. Using published literature on risk factor reductions through diverse lifestyle interventions—group therapy for stopping smoking, Mediterranean diet, aerobic exercise (walking), and yoga—we calculated the risk reduction through each of these interventions to determine the strategy associated with the maximum benefit for each profile. Sensitivity analyses were conducted to test the robustness of the results. In the base‐case analysis, yoga was associated with the largest 10‐year cardiovascular disease risk reductions (maximum absolute reduction 16.7% for the highest‐risk individuals). Walking generally ranked second (max 11.4%), followed by Mediterranean diet (max 9.2%), and group therapy for smoking (max 1.6%). If the individual was a current smoker and successfully quit smoking (ie, achieved complete smoking cessation), then stopping smoking yielded the largest reduction. Probabilistic and 1‐way sensitivity analysis confirmed the demonstrated trend.

Conclusions
This study reports the comparative effectiveness of several forms of lifestyle modifications and found smoking cessation and yoga to be the most effective forms of cardiovascular disease prevention. Future research should focus on patient adherence to personalized therapies, cost‐effectiveness of these strategies, and the potential for enhanced benefit when interventions are performed simultaneously rather than as single measures.
TRAF3
Epigenetic Regulation Is Associated With Vascular Recurrence in Patients With Ischemic Stroke
Authors: Gallego-Fabrega Cristina , Carrera Caty , Reny Jean-Luc , Fontana Pierre , Slowik Agnieszka , Pera Joanna , Pezzini Alessandro , Serrano-Heras Gemma , Segura Tomás , Martí-Fàbregas Joan , Muiño Elena , Cullell Natalia , Montaner Joan , Krupinski Jerzy , Fernandez-Cadenas Israel 
Published: March 2016

Background and Purpose—
Clopidogrel is one of the most used antiplatelet drugs in patients with cardiovascular disease. However, 16% to 50% of patients have a high on-clopidogrel platelet reactivity and an increased risk of ischemic events. The pathogenesis of high on-treatment platelet reactivity in patients with stroke is only partially explained by genetic variations. This study aims to find differentially methylated sites across the genome associated with vascular recurrence in ischemic stroke patients treated with clopidogrel.

Methods—
From a cohort of 1900 patients with ischemic stroke, we selected 42 patients treated with clopidogrel, including 21 with a recurrent vascular event and 21 without vascular recurrence during the first year of follow-up. Over 480 000 DNA methylation sites were analyzed across the genome. Differentially methylated CpG sites were identified by nonparametric testing using R. Replication analysis was performed in a new cohort of 191 subjects and results were correlated with platelet reactivity in a subset of 90 subjects using light transmission aggregometry.

Results—

A total of 73 differentially methylated CpG sites (
P
<1×10
−05
) were identified; 3 of them were selected for further replication: cg03548645 (
P
=1.42×10
−05
,
TRAF3
), cg09533145 (
P
=7.81×10
−06
,
ADAMTS2
), and cg15107336 (
P
=1.89×10
−05
,
XRCC1
). The cg03548645 CpG remained significant in the replication study (
P
=0.034), a deep analysis of this region revealed another methylation site associated with vascular recurrence,
P
=0.037. Lower cg03548645 (
TRAF3
) DNA methylation levels were correlated with an increased platelet aggregation (ρ=−0.29,
P
=0.0075).

Conclusions—
This study suggests for the first time that epigenetics may significantly contribute to the variability of clopidogrel response and recurrence of ischemic events in patients with stroke.
De Novo Aneurysm Formation in Carriers of Saccular Intracranial Aneurysm Disease in Eastern Finland
Authors: Lindgren Antti E. , Räisänen Sari , Björkman Joel , Tattari Hanna , Huttunen Jukka , Huttunen Terhi , Kurki Mitja I. , Frösen Juhana , Koivisto Timo , Jääskeläinen Juha E. , von und zu Fraunberg Mikael 
Published: March 2016

Background and Purpose—
Formation of new (de novo) aneurysms in patients carrying saccular intracranial aneurysm (sIA) disease has been published, but data from population-based cohorts are scarce.

Methods—

Kuopio sIA database (
http://www.uef.fi/ns
) contains all unruptured and ruptured sIA patients admitted to Kuopio University Hospital from its Eastern Finnish catchment population. We studied the incidence and risk factors for de novo sIA formation in 1419 sIA patients with ≥5 years of angiographic follow-up, a total follow-up of 18 526 patient-years.

Results—
There were 42 patients with a total of 56 de novo sIAs, diagnosed in a median of 11.7 years after the first sIA diagnosis. The cumulative incidence of de novo sIAs was 0.23% per patient-year and that of subarachnoid hemorrhage from a ruptured de novo sIA 0.05% per patient-year. The risk of de novo sIA discovery per patient-year increased with younger age at the first sIA diagnosis: 2.2% in the patients aged <20 years and 0.46% in the patients aged between 20 and 39 years. In Cox regression analysis, smoking history and younger age at the first sIA diagnosis significantly associated with de novo sIA formation, but female sex, multiple sIAs, and sIA family did not.

Conclusions—
Patients aged < 40 years at the first sIA diagnosis are in a significant risk of developing de novo sIAs, and they should be scheduled for long-term angiographic follow-up. Smoking increases the risk of de novo sIA formation, suggesting long-term follow-up for smokers. Antismoking efforts are highly recommended for sIA patients.
RNA Sequencing Analysis of Intracranial Aneurysm Walls Reveals Involvement of Lysosomes and Immunoglobulins in Rupture
Authors: Kleinloog Rachel , Verweij Bon H. , van der Vlies Pieter , Deelen Patrick , Swertz Morris A. , de Muynck Louis , Van Damme Philip , Giuliani Fabrizio , Regli Luca , van der Zwan Albert , Berkelbach van der Sprenkel Jan W. , Han K. Sen , Gosselaar Peter , van Rijen Peter C. , Korkmaz Emine , Post Jan A. , Rinkel Gabriel J.E. , Veldink Jan H. , Ruigrok Ynte M. 
Published: March 2016

Background and Purpose—
Analyzing genes involved in development and rupture of intracranial aneurysms can enhance knowledge about the pathogenesis of aneurysms, and identify new treatment strategies. We compared gene expression between ruptured and unruptured aneurysms and control intracranial arteries.

Methods—
We determined expression levels with RNA sequencing. Applying a multivariate negative binomial model, we identified genes that were differentially expressed between 44 aneurysms and 16 control arteries, and between 22 ruptured and 21 unruptured aneurysms. The differential expression of 8 relevant and highly significant genes was validated using digital polymerase chain reaction. Pathway analysis was used to identify enriched pathways. We also analyzed genes with an extreme pattern of differential expression: only expressed in 1 condition without any expression in the other.

Results—
We found 229 differentially expressed genes in aneurysms versus controls and 1489 in ruptured versus unruptured aneurysms. The differential expression of all 8 genes selected for digital polymerase chain reaction validation was confirmed. Extracellular matrix pathways were enriched in aneurysms versus controls, whereas pathways involved in immune response and the lysosome pathway were enriched in ruptured versus unruptured aneurysms. Immunoglobulin genes were expressed in aneurysms, but showed no expression in controls.

Conclusions—
For rupture of intracranial aneurysms, we identified the lysosome pathway as a new pathway and found further evidence for the role of the immune response. Our results also point toward a role for immunoglobulins in the pathogenesis of aneurysms. Immune-modifying drugs are, therefore, interesting candidate treatment strategies in the prevention of aneurysm development and rupture.
Timing of Occurrence Is the Most Important Characteristic of Spot Sign
Authors: Wang Binli , Yan Shenqiang , Xu Mengjun , Zhang Sheng , Liu Keqin , Hu Haitao , Selim Magdy , Lou Min 
Published: March 2016

Background and Purpose—
Most previous studies have used single-phase computed tomographic angiography to detect the spot sign, a marker for hematoma expansion (HE) in spontaneous intracerebral hemorrhage. We investigated whether defining the spot sign based on timing on perfusion computed tomography (CTP) would improve its specificity for predicting HE.

Methods—
We prospectively enrolled supratentorial spontaneous intracerebral hemorrhage patients who underwent CTP within 6 hours of onset. Logistic regression was performed to assess the risk factors for HE and poor outcome. Predictive performance of individual CTP spot sign characteristics were examined with receiver operating characteristic analysis.

Results—

Sixty-two men and 21 women with spontaneous intracerebral hemorrhage were included in this analysis. Spot sign was detected in 46% (38/83) of patients. Receiver operating characteristic analysis indicated that the timing of spot sign occurrence on CTP had the greatest area under receiver operating characteristic curve for HE (0.794; 95% confidence interval, 0.630–0.958;
P
=0.007); the cutoff time was 23.13 seconds. On multivariable analysis, the presence of early-occurring spot sign (ie, spot sign before 23.13 seconds) was an independent predictor not only of HE (odds ratio=28.835; 95% confidence interval, 6.960–119.458;
P
<0.001), but also of mortality at 3 months (odds ratio =22.377; 95% confidence interval, 1.773–282.334;
P
=0.016). Moreover, the predictive performance showed that the redefined early-occurring spot sign maintained a higher specificity for HE compared with spot sign (91% versus 74%).

Conclusions—
Redefining the spot sign based on timing of contrast leakage on CTP to determine early-occurring spot sign improves the specificity for predicting HE and 3-month mortality. The use of early-occurring spot sign could improve the selection of ICH patients for potential hemostatic therapy.
Frontal and Parietal Cortices Show Different Spatiotemporal Dynamics across Problem-solving Stages
Authors: Tschentscher Nadja , Hauk Olaf 
Published: March 2016

Abstract
Arithmetic problem-solving can be conceptualized as a multistage process ranging from task encoding over rule and strategy selection to step-wise task execution. Previous fMRI research suggested a frontal–parietal network involved in the execution of complex numerical and nonnumerical tasks, but evidence is lacking on the particular contributions of frontal and parietal cortices across time. In an arithmetic task paradigm, we evaluated individual participants' “retrieval” and “multistep procedural” strategies on a trial-by-trial basis and contrasted those in time-resolved analyses using combined EEG and MEG. Retrieval strategies relied on direct retrieval of arithmetic facts (e.g., 2 + 3 = 5). Procedural strategies required multiple solution steps (e.g., 12 + 23 = 12 + 20 + 3 or 23 + 10 + 2). Evoked source analyses revealed independent activation dynamics within the first second of problem-solving in brain areas previously described as one network, such as the frontal–parietal cognitive control network: The right frontal cortex showed earliest effects of strategy selection for multistep procedural strategies around 300 msec, before parietal cortex activated around 700 msec. In time–frequency source power analyses, memory retrieval and multistep procedural strategies were differentially reflected in theta, alpha, and beta frequencies: Stronger beta and alpha desynchronizations emerged for procedural strategies in right frontal, parietal, and temporal regions as function of executive demands. Arithmetic fact retrieval was reflected in right prefrontal increases in theta power. Our results demonstrate differential brain dynamics within frontal–parietal networks across the time course of a problem-solving process, and analyses of different frequency bands allowed us to disentangle cortical regions supporting the underlying memory and executive functions.
Physically Based Stochastic Perturbations (PSP) in the Boundary Layer to Represent Uncertainty in Convective Initiation
Authors: Kober Kirstin , Craig George C. 
Published: March 2016

Abstract
Stochastic perturbations allow for the representation of small-scale variability due to unresolved physical processes. However, the properties of this variability depend on model resolution and weather regime. A physically based method is presented for introducing stochastic perturbations into kilometer-scale atmospheric models that explicitly account for these dependencies. The amplitude of the perturbations is based on information obtained from the model’s subgrid turbulence parameterization, while the spatial and temporal correlations are based on physical length and time scales of the turbulent motions. The stochastic perturbations lead to triggering of additional convective cells and improved precipitation amounts in simulations of two days with weak synoptic forcing of convection but different amounts of precipitation. The perturbations had little impact in a third case study, where precipitation was mainly associated with a cold front. In contrast, an unphysical version of the scheme with constant perturbation amplitude performed poorly since there was no perturbation amplitude that would give improved amounts of precipitation during the day without generating spurious convection at other times.
Internal Tide Generation Using Green Function Analysis: To WKB or Not to WKB?
Authors: Mathur Manikandan , Carter Glenn S. , Peacock Thomas 
Published: March 2016

AbstractAn established analytical technique for modeling internal tide generation by barotropic flow over bottom topography in the ocean is the Green function–based approach. To date, however, for realistic ocean studies this method has relied on the WKB approximation. In this paper, the complete Green function method, without the WKB approximation, is developed and tested, and in the process, the accuracy of the WKB approximation for realistic ridge geometries and ocean stratifications is considered. For isolated Gaussian topography, the complete Green function approach is shown to be accurate via close agreement with the results of numerical simulations for a wide range of height ratios and criticality; in contrast, the WKB approach is found to be inaccurate for small height ratios in the subcritical regime and all tall topography that impinges on the pycnocline. Two ocean systems are studied, the Kaena and Wyville Thomson Ridges, for which there is again excellent agreement between the complete Green function approach and numerical simulations, and the WKB approximate solutions have substantial errors. This study concludes that the complete Green function approach, which is typically only modestly more computationally expensive than the WKB approach, should be the go-to analytical method to model internal tide generation for realistic ocean ridge scenarios.
Sudden‐Onset Sensorineural Hearing Loss after Immunization
Authors: Baxter Roger , Lewis Ned , Bohrer Pamela , Harrington Theresa , Aukes Laurie , Klein Nicola P. 
Published: March 2016

ObjectiveCase reports of sudden sensorineural hearing loss (SSHL) following vaccines have led to concerns that vaccines may rarely cause hearing loss. Because of this concern, we analyzed for an association between SSHL and vaccinations.Study DesignWe used a case‐centered method, equivalent to a case control design using immunization dates from all matched members of the population to calculate exposure to vaccines, rather than sampling.SettingKaiser Permanente Northern California (KPNC), 2007 to 2013.Subjects and MethodsWe searched KPNC databases from 2007 to 2013 for all first‐time diagnoses of SSHL. We used the date of any hearing‐ or ear‐related visit in the 60 days prior to the first SSHL diagnosis as the onset date. Using only SSHL cases immunized in the prior 9 months, we compared the vaccine exposure in several risk intervals prior to onset with the exposure to the same vaccine during the same time period in all KPNC membership, matched to sex and age.ResultsDuring the study period, >20 million vaccines were administered at KPNC. In all risk intervals prior to onset of SSHL, we found no evidence of increased risk of immunization compared with matched controls. The odds ratios for vaccination 1 week prior to SSHL were 0.965 (95% confidence interval, 0.61‐1.50) for trivalent inactivated influenza vaccine (TIV); 0.842 (0.39‐1.62) for tetanus, reduced diphtheria, and reduced acellular pertussis; and 0.454 (0.08‐1.53) for zoster vaccine.ConclusionA large‐scale analysis applying a case‐centered method did not detect any association between SSHL and previous receipt of TIV or other vaccines.
Effects of Memantine on Aminoglycoside‐Induced Apoptosis of Spiral Ganglion Cells in Guinea Pigs
Authors: Kim Bo Young , Bae Woo Yong , Hur Dae Young , Kim Jae‐Ryong , Koh Tae Kyung , Lee Tae Hoon , Park Ga Bin 
Published: March 2016

ObjectiveTo explore whether memantine, an N‐methyl‐D‐aspartate receptor antagonist, exerts a neuroprotective effect against apoptosis of spiral ganglion cells (SGCs) induced by gentamicin.Study DesignAn animal experiment.SettingDong‐A University College of Medicine, Busan, Korea.Subjects and MethodsGentamicin was injected into the left cochleae of guinea pigs to induce apoptosis of SGCs; the contralateral cochleae served as controls. Memantine was intraperitoneally injected 12 hours and 1 hour prior to gentamicin injection. At 1 week after gentamicin and/or memantine injection, the cochleae were removed and stained with hematoxylin and eosin to evaluate morphologic changes and apoptosis. Western blotting was performed to measure FasL expression and the extent of caspase activation in SGCs.ResultsSGC numbers remained stable after memantine treatment. Western blotting showed that FasL expression and activation of caspases 3, 8, and 9 were reduced in SGCs after memantine treatment.ConclusionMemantine attenuated the gentamicin‐induced apoptosis of SGCs in guinea pigs. Moreover, memantine may affect Fas‐FasL signaling in the receptor‐mediated apoptotic pathway and caspase activation involved in the receptor‐mediated and mitochondrial apoptotic pathways.
Multivariate Analysis of the Risk Factors for First-Time Noncontact ACL Injury in High School and College Athletes
Authors: Vacek Pamela M. , Slauterbeck James R. , Tourville Timothy W. , Sturnick Daniel R. , Holterman Leigh-Ann , Smith Helen C. , Shultz Sandra J. , Johnson Robert J. , Tourville Kelly J. , Beynnon Bruce D. 
Published: March 2016

Background: Multivariate analysis that identifies the combination of risk factors associated with anterior cruciate ligament (ACL) trauma is important because it provides insight into whether a variable has a direct causal effect on risk or an indirect effect that is mediated by other variables. It can also reveal risk factors that might not be evident in univariate analyses; if a variable’s effect is moderated by other variables, its association with risk may be apparent only after adjustment for the other variables. Most important, multivariate analyses can identify combinations of risk factors that are more predictive of risk than individual risk factors. Hypothesis: A diverse combination of risk factors predispose athletes to first-time noncontact ACL injury, and these relationships are different for male and female athletes. Study Design: Case-control study; Level of evidence, 3. Methods: Athletes competing in organized sports at the high school and college levels participated in this study. Data from injured subjects (109 suffering an ACL injury) and matched controls (227 subjects) from the same athletic team were analyzed with multivariate conditional logistic regression to examine the effects of combinations of variables (demographic characteristics, joint laxity, lower extremity alignment, strength, and personality traits) on the risk of suffering their first ACL injury and to construct risk models. Results: For male athletes, increases in anterior-posterior displacement of the tibia relative to the femur (knee laxity), posterior knee stiffness, navicular drop, and a decrease in standing quadriceps angle were jointly predictive of suffering an ACL injury. For female athletes the combined effects of having a parent who had suffered an ACL injury and increases in anterior-posterior knee laxity and body mass index were predictive of ACL injury. Conclusion: Multivariate models provided more information about ACL injury risk than individual risk factors. Both male and female risk models included increased anterior-posterior knee laxity as a predictor of ACL injury but were otherwise dissimilar.