bluuebunny/crossref_metadata_2025_split huggingface dataset:
Delving Into the Interaction Between Exercise and Diabetes on Methylation of the FKBP5 Gene
Authors: Yang Teng-Chi , Tsai Jen Pi , Hsu Honda , Chen Yen-Chung , Liaw Yi-Chia , Hsu Shu Yi , Yang Hao Jan , Liaw Yung-Po 
Published: February 2025

Objective: FKBP5 is a critical gene involved in regulating the hypothalamic–pituitary–adrenal (HPA) axis and stress response. Aberrant DNA methylation at FKBP5 cytosine–phosphate–guanine (CpG) sites, such as cg22363520 and cg00862770, has been implicated in mental health disorders and metabolic diseases, including Type 2 diabetes. Exercise is a modulator of DNA methylation and metabolic health. This study investigates the interaction between exercise, diabetes, and FKBP5 methylation at cg22363520 and cg00862770 and explores their implications for mental health and disease development.Materials and Methods: FKBP5 methylation levels at cg22363520 and cg00862770 were analyzed in a cohort stratified by diabetes and exercise. Multiple linear regression models assessed the main effects and interactions of exercise and diabetes on FKBP5 methylation, with further stratified analyses for site‐specific effects.Results: Exercise and diabetes showed significant and site‐specific effects on FKBP5 methylation at cg22363520 and cg00862770. At cg22363520, exercise significantly reduced methylation levels in nondiabetic participants (β = −0.00195, p = 0.0157), while no significant effect was observed in diabetic individuals. Conversely, at cg00862770, exercise significantly decreased methylation levels in diabetic participants (β = −0.00611, p = 0.0081), with no significant effect in the nondiabetic group. Diabetes itself was associated with increased FKBP5 methylation at both sites, particularly in individuals without regular exercise. Additionally, significant interaction effects between exercise and diabetes were identified for both cg22363520 (p = 0.0336) and cg00862770 (p = 0.0021), highlighting the interplay between metabolic status and physical activity in regulating FKBP5 methylation.Conclusion: This study demonstrates that the effects of exercise on FKBP5 methylation are site‐specific and influenced by diabetes status. Exercise reduces methylation at cg22363520 in nondiabetics and at cg00862770 in diabetics, indicating its role in modulating epigenetic regulation of stress and metabolic pathways. These findings underscore the interplay between exercise, diabetes, and FKBP5 methylation, with potential implications for improving mental health and metabolic outcomes.
Spatial Transcriptomics of Intraductal Papillary Mucinous Neoplasms Reveals Divergent Indolent and Malignant States
Authors: Iyer Matthew K. , Fletcher Ashley , Okoye Jude Ogechukwu. , Shi Chanjuan , Chen Fengming , Kanu Elishama , Eckhoff Austin M. , Bao Matthew , Pasca di Magliano Marina , Frankel Timothy L. , Chinnaiyan Arul M. , Nussbaum Daniel P. , Allen Peter J. 
Published: February 2025

Abstract
Purpose: Intraductal papillary mucinous neoplasms (IPMN) occur in 5-10% of the population, but only a small minority progress to pancreatic ductal adenocarcinoma (PDAC). The lack of accurate predictors of high-risk disease leads both to unnecessary operations for indolent neoplasms as well as missed diagnoses of PDAC. Digital spatial RNA profiling (DSP-RNA) provides an opportunity to define and associate transcriptomic states with cancer risk. Experimental Design: We performed whole-transcriptome DSP-RNA profiling on 10 IPMN specimens encompassing the spectrum of dysplastic changes from normal duct to cancer. Epithelial regions within each tissue were annotated as normal duct (NL), low-grade dysplasia (LGD), high-grade dysplasia (HGD), or invasive carcinoma (INV). The resulting digital gene expression data were analyzed with R/Bioconductor. Results: Our analysis uncovered three distinct epithelial transcriptomic states – “normal-like” (cNL), “low-risk” (cLR), and “high-risk” (cHR) – which were significantly associated with pathologic grade. Furthermore, the three states were significantly correlated with the exocrine, classical, and basal-like molecular subtypes described in PDAC. Specifically, exocrine function diminished in cHR, classical activation distinguished neoplasia (cLR and cHR) from cNL, and basal-like genes were specifically upregulated in cHR. Intriguingly, markers of cHR were detected in NL and LGD regions from specimens with PDAC but not low-grade IPMN. Conclusions: DSP-RNA of IPMN revealed low-risk (indolent) and high-risk (malignant) expression programs that correlated with the activity of exocrine and basal-like PDAC signatures, respectively, and distinguished pathologically low-grade from malignant specimens. These findings contextualize IPMN pathogenesis and have the potential to improve risk stratification.
Inactive Matrix Gla Protein and Cardiovascular Outcomes: The Multi‐Ethnic Study of Atherosclerosis
Authors: Berlot Ashley A. , Fu Xueyan , Shea M. Kyla , Tracy Russell , Budoff Matthew , Kim Ryung S. , Naveed Mahim , Booth Sarah L. , Kizer Jorge R. , Bortnick Anna E. 
Published: February 2025

Background
MGP (matrix Gla protein) inhibits arterial calcification. Higher inactive MGP, in its dephosphorylated‐uncarboxylated (dp‐uc) form, is positively associated with vascular calcification, possibly portending adverse cardiovascular events. The objective of this study was to determine the association of dp‐ucMGP with incident cardiovascular disease (CVD) events and mortality in MESA (Multi‐Ethnic Study of Atherosclerosis).

Methods
MESA is a prospective cohort study of 45‐ to 84‐year‐old individuals enrolled between 2000 and 2002 with adjudicated outcomes through 2019. Dp‐ucMGP was measured at baseline in n=2663 participants with cardiac computed tomography at Exams 1 (2000–2002) and 5 (2010–2012). Age‐stratified Cox proportional hazard models were used to assess dp‐ucMGP with risk of all CVD (mean follow‐up 16±4 years), hard CVD (17±3 years), hard coronary heart disease (17±3 years), and all‐cause mortality (18±2 years).

Results

The youngest age quartile (45‐ to 53‐years‐old) with higher dp‐ucMGP levels (520–2934 pmol/L) had an increased risk of all CVD (hazard ratio [HR], 3.05 [95% CI, 1.58–5.90],
P
=0.001), hard CVD (HR, 2.85 [95% CI, 1.30–6.23],
P
=0.009), hard coronary heart disease (HR, 3.79 [95% CI, 1.31–10.95],
P
=0.014), and all‐cause mortality (HR, 2.73 [95% CI, 1.19–6.30],
P
=0.018) compared with those with dp‐ucMGP levels between 150 and 519 pmol/L in maximally adjusted models.

Conclusions
Younger individuals 45 to 53 years old with elevated dp‐ucMGP levels (≥520 pmol/L) had an increased risk of incident CVD, coronary heart disease, and all‐cause mortality. No association was seen in older adults. Additional studies are needed to better delineate the relationship of inactive MGP with incident CVD, coronary heart disease, and all‐cause mortality.
Modified Rankin Scale at 90 Days Versus National Institutes of Health Stroke Scale at 24 Hours as Primary Outcome in Acute Stroke Trials
Authors: Ospel Johanna M. , Brown Scott , Bosshart Salome , Stebner Alexander , Uchida Kazutaka , Demchuk Andrew , Saver Jeffrey L. , White Philip , Muir Keith W. , Dippel Diederik W. J. , Majoie Charles B. L. M. , Jovin Tudor G. , Campbell Bruce C. V. , Mitchell Peter J. , Bracard Serge , Guillemin Francis , Hill Michael , Goyal Mayank ,   HERMES Investigators
Published: February 2025

Background
We investigate whether the National Institutes of Health Stroke Scale (NIHSS) at 24 hours could serve as a primary outcome in acute ischemic stroke trials, and whether combining 90‐day modified Rankin Scale (mRS) and 24‐hour NIHSS in a hierarchical outcome could enhance detection of treatment effect, using endovascular treatment (EVT) as an exemplary study intervention.

Methods
This was a post hoc analysis of pooled data from 7 randomized EVT trials. Twenty‐four‐hour NIHSS as a surrogate outcome for 90‐day mRS was assessed in a causal mediation model. A 7‐point ordinal NIHSS score was generated by grouping 24‐hour NIHSS, including death as a separate category (“ordinal” NIHSS). EVT effect sizes and sample sizes required for detecting EVT benefit with 80% power were compared when using granular 24‐hour NIHSS, ordinal 24‐hour NIHSS, 90‐day mRS, and a hierarchical outcome (win ratio) that combines 90‐day mRS and 24‐hour NIHSS.

Results
A total of 1720 patients were included. Twenty‐four‐hour NIHSS mediated the association between EVT and 90‐day mRS and met criteria for a useful surrogate outcome. Effect sizes were highest and sample sizes required to detect EVT benefit smallest for the win ratio approach (228), followed by 90‐day mRS (240) and ordinal 24‐hour NIHSS (242). In patients with baseline NIHSS <10 and ≥25, ordinal 24‐hour NIHSS resulted in the highest effect size.

Conclusions
Twenty‐four‐hour NIHSS is a useful surrogate outcome for 90‐day mRS in patients with acute ischemic stroke undergoing EVT, with a similar EVT effect size compared with 90‐day mRS. It could potentially enhance detection of EVT benefit in patients with very low or high baseline NIHSS. An ordered hierarchical outcome could improve detection of EVT treatment effect.
Association Between Elevated Total Homocysteine and Heart Failure Risk in the Multi‐Ethnic Study of Atherosclerosis Cohort
Authors: Karger Amy B. , Nomura Sarah O. , Guan Weihua , Garg Parveen K. , Tison Geoffrey H. , Szklo Moyses , Budoff Matthew J. , Tsai Michael Y. 
Published: February 2025

Background
Limited studies show an association between elevated total homocysteine (tHcy) and heart failure (HF) risk, but no studies have assessed whether this association differs by HF subtype. This study examines the relationship between tHcy, HF overall, and HF subtype (HF with preserved ejection fraction [HFpEF] and HF with reduced ejection fraction) in the Multi‐Ethnic Study of Atherosclerosis cohort.

Methods
Multi‐Ethnic Study of Atherosclerosis participants with baseline tHcy and HF data were included (N=6765). Cox proportional hazards regression was used to calculate hazard ratios and 95% CI for tHcy and risk of HF. Models were stratified by impaired fasting glucose/type 2 diabetes status, and the combined impact of elevated tHcy and impaired fasting glucose/type 2 diabetes on HF incidence was examined.

Results
Elevated tHcy (>12 μmol/L) was statistically significantly associated with HF overall and HFpEF, and conferred a higher risk for HF overall among individuals with dysglycemia impaired fasting glucose/type 2 diabetes compared with those with normoglycemia. Additionally, there was a statistically significant increased risk of HF overall and HF with reduced ejection fraction and a trend towards increased risk of HFpEF in individuals with both elevated tHcy and dysglycemia. tHcy appears to be a more significant contributor to HFpEF risk than dysglycemia, whereas dysglycemia seems to be more important in driving HF with reduced ejection fraction risk.

Conclusions
Our study confirms an association between hyperhomocysteinemia and HF risk in a large, multi‐ethnic cohort. This is the first study to demonstrate that the impact of tHcy differs by HF subtype and appears to contribute more to HFpEF risk than HF with reduced ejection fraction risk.
Cardiovascular Outcomes With Icosapent Ethyl by Baseline Low‐Density Lipoprotein Cholesterol: A Secondary Analysis of the REDUCE‐IT Randomized Trial
Authors: Aggarwal Rahul , Bhatt Deepak L. , Steg Ph. Gabriel , Miller Michael , Brinton Eliot A. , Dunbar Richard L. , Ketchum Steven B. , Tardif Jean‐Claude , Martens Fabrice M. A. C. , Ballantyne Christie M. , Szarek Michael , Mason R. Preston ,   REDUCE‐IT Investigators
Published: February 2025

Background
The efficacy of icosapent ethyl among patients with very well‐controlled baseline low‐density lipoprotein cholesterol (LDL‐C) is unknown.

Methods
In this post hoc analysis of the REDUCE‐IT (Reduction of Cardiovascular Events With Icosapent Ethyl–Intervention Trial) randomized clinical trial, statin‐treated patients with high cardiovascular risk, elevated triglycerides (135–499 mg/dL), and baseline LDL‐C of 41 to 100 mg/dL were included. Patients were randomized to icosapent ethyl (2 g twice daily) or placebo and then post hoc stratified by baseline LDL‐C (<55 mg/dL versus ≥55 mg/dL). The primary composite end point included cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, coronary revascularization, or unstable angina.

Results

Among 8175 patients with baseline LDL‐C data, 7117 (87.1%) had LDL‐C ≥55 mg/dL and 1058 (12.9%) had LDL‐C <55 mg/dL. In patients with LDL‐C <55 mg/dL, the rate of the primary composite end point was lower in the icosapent ethyl group (16.2% versus 22.8%) than in the placebo group (hazard ratio [HR], 0.66 [95% CI, 0.50–0.87]; absolute risk reduction, 6.6%;
P
=0.003). Among patients with LDL‐C ≥55 mg/dL, a primary composite end point event occurred in a lower proportion of patients in the icosapent ethyl group (17.4% versus 21.9%) than in the placebo group (HR, 0.76 [95% CI, 0.69–0.85]; absolute risk reduction, 4.5%;
P
<0.0001). No significant interaction was observed between baseline LDL‐C and treatment group (
P
for interaction=0.40). Findings were consistent among secondary cardiovascular end points and in sensitivity analyses.

Conclusions
Among statin‐treated patients with elevated triglycerides and high cardiovascular risk, icosapent ethyl reduced the rate of cardiovascular end points irrespective of baseline LDL‐C, including among eligible patients with optimal LDL‐C control.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT01492361.
Prevalence and Mortality of Heart Failure Stages in a Free‐Living Older Adult Population: Data From the Brazilian Longitudinal Study of Adult Health
Authors: Heidemann Altair I. , Santos Angela B. S. , Bittencourt Marcio S. , Ribeiro Antonio L. P. , Rohde Luis E. , Lotufo Paulo A. , Duncan Bruce B. , Foppa Murilo 
Published: February 2025

Background
Heart failure (HF) has a major impact on public health. HF staging helps capture preclinical disease and its progression to advanced stages. There are scarce data on HF staging from longitudinal studies in Latin America. This study aimed to determine the prevalence and mortality of HF stages in a Brazilian adult cohort of participants 60 years old and over.

Methods
The ELSA‐Brasil (Brazilian Longitudinal Study of Adult Health) multicentric cohort comprises 15 105 adults. From 2008 to 2010, ELSA carried out interviews and clinical, laboratory, and cardiovascular tests. In this analysis, we included participants 60 years old and over who had an echocardiogram performed at baseline visit and additional information regarding risk factors and functional capacity.

Results

There were 2356 participants (65±4 years; 53% women) with baseline echocardiogram. Of these, 504 (21%) participants were considered at low risk for developing HF (stage 0). Prevalence of HF was 1026 (44%) for stage A (at risk for HF), 557 (24%) for stage B (pre‐HF), and 269 (11%) for stage C (symptomatic HF), with different distribution between sexes (
P
<0.001). Multivariable risk‐adjusted model for all‐cause mortality over a median follow‐up of 12 years, found 6%, 12%, 18%, and 27% for stages 0, A, B, and C, respectively, with hazard ratios of 1.82 [95% CI, 1.2–2.7], 2.52 [95% CI, 1.7–3.8], and 4.29 [95% CI, 2.8–6.6], using as reference stage 0.

Conclusions
The high prevalence of symptomatic, and preclinical HF in older adults and the increased mortality with disease progression may be responsible for an elevated public health burden. This information is critical for understanding and planning health policies for older adults in middle‐income countries.
Effect of Daily Avocado Intake on Cardiovascular Health Assessed by Life's Essential 8: An Ancillary Study of HAT, a Randomized Controlled Trial
Authors: Damani Janhavi J. , Kris‐Etherton Penny M. , Lichtenstein Alice H. , Matthan Nirupa R. , Sabaté Joan , Li Zhaoping , Reboussin David , Petersen Kristina S. 
Published: February 2025

Background
The effect of single food‐based dietary interventions on the American Heart Association's cardiovascular health score, Life's Essential 8 (LE8), is unclear. The aim of this study was to examine the effect of daily avocado intake for 26 weeks on LE8 in adults with abdominal obesity.

Methods and Results
An ancillary analysis including participants (n=969; aged 51±14 years) from the HAT (Habitual Diet and Avocado Trial), a randomized controlled trial, was conducted. The Avocado‐Supplemented Diet Group was provided with 1 avocado per day, and the Habitual Diet Group was instructed to maintain their usual diet. LE8 component scores (diet, physical activity, nicotine exposure, sleep health, body mass index, blood lipids, blood glucose, and blood pressure) were calculated using a modified American Heart Association algorithm. The LE8 score was calculated as the unweighted average of each component (range, 0–100 points). Between‐group differences in the 26‐week change in LE8 were assessed using general linear models. No significant between‐group difference in the 26‐week change in the LE8 score from baseline was observed (0.79 points [95% CI, −0.41 to 2.00]). However, avocado intake increased the LE8 component scores for diet (3.53 points [95% CI, 1.38–5.68]), sleep health (3.20 points [95% CI, 0.38–6.02]), and blood lipids (3.46 points [95% CI, 1.03–5.90]) compared with the Habitual Diet Group.

Conclusions
Intake of 1 avocado per day for 26 weeks did not significantly affect the total cardiovascular health score in US adults with abdominal obesity. However, diet quality, sleep health, and blood lipids improved with daily avocado intake.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03528031.
Intravenous Thrombolysis in Cervical Artery Dissection–Related Stroke: A Nationwide Study
Authors: Shu Liqi , Lee Elizabeth , Field Thalia S. , Guo Xiaofan , Henninger Nils , Keser Zafer , Khan Muhib , Mistry Eva A. , Nguyen Thanh N. , Siegler James E. , Strelecky Lukas , Mandel Daniel M. , Stretz Christoph , Furie Karen L. , Yaghi Shadi 
Published: February 2025

Background
Although intravenous thrombolysis (IVT) is safe and effective in populations with general stroke, its impact on cervical artery dissection–related acute ischemic stroke (CeAD‐AIS) remains unclear. This retrospective study used the National Inpatient Sample to compare outcomes in patients with CeAD‐AIS treated with and without IVT.

Methods

We included adult patients with concurrent CeAD and AIS diagnoses (
International Classification of Diseases, Tenth Revision
[
ICD‐10
], codes) hospitalized from 2016 to 2019. The primary outcome was home discharge; safety outcomes included inpatient death and intracerebral hemorrhage. We performed survey‐weighted multivariable logistic regressions comparing IVT versus no IVT, followed by interaction analyses to examine effect modifications based on age, medical history, stroke severity, carotid artery involvement, and endovascular treatment.

Results

Between 2016 and 2019, 1360 (12.1%) of 11 285 patients with CeAD‐AIS received IVT. IVT‐treated patients had higher median National Institutes of Health Stroke Scale scores (median [interquartile range], 8 [4–17] versus 3 [1–11];
P
<0.001). Adjusted analyses showed IVT was associated with higher odds of home discharge (adjusted odds ratio [OR], 1.40 [95% CI, 1.01–1.92];
P
=0.042), but not with inpatient death (adjusted OR, 1.29 [95% CI, 0.76–2.20];
P
=0.347) or intracerebral hemorrhage (adjusted OR, 0.69 [95% CI, 0.32–1.48];
P
=0.341). Stroke severity (
P
for interaction=0.001) and carotid artery involvement (
P
for interaction=0.021) significantly modified IVT's effect on home discharge, with IVT being associated with an increased likelihood of home discharge in patients with moderate to severe strokes (National Institutes of Health Stroke Scale score >4) and carotid artery involvement.

Conclusions
IVT improves the likelihood of home discharge in patients with CeAD‐AIS without increasing the risk of inpatient death or intracerebral hemorrhage.
Unraveling Novel Subsets of Lymphocytes Involved in Sac Expansion in the Tertiary Lymphoid Structure Within an Abdominal Aortic Aneurysm
Authors: Hosaka Itaru , Ikegami Ippei , Mikami Takuma , Sato Tatsuya , Ogawa Toshifumi , Mukawa Kei , Tanaka Marenao , Endo Keisuke , Akiyama Yukinori , Ohkawa Akihito , Nakazawa Junji , Shibata Tsuyoshi , Nakajima Tomohiro , Iba Yutaka , Shiiku Chikara , Sumino Satoshi , Koshima Ryuji , Takano Kenichi , Ichimiya Shingo , Kawaharada Nobuyoshi , Furuhashi Masato 
Published: February 2025

Background
Chronic inflammation is involved in the development of abdominal aortic aneurysm (AAA). A tertiary lymphoid structure (TLS) within vascular lesions has recently been focused on for its role in modulation of inflammation in local tissues. We aimed to elucidate the relationships between TLS and pathophysiology of AAA.

Methods
Abdominal aortic samples obtained from 37 patients with AAA (men/women: 34/3, age: 72.8±9.9 years) and 15 autopsied patients who died from non‐aortic events (men/women: 11/4, age: 65.5±9.8 years) were investigated.

Results

TLSs in AAA lesions were confirmed by focal infiltration of CD3‐positive cells surrounding germinal center‐like structures containing CD20‐positive cells between the tunica adventitia and tunica media layers. The formation of a TLS was significantly more prevalent in AAA patients than in autopsied patients. The number of TLSs in AAA lesions was positively correlated with sac diameter (r=0.357,
P
=0.035) and the amount of intraluminal thrombosis (r=0.466,
P
=0.005). T cells and B cells were predominant cellular populations among CD45
+
cells in AAA lesions. There was a significantly positive correlation between the proportions of interfollicular T follicular helper (CD3
+
CD4
+
CD45RA
−
CXCR5
+
PD‐1
+
) cells and double negative B (CD3
−
CD19
+
IgD
−
CD27
−
) cells, and they were positively correlated with sac diameter, intraluminal thrombosis, and serum lipids. Deposited single‐cell RNA‐sequencing data for AAA showed that T follicular helper cells and double negative B cells were associated with lipid metabolism, T cell activation/proliferation and inflammation.

Conclusions
The formation of a TLS in AAA lesions is associated with sac diameter and intraluminal thrombosis in connection with interfollicular T follicular helper cells and double negative B cells, which may contribute to the pathophysiology of AAA and might be novel therapeutic targets for the development of AAA.
The Effect of Fuel Hedging in the Airline Industry on Returns, Volatility, and on the Return-to-risk Relationship Analysis
Authors: Berkowitz Jason P. , Dasari Kavya S. , DeLisle R. Jared 
Published: February 2025

This paper begins with an investigation on the relation between airline fuel hedging and volatility and builds on this idea to consider its effect on the risk and return relationship. The evidence affirms a negative association between an airline’s fuel hedging expense and both its total volatility and idiosyncratic volatility. However, we observe a negative relationship between hedging and the Sharpe ratio, indicating that hedging reduces the return to risk performance. These relationships also appear to be nonlinear as medium or small hedgers can improve their return to risk ratio while large hedgers can reduce their total and idiosyncratic risk. Results indicate large hedgers are effective hedgers while small and/or medium hedgers may be using derivatives more for effective speculation. Employing lagged variables and instrumental variable approaches yield qualitatively similar results. JEL Classification: D81 Criteria for Decision-Making under Risk and Uncertainty & G11 Portfolio Choice; Investment Decisions