bluuebunny/crossref_metadata_2025_split huggingface dataset:
NLRP3 Inflammasome Activation Is Involved in Geniposide‐Induced Hepatotoxicity
Authors: Liu Yixuan , Liu Baoyue , Shi Mingzhu , Ye Tianxiang , Li Huifang 
Published: February 2025

Background: Geniposide, a prominent iridoid glycoside derived from Gardenia jasminoides J. Ellis, has garnered attention due to its association with hepatotoxicity despite its well‐documented pharmacological efficacy in preclinical and clinical contexts. The NOD‐like receptor protein 3 (NLRP3) inflammasome is implicated in numerous pathological conditions, including drug‐induced liver injury. This study aims to explore the involvement of the NLRP3 inflammasome in geniposide‐induced liver toxicity.Methods: Rats were administered geniposide for 5 days, concurrently treated with or without glibenclamide (GLY), an in vivo inhibitor of NLRP3. In vitro, HL‐7702 cells were exposed to genipin (a metabolite of geniposide via hepatointestinal circulation), with or without GLY supplement. Liver tissue was examined through pathological sections. Aspartate aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), γ‐glutamyl transpeptidase (γ‐GT), and total bilirubin (T‐Bil) levels were determined using the enzyme plate method. IL‐1β and IL‐18 levels in the supernatant and serum were quantified through ELISA. Apoptosis‐associated speck‐like protein (ASC), NLRP3, caspase‐1, pro‐IL‐1β, and pro‐IL‐18 mRNA levels in cells or the liver were assessed by RT‐PCR. Protein levels of ASC, NLRP3, caspase‐1, pro‐IL‐1β, and pro‐IL‐18 in cells or the liver were analyzed by Western blot.Results: Rats treated with geniposide displayed notable liver damage characterized by inflammatory infiltration, elevated serum transaminases, and heightened levels of inflammatory factors IL‐1β and IL‐18. This liver damage was concomitant with NLRP3 inflammasome activation within the liver. Furthermore, genipin induction led to reduced cell viability, increased transaminases in the cell supernatant, and an upsurge in inflammatory factors, resulting in heightened NLRP3 inflammasome expression within the cells. However, GLY effectively curtailed excessive NLRP3 activation, dampened the production of inflammatory factors IL‐1β and IL‐18, and ameliorated liver damage caused by geniposide.Conclusions: Our findings collectively elucidate that geniposide induces hepatotoxicity by triggering NLRP3 inflammasome signaling. Inhibition of the inflammasome presents a promising novel therapeutic target for mitigating geniposide‐induced hepatotoxicity.
Waist Circumference, a Body Shape Index, and Molecular Subtypes of Colorectal Cancer: A Pooled Analysis of Four Cohort Studies
Authors: Chalitsios Christos V. , Markozannes Georgios , Papagiannopoulos Christos , Aglago Elom K. , Berndt Sonja I. , Buchanan Daniel D. , Campbell Peter T. , Cao Yin , Chan Andrew T. , Dimou Niki , Drew David A. , French Amy J. , Georgeson Peter , Giannakis Marios , Gruber Stephen B. , Gunter Marc J. , Harrison Tabitha A. , Hoffmeister Michael , Hsu Li , Huang Wen-Yi , Hullar Meredith A.J. , Huyghe Jeroen R. , Lynch Brigid M. , Moreno Victor , Newton Christina C. , Nowak Jonathan A. , Obón-Santacana Mireia , Ogino Shuji , Qu Conghui , Schmit Stephanie L. , Steinfelder Robert S. , Sun Wei , Thomas Claire E. , Toland Amanda E. , Trinh Quang M. , Ugai Tomotaka , Um Caroline Y. , Van Guelpen Bethany , Zaidi Syed H. , Murphy Neil , Peters Ulrike , Phipps Amanda I. , Tsilidis Konstantinos K. 
Published: February 2025

Abstract

Background:
Waist circumference (WC) and its allometric counterpart, “a body shape index” (ABSI), are risk factors for colorectal cancer; however, it is uncertain whether associations with these body measurements are limited to specific molecular subtypes of the disease.

Methods:
Data from 2,772 colorectal cancer cases and 3,521 controls were pooled from four cohort studies within the Genetics and Epidemiology of Colorectal Cancer Consortium. Four molecular markers (BRAF mutation, KRAS mutation, CpG island methylator phenotype, and microsatellite instability) were analyzed individually and in combination (Jass types). Multivariable logistic and multinomial logistic models were used to assess the associations of WC and ABSI with overall colorectal cancer risk and, in case-only analyses, to evaluate heterogeneity by molecular subtype, respectively.

Results:
Higher WC (ORper 5 cm = 1.06, 95% confidence interval, 1.04–1.09) and ABSI (ORper 1-SD = 1.07, 95% confidence interval, 1.00–1.14) were associated with elevated colorectal cancer risk. There was no evidence of heterogeneity between the molecular subtypes. No difference was observed regarding the influence of WC and ABSI on the four major molecular markers in proximal colon, distal colon, and rectal cancers, as well as in early- and late-onset colorectal cancers. Associations did not differ in the Jass-type analysis.

Conclusions:
Higher WC and ABSI were associated with elevated colorectal cancer risk; however, they do not differentially influence all four major molecular mutations involved in colorectal carcinogenesis but underscore the importance of maintaining a healthy body weight in colorectal cancer prevention.

Impact:
The proposed results have potential utility in colorectal cancer prevention.
First-Line Apatinib Combined with Tislelizumab and Chemotherapy for Patients with Advanced Gastric and Gastroesophageal Junction Adenocarcinoma with Poor Prognosis
Authors: Zhang Wenjie , Wang Jing , Shi Wei , Qiu Hu , Ke Shaobo , Tian Yuanyuan , Gong Yi , Zhang Caiyutian , Chen Jiamei , Wu Yong , Zhao Wensi , Chen Yongshun 
Published: February 2025

Abstract
In this prospective, open-label, exploratory study (RENMIN-213), patients with previously untreated, HER2-negative, advanced G/GEJ adenocarcinoma with signet ring cell carcinoma or peritoneal metastasis were enrolled to receive eight cycles of apatinib, tislelizumab, and chemotherapy every 3 weeks, with a maintenance therapy with apatinib plus tislelizumab for a maximum of 1 year. Homogeneous patients receiving immune checkpoint inhibitors combined with chemotherapy at the same time were deemed as the control group for efficacy. The primary endpoint was progression-free survival. Secondary endpoints were objective response rate, disease control rate, duration of response, overall survival, biomarkers, health-related quality of life, and safety. A total of 33 patients [median (range) age, 60 (32–72) years; 21 (63.6%) male; 11 (33.3%) signet ring cell carcinoma; 30 (90.9%) peritoneal metastasis] were enrolled and deemed evaluable for efficacy analysis. Of these patients, 32 (97%) were without disease progression, of whom 1 (3.0%) patient had complete response and 18 (54.6%) had partial response. Six patients (18.2%) were able to undergo surgery after treatment. After propensity score matching, the median progression-free survival was 10.17 months (95% confidence interval, 7.13–13.21) in the apatinib combined with tislelizumab and chemotherapy group, as compared with 6.0 months in the immune checkpoint inhibitor combined with chemotherapy group. The median duration of response increased from 4.5 to 8.7 months. The objective response rate increased from 33.3% to 54.6%, and the disease control rate increased from 87.9% to 97.0%. Treatment-related grade 3 or higher adverse events for evaluable patients occurred in 11 patients (33.3%), and patients’ health-related quality of life improved after treatment.
Economic Outcomes With Precision Diagnostic Testing Versus Usual Testing in Stable Chest Pain: Results From the PRECISE Randomized Trial
Authors: Chew Derek S. , Mark Daniel B. , Li Yanhong , Nanna Michael G. , Kelsey Michelle D. , Daniels Melanie R. , Davidson-Ray Linda , Baloch Khaula N. , Rogers Campbell , Patel Manesh R. , Anstrom Kevin J. , Curzen Nick , Vemulapalli Sreekanth , Douglas Pamela S. ,   on behalf of the PRECISE Investigators
Published: February 2025

BACKGROUND:
The PRECISE (Prospective Randomized Trial of the Optimal Evaluation of Cardiac Symptoms and Revascularization) demonstrated that a precision diagnostic strategy reduced the primary composite of death, nonfatal myocardial infarction, or catheterization without obstructive coronary artery disease by 65% in patients with nonacute chest pain compared with usual testing. Medical cost was a prespecified secondary end point.

METHODS:
PRECISE randomized 2103 patients between December 2018 and May 2021 to usual testing or a precision strategy that used deferred testing for the lowest risk patients (20%) and coronary computed tomographic angiography with selective computed tomography–derived fractional flow reserve for the remainder. Resource use consumption data were collected from all study participants and hospital cost data from US participants (n=1125) to estimate total medical costs. The primary and secondary economic outcomes were total costs at 12 months and at 45 days, respectively, from the US health care system perspective. The mean cost differences between the 2 strategies were reported by intention-to-treat.

RESULTS:

At 45 days, total costs were similar between the precision strategy and usual testing (mean difference, $182 [95% CI, −$555 to $661]). By 12 months, percutaneous coronary intervention and coronary artery bypass surgery had been performed in 7.2% and 2.0% of precision strategy patients and 3.5% and 1.7% of usual testing patients, respectively. At 1 year, precision strategy costs were $5299 versus $4821 for usual testing (mean difference, $478 [95% CI, −$889 to $1437];
P
=0.43). Precision care decreased mean per-patient diagnostic cost by 27% and increased mean per-patient revascularization costs by 67%.

CONCLUSIONS:
In the PRECISE trial, the precision strategy, a risk-based approach endorsed by current clinical practice guidelines, improved the clinical efficiency of testing and had similar costs to usual testing at 45 days and a nonsignificant $478 cost difference at 1 year.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03702244.
Quality of Life Outcomes With a Risk-Based Precision Testing Strategy Versus Usual Testing in Stable Patients With Suspected Coronary Disease: Results From the PRECISE Randomized Trial
Authors: Mark Daniel B. , Li Yanhong , Nanna Michael G. , Kelsey Michelle D. , Daniels Melanie R. , Rogers Campbell , Patel Manesh R. , Baloch Khaula N. , Chow Benjamin J.W. , Anstrom Kevin J. , Vemulapalli Sreekanth , Weir-McCall Jonathan R. , Stone Gregg W. , Chew Derek S. , Douglas Pamela S. ,   on behalf of the PRECISE Investigators
Published: February 2025

BACKGROUND:
The PRECISE (Prospective Randomized Trial of the Optimal Evaluation of Cardiac Symptoms and Revascularization) trial compared an investigational precision diagnostic testing strategy (n=1057) with usual testing (n=1046) in patients with stable chest pain and suspected coronary artery disease. Quality of life (QOL) outcomes were a prespecified secondary end point.

METHODS:
We assessed QOL by structured interviews in all trial participants at baseline and 45 days, 6 months, and 12 months postrandomization. QOL assessments included angina-related QOL (19-item Seattle Angina Questionnaire [SAQ-19]), generic health status (EQ-5D), and a 4-item care satisfaction survey (at 45 days only). The prespecified primary comparison was the 6-month SAQ Summary score outcomes (scale, 0 to 100; higher scores indicate greater health status). QOL data collection rates were high, with 99% complete baseline SAQ scores and 86.5% complete at the 6-month primary comparison follow-up. All comparisons were made as randomized.

RESULTS:
At baseline, mean SAQ Summary scores were 70.9 in the Precision Strategy group (n=1050) and 70.4 in the Usual Testing group (n=1042). By 6 months, mean SAQ Summary scores had improved to 89.9 in the Precision Strategy group and 89.2 in the Usual Testing group, with a mean adjusted difference of 0.8 (95% CI, −0.3 to 2.0). The SAQ component scores showed similar improvement from baseline in both groups and no statistically significant or clinically meaningful differences between the 2 groups at any follow-up time point. By 6 months, 66% of patients in both groups were chest pain-free. EQ-5D visual analog scores also improved from baseline and showed no difference between groups during follow-up. Care satisfaction scores were high and similar at 45 days.

CONCLUSIONS:
In stable patients with symptoms suggesting coronary artery disease, angina-related and overall QOL improved substantially over the initial 6 months independent of the testing strategy assigned.

REGISTRATION:

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03702244.
Systematic Review, Meta-Analysis, and Population Study to Determine the Biologic Sex Ratio in Dilated Cardiomyopathy
Authors: Bergan Natalie , Prachee Ishika , Curran Lara , McGurk Kathryn A. , Lu Chang , de Marvao Antonio , Bai Wenjia , Halliday Brian P. , Gregson John , O’Regan Declan P. , Ware James S. , Tayal Upasana 
Published: February 2025

BACKGROUND:
Dilated cardiomyopathy (DCM) appears to be diagnosed twice as often in male than in female patients. This could be attributed to underdiagnosis in female patients or sex differences in susceptibility. Up to 30% of cases have an autosomal dominant monogenic cause, where equal sex prevalence would be expected. The aim of this systematic review, meta-analysis, and population study was to assess the sex ratio in patients with DCM, stratified by genetic status, and evaluate whether this is influenced by diagnostic bias.

METHODS:

A literature search identified DCM patient cohorts with discernible sex ratios. Exclusion criteria were studies with a small (n<100), pediatric, or peripartum population. Meta-analysis and metaregression compared the proportion of female participants for an overall DCM cohort and the following subtypes: all genetic DCM, individual selected DCM genes (
TTN
and
LMNA
), and gene-elusive DCM. Population DCM sex ratios generated from diagnostic codes were also compared with those from sex-specific means using the UK Biobank imaging cohort; this established ICD coded, novel imaging-first, and genotype first determined sex ratios.

RESULTS:

A total of 99 studies, with 37 525 participants, were included. The overall DCM cohort had a 0.30 female proportion (95% CI, 0.28–0.32), corresponding to a male:female ratio (M:F) of 2.38:1. This was similar to patients with an identified DCM variant (0.31 [95% CI, 0.26–0.36]; M:F 2.22:1;
P
=0.56). There was also no significant difference when compared with patients with gene-elusive DCM (0.30 [95% CI, 0.24–0.37]; M:F 2.29:1;
P
=0.81). Furthermore, the ratio within autosomal dominant gene variants was not significantly different for
TTN
(0.28 [95% CI, 0.22–0.36]; M:F 2.51:1;
P
=0.82) or
LMNA
(0.35 [95% CI, 0.27–0.44]; M:F 1.84:1;
P
=0.41). Overall, the sex ratio for DCM in people with disease attributed to autosomal dominant gene variants was similar to the all-cause group (0.34 [95% CI, 0.28–0.40]; M:F 1.98:1;
P
=0.19). In the UK Biobank (n=47 549), DCM defined by International Classification of Diseases, 10th revision, coding had 4.5:1 M:F. However, implementing sex-specific imaging-first and genotype-first diagnostic approaches changed this to 1.7:1 and 2.3:1, respectively.

CONCLUSIONS:
This study demonstrates that DCM is twice as prevalent in male patients. This was partially mitigated by implementing sex-specific DCM diagnostic criteria. The persistent male excess in genotype-positive patients with an equally prevalent genetic risk suggests additional genetic or environmental drivers for sex-biased penetrance.

REGISTRATION:

URL:
https://www.crd.york.ac.uk/prospero
; Unique identifier: CRD42023451944.
Cerebral Microhemorrhages in Children With Congenital Heart Disease: Prevalence, Risk Factors, and Association With Neurodevelopmental Outcomes
Authors: Andersen Kristen N. , Yao Sicong , White Brian R. , Jacobwitz Marin , Breimann Jake , Jahnavi Jharna , Schmidt Alexander , Baker Wesley B. , Ko Tiffany S. , Gaynor J. William , Vossough Arastoo , Xiao Rui , Licht Daniel J. , Shih Evelyn K. 
Published: February 2025

Background
Infants with congenital heart disease require early lifesaving heart surgery, which increases risk for brain injury and neurodevelopmental delay. Cerebral microhemorrhages (CMH) are frequently seen after surgery, but whether they are benign or constitute injury is unknown.

Methods and Results

One hundred ninety‐two infants with congenital heart disease undergoing cardiac surgery with cardiopulmonary bypass were evaluated with pre‐ (n=183) and/or postoperative (n=162) magnetic resonance imaging. Perioperative risk factors for CMH and neurodevelopmental outcomes were analyzed using linear regression. Eighteen‐month neurodevelopmental outcomes were assessed in a subset of patients (n=82). The most common congenital heart disease subtypes were hypoplastic left heart syndrome (37%) and transposition of the great arteries (33%). Forty‐two infants (23%) had CMH present on magnetic resonance imaging presurgery and 137 infants (85%) postsurgery. We found no significant risk factors for preoperative CMH. In multivariable analysis, neurodevelopmental duration (
P
<0.0001), use of extracorporeal membrane oxygenation support (
P
<0.0005), postoperative seizure(s) (
P
=0.02), and lower birth weight (
P
=0.03) were associated with new or worsened CMH postoperatively. A higher CMH number was associated with lower motor scores (
P
=0.01) at 18 months.

Conclusions
CMH are common imaging findings in infants with congenital heart disease, particularly after cardiopulmonary bypass conferring adverse impact on neurodevelopmental outcomes at 18 months. Longer duration of cardiopulmonary bypass and extracorporeal membrane oxygenation use demonstrated greatest risk for developing CMH. However, the presence of CMH on preoperative scans indicates yet unidentified nonperioperative risk factors. Neuroprotective strategies to mitigate CMH risk may improve neurodevelopmental outcomes in this vulnerable population.
Prior Anticoagulation and Risk of Hemorrhagic Transformation in Acute Stroke: A Post Hoc Analysis of the PRODAST Study
Authors: Grosse Gerrit M. , Hüsing Anika , Stang Andreas , Kuklik Nils , Brinkmann Marcus , Grond Martin , Rollnik Jens D. , Marquardt Lars , Kraft Andrea , Schlemm Eckhard , Eggers Carsten , Eschenfelder Christoph C. , Weimar Christian , Diener Hans‐Christoph 
Published: February 2025

Background
Oral anticoagulation is highly effective in preventing ischemic events in patients with atrial fibrillation. Still, a considerable number of patients have an acute ischemic stroke or transient ischemic attack despite anticoagulation. In this study, we investigated the association of prior antithrombotic regimens with stroke severity, volume, and hemorrhagic transformation.

Methods and Results
This is a post hoc analysis of the prospective, multicenter, observational PRODAST (Prospective Record of the Use of Dabigatran in Patients With Acute Stroke or TIA) study, which was conducted in 86 stroke units in Germany between July 2015 and November 2020. In 9030 patients with atrial fibrillation who had an acute ischemic stroke or transient ischemic attack within 7 days before enrollment, we analyzed the association of anticoagulants in comparison to lack of prevalent antithrombotic treatment with clinical stroke severity, infarct size, and risk for hemorrhagic transformation. A total of 4479 patients had prior anticoagulation at the time of index event. After adjustment for confounders (arterial hypertension, diabetes, heart failure, age, and sex), patients with prior anticoagulation had less severe strokes (−2.5 National Institutes of Health Stroke Scale points [95% CI, −2.8 to −2.2]), smaller infarct sizes (−23 mL [95% CI, −44 mL to −2 mL], n=4041), and reduced odds for hemorrhagic transformation (5% versus 10%; odds ratio, 0.48 [95% CI, 0.40–0.57]) compared with patients without antithrombotic treatment. These findings were confirmed using sensitivity analyses accounting for thrombolysis and mechanical thrombectomy, as well as timing of brain imaging. Antiplatelet therapy had hardly any association with the end points compared with no antithrombotic pretreatment.

Conclusions
Prior anticoagulation was not only associated with less severe stroke and smaller infarct size but also with a reduced risk of hemorrhagic transformation compared with no antithrombotic pretreatment.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT02507856.
Development and Validation of Risk Stratification for Heart Failure After Acute Coronary Syndrome Based on Dynamic S100A8/A9 Levels
Authors: Ma Jie , Ma Ke , Chen Jing , Yang Xinying , Gao Fei , Gao Hai , Zhang Hui , Ma Xin‐Liang , Du Jie , Li Ping , Li Yulin 
Published: February 2025

Background
The early assessment of heart failure (HF) risk in patients with acute coronary syndrome (ACS) can help reduce mortality. S100A8/A9 is not only rapidly released after myocardial ischemia, but is also involved in reperfusion injury, which is an important predictor of HF after ACS. We attempted to construct a reliable HF risk stratification tool for evaluating patients with ACS after reperfusion therapy based on S100A8/A9 dynamic changes.

Methods and Results
This prospective study included 3 independent cohorts of patients with ACS who received reperfusion therapy. The discovery cohort was divided into 2 subgroups: the longitudinal subgroup (n=264) with serum S100A8/A9 levels measured at admission and on days 1, 2, 3, and 4 postadmission, respectively, and the 2‐point subgroup (n=798) with S100A8/A9 levels measured at admission and on day 1 postadmission, respectively. Validation cohorts 1 (n=1399) and 2 (n=1183) both had S100A8/A9 levels measured on day 1 postadmission. HF events included in‐hospital HF events after the initial presentation and long‐term HF events after discharge. The median follow‐up for the discovery cohort, validation cohort 1, and validation cohort 2 was 4.2, 2.6, and 1.8 years, respectively. In the discovery cohort, S100A8/A9's predictive ability at day 1 surpassed other time points. Through the S100A8/A9‐guided risk stratification, patients deemed high risk (>7900 ng/mL) exhibited a higher 1‐year HF event rate (46% versus 2%, 38% versus 5%) than patients at low risk (<2100 ng/mL) in both validation cohorts. Among patients without left ventricular dysfunction after ACS, β‐blocker therapy correlated with reduced 1‐year HF events in intermediate‐to‐ high‐risk patients but not in low‐risk patients.

Conclusions
S100A8/A9 levels on day 1 accurately classified patients at varying risks of HF, serving as a robust tool for HF risk prediction and treatment guidance.

Registration

URL:
https://www.clinicaltrials.gov
; Unique identifier: NCT03752515.