bluuebunny/crossref_metadata_2025_split huggingface dataset:
Arthroscopic Repair of the Anterior Talofibular Ligament Produces Good Clinical Outcome Scores Both with and without Inferior Extensor Retinaculum Reinforcement: A Meta-Analysis
Authors: Murray Benjamin , Mirghasemi Ali , Shaffer Gene , Raphael James 
Published: December 2024

Category: Arthroscopy; Ankle Introduction/Purpose: Arthroscopic techniques for lateral ankle instability generally involve either direct repair solely of the anterior talofibular ligament (ATFL) remnant or repair of the ATFL with inferior extensor retinaculum (IER) reinforcement. Both techniques produce strong clinical outcomes, which questions the necessity of IER reinforcement. Studies comparing arthroscopic lateral ankle ligament stabilization techniques are limited, especially those directly comparing pure ATFL repair to ATFL repair with IER reinforcement. The purpose of this study is to compare clinical outcomes of arthroscopic repair of the ATFL without IER reinforcement to arthroscopic ATFL repair procedures involving IER reinforcement Methods: A meta-analysis per PRISMA guidelines was conducted. Search keywords included arthroscopic, all-inside, ankle stabilization, lateral ankle sprain, anterior talofibular ligament, and lateral ankle instability. To assess the relationship of type of surgical procedure (ATFL repair with versus without IER reinforcement) to reported clinical outcomes based on the American Orthopaedic Foot and Ankle Society (AOFAS) score, the Karlsson and Peterson Scoring System for Ankle Function (KAFS), and the Visual Analogue Score (VAS), we used the standardized mean difference (SMD) with a 95% confidence interval of preoperative to postoperative scores as an effect size. The method of random-effects model was used to calculate the overall summary estimates. Results: 638 studies met the initial search criteria. 34 studies met final inclusion criteria and were included in the meta-analysis. Patients receiving arthroscopic ATFL repair both with and without IER reinforcement had significantly improved pre-operative to post-operative clinical outcome scores. Arthroscopic ATFL repair with IER reinforcement resulted in a significantly higher pre-operative to post-operative SMD for KAFS (p=0.091) and VAS (p=0.065) scores compared to arthroscopic ATFL repair without IER reinforcement. There was no significant difference in the pre-operative to post-operative SMD of AOFAS (p=0.453) scores when comparing surgical procedures. Conclusion: Arthroscopic ATFL repair produces strong clinical outcome scores both with and without IER reinforcement.
The pleiotropic effects of statins: a comprehensive exploration of neurovascular unit modulation and blood–brain barrier protection
Authors: Liu Jia-Cheng , Lei Shuang-Yin , Zhang Dian-Hui , He Qian-Yan , Sun Ying-Ying , Zhu Hong-Jing , Qu Yang , Zhou Sheng-Yu , Yang Yi , Li Chao , Guo Zhen-Ni 
Published: December 2024

AbstractThe blood–brain barrier (BBB) is the most central component of the neurovascular unit (NVU) and is crucial for the maintenance of the internal environment of the central nervous system and the regulation of homeostasis. A multitude of neuroprotective agents have been developed to exert neuroprotective effects and improve the prognosis of patients with ischemic stroke. These agents have been designed to maintain integrity and promote BBB repair. Statins are widely used as pharmacological agents for the treatment and prevention of ischemic stroke, making them a cornerstone in the pharmacological armamentarium for this condition. The primary mechanism of action is the reduction of serum cholesterol through the inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, which results in a decrease in low-density lipoprotein cholesterol (LDL-C) and an increase in cholesterol clearance. Nevertheless, basic and clinical research has indicated that statins may exert additional pleiotropic effects beyond LDL-C reduction. Previous studies on ischemic stroke have demonstrated that statins can enhance neurological function, reduce inflammation, and promote angiogenic and synaptic processes following ischemic stroke. The BBB has been increasingly recognized for its role in the development and progression of ischemic stroke. Statins have also been found to play a potential BBB protective role by affecting members of the NVU. This review aimed to provide a comprehensive theoretical basis for the clinical application of statins by systematically detailing how statins influence the BBB, particularly focusing on the regulation of the function of each member of the NVU.
Graphical Abstract
GLUT1 exacerbates trophoblast ferroptosis by modulating AMPK/ACC mediated lipid metabolism and promotes gestational diabetes mellitus associated fetal growth restriction
Authors: Zhang Qin , Yuan Xi , Luan Xiaojin , Lei Ting , Li Yiran , Chu Wei , Yao Qi , Baker Philip N. , Qi Hongbo , Li Hui 
Published: December 2024

Abstract
Background
Gestational diabetes mellitus (GDM) has been associated with several fetal complications, such as macrosomia and fetal growth restriction (FGR). Infants from GDM associated FGR are at increased risk for adult-onset obesity and associated metabolic disorders. However, the underlying mechanisms of GDM associated FGR remain to be explored.

Methods
We analyzed placentas from GDM patients with FGR for ferroptosis markers and GLUT1 expression. High glucose conditions were established by adding different concentrations of D-Glucose to the 1640 cell culture medium. RSL3 were used to test ferroptosis sensitivity in trophoblast cells. GLUT1 was inhibited using siRNA or its inhibitor WZB117 to assess its impact on ferroptosis inhibition in HTR8/SVneo cell line. Mechanistic studies explored the effects of GLUT1 on AMPK and ACC phosphorylation, which in turn impacted lipid metabolism and ferroptosis. In mouse models, streptozotocin (STZ)-induced GDM was treated with WZB117 and the ferroptosis inhibitor liproxstatin-1 (Lip-1). Finally, AMPK and ACC phosphorylation levels were evaluated in GDM patient samples.

Results
In this study, placentas from GDM patients with FGR showed signs of ferroptosis and upregulation of GLUT1. In cell models, high glucose conditions sensitized trophoblast cells to ferroptosis and induced GLUT1 expression. Interestingly, GLUT1 inhibition significantly suppressed ferroptosis in trophoblast cells under high glucose conditions. Mechanistically, elevated GLUT1 inhibited AMPK phosphorylation and reduced ACC phosphorylation, thereby promoting lipid synthesis and facilitating ferroptosis. In pregnant mice, STZ-induced hyperglycemia led to FGR, and treatment with either the GLUT1 inhibitor WZB117 or the ferroptosis inhibitor Lip-1 alleviated the FGR phenotype. Moreover, in vivo elevation of GLUT1 increased ferroptosis markers, decreased AMPK/ACC phosphorylation, and resulted in altered lipid metabolism, which likely contributed to the observed phenotype. Finally, placental samples from GDM patients showed reduced AMPK and ACC phosphorylation.

Conclusions
Our findings suggest a potential role of ferroptosis in GDM associated FGR and indicate that the dysregulated GLUT1-AMPK-ACC axis may be involved in the pathogenesis of GDM associated FGR in clinicals.
Crosstalk between CD180-overexpression macrophages and glioma cells worsens patient survival through malignant phenotype promotion and immunosuppressive regulation
Authors: Wang Wen , Li Junsheng , He Qiheng , Liu Chenglong , Zheng Zhiyao , Zhang Bojian , Mou Siqi , Sun Wei , Zhao Jizong 
Published: December 2024

Abstract
Background
Understanding the molecular mechanisms in immunosuppressive regulation is crucial for improving immunotherapeutic strategies. Macrophages, the major immune cells in tumor microenvironment (TME), play a dual role in tumor progression. CD180, primarily expressed in macrophages, remains unclear and requires further investigation.

Methods
RNA-seq data were obtained to analyze CD180 expression in gliomas and assess its prognostic value. The comprehensive immune infiltration analysis was performed. Single-cell RNA-seq (scRNA-seq) data were used to examine CD180 expression distribution at the cellular level. CD180-overexpression macrophages were co-cultured with three glioma cell lines. The effects on glioma cell behavior were evaluated through qRT-PCR, Western blot, CCK-8 assay, EdU assay, Transwell assay, TUNEL assay, and flow cytometry. Differentially expressed genes (DEGs) and their potential biological functions were analyzed between different CD180 expression groups. Consensus clustering was used to identify CD180-related glioma subtypes.

Results
CD180 was significantly upregulated in glioma samples and associated with poor prognosis. High CD180 expression was correlated with increased immune cell infiltration, particularly macrophages, and elevated levels of immune checkpoints. Analysis of scRNA-seq data revealed the predominant expression of CD180 in macrophages within the glioma TME. In vitro experiments demonstrated that CD180-overexpression macrophages promoted glioma cell proliferation, migration, invasion, and epithelial-mesenchymal transition (EMT), while decreasing apoptosis. Mutations in TP53 and PTEN were significantly more prevalent in the high CD180 expression group. We identified nine chemotherapeutic agents that were more effective in glioma patients with high CD180 expression. Additionally, two CD180-related glioma subtypes with distinct prognosis were identified.

Conclusions
This study confirmed the prognostic role of CD180 in glioma and its involvement in immunosuppressive regulation and malignant phenotype promotion. Therefore, CD180 was considered as a promising target for immunotherapeutic strategies in glioma treatment.
Elucidating the role of gut microbiota metabolites in diabetes by employing network pharmacology
Authors: Yao Weiguo , Huo Jinlin , Ji Jing , liu Kun , Tao Pengyu 
Published: December 2024

Abstract
Background
Extensive research has underscored the criticality of preserving diversity and equilibrium within the gut microbiota for optimal human health. However, the precise mechanisms by which the metabolites and targets of the gut microbiota exert their effects remain largely unexplored. This study utilizes a network pharmacology methodology to elucidate the intricate interplay between the microbiota, metabolites, and targets in the context of DM, thereby facilitating a more comprehensive comprehension of this multifaceted disease.

Methods
In this study, we initially extracted metabolite information of gut microbiota metabolites from the gutMGene database. Subsequently, we employed the SEA and STP databases to discern targets that are intricately associated with these metabolites. Furthermore, we leveraged prominent databases such as Genecard, DisGeNET, and OMIM to identify targets related to diabetes. A protein-protein interaction (PPI) network was established to screen core targets. Additionally, we conducted comprehensive GO and KEGG enrichment analyses utilizing the DAVID database. Moreover, a network illustrating the relationship among microbiota-substrate-metabolite-target was established.

Results
We identified a total of 48 overlapping targets between gut microbiota metabolites and diabetes. Subsequently, we selected IL6, AKT1 and PPARG as core targets for the treatment of diabetes. Through the construction of the MSMT comprehensive network, we discovered that the three core targets exert therapeutic effects on diabetes through interactions with 8 metabolites, 3 substrates, and 5 gut microbiota. Additionally, GO analysis revealed that gut microbiota metabolites primarily regulate oxidative stress, inflammation and cell proliferation. KEGG analysis results indicated that IL-17, PI3K/AKT, HIF-1, and VEGF are the main signaling pathways involved in DM.

Conclusion
Gut microbiota metabolites primarily exert their therapeutic effects on diabetes through the IL6, AKT1, and PPARG targets. The mechanisms of gut microbiota metabolites regulating DM might involve signaling pathways such as IL-17 pathways, HIF-1 pathways and VEGF pathways.
Influence of liberal versus conservative oxygen therapies on the hemodynamic parameters of mechanically ventilated patients with sepsis: a randomized clinical trial
Authors: Ghazaly Huda F. , Aly Ahmed Alsaied A. , Tammam Ahmed S. , Hassan Mahmoud M. , Hammad Soudy S. , Mahmoud Naggeh M. , Hemaida Tarek S. 
Published: December 2024

Abstract
Background
There is no significant evidence verifying the efficacy of liberal versus conservative oxygen therapy on hemodynamics in patients with sepsis. We investigated how liberal and conservative oxygen therapy influenced stroke volume, cardiac output, and vasopressor needs in patients with sepsis undergoing mechanical ventilation.

Methods
This randomized clinical trial included 106 patients with an admission diagnosis of infection, a Sequential Organ Failure Assessment (SOFA) score of two points or higher and required invasive mechanical ventilation for at least 72 h. Patients were randomly assigned to one of two oxygenation strategies: liberal (n = 53) with a target SpO2 of ≥ 96% or conservative (n = 53) with a target SpO2 of 88–92%. Transthoracic Doppler echocardiography was done twice to measure stroke volume and cardiac output, initially upon enrollment in the trial and then 72 h later. The primary outcome was stroke volume. Secondary outcomes were cardiac output, vasopressor use, mechanical ventilation duration, ICU stay length, and adverse events.

Results
Stroke volume and cardiac output measurements did not differ significantly between research groups after 72 h of oxygenation treatment (p = 0.459 and 0.637, respectively). Forty-five patients (84.9%) in the conservative oxygen therapy group needed vasopressors to maintain their mean arterial pressure above 65 mmHg, whereas 35 patients (66.0%) in the liberal group did (p = 0.024). A multivariate logistic regression analysis of the independent variables for vasopressor requirements revealed that patients in the conservative oxygen group were 3.83 times more likely to require vasopressors (AOR = 3.83, 95% CI: 1.31–11.18, p = 0.014) than those in the liberal group. Older patients (AOR = 1.03, 95% CI: 1.01–1.07, p = 0.038) and those with higher SOFA scores (AOR = 1.36, CI: 1.09–1.68, P = 0.005) were significantly more likely to need vasopressors.

Conclusions
Liberal or conservative oxygen therapy did not influence stroke volume or cardiac output measurements in mechanically ventilated patients with sepsis. Patients in the conservative oxygen group were more likely to require vasopressors than those in the liberal group.

Trial registration
This study was approved by the Ethics Committee of Aswan University Hospital (approval number: Aswu/460/5/20) (registration date: 05/05/2020) and registered on ClinicalTrials.gov (NCT04824703) (03/30/2021).
Strain echocardiography predictors in patients with concomitant cardiac amyloidosis and aortic stenosis: a cross-sectional study
Authors: Jafarisis Samira , Masoumi Shahab , Khezerlouy-Aghdam Naser , Toutounchi Kia Seyed , Sarmadian Amirreza Jabbaripour , Hamzehzadeh Sina , Shariati Akram , Parizad Razieh , Rabori Venus Shahabi 
Published: December 2024

Abstract
Background
Concomitant cardiac amyloidosis (CA) and aortic stenosis (AS) may be mistaken for isolated AS, potentially impacting the treatment strategy and patient’s prognosis. Therefore, it is crucial to distinguish between these conditions, as failure to promptly diagnose CA may lead to considerable complications. The aim of this study is to investigate the diagnostic value of strain predictors in patients with concomitant CA and AS compared to isolated AS.

Methods
Forty-two patients with severe AS suspected of concomitant CA based on a comprehensive clinical evaluation were selected to undergo 99mTc-DPD scintigraphy. Those showing Perugini grade 2 or 3 tracer uptakes without evidence of monoclonal gammopathy were diagnosed with CA and underwent speckle-tracking echocardiography. Furthermore, strain analysis was performed to evaluate myocardial deformation, with a focus on detecting apical sparing and reduction in bull’s eye mapping, resulting in the characteristic “cherry on top” sign.

Results
Eight patients were diagnosed with CA, representing 19.0% of those suspected of concomitant CA and 7.8% of the overall cohort with severe AS. AF arrhythmia was significantly more frequent in these patients compared to those with isolated AS. Echocardiography findings revealed that E/E’ ratio and RALS were significantly higher in patients with concomitant CA, while GLS and mean basal LS were significantly lower in this group. The “cherry on top” sign was detected in 19 patients (45.2%), present in 100% of those with concomitant CA and AS, versus 32.4% in isolated AS cases (P = 0.04). This sign demonstrated a sensitivity of 100% and a specificity of 67.6% for predicting concomitant CA and AS.

Conclusions
In conclusion, the “cherry on top” sign was significantly more prevalent in patients with concomitant CA and AS, compared to those with isolated AS, demonstrating a sensitivity of 100% and a specificity of 67.6% for predicting concomitant CA. Moreover, RALS and E/E’ ratios were significantly higher in patients with concomitant CA, whereas GLS and mean basal LS were significantly lower in this group.
Addressing treatment switching in the ALTA-1L trial with g-methods: exploring the impact of model specification
Authors: Al Tawil Amani , McGrath Sean , Ristl Robin , Mansmann Ulrich 
Published: December 2024

Abstract
Background
Treatment switching in randomized clinical trials introduces challenges in performing causal inference. Intention To Treat (ITT) analyses often fail to fully capture the causal effect of treatment in the presence of treatment switching. Consequently, decision makers may instead be interested in causal effects of hypothetical treatment strategies that do not allow for treatment switching. For example, the phase 3 ALTA-1L trial showed that brigatinib may have improved Overall Survival (OS) compared to crizotinib if treatment switching had not occurred. Their sensitivity analysis using Inverse Probability of Censoring Weights (IPCW), reported a Hazard Ratio (HR) of 0.50 (95% CI, 0.28-0.87), while their initial ITT analysis estimated an HR of 0.81 (0.53-1.22).

Methods
We used a directed acyclic graph to depict the clinical setting of the ALTA-1L trial in the presence of treatment switching, illustrating the concept of treatment-confounder feedback and highlighting the need for g-methods. In a re-analysis of the ALTA-1L trial data, we used IPCW and the parametric g-formula to adjust for baseline and time-varying covariates to estimate the effect of two hypothetical treatment strategies on OS: “always treat with brigatinib” versus “always treat with crizotinib”. We conducted various sensitivity analyses using different model specifications and weight truncation approaches.

Results
Applying the IPCW approach in a series of sensitivity analyses yielded Cumulative HRs (cHRs) ranging between 0.38 (0.12, 0.98) and 0.73 (0.45,1.22) and Risk Ratios (RRs) ranging between 0.52 (0.32, 0.98) and 0.79 (0.54,1.17). Applying the parametric g-formula resulted in cHRs ranging between 0.61 (0.38,0.91) and 0.72 (0.43,1.07) and RRs ranging between 0.71 (0.48,0.94) and 0.79 (0.54,1.05).

Conclusion
Our results consistently indicated that our estimated ITT effect estimate (cHR: 0.82 (0.51,1.22) may have underestimated brigatinib’s benefit by around 10-45 percentage points (using IPCW) and 10-20 percentage points (using the parametric g-formula) across a wide range of model choices. Our analyses underscore the importance of performing sensitivity analyses, as the result from a single analysis could potentially stand as an outlier in a whole range of sensitivity analyses.

Trial registration
Clinicaltrials.gov Identifier: NCT02737501 on April 14, 2016.
Historical and future heat-related mortality in Portugal’s Alentejo region
Authors: Neto Dora , Araújo Miguel Bastos 
Published: December 2024

Abstract
Background
The increased severity of extreme weather and anticipated climate change has intensified heat stress-related mortality worldwide. This study examines the historical short-term effects of heat on mortality in Alentejo, Portugal’s warmest region, and projects it up to the end of the century.

Methods
Using data from 1980 to 2015 during warm seasons (May-September), the association between daily mortality by all-causes and mean temperature was examined following a case time series design, applied at both regional and subregional scales. Projections for daily temperatures were obtained from regional climate models and greenhouse gas emission scenarios (RCP4.5, RCP8.5). We also examined temporal shifts in mortality considering potential long-term and seasonal adaptative responses to heat. We then quantified the yearly effects of heat by calculating absolute and relative excess mortality from 1980 to 2015, specifically during the heatwave of 2003 (July 27 to August 15), and in future projections at 20-year intervals through 2100.

Results
The analysis revealed a significant rise in mortality risk at temperatures exceeding a minimum mortality temperature (MMT) of 19.0 °C, with an exponential trend and delayed effects lasting up to 5 days. The risk increased by 413% at the maximum extreme temperature of 36.6 °C. From 1980 to 2015, 2.32% of total deaths, equating to over 5,296 deaths, were heat-associated. No significant shifts over time were noted in the population’s response to heat. Future projections, without adaptation and demographic changes, show a potential increase in mortality by 15.88% under a “no mitigation policy” scenario by 2100, while mitigation measures could limit the rise to 6.61%.

Conclusion
Results underscore the urgent need for protective health policies to reduce regional population vulnerability and prevent premature heat-related deaths across the century.