bluuebunny/crossref_metadata_2025_split huggingface dataset:
“Naloxone? Not for me!” First cross-assessment by patients and healthcare professionals of the risk of opioid overdose
Authors: Aquizerate Aurélie , Rousselet Morgane , Cochard Axel , Guerlais Marylène , Gerardin Marie , Lefebvre Emilie , Duval Mélanie , Laforgue Edouard-Jules , Victorri-Vigneau Caroline 
Published: January 2024

Abstract
Background
Opioid-related mortality is a rising public health concern in France, where opioids were in 2021 implicated in 75% of overdose deaths. Opioid substitution treatment (OST) was implicated in almost half of deaths related to substance and drug abuse. Although naloxone could prevent 80% of these deaths, there are a number of barriers to the distribution of take-home naloxone (THN) among opioid users in France. This study is the first one which compares patients' self-assessment of the risk of future opioid overdose with the hetero-assessment provided by healthcare professionals in a population of individuals eligible for naloxone.

Methods
This was a multicenter descriptive observational study carried out in pharmacies across the Pays de la Loire region (France) during April and May 2022. All adult patients who visited a participating pharmacy for a prescription of OST and provided oral informed consent were enrolled in the study. Retrospective data were collected through cross-sectional interviews conducted by the pharmacist with the patient, utilizing an ad hoc questionnaire. The patient’s self-assessment of overdose risk was evaluated using a Likert scale from 0 to 10. The pharmacist relied on the presence or absence of overdose risk situations defined by the French Health Authority (HAS). The need to hold THN was assessed using a composite criterion.

Results
A total of 34 patients were interviewed; near one third were aware of the existence of THN and a minority had THN in their possession. Out of the 34 participants, 29 assessed their own risk of future opioid overdose: 65.5% reported having zero risk, while 6.9% believed they had a high risk. Nevertheless, at least one risk situation of opioid overdose was identified according to HAS criteria in 73.5% of the participants (n = 25). Consequently, 55% of the participants underestimated their risk of experiencing a future opioid overdose. Yet, dispensing THN has been judged necessary for 88.2% of the participants.

Conclusion
This study underscored the imperative need to inform not only healthcare professionals but also the patients and users themselves on the availability of THN and the risk situations of opioid overdose.
Immune characteristics of dedifferentiated retroperitoneal liposarcomas and the reliability of regional samples in evaluating their tumor immune microenvironments
Authors: Zhou Changsheng , Li Ming , Ren Yantao , Miao Fenglin , Wang Yue , Wu Ting , Gou Xin , Li Wengang 
Published: January 2024

Abstract
Background
Tumor immunotherapy is a new treatment breakthrough for retroperitoneal liposarcoma (RPLS), which is highly invasive and has few effective treatment options other than tumor resection. However, the heterogeneity of the tumor immune microenvironment (TIME) leads to missed clinical diagnosis and inappropriate treatment. Therefore, it is crucial to evaluate whether the TIME of a certain part of the tumor reliably represents the whole tumor, particularly for very large tumors, such as RPLS.

Methods
We conducted a prospective study to evaluate the TIME in different regions of dedifferentiated RPLS (DDRPLS) by detecting the expressions of markers such as CD4+, CD8+, Foxp3+, CD20+, CD68+, LAMP3+, PD-1+ tumor-infiltrating lymphocytes (TILs), and PD-L1 in tumors and corresponding paratumor tissues via immunohistochemistry and RNA sequencing.

Results
In DDRPLS, very few TILs were observed. Differentially expressed genes were significantly enriched in cell part and cell functions, as well as the metabolic pathway and PI3K-Akt signaling pathway. In addition, for most tumors (70–80%), the TIME was similar in different tumor regions.

Conclusions
For most tumors (70–80%), the TIME in any region of the tumor reliably represents the whole tumor. DDRPLS may regulate cell functions by modulating the metabolic and PI3K-Akt signaling pathways to promote its malignant behavior.
Patients with high nuclear grade pT1-ccRCC are more suitable for radical nephrectomy than partial nephrectomy: a multicenter retrospective study using propensity score
Authors: Xu Haozhe , Xing Zhuo , Ai Kai , Wang Jie , Lv Zhengtong , Deng Haitao , Li Ke , Wang Yang , Li Yuan 
Published: January 2024

Abstract
Background
Partial nephrectomy (PN) is usually recommended for T1 stage clear cell renal cell carcinoma (ccRCC) regardless of the nuclear grades. However, the question remains unresolved as to whether PN is non-inferior to RN in patients with T1-ccRCC at higher risk of recurrence. In fact, we found that patients with high nuclear grades treated with PN had poorer prognosis compared with those treated with radical nephrectomy (RN). Therefore, this study was designed to evaluate the associations of PN and RN in the four nuclear grade subsets with oncologic outcomes.

Methods
A retrospective study was conducted in three Chinese urological centers that included 1,714 patients who underwent PN or RN for sporadic, unilateral, pT1, N0, and M0 ccRCC without positive surgical margins and neoadjuvant therapy between 2010 and 2019. Associations of nephrectomy type with local ipsilateral recurrence, distant metastases, and all-cause mortality (ACM) were evaluated using the Kaplan–Meier method and multivariable Cox proportional hazards regression models after overlap weighting (OW).

Results
A total of 1675 patients entered the OW cohort. After OW, in comparison to PN, RN associated with a reduced risk of local ipsilateral recurrence in the G2 subset (HR = 0.148, 95% CI 0.046–0.474; p < 0.05), G3 subset (HR = 0.097, 95% CI 0.021–0.455; p < 0.05), and G4 subset (HR = 0.091, 95% CI 0.011–0.736; p < 0.05), and resulting in increased five-year local recurrence-free survival rates of 7.0%, 17.9%, and 36.2%, respectively. An association between RN and a reduced risk of distant metastases in the G4 subset (HR = 0.071, 95% CI 0.016–0.325; p < 0.05), with the five-year distant metastases-free survival rate increasing by 33.1% was also observed. No significant difference in ACM between PN and RN was identified.

Conclusions
Our findings substantiate that opting for RN, as opposed to PN, is more advantageous for local recurrence-free survival and distant metastases-free survival in patients with high nuclear grade (especially G4) pT1-ccRCC. We recommend placing a heightened emphasis on enhancing preoperative nuclear grade assessment, as it can significantly influence the choice of surgical plan.

Trial registration
This study was registered at Chinese Clinical Trial Registry (ID: ChiCTR2200063333).
What can we learn from general practitioners who left Spain? A mixed methods international study
Authors: Calderón-Larrañaga Sara , González-De-La-Fuente Ángel , Espinosa-González Ana Belén , Casado-Vicente Verónica , Brito-Fernandes Óscar , Klazinga Niek , Kringos Dionne 
Published: January 2024

Abstract
Background
International mobility of health workforce affects the performance of health systems and has major relevance in human resources for health policy and planning. To date, there has been little research exploring the reasons why general practitioners (GPs) migrate. This mixed methods study aimed to investigate the reasons why Spain-trained GPs migrate and develop GP retention and recruitment health policy recommendations relevant to Spanish primary care.

Methods
The study followed an explanatory sequential mixed methods study design combining surveys with semi-structured interviews and focus groups with GPs who qualified in Spain and were living overseas at the time of the study. The survey data examined the reasons why GPs left Spain and their intention to return and were analysed using quantitative methods. The transcripts from interviews and focus groups centred on GPs’ insights to enhance retention and recruitment in Spain and were analysed thematically.

Results
The survey had 158 respondents with an estimated 25.4% response rate. Insufficient salary (75.3%), job insecurity and temporality (67.7%), excessive workload (67.7%), poor primary care governance (55.7%), lack of flexibility in the workplace (43.7%) and personal circumstances (43.7%) were the main reasons for leaving Spain. Almost half of the respondents (48.7%) would consider returning to Spanish general practice if their working conditions improved. Interviews and focus groups with respondents (n = 24) pointed towards the need to improve the quality of employment contracts, working conditions, opportunities for professional development, and governance in primary care for effective retention and recruitment.

Conclusion
Efforts to improve GP retention and recruitment in Spain should focus on salary, job security, flexibility, protected workload, professional development, and governance. We draw ten GP retention and recruitment recommendations expected to inform urgent policy action to tackle existing and predicted GP shortages in Spanish primary care.
Fibronectin mediates activin A-promoted human trophoblast migration and acquisition of endothelial-like phenotype
Authors: Lan Xiangxin , Guo Ling , Hu Cuiping , Zhang Qian , Deng Jianye , Wang Yufeng , Chen Zi-Jiang , Yan Junhao , Li Yan 
Published: January 2024

Abstract
Background
During human early placentation, a proportion of extravillous trophoblasts (EVTs) migrate to the maternal decidua, differentiating into endovascular EVTs to remodel spiral arteries and ensure the establishment of blood circulation at the maternal-fetal interface. Inadequate EVT migration and endovascular differentiation are closely associated with adverse pregnancy outcomes such as miscarriage. Activin A and fibronectin are both secretory molecules abundantly expressed at the maternal-fetal interface. Activin A has been reported to regulate EVT biological functions. However, whether fibronectin mediates activin A-promoted EVT migration and acquisition of endothelial-like phenotype as well as the underlying molecular mechanisms remain unknown. Additionally, the role of fibronectin in pregnancy establishment and maintenance warrants further investigation.

Methods
Primary and immortalized (HTR8/SVneo) human EVTs were used as in vitro study models. Cultured human first-trimester chorionic villous explants were utilized for ex vivo validation. A local fibronectin knockdown model in ICR mouse uteri, achieved by nonviral in vivo transfection with small interfering RNA (siRNA) targeting fibronectin 1 (si-Fn1), was employed to explore the roles of fibronectin in the establishment and maintenance of early pregnancy.

Results
Our results showed that activin A treatment significantly induced fibronectin 1 (FN1) mRNA expression and fibronectin protein production, which is essential for human trophoblast migration and endothelial-like tube formation. Both basal and activin A-upregulated fibronectin expression were abolished by the TGF-β type I receptor inhibitor SB431542 or siRNA-mediated knockdown of activin receptor-like kinase (ALK4) or SMAD4. Moreover, activin A-increased trophoblast migration and endothelial-like tube formation were attenuated following the depletion of fibronectin. Fibronectin knockdown via intrauterine siRNA administration reduced CD31 and cytokeratin 8 (CK8) expression at the maternal-fetal interface, resulting in a decrease in the number of implantation sites and embryos.

Conclusions
Our study demonstrates that activin A promotes trophoblast cell migration and acquisition of endothelial-like phenotype via ALK4-SMAD2/3-SMAD4-mediated fibronectin upregulation. Furthermore, through a local fibronectin knockdown model in mouse uteri, we found that the absence of fibronectin at the maternal-fetal interface impedes endovascular migration of trophoblasts and decidual vascularization, thereby interfering with early embryo implantation and the maintenance of pregnancy. These findings provide novel insights into placental development during early pregnancy establishment and contribute to the advancement of therapeutic approaches for managing pregnancy complications related to trophoblast dysfunction.
Emerging applications of single-cell profiling in precision medicine of atherosclerosis
Authors: Lin Huiling , Zhang Ming , Hu Mi , Zhang Yangkai , Jiang WeiWei , Tang Wanying , Ouyang Yuxin , Jiang Liping , Mi Yali , Chen Zhi , He Pingping , Zhao Guojun , Ouyang Xinping 
Published: January 2024

AbstractAtherosclerosis is a chronic, progressive, inflammatory disease that occurs in the arterial wall. Despite recent advancements in treatment aimed at improving efficacy and prolonging survival, atherosclerosis remains largely incurable. In this review, we discuss emerging single-cell sequencing techniques and their novel insights into atherosclerosis. We provide examples of single-cell profiling studies that reveal phenotypic characteristics of atherosclerosis plaques, blood, liver, and the intestinal tract. Additionally, we highlight the potential clinical applications of single-cell analysis and propose that combining this approach with other techniques can facilitate early diagnosis and treatment, leading to more accurate medical interventions.
Hypoxia upregulating ACSS2 enhances lipid metabolism reprogramming through HMGCS1 mediated PI3K/AKT/mTOR pathway to promote the progression of pancreatic neuroendocrine neoplasms
Authors: Gu Danyang , Ye Mujie , Zhu Guoqin , Bai Jianan , Chen Jinhao , Yan Lijun , Yu Ping , Lu Feiyu , Hu Chunhua , Zhong Yuan , Liu Pengfei , He Qibin , Tang Qiyun 
Published: January 2024

Abstract
Background
Pancreatic neuroendocrine neoplasms (pNENs) are relatively rare. Hypoxia and lipid metabolism-related gene acetyl-CoA synthetase 2 (ACSS2) is involved in tumor progression, but its role in pNENs is not revealed. This study showed that hypoxia can upregulate ACSS2, which plays an important role in the occurrence and development of pNENs through lipid metabolism reprogramming. However, the precise role and mechanisms of ACSS2 in pNENs remain unknown.

Methods
mRNA and protein levels of ACSS2 and 3-hydroxy-3-methylglutaryl-CoA synthase1 (HMGCS1) were detected using quantitative real-time PCR (qRT-PCR) and Western blotting (WB). The effects of ACSS2 and HMGCS1 on cell proliferation were examined using CCK-8, colony formation assay and EdU assay, and their effects on cell migration and invasion were examined using transwell assay. The interaction between ACSS2 and HMGCS1 was verified by Co-immunoprecipitation (Co-IP) experiments, and the functions of ACSS2 and HMGCS1 in vivo were determined by nude mouse xenografts.

Results
We demonstrated that hypoxia can upregulate ACSS2 while hypoxia also promoted the progression of pNENs. ACSS2 was significantly upregulated in pNENs, and overexpression of ACSS2 promoted the progression of pNENs and knockdown of ACSS2 and ACSS2 inhibitor (ACSS2i) treatment inhibited the progression of pNENs. ACSS2 regulated lipid reprogramming and the PI3K/AKT/mTOR pathway in pNENs, and ACSS2 regulated lipid metabolism reprogramming through the PI3K/AKT/mTOR pathway. Co-IP experiments indicated that HMGCS1 interacted with ACSS2 in pNENs. Overexpression of HMGCS1 can reverse the enhanced lipid metabolism reprogramming and tumor-promoting effects of knockdown of ACSS2. Moreover, overexpression of HMGCS1 reversed the inhibitory effect of knockdown of ACSS2 on the PI3K/AKT/mTOR pathway.

Conclusion
Our study revealed that hypoxia can upregulate the lipid metabolism-related gene ACSS2, which plays a tumorigenic effect by regulating lipid metabolism through activating the PI3K/AKT/mTOR pathway. In addition, HMGCS1 can reverse the oncogenic effects of ACSS2, providing a new option for therapeutic strategy.
The gut microbiota participates in the effect of linaclotide in patients with irritable bowel syndrome with constipation (IBS-C): a multicenter, prospective, pre-post study
Authors: Zhou Jianyun , Wei Haoqi , Zhou An , Xiao Xu , Xie Xia , Tang Bo , Lin Hui , Tang Li , Meng Ruiping , Yuan Xiaoying , Zhang Jing , Huang Cheng , Huang Baobao , Liao Xiping , Zhong Tingting , He Suyu , Gu Sai , Yang Shiming 
Published: January 2024

Abstract
Background
Interindividual variation characterizes the relief experienced by constipation-predominant irritable bowel syndrome (IBS-C) patients following linaclotide treatment. Complex bidirectional interactions occur between the gut microbiota and various clinical drugs. To date, no established evidence has elucidated the interactions between the gut microbiota and linaclotide. We aimed to explore the impact of linaclotide on the gut microbiota and identify critical bacterial genera that might participate in linaclotide efficacy.

Methods
IBS-C patients were administered a daily linaclotide dose of 290 µg over six weeks, and their symptoms were then recorded during a four-week posttreatment observational period. Pre- and posttreatment fecal samples were collected for 16S rRNA sequencing to assess alterations in the gut microbiota composition. Additionally, targeted metabolomics analysis was performed for the measurement of short-chain fatty acid (SCFA) concentrations.

Results
Approximately 43.3% of patients met the FDA responder endpoint after taking linaclotide for 6 weeks, and 85% of patients reported some relief from abdominal pain and constipation. Linaclotide considerably modified the gut microbiome and SCFA metabolism. Notably, the higher efficacy of linaclotide was associated with enrichment of the Blautia genus, and the abundance of Blautia after linaclotide treatment was higher than that in healthy volunteers. Intriguingly, a positive correlation was found for the Blautia abundance and SCFA concentrations with improvements in clinical symptoms among IBS-C patients.

Conclusion
The gut microbiota, especially the genus Blautia, may serve as a significant predictive microbe for symptom relief in IBS-C patients receiving linaclotide treatment.
Trial registration: This trial was registered with the Chinese Clinical Trial Registry (Chictr.org.cn, ChiCTR1900027934).
Analyzing the psychometric properties of the PHQ-9 using item response theory in a Chinese adolescent population
Authors: Gao Xuliang , Liu Ziyu 
Published: January 2024

Abstract
Background
People are more likely to fall victim to depression during adolescence since it is a period of rapid biopsychosocial transformation. Despite this, most depression research has concentrated on clinical issues, and evaluating depressive symptoms in teenagers is not as widespread. This study used item response theory (IRT) to examine the psychometric properties of the Patient Health Report scale (PHQ-9) in Chinese adolescents. Meanwhile, item function difference tests were used to check whether there were differences in depression symptoms in this group based on education and gender.

Methods
In this research, the PHQ-9 was employed as a measurement tool, and 5958 valid data points were obtained from 12 secondary schools in China (Mage = 13.484; SDage = 1.627; range 11–19 years; 52.17% boys).

Results
IRT shows that all items of the PHQ-9 satisfy monotonicity, unidimensionality and local independence and that they have good psychometric properties. Furthermore, DIF analysis revealed gender and educational disparities in adolescent depressive symptoms.

Conclusion
The study indicates that the PHQ-9 possesses favourable psychometric properties for use in Chinese adolescents. As a result, it serves as a valuable tool for effectively screening depressive symptoms in adolescents. It provides a foundation for prioritizing the development of secondary school students' physical and mental health.
The effectiveness of multivariate and univariate spectrophotometric techniques for the concurrent estimation of ornidazole and ciprofloxacin HCl in tablet formulation and spiked serum: estimating greenness and whiteness profile
Authors: Sakur Amir A. , Al Zakri Duaa 
Published: January 2024

AbstractIn this manuscript, the effectiveness of multivariate and univariate tools in conjunction with spectrophotometric techniques was evaluated for the concurrent analysis of ciprofloxacin (CI) and ornidazole (OR) in prepared mixtures, tablets, and human serum. The artificial neural network was chosen as the multivariate Technique. Bayesian regularization (trainbr) and Levenberg–Marquardt algorithms (trainlm), were constructed and trained using feed-forward back-propagation learning. The optimal logarithm was determined based on mean recovery, mean square error of prediction (MSEP), relative root mean square error of prediction (RRMSEP), and bias-corrected MSEP (BCMSEP) scores. Trainbr outperformed trainlm, yielding a mean recovery of 100.05% for CI and 99.84% for OR, making it the preferred algorithm. Fourier self-deconvolution and mean-centering transforms were chosen as the univariate Techniques. Fourier self-deconvolution was applied to the zero-order spectra of ciprofloxacin and ornidazole by electing an appropriate full width at half maximum, enhancing peak resolution at 380.1 nm and 314.2 nm for CI and OR, respectively. Mean centering transform was applied to CI and OR ratio spectra to eliminate constant signals, enabling accurate quantification of CI and OR at 272.0 nm and 306.2 nm, respectively. The introduced approaches were optimized and validated for precise CI and OR analysis, with statistical comparison against the HPLC method revealing no notable differences. The sustainability of these approaches was confirmed through the green certificate (modified eco-scale), AGP, and whiteness-evaluation tool, corroborating their ecological viability.
Chromatin accessibility and cell cycle progression are controlled by the HDAC-associated Sin3B protein in murine hematopoietic stem cells
Authors: Calderon Alexander , Mestvirishvili Tamara , Boccalatte Francesco , Ruggles Kelly V. , David Gregory 
Published: January 2024

Abstract
Background
Blood homeostasis requires the daily production of millions of terminally differentiated effector cells that all originate from hematopoietic stem cells (HSCs). HSCs are rare and exhibit unique self-renewal and multipotent properties, which depend on their ability to maintain quiescence through ill-defined processes. Defective control of cell cycle progression can eventually lead to bone marrow failure or malignancy. In particular, the molecular mechanisms tying cell cycle re-entry to cell fate commitment in HSCs remain elusive. Previous studies have identified chromatin coordination as a key regulator of differentiation in embryonic stem cells.

Results
Here, we utilized genetic inactivation of the chromatin-associated Sin3B protein to manipulate cell cycle control and found dysregulated chromatin accessibility and cell cycle progression in HSCs. Single cell transcriptional profiling of hematopoietic stem and progenitor cells (HSPCs) inactivated for Sin3B reveals aberrant progression through the G1 phase of the cell cycle, which correlates with the engagement of specific signaling pathways, including aberrant expression of cell adhesion molecules and the interferon signaling program in LT-HSCs. In addition, we uncover the Sin3B-dependent accessibility of genomic elements controlling HSC differentiation, which points to cell cycle progression possibly dictating the priming of HSCs for differentiation.

Conclusions
Our findings provide new insights into controlled cell cycle progression as a potential regulator of HSC lineage commitment through the modulation of chromatin features.