bluuebunny/crossref_metadata_2025_split huggingface dataset:
Butyrate inhibits the mitochondrial complex Ι to mediate mitochondria-dependent apoptosis of cervical cancer cells
Authors: Zhang Ke , Ji Xiawei , Song Zhengyang , Song Wenjing , Huang Qunjia , Yu Tiantian , Shi Dibang , Wang Fangyan , Xue Xiangyang , Guo Junping 
Published: June 2023

Abstract
Background
Cervical cancer (CC) is a common gynecological malignancy with high morbidity worldwide. Butyrate, a short-chain fatty acid produced by intestinal flora, has been reported to inhibit cervical carcinogenesis. This study aimed to investigate the pro-apoptotic effects of butyrate on CC and the underlying mechanisms.

Methods
Human HeLa and Ca Ski cells were used in this study. Cell proliferation, cell migration and invasion were detected by CCK-8 and EdU staining, transwell and wound healing assay, respectively. Cell cycle, mitochondrial membrane potential and apoptosis were evaluated by flow cytometry. Western blot and RT-qPCR were carried out to examine the related genes and proteins to the mitochondrial complex Ι and apoptosis. Metabolite changes were analyzed by energy metabolomics and assay kits. The association between G protein-coupled receptor 41, 43, 109a and CC prognosis was analyzed using data from The Cancer Genome Atlas (TCGA).

Results
CCK-8 results showed significant inhibition of CC cell proliferation induced by butyrate treatment, which was confirmed by EdU staining and cell cycle detection. Data from the transwell and wound healing assay revealed that CC cell migration was dramatically reduced following butyrate treatment. Additionally, invasiveness was also decreased by butyrate. Western blot analysis showed that cleaved Caspase 3 and cleaved PARP, the enforcers of apoptosis, were increased by butyrate treatment. The results of Annexin V/PI staining and TUNEL also showed an increase in butyrate-induced apoptotic cells. Expression of Cytochrome C (Cytc), Caspase 9, Bax, but not Caspase 12 or 8, were up-regulated under butyrate exposure. Mechanistically, the decrease in mitochondrial NADH and NAD + levels after treatment with butyrate was observed by energy metabolomics and the NAD+/NADH Assay Kit, similar to the effects of the complex Ι inhibitor rotenone. Western blot results also demonstrated that the constituent proteins of mitochondrial complex Ι were reduced by butyrate. Furthermore, mitochondria-dependent apoptosis has been shown to be initiated by inhibition of the complex Ι.

Conclusion
Collectively, our results revealed that butyrate inhibited the proliferation, migration and invasion of CC cells, and induced mitochondrial-dependent apoptosis by inhibiting mitochondrial complex Ι.
What can we learn from experiences in general practice during the COVID-19 pandemic? A qualitative study
Authors: Rijpkema Corinne , Bos Nanne , Brandenbarg Daan , Homburg Maarten , Beugel Gina , Barkema Wietske S. , olde Hartman Tim , Muris Jean , Peters Lilian , Berger Marjolein , Verheij Robert A. , Ramerman Lotte 
Published: June 2023

Abstract
Background
Experiences with organizational changes in daytime general practices and out-of-hours (OOH) services during the COVID-19 pandemic may help to address the challenges in general practice care that were already a concern before the crisis. This study aimed to describe these experiences and the potential usefulness of the organizational changes for future general practice care and any future pandemics.

Methods
Semi-structured interviews were performed among 11 directors of OOH services, and 19 (locum) general practitioners (GPs) or practice managers, who were purposively sampled. Video or telephone interviews were performed in two rounds: between November 2020 and January 2021 and between May 2021 and August 2021. The data were analyzed using thematic analysis methods.

Results
Three themes emerged from the data: (1) Changes in the triage procedures; in GP practices and OOH services, stricter triage criteria were implemented, and GPs were more actively involved in the triage process. These measures helped to reduce the number of ‘low urgency’ face-to-face consultations. (2) Changes in GP care; there was a shift towards video and telephone consultations, allowing GPs to spend more time with patients during the remaining face-to-face consultations. For chronic patients, the shift towards telemonitoring appeared to encourage self-care, and postponing face-to-face consultations for regular checkups appeared to be unproblematic for stable patients. (3) Coordination of GP care and information communication flow during the COVID-19 pandemic; OOH directors perceived a lack of consistency in the information from various governmental and non-governmental parties on containment measures and guidelines related to COVID-19, making it difficult to act on them. The COVID-19 pandemic intensified collaboration between GPs, OOH services, and other healthcare professionals.

Conclusions
The results of this study indicate that some of the organizational changes, such as stricter triage, remote consultations, and changes in managed care of chronic patients, may help in tackling the pre-existing challenges in GP care from before the COVID-19 pandemic. However, more extensive research and continuous monitoring are necessary to establish the effects on patients and their health outcomes. To navigate future pandemics, the intensified collaboration between health professionals should be maintained, while there is considerable room for improvement in the provision of unambiguous information.
Exploring a competency framework for the chief financial officer of a hospital: a qualitative study from China
Authors: Wang Hongzhi , Xiang Xin , Dong Luping 
Published: June 2023

AbstractBackgroundHospital chief financial officer (CFO) plays a vital role in supporting the effective management of organization. Understanding their competencies is essential to improve hospital development and health care services in China. This paper aims to explore competencies necessary for hospital CFOs to fulfil their management responsibilities and develop a competency framework for hospital CFOs in China.MethodsA qualitative study was applied by conducting in-depth interviews with 151 participants from 15 Chinese provinces, comprising 89 individuals from 67 hospitals, and 62 individuals from 39 medical universities. Interviews were anonymised, recorded and transcribed. Qualitative thematic analysis was applied through a multi-stage review process and modified via the Delphi process using a national panel of 36 experts.ResultsUsing content analysis, we identified 17 competencies organized into three themes (personal attitudes, leadership competencies and managerial competencies) to conduct a competency framework for hospital CFO to fulfil their management practices. Those competencies emphasized the integration of different competencies required by the hospital CFO.ConclusionsThis paper identified the detailed expertise, abilities and personal traits required by hospital CFOs in China, expanding the insights and perspectives of hospital CFOs currently working in China to literature. The proposed framework will help hospitals establish selection criteria, coaching tools, and development plans for CFOs.
Fibrin degradation products and survival in patients with chronic obstructive pulmonary disease: a protocolized prospective observational study
Authors: Kamstrup Peter , Sivapalan Pradeesh , Rønn Christian , Rastoder Ema , Modin Daniel , Kristensen Anna Kjaer , Bendstrup Elisabeth , Sørensen Rikke , Biering-Sørensen Tor , Ulrik Charlotte Suppli , Vestbo Jørgen , Jensen Jens-Ulrik 
Published: June 2023

Abstract
Background
Patients with chronic obstructive pulmonary disease (COPD) have a high incidence of cardiovascular disease including thromboembolisms. Fibrin degradation products, like D-dimer, have been associated with death from all causes in healthy individuals and COPD patients. We aimed to determine the (i) association between D-dimer levels and all-cause mortality and time being alive and out of a hospital, (ii) possible modifying effect of anticoagulant treatment,, and (iii) distribution of D-dimer in patients with moderate to severe COPD.

Methods
Results of routinely measured stable phase D-dimer samples from COPD-outpatients at Copenhagen University Hospital – Herlev and Gentofte, COPD-outpatient clinic were collected using the Danish registries. These were used to examine whether COPD-patients with a D-dimer level in the upper quartile, had a higher risk of death from all causes within 365 days.

Results
In the unadjusted Cox proportional hazards regression we found an association between high D-dimer and all-cause mortality: Hazard ratio (HR): 2.3 (95% Confidence Interval (CI) 1.1–4.7). In the fully adjusted regression, the HR was 1.8 (CI 0.8–3.9). We did not find any interaction between D-dimer and anticoagulant or antiplatelet therapy. For the secondary outcome, proportion of days alive and out of hospital in 365 days (pDAOH), the unadjusted multiple linear regression had an association between high D-dimer level and pDAOH: -2.7% points (pp) (CI -3.9 pp - -1.5 pp), which was attenuated to -1,7pp (-2.9pp – -0.4pp) in the fully adjusted regression.

Conclusions
In patients with moderate to severe COPD, patients with a high level of D-dimer were more likely to die; however, the signal was not strong in the adjusted analyses and our results do not support unselected risk stratification with D-dimer in COPD-outpatients.
Stem cell-derived brainstem mouse astrocytes obtain a neurotoxic phenotype in vitro upon neuroinflammation
Authors: Lindblad Caroline , Neumann Susanne , Kolbeinsdóttir Sólrún , Zachariadis Vasilios , Thelin Eric P. , Enge Martin , Thams Sebastian , Brundin Lou , Svensson Mikael 
Published: June 2023

AbstractBackgroundAstrocytes respond to injury and disease through a process known as reactive astrogliosis, of which inflammatory signaling is one subset. This inflammatory response is heterogeneous with respect to the inductive stimuli and the afflicted central nervous system region. This is of plausible importance in e.g. traumatic axonal injury (TAI), where lesions in the brainstem carries a particularly poor prognosis. In fact, astrogliotic forebrain astrocytes were recently suggested to cause neuronal death following axotomy. We therefore sought to assess if ventral brainstem- or rostroventral spinal astrocytes exert similar effects on motor neurons in vitro.MethodsWe derived brainstem/rostroventral spinal astrocyte-like cells (ES-astrocytes) and motor neurons using directed differentiation of mouse embryonic stem cells (ES). We activated the ES-astrocytes using the neurotoxicity-eliciting cytokines interleukin- (IL-) 1α and tumor necrosis factor-(TNF-)α and clinically relevant inflammatory mediators. In co-cultures with reactive ES-astrocytes and motor neurons, we assessed neurotoxic ES-astrocyte activity, similarly to what has previously been shown for other central nervous system (CNS) regions.ResultsWe confirmed the brainstem/rostroventral ES-astrocyte identity using RNA-sequencing, immunocytochemistry, and by comparison with primary subventricular zone-astrocytes. Following cytokine stimulation, the c-Jun N-terminal kinase pathway down-stream product phosphorylated c-Jun was increased, thus demonstrating ES-astrocyte reactivity. These reactive ES-astrocytes conferred a contact-dependent neurotoxic effect upon co-culture with motor neurons. When exposed to IL-1β and IL-6, two neuroinflammatory cytokines found in the cerebrospinal fluid and serum proteome following human severe traumatic brain injury (TBI), ES-astrocytes exerted similar effects on motor neurons. Activation of ES-astrocytes by these cytokines was associated with pathways relating to endoplasmic reticulum stress and altered regulation of MYC.ConclusionsVentral brainstem and rostroventral spinal cord astrocytes differentiated from mouse ES can exert neurotoxic effects in vitro. This highlights how neuroinflammation following CNS lesions can exert region- and cell-specific effects. Our in vitro model system, which uniquely portrays astrocytes and neurons from one niche, allows for a detailed and translationally relevant model system for future studies on how to improve neuronal survival in particularly vulnerable CNS regions following e.g. TAI.
A nomogram to predict postoperative deep vein thrombosis in patients with femoral fracture: a retrospective study
Authors: Wu Linqin , Cheng Bo 
Published: June 2023

AbstractObjectiveThe implementation of more active anticoagulant prevention and treatment measures has indeed led to a significant reduction in the incidence of perioperative deep vein thrombosis (DVT) among patients with bone trauma. However, it is important to note that despite these efforts, the incidence of DVT still remains relatively high. According to the Caprini score, all patients undergoing major orthopedic surgery were defined as the high-risk group for DVT. Stratifying the risk further within high-risk groups for DVT continues to present challenges. As a result, the commonly used Caprini score during the perioperative period is not applicable to orthopedic patients. We attempt to establish a specialized model to predict postoperative DVT risk in patients with femoral fracture.MethodsWe collected the clinical data of 513 patients undergoing femoral fracture surgery in our hospital from May 2018 to December 2019. According to the independent risk factors of DVT obtained by univariate and multivariate logistic regression analysis, the corresponding nomogram model was established and verified internally. The discriminative capacity of nomogram was evaluated by receiver operating characteristic (ROC) curve and area under the curve (AUC). The calibration curve used to verify model consistency was the fitted line between predicted and actual incidences. The clinical validity of the nomogram model was assessed using decision curve analysis (DCA) which could quantify the net benefit of different risk threshold probabilities. Bootstrap method was applied to the internal validation of the nomogram model. Furthermore, a comparison was made between the Caprini score and the developed nomogram model.ResultsThe Caprini scores of subjects ranged from 5 to 17 points. The incidence of DVT was not positively correlated with the Caprini score. The predictors of the nomogram model included 10 risk factors such as age, hypoalbuminemia, multiple trauma, perioperative red blood cell infusion, etc. Compared with the Caprini scale (AUC = 0.571, 95% CI 0.479–0.623), the calibration accuracy and identification ability of nomogram were higher (AUC = 0.865,95% CI 0.780–0.935). The decision curve analysis (DCA) indicated the clinical effectiveness of nomogram was higher than the Caprini score.ConclusionsThe nomogram was established to effectively predict postoperative DVT in patients with femoral fracture. To further reduce the incidence, more specialized risk assessment models for DVT should take into account the unique risk factors and characteristics associated with specific patient populations.
Post-prandial analysis of fluctuations in the platelet count and platelet function in patients with the familial chylomicronemia syndrome
Authors: Larouche Miriam , Brisson Diane , Morissette Marie-Claude , Gaudet Daniel 
Published: June 2023

Abstract
Background
The familial chylomicronemia syndrome (FCS) is an ultra rare disease caused by lipoprotein lipase (LPL) deficiency associated with potentially lethal acute pancreatitis risk. Thrombocytopenia (platelet count < 150,000 × 109/L) has been reported in patients with FCS, treated or not with volanesorsen, a second generation APOC3 anti-sense oligonucleotide. Chylomicrons are the lipoproteins delivering fat after a meal and FCS thus has a post-prandial origin. Platelet count and function have not been studied post-prandially in FCS.

Objective
To evaluate post-prandial fluctuations in the platelet count (PLC) and functional defects of hemostasis in FCS.

Methods
PLC, functional defects in hemostasis and hematologic variables were measured up-to 5 h after a meal in 6 homozygotes for FCS causing gene variants (HoLPL), 6 heterozygotes for LPL loss-of-function variants (HeLPL) and 7 normolipidemic controls.

Results
Hourly post-prandial PLC was significantly lower in HoLPL than in controls (P < 0.009). Compared to the other groups, the PLC tended to decrease rapidly (in the first hour) post-meal in HoLPL (P = 0.03) and remained lower than baseline 5-h post-meal (P = 0.02) whereas it tended to slightly increase in normolipidemic controls (P = 0.02). Platelet function was not affected by the prandial status. In HoLPL, post-prandial fluctuations in the PLC positively correlated with the lymphocyte count (P = 0.005) and negatively with neutrophil/lymphocyte ratio (NLR).

Conclusion
The PLC decreases post-prandially in FCS (HoLPL), is not associated with changes in functional defects of hemostasis and correlates with the NLR, a marker of acute pancreatitis severity.
Targeting the oncogenic transcription factor FOXM1 to improve outcomes in all subtypes of breast cancer
Authors: Katzenellenbogen Benita S. , Guillen Valeria Sanabria , Katzenellenbogen John A. 
Published: June 2023

AbstractFOXM1 (Forkhead box M1) is an oncogenic transcription factor that is greatly upregulated in breast cancer and many other cancers where it promotes tumorigenesis, and cancer growth and progression. It is expressed in all subtypes of breast cancer and is the factor most associated with risk of poor patient survival, especially so in triple negative breast cancer (TNBC). Thus, new approaches to inhibiting FOXM1 and its activities, and combination therapies utilizing FOXM1 inhibitors in conjunction with known cancer drugs that work together synergistically, could improve cancer treatment outcomes. Targeting FOXM1 might prove especially beneficial in TNBC where few targeted therapies currently exist, and also in suppressing recurrent advanced estrogen receptor (ER)-positive and HER2-positive breast cancers for which treatments with ER or HER2 targeted therapies that were effective initially are no longer beneficial. We present these perspectives and future directions in the context of what is known about FOXM1, its regulation, and its key roles in promoting cancer aggressiveness and metastasis, while being absent or very low in most normal non-regenerating adult tissues. We discuss new inhibitors of FOXM1 and highlight FOXM1 as an attractive target for controlling drug-resistant and difficult-to-suppress breast cancers, and how blocking FOXM1 might improve outcomes for patients with all subtypes of breast cancer.
SMA-TB: study protocol for the phase 2b randomized double-blind, placebo-controlled trial to estimate the potential efficacy and safety of two repurposed drugs, acetylsalicylic acid and ibuprofen, for use as adjunct therapy added to, and compared with, the standard WHO recommended TB regimen
Authors: Arias Lilibeth , Otwombe Kennedy , Waja Ziyaad , Tukvadze Nestani , Korinteli Tamta , Moloantoa Tumelo , Fonseca Kaori L , Pillay Natasha , Seiphetlo Thabiso , Ouchi-Vernet Dan , Siles Adrian , Carabias Lidia , Quiñones Carles , Vashakidze Sergo , Martinson Neil , Vilaplana Cristina 
Published: June 2023

Abstract
Background
The duration and regimen of tuberculosis (TB) treatment is currently based predominantly on whether the M. tuberculosis (Mtb) strain is drug-sensitive (DS) or multidrug-resistant (MDR) with doses adjusted by patients’ weight only. The systematic stratification of patients for personalized treatment does not exist for TB. As each TB case is different, individualized treatment regimens should be applied to obtain better outcomes. In this scenario, novel therapeutic approaches are urgently needed to (1) improve outcomes and (2) shorten treatment duration, and host-directed therapies (HDT) might be the best solution. Within HDT, repurposed drugs represent a shortcut in drug development and can be implemented at the short term. As hyperinflammation is associated with worse outcomes, HDT with an anti-inflammatory effect might improve outcomes by reducing tissue damage and thus the risk of permanent sequelae.

Methods
SMA-TB is a multicentre randomized, phase IIB, placebo-controlled, three-arm, double-blinded clinical trial (CT) that has been designed in the context of the EC-funded SMA-TB Project (www.smatb.eu) in which we propose to use 2 common non-steroidal anti-inflammatory drugs (NSAID), acetylsalicylic acid (ASA) and ibuprofen (Ibu), as an HDT for use as adjunct therapy added to, and compared with, the standard of care (SoC) World Health Organization (WHO)-recommended TB regimen in TB patients. A total of 354 South African and Georgian adults diagnosed with confirmed pulmonary TB will be randomized into SoC TB treatment + placebo, SoC + acetylsalicylic acid or SoC + ibuprofen.

Discussion
SMA-TB will provide proof of concept of the HDT as a co-adjuvant treatment and identify the suitability of the intervention for different population groups (different epidemiological settings and drug susceptibility) in the reduction of tissue damage and risk of bad outcomes for TB patients. This regimen potentially will be more effective and targeted: organ saving, reducing tissue damage and thereby decreasing the length of treatment and sequelae, increasing cure rates and pathogen clearance and decreasing transmission rates. It will result in better clinical practice, care management and increased well-being of TB patients.

Trial registration
Clinicaltrials.gov NCT04575519. Registered on October 5, 2020.