bluuebunny/crossref_metadata_2025_split huggingface dataset:
The challenges of becoming and being a clinician manager: a qualitative exploration of the perception of medical doctors in senior leadership roles at a large Australian health service
Authors: Imran Didir , Rog Karen , Gallichio John , Alston Laura 
Published: April 2021

Abstract
Background
In Australia, activity-based funding models have emphasized the need for hospitals to be accountable for their clinical performance. Clinician managers, with medical backgrounds are essential to ensuring high quality clinical performance and operational management of hospital services. The purpose of this study is to 1. Identify factors influencing doctors to become clinician managers in the Australian healthcare setting. 2. Understand the pathways and challenges faced by doctors in becoming clinician managers.

Methods
We undertook a qualitative study with semi-structured interviews of 18 clinician managers (who have medical practitioner backgrounds) with formal leadership administrative roles. Interview transcripts were analysed with systematic text condensation.

Results
All eligible participants approached in this context, agreed to participate and over 80% of the participants were male. We identified five themes: ‘Motivations for leadership’, ‘Pathways to managerial role’, ‘Challenges faced in management roles’, ‘Credibility through clinical practice’ and ‘Management skill cultivation and support’. Clinician managers progressed from being doctors to leadership roles through being encouraged to take on roles, while others felt pressure to take on leadership roles even if this was not a personal goal. Clinician managers described challenges such as feeling under-prepared, maintaining respect form colleagues through still participating in a clinical load, along with juggling priorities such as administrative tasks, managing budgets and performance managing other doctors.

Conclusions
There needs to be an intentional and more structured approach to training and supporting clinician managers that considers the complex challenges faced by individuals (especially women) as they progress into these roles in the Australian tertiary health services context. There is a need to consider ways of supporting clinician managers to focus on management skills, effective mentorship and address perceptions around losing respect from colleagues if clinician managers cease their clinical loads. Further research is needed among the female medical workforce, along with research to understand if maintaining clinical loads when undertaking a clinical management role in fact leads to better effectiveness in contributing to better patient safety and quality outcomes. Such evidence may assist in addressing these social pressures among clinician managers, and contribute to addressing gender inequality among the clinical management workforce.
Formative process evaluation of a guideline-driven process for improving the cultural responsiveness of alcohol and drug treatment services
Authors: Farnbach Sara , Allan Julaine , Wallace Raechel , Aiken Alexandra , Shakeshaft Anthony 
Published: April 2021

Abstract
Background
To improve Australian Aboriginal and Torres Strait Islander people’s access to, and experience of, healthcare services, including Alcohol and other Drug (AoD) treatment services, principles and frameworks have been developed to optimise cultural responsiveness. Implementing those principles in practice, however, can be difficult to achieve. This study has five aims: i) to describe a five-step process developed to operationalise improvements in culturally responsive practice in AoD services; ii) to evaluate the fidelity of implementation for this five-step process; iii) to identify barriers and enablers to implementation; iv) to assess the feasibility and acceptability of this approach; and v) to describe iterative adaptation of implementation processes based on participant feedback.

Methods
Participating services were 15 non-Aboriginal AoD services in New South Wales, Australia. Implementation records were used to assess the implementation fidelity of the project. Structured interviews with chief executive officers or senior management were conducted, and interview data were thematically analysed to identify project acceptability, and the key enablers of, and barriers to, project implementation. Quantitative descriptive analyses were performed on the post-implementation workshop survey data, and responses to the free text questions were thematically analysed.

Results
A high level of implementation fidelity was achieved. Key enablers to improving culturally responsive practice were the timing of the introduction of the five-step process, the active interest of staff across a range of seniority and the availability of resources and staff time to identify and implement activities. Key barriers included addressing the unique needs of a range of treatment sub-groups, difficulty adapting activities to different service delivery models, limited time to implement change in this evaluation (three months) and the varied skill level across staff. The project was rated as being highly acceptable and relevant to service CEOs/managers and direct service staff, with planned changes perceived to be achievable and important. Based on CEO/management feedback after the project was implemented at the initial services, several improvements to processes were made.

Conclusion
The operationalisation of the five-step process developed to improve cultural responsiveness was feasible and acceptable and may be readily applicable to improving the cultural responsiveness of a wide variety of health and human services.
Multi-omic profiling of pituitary thyrotropic cells and progenitors
Authors: Daly Alexandre Z. , Dudley Lindsey A. , Peel Michael T. , Liebhaber Stephen A. , Parker Stephen C. J. , Camper Sally A. 
Published: April 2021

AbstractBackgroundThe pituitary gland is a neuroendocrine organ containing diverse cell types specialized in secreting hormones that regulate physiology. Pituitary thyrotropes produce thyroid-stimulating hormone (TSH), a critical factor for growth and maintenance of metabolism. The transcription factors POU1F1 and GATA2 have been implicated in thyrotrope fate, but the transcriptomic and epigenomic landscapes of these neuroendocrine cells have not been characterized. The goal of this work was to discover transcriptional regulatory elements that drive thyrotrope fate.ResultsWe identified the transcription factors and epigenomic changes in chromatin that are associated with differentiation of POU1F1-expressing progenitors into thyrotropes using cell lines that represent an undifferentiatedPou1f1lineage progenitor (GHF-T1) and a committed thyrotrope line that produces TSH (TαT1). We compared RNA-seq, ATAC-seq, histone modification (H3K27Ac, H3K4Me1, and H3K27Me3), and POU1F1 binding in these cell lines. POU1F1 binding sites are commonly associated with bZIP transcription factor consensus binding sites in GHF-T1 cells and Helix-Turn-Helix (HTH) or basic Helix-Loop-Helix (bHLH) factors in TαT1 cells, suggesting that these classes of transcription factors may recruit or cooperate with POU1F1 binding at unique sites. We validated enhancer function of novel elements we mapped nearCga, Pitx1, Gata2,andTshbby transfection in TαT1 cells. Finally, we confirmed that an enhancer element nearTshbcan drive expression in thyrotropes of transgenic mice, and we demonstrate that GATA2 enhancesTshbexpression through this element.ConclusionThese results extend the ENCODE multi-omic profiling approach to the pituitary gland, which should be valuable for understanding pituitary development and disease pathogenesis.Graphical abstract
Cooking oil/fat consumption and deaths from cardiometabolic diseases and other causes: prospective analysis of 521,120 individuals
Authors: Zhang Yu , Zhuang Pan , Wu Fei , He Wei , Mao Lei , Jia Wei , Zhang Yiju , Chen Xiaoqian , Jiao Jingjing 
Published: April 2021

Abstract
Background
Increasing evidence highlights healthy dietary patterns and links daily cooking oil intake with chronic diseases including cardiovascular disease (CVD) and diabetes. However, food-based evidence supporting the consumption of cooking oils in relation to total and cardiometabolic mortality remains largely absent. We aim to prospectively evaluate the relations of cooking oils with death from cardiometabolic (CVD and diabetes) and other causes.

Methods
We identified and prospectively followed 521,120 participants aged 50–71 years from the National Institutes of Health-American Association of Retired Persons Diet and Health Study. Individual cooking oil/fat consumption was assessed by a validated food frequency questionnaire. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated for mortality through the end of 2011.

Results
Overall, 129,328 deaths were documented during a median follow-up of 16 years. Intakes of butter and margarine were associated with higher total mortality while intakes of canola oil and olive oil were related to lower total mortality. After multivariate adjustment for major risk factors, the HRs of cardiometabolic mortality for each 1-tablespoon/day increment were 1.08 (95% CI 1.05–1.10) for butter, 1.06 (1.05–1.08) for margarine, 0.99 (0.95–1.03) for corn oil, 0.98 (0.94–1.02) for canola oil, and 0.96 (0.92–0.99) for olive oil. Besides, butter consumption was positively associated with cancer mortality. Substituting corn oil, canola oil, or olive oil for equal amounts of butter and margarine was related to lower all-cause mortality and mortality from certain causes, including CVD, diabetes, cancer, respiratory disease, and Alzheimer’s disease.

Conclusions
Consumption of butter and margarine was associated with higher total and cardiometabolic mortality. Replacing butter and margarine with canola oil, corn oil, or olive oil was related to lower total and cardiometabolic mortality. Our findings support shifting the intake from solid fats to non-hydrogenated vegetable oils for cardiometabolic health and longevity.
A hemizygous p.R204Q mutation in the ALAS2 gene underlies X-linked sideroblastic anemia in an adult Chinese Han man
Authors: Huang Jinbo , Ge Meili , Shao Yingqi , Wang Min , Jin Peng , Huo Jiali , Li Xingxin , Zhang Jing , Nie Neng , Zheng Yizhou 
Published: April 2021

Abstract
Background
X-linked sideroblastic anemia (XLSA) is the most common form of congenital sideroblastic anemia (CSA), and is associated with the mutations in the 5-aminolevulinate synthase 2 (ALAS2). The genetic basis of more than 40% of CSA cases remains unknown.

Methods
A two-generation Chinese family with XLSA was studied by next-generation sequencing to identify the underlying CSA-related mutations.

Results
In the study, we identified a missense ALAS2 R204Q mutation in a hemizygous Chinese Han man and in his heterozygous daughter. The male proband presented clinical manifestations at 38 years old and had a good response to pyridoxine.

Conclusions
XLSA, as a hereditary disease, can present clinical manifestations later in lives, for adult male patients with ringed sideroblasts and hypochromic anemia, it should be evaluated with gene analyses to exclude CSA.
Circular RNA hsa_circ_0003288 induces EMT and invasion by regulating hsa_circ_0003288/miR-145/PD-L1 axis in hepatocellular carcinoma
Authors: Xu Guili , Zhang Peng , Liang Hansi , Xu Yunhua , Shen Jian , Wang Wansheng , Li Mingming , Huang Jintao , Ni Caifang , Zhang Xueguang , Zhu Xiaoli 
Published: April 2021

Abstract
Background
Epithelial-mesenchymal transition (EMT) has been associated with wound healing, tumorigenesis, and metastasis. Circular RNAs (circRNAs) are functional non-coding RNAs involved in multiple human cancers. However, whether and how circRNAs contribute to the EMT in hepatocellular carcinomas (HCC) remains to be deciphered. In this study, we investigated the regulation and function of hsa_circ_0003288 on programmed death-1 ligand 1 (PD-L1) during EMT and HCC invasiveness.

Methods
Hsa_circ_0003288 expression was measured by real-time quantitative reverse transcriptase PCR (qRT-PCR). Luciferase reporter assays, RNA pull-down assay and fluorescence in situ hybridization (FISH) were used to determine the correlation between hsa_circ_0003288 and miR-145 and between miR-145 and PD-L1. Furthermore, ectopic overexpression and siRNA-mediated downregulation of hsa_circ_0003288, transwell assays, and in vivo studies were used to determine the function of hsa_circ_0003288 on the EMT and invasiveness of L02 and HCC cells.

Results
miR-145 directly targeted the PD-L1 3′-untranslated region (UTR) region, and hsa_circ_0003288 acted as a miR-145 sponge to regulate PD-L1 expression. Overexpression of hsa_circ_0003288 increased PD-L1 levels and promoted EMT, migration, and invasiveness of L02 cells. These observations were reversed after knockdown of hsa_circ_0003288 in HepG2 and Huh7 cells. Overexpression of PD-L1 rescued EMT, migration, and invasiveness of HepG2 and Huh7 cells after knockdown of hsa_circ_0003288. Furthermore, hsa_circ_0003288 knockdown reduced EMT in in vivo studies. Hsa_circ_0003288/PD-L1 axis was found to mediate the metastatic phenotypes via the PI3K/Akt pathway in HCC. Additionally, expression levels of hsa_circ_0003288 were increased and positively correlated with PD-L1 expression in HCC tissues.

Conclusion
Our findings demonstrated that hsa_circ_0003288 promoted EMT and invasion of HCC via the hsa_circ_0003288/miR-145/PD-L1 axis through the PI3K/Akt pathway. Targeting hsa_circ_0003288 may be a therapeutic strategy for the treatment of HCC.
Emerging cellular and molecular mechanisms underlying anticancer indications of chrysin
Authors: Talebi Marjan , Talebi Mohsen , Farkhondeh Tahereh , Simal-Gandara Jesus , Kopustinskiene Dalia M. , Bernatoniene Jurga , Samarghandian Saeed 
Published: April 2021

AbstractChrysin has been shown to exert several beneficial pharmacological activities. Chrysin has anti-cancer, anti-viral, anti-diabetic, neuroprotective, cardioprotective, hepatoprotective, and renoprotective as well as gastrointestinal, respiratory, reproductive, ocular, and skin protective effects through modulating signaling pathway involved in apoptosis, oxidative stress, and inflammation. In the current review, we discussed the emerging cellular and molecular mechanisms underlying therapeutic indications of chrysin in various cancers. Online databases comprising Scopus, PubMed, Embase, ProQuest, Science Direct, Web of Science, and the search engine Google Scholar were searched for available and eligible research articles. The search was conducted by using MeSH terms and keywords in title, abstract, and keywords. In conclusion, experimental studies indicated that chrysin could ameliorate cancers of the breast, gastrointestinal tract, liver and hepatocytes, bladder, male and female reproductive systems, choroid, respiratory tract, thyroid, skin, eye, brain, blood cells, leukemia, osteoblast, and lymph. However, more studies are needed to enhance the bioavailability of chrysin and evaluate this agent in clinical trial studies.
Graphic abstract
Trichostatin A downregulates bromodomain and extra-terminal proteins to suppress osimertinib resistant non-small cell lung carcinoma
Authors: Meng Yuting , Qian Xixi , Zhao Li , Li Nan , Wu Shengjie , Chen Baoan , Sun Tong , Wang Xuerong 
Published: April 2021

Abstract
Background
The third-generation epithelial growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) have shown significant therapeutic effects on patients with non-small cell lung carcinoma (NSCLC) who carry active EGFR mutations, as well as those who have developed acquired resistance to the first-generation of EGFR-TKIs due to the T790M mutation. However, most patients develop drug resistance after 8–10 months of treatment. Currently, the mechanism has not been well clarified, and new therapeutic strategies are urgently needed.

Methods
Osimertinib resistant cell lines were established by culturing sensitive cells in chronically increasing doses of osimertinib. The anticancer effect of reagents was examined both in vitro and in vivo using the sulforhodamine B assay and a xenograft mouse model. The molecular signals were detected by western blotting. The combination effect was analyzed using CompuSyn software.

Results
We found that bromodomain and extra-terminal proteins (BETs) were upregulated in osimertinib resistant (H1975-OR) cells compared with those in the paired parental cells (H1975-P), and that knockdown of BETs significantly inhibited the growth of H1975-OR cells. The BET inhibitor JQ1 also exhibited stronger growth-inhibitory effects on H1975-OR cells and a greater expression of BETs and the downstream effector c-Myc than were observed in H1975-P cells. The histone deacetylase (HDAC) inhibitor trichostatin A (TSA) showed stronger growth suppression in H1975-OR cells than in H1975-P cells, but vorinostat, another HDAC inhibitor, showed equal inhibitory efficacy in both cell types. Consistently, downregulation of BET and c-Myc expression was greater with TSA than with vorinostat. TSA restrained the growth of H1975-OR and H1975-P xenograft tumors. The combination of TSA and JQ1 showed synergistic growth-inhibitory effects in parallel with decreased BET and c-Myc expression in both H1975-OR and H1975-P cells and in xenograft nude mouse models. BETs were not upregulated in osimertinib resistant HCC827 cells compared with parental cells, while TSA and vorinostat exhibited equal inhibitory effects on both cell types.

Conclusion
Upregulation of BETs contributed to the osimertinib resistance of H1975 cells. TSA downregulated BET expression and enhanced the growth inhibitory effect of JQ1 both in vitro and in vivo. Our findings provided new strategies for the treatment of osimertinib resistance.
Establishment and validation of a prognostic signature for lung adenocarcinoma based on metabolism‐related genes
Authors: Wang Zhihao , Embaye Kidane Siele , Yang Qing , Qin Lingzhi , Zhang Chao , Liu Liwei , Zhan Xiaoqian , Zhang Fengdi , Wang Xi , Qin Shenghui 
Published: April 2021

Abstract
Background
Given that dysregulated metabolism has been recently identified as a hallmark of cancer biology, this study aims to establish and validate a prognostic signature of lung adenocarcinoma (LUAD) based on metabolism-related genes (MRGs).

Methods
The gene sequencing data of LUAD samples with clinical information and the metabolism-related gene set were obtained from The Cancer Genome Atlas (TCGA) and Molecular Signatures Database (MSigDB), respectively. The differentially expressed MRGs were identified by Wilcoxon rank sum test. Then, univariate cox regression analysis was performed to identify MRGs that related to overall survival (OS). A prognostic signature was developed by multivariate Cox regression analysis. Furthermore, the signature was validated in the GSE31210 dataset. In addition, a nomogram that combined the prognostic signature was created for predicting the 1-, 3- and 5-year OS of LUAD. The accuracy of the nomogram prediction was evaluated using a calibration plot. Finally, cox regression analysis was applied to identify the prognostic value and clinical relationship of the signature in LUAD.

Results
A total of 116 differentially expressed MRGs were detected in the TCGA dataset. We found that 12 MRGs were most significantly associated with OS by using the univariate regression analysis in LUAD. Then, multivariate Cox regression analyses were applied to construct the prognostic signature, which consisted of six MRGs-aldolase A (ALDOA), catalase (CAT), ectonucleoside triphosphate diphosphohydrolase-2 (ENTPD2), glucosamine-phosphate N-acetyltransferase 1 (GNPNAT1), lactate dehydrogenase A (LDHA), and thymidylate synthetase (TYMS). The prognostic value of this signature was further successfully validated in the GSE31210 dataset. Furthermore, the calibration curve of the prognostic nomogram demonstrated good agreement between the predicted and observed survival rates for each of OS. Further analysis indicated that this signature could be an independent prognostic indicator after adjusting to other clinical factors. The high-risk group patients have higher levels of immune checkpoint molecules and are therefore more sensitive to immunotherapy. Finally, we confirmed six MRGs protein and mRNA expression in six lung cancer cell lines and firstly found that ENTPD2 might played an important role on LUAD cells colon formation and migration.

Conclusions
We established a prognostic signature based on MRGs for LUAD and validated the performance of the model, which may provide a promising tool for the diagnosis, individualized immuno-/chemotherapeutic strategies and prognosis in patients with LUAD.
Characterization of antimicrobial susceptibility, extended-spectrum β-lactamase genes and phylogenetic groups of Shigatoxin producing Escherichia coli isolated from patients with diarrhea in Iran
Authors: Jafari Erfaneh , Oloomi Mana , Bouzari Saeid 
Published: April 2021

Abstract
Background
Shiga toxin‐producing Escherichia coli (STEC) are among common foodborne bacterial pathogens and healthy livestock are the main source of this bacterium. Severe diseases attribute to two types of cytotoxin Stx1 and Stx2, which are also called Shiga toxin (Stx). Infection of humans with STEC may result in Acute diarrhea with or without bleeding, hemorrhagic colitis (HC) and the hemolytic uremic syndrome (HUS). As antibiotic resistance is increasingly being reported among STEC isolates obtained from livestock and patients worldwide, in this study the pattern of antibiotic resistance in clinical isolates was determined.

Methods
Stool samples were collected from patients with diarrhea. All samples were cultured and identified by biochemical and molecular tests. Antimicrobial susceptibility test and assessment of extended-spectrum β-lactamase (ESBL)-related genes were conducted. Moreover, phylogenetic groups were analyzed using quadruplex PCR, and DNA analysis assessed multi-locus sequence types (MLST).

Results
Out of 340 E. coli samples, 174 were identified as STEC by PCR. Antimicrobial susceptibility test results showed that, 99.4%, 96% and 93.1% of isolates were susceptible to imipenem/ertapenem, piperacillin–tazobactam and amikacin, respectively. The highest resistance was towards ampicillin (68.4%), followed by trimethoprim–sulfamethoxazole (59.8%), and tetracycline (57.5%). A total of 106 (60.9%) isolates were multidrug resistance (MDR) and 40.8% of isolates were determined to be extended spectrum β-lactamase producers. In 94.4% of isolates, genes responsible for ESBL production could be detected, and blaTEM was the most prevalent, followed by blaCTX-M9. Furthermore, phylogenetic grouping revealed that majority of STEC strains belonged to Group C, followed by Groups E, B2 and A. MLST unveiled diverse ST types.

Conclusion
A periodical surveillance studies and thorough understanding of antibiotic resistant profiles in STEC isolates could help select effective antibiotic treatment for patients and develop strategies to effectively manage food contamination and human infections.