bluuebunny/crossref_metadata_2025 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

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

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

Background

The 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.

Results

We 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.

Conclusion

These 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

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

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

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

Chrysin 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

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

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

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.
Green Phellodendri Chinensis Cortex-based carbon dots for ameliorating imiquimod-induced psoriasis-like inflammation in mice
Authors: Zhang Meiling , Cheng Jinjun , Hu Jie , Luo Juan , Zhang Yue , Lu Fang , Kong Hui , Qu Huihua , Zhao Yan
Published: April 2021

Background

Carbon dots (CDs) with multifaceted advantages have provided hope for development brand-new nanodrug for treating thorny diseases. This study developed a green and simple calcination method to prepare novel CDs as promising drug for psoriasis treatment. The as-prepared CDs using Phellodendri Chinensis Cortex (PCC) as sole precursor were characterized by a series of methods, mainly including electron microscopy, optical technology and X-ray photoelectron spectroscopy (XPS).

Results

Results displayed that fluorescence (Quantum yield = 5.63%) and nontoxic PCC-based CDs (PCC-CDs) with abundant chemical groups exhibited solubility and tiny sizes at average of (1.93 ± 0.53) nm, which may be beneficial for its inherent biological activity. Moreover, by using the typical imiquimod (IMQ)-induced psoriasis-like skin mouse model, we firstly demonstrated the pronounced anti-psoriasis activity of as-prepared PCC-CDs on ameliorating the appearance, psoriasis area and severity index (PASI) scores as well as histopathological morphology of both back skin tissues and right ears in IMQ-induced mouse. Further potential mechanisms behind the anti-psoriasis activities may be related to suppress M1 polarization and relatively promote M2 polarization of macrophage both in vitro and in vivo.

Conclusion

These results suggested that PCC-CDs have potential to be an anti-psoriasis candidate for clinical applications to treat psoriasis, which not only provided an evidence for further broadening the biological application of CDs, but also provided a potential hope for application nanodrugs to treat thorny diseases.

Graphic Abstract
Development and validation of behavioral intention measures of an E-vapor product: intention to try, use, dual use, and switch
Authors: McCaffrey Stacey A. , Zdinak Jessica Parker , Plunkett Stephanie , Becker Elizabeth , Lewis Jennifer N. , Black Ryan A.
Published: April 2021

Background

The harm caused by tobacco use is primarily attributable to cigarette smoking. Switching completely to non-combustible products may reduce disease risks in adult cigarette smokers who are unable or unwilling to quit. Before a new tobacco product can enter the market or can be marketed as a modified risk tobacco product, the manufacturer must determine the impact that the product will have on the likelihood of changes in tobacco use behavior among both tobacco users and nonusers. One way to estimate change in tobacco use behavior is to assess tobacco users’ and nonusers’ behavioral intentions toward the product and its marketing, including intentions to try, use, dual use, and switch to the product from cigarettes. The purpose of this study was to develop and validate behavioral intention metrics appropriate for use with current, former, and never adult tobacco users.

Methods

Preliminary items were subjected to cognitive testing with adult (1) smokers planning to quit cigarettes in the next 30 days, (2) smokers not planning to quit cigarettes in the next 30 days, (3) e-vapor users, (4) former tobacco users, and (5) never tobacco users. Items were iteratively revised based on feedback during cognitive testing, and surviving items were administered to a large sample of adults (N = 2943) representing the aforementioned sub-groups. Rating scale functioning, reliability, validity, bias, and ability to detect change were evaluated.

Results

Examination of the response category thresholds generated by the Rasch model provided evidence that the rating scales were functioning appropriately. Results revealed good stability and excellent internal consistency and person reliability and provided evidence of unidimensionality and convergent validity. Estimates of reliability and validity were similar across sub-groups. A cross-validation sample generally confirmed findings from the validation sample. No items were discarded due to differential item function. Exploratory analyses provided support for ability to detect change.

Conclusions

Results from this rigorous, empirical evaluation using large validation and cross-validation samples provide strong support for the psychometric properties of the Intention to Try, Use, Dual Use, and Switch scales with current, former, and never adult tobacco users.
Association between cigarette smoking and colorectal cancer sidedness: A multi-center big-data platform-based analysis
Authors: Yang Lu-Ping , Wang Zi-Xian , Zhang Rui , Zhou Na , Wang A-Man , Liang Wei , Wang Zhi-Qiang , Luo Hui-Yan , Wang Feng , Liu Ji-Wei , Liu Fang , Zhang Xiao-Chun , Liu Yun-Peng , Jin Ying
Published: April 2021

Background

Sidedness (right/left) of colorectal cancer (CRC) is essential for treatment. Whether carcinogenesis of tobacco varies by sidedness remains unclear. The present study aims to evaluate the sidedness tendency of cigarette smoking and to explore its impact on prognosis.

Methods

In the multi-center retrospective study, data on 46 166 Chinese CRC patients were extracted from a big-data platform. Logistic regression analyses were performed to evaluate qualitative and quantitative associations between smoking and tumor sidedness. Survival analyses were conducted in metastatic CRC.

Results

History of smoking was associated with left-sided CRC (LSCRC; Adjusted odds ratio, 1.25; 95% CI, 1.16 − 1.34; P < .001). The sidedness tendency towards LSCRC increased from non-smokers, to ex-smokers, and to current smokers (P for trend < .001). Longer duration (P for trend < .001) and larger total amount of cigarette smoking (P for trend < .001) were more associated with LSCRC, respectively. The association was confirmed in both left-sided colon cancer and rectal cancer, but was stronger for rectal cancer (P = .016). Alcoholism significantly enhanced the association by 7% (P = .027). Furthermore, prognostic advantage of metastatic LSCRC diminished among ever-smokers, with contrary survival impacts of smoking on either side of CRC.

Conclusions

History of smoking was associated with LSCRC in a positive dose–response relationship, and presented opposite prognostic impacts on right- and left-sided tumors. Smoking potentially plays an instrumental role in the mechanism for sidedness heterogeneity in CRC.
Clinical pharmacogenomics in action: design, assessment and implementation of a novel pharmacogenetic panel supporting drug selection for diseases of the central nervous system (CNS)
Authors: Bothos E. , Ntoumou E. , Kelaidoni K. , Roukas D. , Drakoulis N. , Papasavva M. , Karakostis F. A. , Moulos P. , Karakostis K.
Published: April 2021

Background

Pharmacogenomics describes the link between gene variations (polymorphisms) and drug responses. In view of the implementation of precision medicine in personalized healthcare, pharmacogenetic tests have recently been introduced in the clinical practice. However, the translational aspects of such tests have been limited due to the lack of robust population-based evidence.

Materials

In this paper we present a novel pharmacogenetic panel (iDNA Genomics-PGx–CNS or PGx–CNS), consisting of 24 single nucleotide polymorphisms (SNPs) on 13 genes involved in the signaling or/and the metabolism of 28 approved drugs currently administered to treat diseases of the Central Nervous System (CNS). We have tested the PGx–CNS panel on 501 patient-derived DNA samples from a southeastern European population and applied biostatistical analyses on the pharmacogenetic associations involving drug selection, dosing and the risk of adverse drug events (ADEs).

Results

Results reveal the occurrences of each SNP in the sample and a strong correlation with the European population. Nonlinear principal component analysis strongly indicates co-occurrences of certain variants. The metabolization efficiency (poor, intermediate, extensive, ultra-rapid) and the frequency of clinical useful pharmacogenetic, associations in the population (drug relevance), are also described, along with four exemplar clinical cases illustrating the strong potential of the PGx–CNS panel, as a companion diagnostic assay. It is noted that pharmacogenetic associations involving copy number variations (CNVs) or the HLA gene were not included in this analysis.

Conclusions

Overall, results illustrate that the PGx–CNS panel is a valuable tool supporting therapeutic medical decisions, urging its broad clinical implementation.
Metabolic analysis of early nonalcoholic fatty liver disease in humans using liquid chromatography-mass spectrometry
Authors: Hu Cheng , Wang Tao , Zhuang Xiaoyu , Sun Qiaoli , Wang Xiaochun , Lin Hui , Feng Mingli , Zhang Jiaqi , Cao Qin , Jiang Yuanye
Published: April 2021

Background

Nonalcoholic fatty liver disease (NAFLD) is a common metabolic disease that affects 20–30% of individuals worldwide. Liver puncture remains the gold standard for the diagnosis of liver diseases despite limitations regarding invasive nature and sample variability. It is of great clinical significance to find noninvasive biomarkers to detect and predict NAFLD.

Objective

The aims of this study were to identify potential serum markers in individuals with early-stage NAFLD and to advance the mechanistic understanding of this disease using a high-throughput mass spectrometry-based untargeted metabolomics approach.

Methods

One hundred and twelve patients with early-stage NAFLD aged 18–55 were recruited according to the guidelines. The control group included 112 healthy participants. The demographic, anthropometric, clinical and laboratory data of all participants were systematically collected. Serum samples were obtained after an overnight fast. The comprehensive serum metabolomic analysis was performed by ultra-performance liquid chromatography-Orbitrap mass spectrometry. The resultant data was processed by Compound Discover and SIMCA-P software to validate the potential biomarkers. Significantly altered metabolites were evaluated by variable importance in projection value (VIP > 1) and ANOVA (p < 0.01). Pathway analysis was performed using MetaboAnalyst 4.0.

Results

The liver function test of early NAFLD patients showed no statistical differences to control group (p > 0.05). However, obvious differences in blood lipids were observed between subjects with NAFLD and controls (p < 0.001). In total, 55 metabolites showed significant changes in experimental group were identified. The area under curve (AUC) values deduced by receiver operating curve (ROC) analysis indicated that these newly identified biomarkers have high predictability and reliability. Of these, 15 metabolites with AUC greater than 0.9 were of great diagnostic value in early NAFLD patients.

Conclusion

In this study, a total of 15 serum metabolites were found to strongly associate with early NAFLD. These biomarkers may have great clinical significance in the early diagnosis of NAFLD, as well as to follow response to therapeutic interventions.
Autism-associated synaptic vesicle transcripts are differentially expressed in maternal plasma exosomes of physiopathologic pregnancies
Authors: Fang Yangwu , Wan Chan , Wen Youlu , Wu Ze , Pan Jing , Zhong Mei , Zhong Nanbert
Published: April 2021

Background

During intrauterine development, the formation and function of synaptic vesicles (SVs) are thought to be fundamental conditions essential for normal development of the brain. Lacking advanced technology during the intrauterine period, such as longitudinal real-time monitoring of the SV-associated transcripts (SVATs), which include six pairs of lncRNA-mRNA, has limited acquisition of the dynamic gene expression profile (GEP) of SVATs. We previously reported the differential expression of SVATs in the peripheral blood of autistic children. The current study was designed to determine the dynamic profiles of differentially-expressed SVATs in circulating exosomes (EXs) derived from autistic children and pregnant women at different gestational ages.

Methods

Blood samples were collected from autistic children and women with variant physiopathologic pregnancies. EXs were isolated with an ExoQuick Exosome Precipitation Kit and characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and Western blotting. The expression of lncRNAs and lncRNA-targeted mRNAs were quantified using real-time PCR.

Results

SVAT-associated lncRNAs-mRNAs were detected in autistic children and differentially expressed from the first trimester of pregnancy to the term of delivery. Pathologic pregnancies, including spontaneous preterm birth (sPTB), preeclampsia (PE), and gestational diabetes mellitus (GDM), were compared to normal physiologic pregnancies, and shown to exhibit specific correlations between SVAT-lncRNA and SVAT-mRNA ofSTX8,SLC18A2, andSYPwith sPTB; SVAT-lncRNA and SVAT-mRNA ofSTX8with PE; and SVAT-lncRNA and SVAT-mRNA ofSV2Cas well as SVAT-mRNA ofSYPwith GDM.

Conclusion

Variant complications in pathologic pregnancies may alter the GEP of SVATs, which is likely to affect the intrauterine development of neural circuits and consequently influence fetal brain development.
Pilot evaluation of an enzymatic assay for rapid measurement of antiretroviral drug concentrations
Authors: Olanrewaju Ayokunle O. , Sullivan Benjamin P. , Bardon Ashley R. , Lo Tiffany J. , Cressey Tim R. , Posner Jonathan D. , Drain Paul K.
Published: April 2021

Objective

Maintaining adequate drug adherence is crucial to ensure the HIV prevention benefits of pre-exposure prophylaxis (PrEP). We developed an enzymatic assay for rapidly measuring tenofovir-diphosphate (TFV-DP) concentrations—a metabolite that indicates long-term PrEP adherence.

Setting

The study was conducted at the Madison HIV Clinic at Harborview Medical Center in Seattle.

Methods

We enrolled adults receiving standard oral PrEP, and individuals not receiving any antiretrovirals. We measured TFV-DP concentrations in diluted whole blood using our novel REverSe TRanscrIptase Chain Termination (RESTRICT) assay, based on inhibition of HIV reverse transcriptase (RT) enzyme. Blood samples were diluted in water, DNA templates, nucleotides, RT, and intercalating dye added, and results measured with a fluorescence reader—stronger fluorescence indicated higher RT activity. We compared RESTRICT assay results to TFV-DP concentrations from matched dried blood spot samples measured by liquid chromatography tandem mass spectrometry (LC–MS/MS) using ≥ 700 fmol/punch TFV-DP as a threshold for adequate adherence (≥ 4 doses/week).

Results

Among 18 adults enrolled, 4 of 7 participants receiving PrEP had TFV-DP levels ≥ 700 fmol/punch by LC–MS/MS. RESTRICT fluorescence correlated with LC–MS/MS measurements (r = − 0.845,p < 0.0001). Median fluorescence was 93.3 (95% confidence interval [CI] 90.9 to 114) for samples < 700 fmol/punch and 54.4 (CI 38.0 to 72.0) for samples ≥ 700 fmol/punch. When calibrated to an a priori defined threshold of 82.7, RESTRICT distinguished both groups with 100% sensitivity and 92.9% specificity.

Conclusions

This novel enzymatic assay for measuring HIV reverse transcriptase activity may be suitable for distinguishing TFV-DP concentrations in blood that correspond to protective PrEP adherence.
Radiographic assessment of radiolucent lines around a highly porous titanium cup (Tritanium) using digital tomosynthesis, after total hip arthroplasty
Authors: Oishi Kazuki , Yamamoto Yuji , Harada Yoshifumi , Inoue Ryo , Sasaki Eiji , Ishibashi Yasuyuki
Published: April 2021

Background

The objectives of this study were to assess radiolucent lines around a highly porous titanium cup (Tritanium) using digital tomosynthesis and to investigate the clinical and radiographic factors associated with radiolucent lines on tomosynthesis.

Methods

Fifty-five patients underwent total hip arthroplasty using a Tritanium cup, and digital tomosynthesis and plain radiography were performed at 1 week, 6 months, 1 year, and 2 years after surgery. The radiolucent lines around the cup were measured on both DTS and plain radiography at each postoperative period. Clinical evaluations were performed by the Japanese Orthopaedic Association hip disease evaluation questionnaire (JHEQ), and revision surgeries were examined. Based on the presence of radiolucent lines on digital tomosynthesis at 2 years postoperatively, patients were divided into RL (+) and RL (−) groups and investigated for related factors.

Results

There were 20 cases in the RL (+) group and 35 cases in the RL (−) group, and no revision surgeries were required. Statistically, there were more cases with radiolucent lines on digital tomosynthesis (45.4% at 1 week and 36.3% at 2 years) than on plain radiography (9.1% at 1 week and 9.1% at 2 years) at each postoperative point. Logistic analysis showed no significant associations between the presence of radiolucent lines at 2 years on digital tomosynthesis, and the JHEQ parameters of pain (p = 0.937), movement (p = 0.266), or mental status (p = 0.404).

Conclusion

In a short-term evaluation up to 2 years, digital tomosynthesis detected more radiolucent lines around the titanium cups than plain radiography. The occurrence of radiolucent lines was not related to the postoperative clinical evaluation.
Association between glucose variability and postoperative delirium in acute aortic dissection patients: an observational study
Authors: Lin Yan-Juan , Lin Ling-Yu , Peng Yan-Chun , Zhang Hao-Ruo , Chen Liang-wan , Huang Xi-Zhen , Chen Qiong
Published: April 2021

Background

Blood glucose variability is associated with poor prognosis after cardiac surgery, but the relationship between glucose variability and postoperative delirium in patients with acute aortic dissection is unclear. The study aims to investigate the association of blood glucose variability with postoperative delirium in acute aortic dissection patients.

Methods

We prospectively analyzed 257 patients including 103 patients with delirium. The patients were divided into two groups according to whether delirium was present. The outcome measures were postoperative delirium, the length of the Intensive Care Unit stay, and the duration of hospital stay. Multivariable Cox competing risk survival models was used to assess.

Results

A total of 257 subjects were enrolled, including 103 patients with delirium. There were statistically significant differences between the two groups in body mass index, history of cardiac surgery, first admission blood glucose, white blood cell counts, Acute Physiology and Chronic Health Evaluation II score, hypoxemia, mechanical ventilation duration, and the length of Intensive Care Unit stay(P < 0.05). The delirium group exhibited significantly higher values of the mean of blood glucose (MBG) and the standard deviation of blood glucose (SDBG) than in the non-delirium group(P < 0.05). In model 1, the adjusted hazard ratio (AHR) of the standard deviation of blood glucose was 1.436(P < 0.05). In Model 2, the standard deviation of blood glucose (AHR = 1.418, 95%CI = 1.195–1.681, P < 0.05) remained significant after adjusting for confounders. The area under the curve of the SDBG was 0.763(95%CI = 0.704–0.821, P < 0.01). The sensitivity was 81.6%, and the specificity was 57.8%.

Conclusions

Glucose variability is associated with the risk of delirium in patients after aortic dissection surgery, and high glycemic variability increases the risk of postoperative delirium.
Video-assisted pulmonary metastectomy is equivalent to thoracotomy regarding resection status and survival
Authors: Markowiak Till , Dakkak Beshir , Loch Elena , Großer Christian , Klinkhammer-Schalke Monika , Hofmann Hans-Stefan , Ried Michael
Published: April 2021

Background

Surgical resection of pulmonary metastases leads to prolonged survival if strictly indicated. Usually, thoracotomy with manual palpation of the entire lung with lymph node dissection or sampling is performed. The aim of this study was to evaluate the role of video-assisted thoracoscopic surgery (VATS) in pulmonary metastectomy with curative intent.

Methods

In this study, all patients with suspected pulmonary metastasis (n = 483) who visited the Center for Thoracic Surgery in Regensburg, between January 2009 and December 2017 were analysed retrospectively.

Results

A total of 251 patients underwent metastectomy with curative intent. VATS was performed in 63 (25.1%) patients, 54 (85.7%) of whom had a solitary metastasis. Wedge resection was the most performed procedure in patients treated with VATS (82.5%, n = 52) and thoracotomy (72.3%, n = 136). Postoperative revisions were necessary in nine patients (4.8%), and one patient died of pulmonary embolism after thoracotomy (0.5%). Patients were discharged significantly faster after VATS than after thoracotomy (p < 0.001). Complete (R0) resection was achieved in 89% of patients. The median recurrence-free survival was 11 months (95% confidence interval 7.9–14.1). During follow-up, eight (12.7%) patients in the VATS group and 42 (22.3%) patients in the thoracotomy group experienced recurrence (p = 0.98). The median overall survival was 61 months (95% confidence interval 46.1–75.9), and there was no significant difference with regard to the surgical method used (p = 0.34).

Conclusions

VATS metastasectomy can be considered in patients with a solitary lung metastasis. An open surgical approach with palpation of the lung showed no advantage in terms of surgical outcome or survival.
Lung segmentectomy assisted by highly selective independent segmental ventilation: a series of three cases
Authors: Shi Xiaoshun , Ye Jing , Chen Junyong , Zhai Jianxue , Liu Xiguang , Lu Di , Lin Zishi , Ni Zhen , Wu Hua , Cai Kaican
Published: April 2021

Background

The identification of targeted intersegmental planes and resection with adequate surgical margins are among the crucial steps in anatomical pulmonary segmentectomy, and technical improvements are still needed.

Case presentation

We reported three cases of intersegmental plane identification using highly selective independent segmental ventilation during segmentectomy. All cases required cooperation with an anesthesiologist who was able to perform segmental ventilation and double confirmation of segmental bronchus branches by the surgeon. The surgical procedure provides a direct visualization of spare segment inflation and saves time in deflation over the conventional residual segment inflation method.

Conclusions

Highly selective independent segmental ventilation could be considered a suitable option for pulmonary intersegmental plane identification and could be universally used for lung segmentectomy.
Large cardiac wall hematoma with rapid growth: a case report of a potentially catastrophic complication during cardiac surgery
Authors: Kobayashi Kimihiro , Uchida Tetsuro , Kuroda Yoshinori , Yamashita Atsushi , Ohba Eiichi , Nakai Shingo , Ochiai Tomonori
Published: April 2021

Background

Rapid growth of cardiac wall hematoma is a rare but potentially fatal complication of cardiac surgery. However, its pathophysiology and optimal management remain undefined.

Case presentation

Here we present a rare case of a large cardiac wall hematoma in the right ventricle during a thoracic aortic and valvular surgery. The hematoma expanded rapidly with epicardial rupture during cardiopulmonary bypass. We could establish non-surgical hemostasis and prevent further expansion of hematoma by early weaning of the cardiopulmonary bypass, followed by the administration of protamine and manual compression by hemostatic agent application. His postoperative recovery was uneventful and upon computed tomography analysis, the hematoma was observed to have absorbed completely at 1 week postoperatively. The patient is doing well 1 year after the surgery without evidence of recurrent cardiac wall hematoma on follow-up computed tomography.

Conclusions

Cardiovascular surgeons should bear in mind this potentially catastrophic complication during cardiac surgery. Because of the vulnerability of the cardiac wall at the area of the hematoma, we believe that a hemostatic approach without sutures may be effective for this lethal complication.