bluuebunny/crossref_metadata_2025_split huggingface dataset:
Small Area Variation of Adherence to Clinical Recommendations: An Example from Switzerland
Authors: Gruebner Oliver , Wei Wenjia , Ulyte Agne , Wyl Viktor von , Dressel Holger , Brüngger Beat , Bähler Caroline , Blozik Eva , Schwenkglenks Matthias 
Published: May 2022

Background Unwarranted variation in healthcare utilization can only partly be explained by variation in the health care needs of the population, yet it is frequently found globally. This is the first cross-sectional study that systematically assessed geographic variation in the adherence to clinical recommendations in Switzerland. Specifically, we explored 1) the geographic variation of adherence to clinical recommendations across 24 health services at the sub-cantonal level, 2) assessed and mapped statistically significant spatial clusters, and 3) explored possible influencing factors for the observed geographic variation. Methods Exploratory spatial analysis using the Moran’s I statistic on multivariable multilevel model residuals to systematically identify small area variation of adherence to clinical recommendations across 24 health services. Results Although there was no overall spatial pattern in adherence to clinical recommendations across all health care services, we identified health services that exhibited statistically significant spatial dependence in adherence. For these, we provided evidence about the locations of local clusters. Interpretation We identified regions in Switzerland in which specific recommended or discouraged health care services are utilized less or more than elsewhere. Future studies are needed to investigate the place-based social determinants of health responsible for the sub-cantonal variation in adherence to clinical recommendations in Switzerland and elsewhere over time.
Aligning Student-Faculty Mentorship Expectations and Needs to Promote Professional Identity Formation in Undergraduate Medical Education
Authors: Kusner Jonathan J. , Chen Jie Jane , Saldaña Fidencio , Potter Jennifer 
Published: May 2022

Background During professional identity formation, medical students integrate their newly developing professional identities with their longstanding personal identities. Longitudinal mentorship has been shown to aid students in this process. Lack of clear relationship expectations among students and faculty is a barrier to effective longitudinal mentorship relationships. Methods A cross-sectional, survey-based study collected information about experiences from both students (mentees) and faculty (mentors). Surveys focused on collecting participants’ attitudes and expectations regarding ideal and actual mentorship experiences. Descriptive statistics and Fisher's exact test analyses were used to compare the responses within and between students and faculty. Results A total of 234 faculty and 181 medical students completed the survey. There were 187 faculty respondents (79.9%) who had previously mentored students. Faculty who had versus had not previously mentored students differed significantly in their responses on the importance of mentors discussing aspects of their personal lives (71.1% vs. 54.3%, respectively, p = 0.0491), a quality valued by the majority of student respondents. As students progressed through medical school, they expressed increasing needs for personal mentorship and conversations regarding work/life integration and wellness (M1: 12.2%, M2: 18.8%, M3: 29.3%, M4: 51.7%). A minority of students (27% of M3 and 14.8% of M4 students) reported meeting faculty mentors through their clinical year experiences. Conclusions Faculty mentoring experience may improve student-faculty value alignment, which may in turn help to address student-identified needs pertaining to personal development and professional identity formation in medical school. By contrasting student-identified mentorship expectations with those of faculty at various stages of mentorship experience, this study lays the groundwork for the formation of more effective longitudinal mentorship programs.
Therapeutic targeting of LCK tyrosine kinase and mTOR signaling in T-cell acute lymphoblastic leukemia
Authors: Laukkanen Saara , Veloso Alexandra , Yan Chuan , Oksa Laura , Alpert Eric J. , Do Daniel , Hyvärinen Noora , McCarthy Karin , Adhikari Abhinav , Yang Qiqi , Iyer Sowmya , Garcia Sara P. , Pello Annukka , Ruokoranta Tanja , Moisio Sanni , Adhikari Sadiksha , Yoder Jeffrey A. , Gallagher Kayleigh , Whelton Lauren , Allen James R. , Jin Alex H. , Loontiens Siebe , Heinäniemi Merja , Kelliher Michelle , Heckman Caroline A. , Lohi Olli , Langenau David M. 
Published: May 2022

AbstractRelapse and refractory T-cell acute lymphoblastic leukemia (T-ALL) has a poor prognosis, and new combination therapies are sorely needed. Here, we used an ex vivo high-throughput screening platform to identify drug combinations that kill zebrafish T-ALL and then validated top drug combinations for preclinical efficacy in human disease. This work uncovered potent drug synergies between AKT/mTORC1 (mammalian target of rapamycin complex 1) inhibitors and the general tyrosine kinase inhibitor dasatinib. Importantly, these same drug combinations effectively killed a subset of relapse and dexamethasone-resistant zebrafish T-ALL. Clinical trials are currently underway using the combination of mTORC1 inhibitor temsirolimus and dasatinib in other pediatric cancer indications, leading us to prioritize this therapy for preclinical testing. This combination effectively curbed T-ALL growth in human cell lines and primary human T-ALL and was well tolerated and effective in suppressing leukemia growth in patient-derived xenografts (PDX) grown in mice. Mechanistically, dasatinib inhibited phosphorylation and activation of the lymphocyte-specific protein tyrosine kinase (LCK) to blunt the T-cell receptor (TCR) signaling pathway, and when complexed with mTORC1 inhibition, induced potent T-ALL cell killing through reducing MCL-1 protein expression. In total, our work uncovered unexpected roles for the LCK kinase and its regulation of downstream TCR signaling in suppressing apoptosis and driving continued leukemia growth. Analysis of a wide array of primary human T-ALLs and PDXs grown in mice suggest that combination of temsirolimus and dasatinib treatment will be efficacious for a large fraction of human T-ALLs.
Functional, structural, and molecular characterizations of the leukemogenic driver MEF2D-HNRNPUL1 fusion
Authors: Zhang Ming , Zhang Hao , Li Zhihui , Bai Ling , Wang Qianqian , Li Jianfeng , Jiang Minghao , Xue Qing , Cheng Nuo , Zhang Weina , Mao Dongdong , Chen Zhiming , Huang Jinyan , Meng Guoyu , Chen Zhu , Chen Sai-Juan 
Published: May 2022

Abstract
Recurrent MEF2D fusions with poor prognosis have been identified in B-cell precursor ALL (BCP-ALL). The molecular mechanisms underlying the pathogenic function of MEF2D fusions are poorly understood. Here, we show that MEF2D-HNRNPUL1 (MH) knock-in mice developed a progressive disease from impaired B-cell development at the pre–pro-B stage to pre-leukemia over 10 to 12 months. When cooperating with NRASG12D, MH drove an outbreak of BCP-ALL, with a more aggressive phenotype than the NRASG12D-induced leukemia. RNA-sequencing identified key networks involved in disease mechanisms. In chromatin immunoprecipitation–sequencing experiments, MH acquired increased chromatin-binding ability, mostly through MEF2D-responsive element (MRE) motifs in target genes, compared with wild-type MEF2D. Using X-ray crystallography, the MEF2D-MRE complex was characterized in atomic resolution, whereas disrupting the MH-DNA interaction alleviated the aberrant target gene expression and the B-cell differentiation arrest. The C-terminal moiety (HNRNPUL1 part) of MH was proven to contribute to the fusion protein’s trans-regulatory activity, cofactor recruitment, and homodimerization. Furthermore, targeting MH-driven transactivation of the HDAC family by using the histone deacetylase inhibitor panobinostat in combination with chemotherapy improved the overall survival of MH/NRASG12D BCP-ALL mice. Altogether, these results not only highlight MH as an important driver in leukemogenesis but also provoke targeted intervention against BCP-ALL with MEF2D fusions.
Brain region-specific effects of nearly fixed sapiens-derived alleles
Authors: Andirkó Alejandro , Boeckx Cedric 
Published: May 2022

AbstractThe availability of high-coverage genomes of our extinct relatives, the Neanderthals and Denisovans, and the emergence of large, tissue-specific databases of modern human genetic variation, offer the possibility of probing the effects of modern-derived alleles in specific tissues, such as the brain, and its specific regions. While previous research has explored the effects of introgressed variants in gene expression, the effects of Homo sapiens-specific gene expression variability are still understudied. Here we identify derived, Homo sapiens-specific high-frequency (≥90%) alleles that are associated with differential gene expression across 15 brain structures derived from the GTEx database. We show that regulation by these derived variants targets regions under positive selection more often than expected by chance, and that high-frequency derived alleles lie in functional categories related to transcriptional regulation. Our results highlight the role of these variants in gene regulation in specific regions like the cerebellum and pituitary.
SCSilicon: a tool for synthetic single-cell DNA sequencing data generation
Authors: Feng Xikang , Chen Lingxi 
Published: May 2022

Abstract
Background
Single-cell DNA sequencing is getting indispensable in the study of cell-specific cancer genomics. The performance of computational tools that tackle single-cell genome aberrations may be nevertheless undervalued or overvalued, owing to the insufficient size of benchmarking data. In silicon simulation is a cost-effective approach to generate as many single-cell genomes as possible in a controlled manner to make reliable and valid benchmarking.

Results
This study proposes a new tool, SCSilicon, which efficiently generates single-cell in silicon DNA reads with minimum manual intervention. SCSilicon automatically creates a set of genomic aberrations, including SNP, SNV, Indel, and CNV. Besides, SCSilicon yields the ground truth of CNV segmentation breakpoints and subclone cell labels. We have manually inspected a series of synthetic variations. We conducted a sanity check of the start-of-the-art single-cell CNV callers and found SCYN was the most robust one.

Conclusions
SCSilicon is a user-friendly software package for users to develop and benchmark single-cell CNV callers. Source code of SCSilicon is available at https://github.com/xikanfeng2/SCSilicon.
Identification of functionally important miRNA targeted genes associated with child obesity trait in genome-wide association studies
Authors: Song Melinda , Yu Jiaqi , Li Binze , Dong Julian , Gao Jeslyn , Shang Lulu , Zhou Xiang , Bai Yongsheng 
Published: May 2022

AbstractBackgroundGenome-wide association studies (GWAS) have uncovered thousands of genetic variants that are associated with complex human traits and diseases. miRNAs are single-stranded non-coding RNAs. In particular, genetic variants located in the 3’UTR region of mRNAs may play an important role in gene regulation through their interaction with miRNAs. Existing studies have not been thoroughly conducted to elucidate 3’UTR variants discovered through GWAS. The goal of this study is to analyze patterns of GWAS functional variants located in 3’UTRs about their relevance in the network between hosting genes and targeting miRNAs, and elucidate the association between the genes harboring these variants and genetic traits.MethodsWe employed MIGWAS, ANNOVAR, MEME, and DAVID software packages to annotate the variants obtained from GWAS for 31 traits and elucidate the association between their harboring genes and their related traits. We identified variants that occurred in the motif regions that may be functionally important in affecting miRNA binding. We also conducted pathway analysis and functional annotation on miRNA targeted genes harboring 3’UTR variants for a trait with the highest percentage of 3’UTR variants occurring.ResultsThe Child Obesity trait has the highest percentage of 3’UTR variants (75%). Of the 16 genes related to the Child Obesity trait, 5 genes (ETV7, GMEB1, NFIX, ZNF566, ZBTB40) had a significant association with the term DNA-Binding (p < 0.05). EQTL analysis revealed 2 relevant tissues and 10 targeted genes associated with the Child Obesity trait.In addition, Red Blood Cells (RBC), Hemoglobin (HB), and Package Cell Volume (PCV) have overlapping variants. In particular, thePIM1variant occurred inside the HB Motif region 37,174,641–37,174,660, andLUC7L3variant occurred inside RBC Motif region 50,753,918–50,753,937.ConclusionVariants located in 3’UTR can alter the binding affinity of miRNA and impact gene regulation, thus warranting further annotation and analysis. We have developed a bioinformatics bash pipeline to automatically annotate variants, determine the number of variants in different categories for each given trait, and check common variants across different traits. This is a valuable tool to annotate a large number of GWAS result files.
B-assembler: a circular bacterial genome assembler
Authors: Huang Fengyuan , Xiao Li , Gao Min , Vallely Ethan J. , Dybvig Kevin , Atkinson T. Prescott , Waites Ken B. , Chong Zechen 
Published: May 2022

Abstract
Background
Accurate bacteria genome de novo assembly is fundamental to understand the evolution and pathogenesis of new bacteria species. The advent and popularity of Third-Generation Sequencing (TGS) enables assembly of bacteria genomes at an unprecedented speed. However, most current TGS assemblers were specifically designed for human or other species that do not have a circular genome. Besides, the repetitive DNA fragments in many bacterial genomes plus the high error rate of long sequencing data make it still very challenging to accurately assemble their genomes even with a relatively small genome size. Therefore, there is an urgent need for the development of an optimized method to address these issues.

Results
We developed B-assembler, which is capable of assembling bacterial genomes when there are only long reads or a combination of short and long reads. B-assembler takes advantage of the structural resolving power of long reads and the accuracy of short reads if applicable. It first selects and corrects the ultra-long reads to get an initial contig. Then, it collects the reads overlapping with the ends of the initial contig. This two-round assembling procedure along with optimized error correction enables a high-confidence and circularized genome assembly. Benchmarked on both synthetic and real sequencing data of several species of bacterium, the results show that both long-read-only and hybrid-read modes can accurately assemble circular bacterial genomes free of structural errors and have fewer small errors compared to other assemblers.

Conclusions
B-assembler provides a better solution to bacterial genome assembly, which will facilitate downstream bacterial genome analysis.
Methylated Septin9 has moderate diagnostic value in colorectal cancer detection in Chinese population: a multicenter study
Authors: Lu Dong-cheng , Zhang Qi-fang , Li Li , Luo Xian-ke , Liang Bin , Lu Yi-han , Hu Bang-li , Jiang Hai-xing 
Published: May 2022

Abstract
Background
The detection rate of methylated Septin9 (mSEPT9) in colorectal cancer (CRC) is varied greatly across the studies. This study aimed to evaluate the diagnostic ability of mSEPT9 in CRC, and compare the diagnostic efficacy with fecal immunochemical test (FIT).

Methods
326 subjects from four centers were prospectively recruited, including 179 CRC and 147 non-CRC subjects. The plasma was collected for mSEPT9 and CEA, AFP, CA125, CA153 and CA199 test, and fecal samples for FIT tests. Sensitivity, specificity and area under the curve (AUC) of receiver operating characteristic curve were calculated to evaluate the diagnostic value of each biomarker.

Results
The positive rate in mSEPT9 and FIT, and the level of CEA, CA125 and CA199 were significantly higher in CRC compared with non-CRC subjects. The mSEPT9 positive rate was not associated with TNM stage and tumor stage. The sensitivity, specificity and AUC of mSEPT9 in diagnostic CRC were 0.77, 0.88 and 0.82, respectively, while the value in FIT was 0.88, 0.80 and 0.83, respectively. mSEPT9 and FIT have higher AUC value than that of CEA, CA125 and CA199. Combination of both mSEPT9 and FIT positive increased sensitivity and AUC to 0.98 and 0.83, respectively, but the specificity was declined. mSEPT9 has a slightly low sensitivity in diagnosis of colon cancer (0.87) compared with rectal cancer (0.93).

Conclusion
mSEPT9 demonstrated moderate diagnostic value in CRC detection, which was similar to the FIT but superior to the CEA, CA125 and CA199. Combination of mSEPT9 and FIT further improved diagnostic sensitivity in CRC.
Trial registration: ChiCTR2000038319.
Characteristics of acute kidney injury and its impact on outcome in patients with acute-on-chronic liver failure
Authors: Huang Yue , Cai Junjun , Ha Fushuang , Guo Beichen , Xin Shaojie , Duan Zhongping , Han Tao 
Published: May 2022

Abstract
Objective
Acute kidney injury (AKI) is a common and life-threatening complication of liver failure. The purpose of this study is to construct a nomogram and online calculator to predict the development of hospital-acquired acute kidney injury (HA-AKI) in patients with acute-on-chronic liver failure (ACLF), which may contribute to the prognosis of ACLF.

Methods
574 ACLF patients were evaluated retrospectively. AKI was defined by criteria proposed by International Club of Ascites (ICA) and divided into community-acquired and hospital-acquired AKI (CA-AKI and HA-AKI). The difference between CA-AKI and HA-AKI, factors associated with development into and recovered from AKI periods. The risk factors were identified and nomograms were developed to predict the morbidity of HA-AKI in patients with ACLF.

Results
Among 574 patients, 217(37.8%) patients had AKI, CA-AKI and HA-AKI were 56 (25.8%) and 161 (74.2%) respectively. The multivariate logistic regression model (KP-AKI) for predicting the occurrence of HA-AKI were age, gastrointestinal bleeding, bacterial infections, albumin, total bilirubin, blood urea nitrogen and prothrombin time. The AUROC of the KP-AKI in internal and external validations were 0.747 and 0.759, respectively. Among 217 AKI patients, 81(37.3%), 96(44.2%) and 40(18.4%) patients were with ICA-AKI stage progression, regression and fluctuated in-situ, respectively. The 90-day mortality of patients with AKI was 55.3% higher than non-AKI patients 21.6%. The 90-day mortality of patients with progression of AKI was 88.9%, followed by patients with fluctuated in-situ 40% and regression of AKI 33.3%.

Conclusions
The nomogram constructed by KP-AKI can be conveniently and accurately in predicting the development of HA-AKI, and AKI can increase the 90-day mortality significantly in ACLF patients.
Trial registration Chinese clinical trials registry: ChiCTR1900021539.
Sleep characteristic profiles and the correlation with spectrum of metabolic syndrome among older adult: a cross-sectional study
Authors: Liu Xin , Huang Limei , Wu Qiang , Chen Yingwei , Chen Xiuqin , Chen Hao , Gao Junling , Xiao Qianyi 
Published: May 2022

Abstract
Background
Metabolic Syndrome (MetS) is a common health problem among older adults. Previous studies have revealed the relationship between sleep duration as well as global sleep status and MetS.

Objectives
This study aims to examine the association between the specific sleep characteristic and MetS as well as MetS components among community-dwelling old adults.

Methods
This cross-sectional study included 1499 community residents aged ≥ 60 years. Sleep characteristics were assessed using the Pittsburgh Sleep Quality Index (PSQI) and bed/rise time of the residents. Logistic regression analysis and multiple linear regression analysis were used to examine the associations between sleep characteristics and MetS as well as MetS components. A generalized additive model was built to assess the smooth relationship between triglyceride (TG) levels and sleep duration.

Results
Of the 1499 participants, 449 (30.0%) had MetS, and 443 (29.6%) had poor sleep quality. The rise time was found to be associated with MetS (> 6:00 vs. 5:00 ~ 6:00: adjusted OR (95%) = 1.77 (1.17–2.69), P = 0.007). For the MetS components, a U-shaped relationship was first revealed for sleep duration and TG levels (EDF = 1.85, P < 0.001). Furthermore, significant associations also included the associations of subjective sleep quality and daytime dysfunction with hypertension, the associations of sleep efficiency and rise time with hyperglycemia, the associations of rise time with TG levels, and the association of bedtime with waist circumference.

Conclusions
The different sleep characteristics were associated with different MetS components.
Monocyte count and soluble markers of monocyte activation in people living with HIV and uninfected controls
Authors: Knudsen Andreas D. , Bouazzi Randa , Afzal Shoaib , Gelpi Marco , Benfield Thomas , Høgh Julie , Thomsen Magda Teresa , Trøseid Marius , Nordestgaard Børge G. , Nielsen Susanne D. 
Published: May 2022

Abstract
Background
Monocytes play an important role in inflammation, and monocytosis and monocyte activation are features of chronic inflammation. We aimed to investigate if HIV status was associated with monocyte count and monocyte activation and to assess the relationship between monocyte count and monocyte activation markers and HIV-related factors.

Methods
Persons living with HIV (PLWH) with measured monocyte count and sCD14 and sCD163 were included from the Copenhagen Comorbidity in HIV infection (COCOMO) study and matched 1:5 on sex and age with uninfected controls. In addition, 74 uninfected individuals from COCOMO with measured sCD14 and sCD163 were included. Identical protocols and equipment were used to determine monocyte counts and monocyte activation in PLWH and uninfected controls. Linear regression adjusted for age, sex, smoking and waist-to-hip-ratio was used to analyze the association between possible risk factors and monocyte outcomes.

Results
We included 871 PLWH and 4355 uninfected controls. PLWH had − 0.021 [− 0.031 − 0.011] × 109/L) lower monocyte count than uninfected controls, and in adjusted analyses HIV status was independently associated with − 0.035 [− 0.045, − 0.025] × 109/L lower monocyte count. In contrast, PLWH had higher sCD163 and sCD14 concentrations than uninfected controls. After adjustment, HIV-status was associated with higher sCD14 and sCD163 concentrations (588 [325, 851] ng/ml, and 194 [57, 330] ng/ml, respectively).

Conclusion
PLWH had lower monocyte counts than controls, but the absolute difference was small, and any clinical impact is likely limited. In contrast, concentrations of monocyte activation markers, previously implicated as drivers of non-AIDS comorbidity, were higher in PLWH than in controls.