bluuebunny/crossref_metadata_2025_split huggingface dataset:
Decomposition of outpatient health care spending by disease - a novel approach using insurance claims data
Authors: Stucki Michael , Nemitz Janina , Trottmann Maria , Wieser Simon 
Published: November 2021

Abstract
Background
Decomposing health care spending by disease, type of care, age, and sex can lead to a better understanding of the drivers of health care spending. But the lack of diagnostic coding in outpatient care often precludes a decomposition by disease. Yet, health insurance claims data hold a variety of diagnostic clues that may be used to identify diseases.

Methods
In this study, we decompose total outpatient care spending in Switzerland by age, sex, service type, and 42 exhaustive and mutually exclusive diseases according to the Global Burden of Disease classification. Using data of a large health insurance provider, we identify diseases based on diagnostic clues. These clues include type of medication, inpatient treatment, physician specialization, and disease specific outpatient treatments and examinations. We determine disease-specific spending by direct (clues-based) and indirect (regression-based) spending assignment.

Results
Our results suggest a high precision of disease identification for many diseases. Overall, 81% of outpatient spending can be assigned to diseases, mostly based on indirect assignment using regression. Outpatient spending is highest for musculoskeletal disorders (19.2%), followed by mental and substance use disorders (12.0%), sense organ diseases (8.7%) and cardiovascular diseases (8.6%). Neoplasms account for 7.3% of outpatient spending.

Conclusions
Our study shows the potential of health insurance claims data in identifying diseases when no diagnostic coding is available. These disease-specific spending estimates may inform Swiss health policies in cost containment and priority setting.
Stabilization of UCA1 by N6-methyladenosine RNA methylation modification promotes colorectal cancer progression
Authors: He Rong-Zhang , Jiang Jing , Hu Xinglin , Lei Ming , Li Jia , Luo Weihao , Duan Lili , Hu Zheng , Mo Yin-Yuan , Luo Di-Xian , Peng Wan-Xin 
Published: November 2021

AbstractBackgroundUCA1 is frequently upregulated in a variety of cancers, including CRC, and it can play an oncogenic role by various mechanisms. However, how UCA1 is regulated in cancer is largely unknown. In this study, we aimed to determine whether RNA methylation at N6-methyladenosine (m6A) can impact UCA1 expression in colorectal cancer (CRC).MethodsqRT-PCR was performed to detect the level of UCA1 and IGF2BP2 in CRC samples. CRISPR/Cas9 was employed to knockout (KO) UCA1, METTL3 and WTAP in DLD-1 and HCT-116 cells, while rescue experiments were carried out to re-express METTL3 and WTAP in KO cells. Immunoprecipitation using m6A antibody was performed to determine the m6A modification of UCA1. In vivo pulldown assays using S1m tagging combined with site-direct mutagenesis was carried out to confirm the recognition of m6A-modified UCA1 by IGF2BP2. Cell viability was measured by MTT and colony formation assays. The expression of UCA1 and IGF2BP2 in TCGA CRC database was obtained from GEPIA (http://gepia.cancer-pku.cn).ResultsOur results revealed that IGF2BP2 serves as a reader for m6A modified UCA1 and that adenosine at 1038 of UCA1 is critical to the recognition by IGF2BP2. Importantly, we showed that m6A writers, METTL3 and WTAP positively regulate UCA1 expression. Mechanically, IGF2BP2 increases the stability of m6A-modified UCA1. Clinically, IGF2BP2 is upregulated in CRC tissues compared with normal tissues.ConclusionThese results suggest that m6A modification is an important factor contributing to upregulation of UCA1 in CRC tissues.
Risk of non-melanoma skin cancer with biological therapy in common inflammatory diseases: a systemic review and meta-analysis
Authors: Liu Ruolin , Wan Qianyi , Zhao Rui , Xiao Haitao , Cen Ying , Xu Xuewen 
Published: November 2021

Abstract
Background
Most previous studies compared the risk for non-melanoma skin cancer (NMSC) in biologic-treated common inflammatory diseases with the general population. Whether the increased NMSC risk is caused by the disease itself, the biologics, or both remains unknown.

Methods
We systematically searched PubMed, Embase, Medline, Web of Science, and Cochrane Library from inception to May 2021. Studies were included if they assessed the risk of NMSC for rheumatoid arthritis (RA), inflammatory bowel disease (IBD), or psoriasis patients treated with biologics compared with patients not receiving biologics. Pooled relative risks (RRs) and 95% confidence intervals (CIs) were calculated using the fixed- or random-effects model.

Results
The current meta-analysis included 12 studies. Compared with patients with the inflammatory disease without biologics, patients receiving biological therapy were associated with an increased risk for NMSC (RR 1.25, 95% CI 1.14 to 1.37), especially in patients with RA (RR 1.24, 95% CI 1.13 to 1.36) and psoriasis (RR 1.28, 95% CI 1.07 to 1.52), but not in patients with IBD (RR 1.49, 95% CI 0.46 to 4.91). The risks for squamous cell skin cancer and basal cell skin cancer were both increased for patients receiving biologics. However, the risk of NMSC did not increase in patients treated with biologics less than 2 years.

Conclusions
Current evidence suggests that increased risk of NMSC was identified in RA and psoriasis treated with biologics compared with patients not receiving biologics, but not in patients with IBD. The inner cause for the increased risk of NMSC in IBD patients should be further discussed.
Distinct associations of NEDD4L expression with genetic abnormalities and prognosis in acute myeloid leukemia
Authors: Chu Ming-qiang , Zhang Liu-chao , Yuan Qian , Zhang Ting-juan , Zhou Jing-dong 
Published: November 2021

AbstractBackgroundThere is mounting evidence that demonstrated the association of aberrantNEDD4Lexpression with diverse human cancers. However, the expression pattern and clinical implication ofNEDD4Lin acute myeloid leukemia (AML) remains poorly defined.MethodsWe systemically determinedNEDD4Lexpression with its clinical significance in AML by both public data and our research cohort. Moreover, biological functions ofNEDD4Lin leukemogenesis were further tested by in vitro experiments.ResultsBy the public data, we identified that lowNEDD4Lexpression was correlated with AML among diverse human cancers. Expression ofNEDD4Lwas remarkably decreased in AML compared with controls, and was confirmed by our research cohort. Clinically, low expression ofNEDD4Lwas correlated with greatly lower age, higher white blood cells, and higher bone marrow/peripheral blood blasts. Moreover,NEDD4Lunderexpression was positively correlated with normal karyotype,FLT3andNPM1mutations, but negatively associated with complex karyotype andTP53mutations. Importantly, the association betweenNEDD4Lexpression and survival was also discovered in cytogenetically normal AML patients. Finally, a number of 1024 RNAs and 91 microRNAs were identified to be linked toNEDD4Lexpression in AML. Among the negatively correlated microRNAs,miR-10awas also discovered as a microRNA that may directly targetNEDD4L. Further functional studies revealed thatNEDD4Lexhibited anti-proliferative and pro-apoptotic effects in leukemic cell line K562.ConclusionsOur findings indicated thatNEDD4Lunderexpression, as a frequent event in AML, was associated with genetic abnormalities and prognosis in AML. Moreover,NEDD4Lexpression may be involved in leukemogenesis with potential therapeutic target value.
Hydroxypropylmethylcellulose as a film and hydrogel carrier for ACP nanoprecursors to deliver biomimetic mineralization
Authors: Wang Zhe , Zhou Zihuai , Fan Jiayan , Zhang Leiqing , Zhang Zhixin , Wu Zhifang , Shi Ying , Zheng Haiyan , Zhang Zhengyi , Tang Ruikang , Fu Baiping 
Published: November 2021

AbstractDemineralization of hard tooth tissues leads to dental caries, which cause health problems and economic burdens throughout the world. A biomimetic mineralization strategy is expected to reverse early dental caries. Commercially available anti-carious mineralizing products lead to inconclusive clinical results because they cannot continuously replenish the required calcium and phosphate resources. Herein, we prepared a mineralizing film consisting of hydroxypropylmethylcellulose (HPMC) and polyaspartic acid-stabilized amorphous calcium phosphate (PAsp-ACP) nanoparticles. HPMC which contains multiple hydroxyl groups is a film-forming material that can be desiccated to form a dry film. In a moist environment, this film gradually changes into a gel. HPMC was used as the carrier of PAsp-ACP nanoparticles to deliver biomimetic mineralization. Our results indicated that the hydroxyl and methoxyl groups of HPMC could assist the stability of PAsp-ACP nanoparticles and maintain their biomimetic mineralization activity. The results further demonstrated that the bioinspired mineralizing film induced the early mineralization of demineralized dentin after 24 h with increasing mineralization of the whole demineralized dentin (3–4 µm) after 72–96 h. Furthermore, these results were achieved without any cytotoxicity or mucosa irritation. Therefore, this mineralizing film shows promise for use in preventive dentistry due to its efficient mineralization capability.
Graphical Abstract
A systems approach to the exploration of research activity and relationships within a local authority
Authors: Fynn Judith F. , Jones John , Jones Andy 
Published: November 2021

AbstractBackgroundOrganizations with responsibilities for public health are increasingly required to use evidence-based practice to inform programme delivery, requiring research to generate relevant evidence, and dissemination and use of evidence to inform decisions and practices. Understanding how relationships between organizational structures, systems and processes influence evidence-based practices is critical to improving practice at both an institutional and system level, yet how these relationships should best operate is not well understood. Understanding how to better support research within local authorities, the elected administrative bodies responsible for services including public health at a regional level in the United Kingdom, is a priority for the National Institute for Health Research (NIHR) Public Health Research. This study is based on Norfolk County Council, a local authority in the east of England. We aimed to apply a systems perspective to develop a better understanding of the structures, systems and processes that support a local authority in becoming research-active, identifying gaps in understanding and recommendations for action to address them.MethodsTaking a participatory action research approach, we applied qualitative methods to explore research activity and relationships in Norfolk County Council. We surveyed employees and used network analysis to map individuals, departments and external partners involved in research activities and the connections between them. We then applied participatory approaches to conduct a series of focus groups and semi-structured interviews to explore stakeholders’ experiences and perceptions of being involved in research at, or with, the authority, and their ideas for recommendations for future actions.ResultsA range of research activity is undertaken at the local authority, with an emphasis on applied work to improve service delivery. We identified several examples of effective practice and models of research collaboration in some departments. Challenges such as limitations in resources, capacity and knowledge exchange were evident, yet there was a readiness amongst key stakeholders to develop and implement actions that may better support the authority in becoming more research-active.ConclusionIn large complex organizations, a key challenge is how to share learning across teams and implement good practice at an organizational and system level. Our findings highlight the potential for developing improved collaborative partnership models and systems to support sustainable processes and practices for research and knowledge exchange at an institutional and interorganizational level. The insights gained and shared will support other local authorities and similar large, multilevel organizations with responsibilities for evidence-based public health to explore their own setting and implement change where needed, and provide stimulus for further research into system-level change.
Ibrutinib protects T cells in patients with CLL from proliferation-induced senescence
Authors: Davis Joanne E. , Sharpe Chia , Mason Kylie , Tam Constantine S. , Koldej Rachel M. , Ritchie David S. 
Published: November 2021

AbstractBackgroundThe development of Bruton’s tyrosine kinase inhibitors (BTKi) for the treatment of chronic lymphocytic leukaemia (CLL) has provided a highly effective and relatively non-toxic alternative to conventional chemotherapy. Some studies have shown that BTKi can also lead to improvements in T cell immunity in patients despite in vitro analyses suggesting an immunosuppressive effect of BTKi on T cell function.MethodsIn this study, we examined both the in vitro effect and long-term in vivo effect of two clinically available BTKi, ibrutinib and zanubrutinib. Additional in vitro assessments were undertaken for a third BTKi, acalabrutinib. Immune subset phenotyping, cytokine secretion, T cell degranulation and proliferation assays were performed on peripheral blood mononuclear cells isolated from untreated CLL patients, and CLL patients on long-term (> 12 months) BTKi treatment.ResultsSimilar to prior studies we observed that long-term BTKi treatment normalises lymphocyte subset frequency and reduces PD-1 expression on T cells. We also observed that T cells from patients taken prior to BTKi therapy showed an abnormal hyper-proliferation pattern typical of senescent T cells, which was normalised by long-term BTKi treatment. Furthermore, BTKi therapy resulted in reduced expression of the T cell exhaustion markers PD-1, TIM3 and LAG3 in late generations of T cells undergoing proliferation.ConclusionsCollectively, these findings indicate that there are critical differences between the in vitro effects of BTKi on T cell function and the effects derived from long-term BTKi exposure in vivo. Overall long-term exposure to BTKi, and particularly ibrutinib, resulted in improved T cell fitness in part due to suppressing the abnormal hyper-proliferation of CLL T cells and the associated development of T cell senescence.
Six splice site variations, three of them novel, in the ABO gene occurring in nine individuals with ABO subtypes
Authors: Hong Xiaozhen , Ying Yanling , Zhang Jingjing , Chen Shu , Xu Xianguo , He Ji , Zhu Faming 
Published: November 2021

AbstractBackgroundNucleotide mutations in theABOgene may reduce the activity of glycosyltransferase, resulting in lower levels of A or B antigen expression in red blood cells. Six known splice sites have been identified according to the database of red cell immunogenetics and the blood group terminology of the International Society of Blood Transfusion. Here, we describe six distinct splice site variants in individuals with ABO subtypes.MethodsThe ABO phenotype was examined using a conventional serological method. A polymerase chain reaction sequence-based typing method was used to examine the whole coding sequence of theABOgene. TheABOgene haplotypes were studied using allele-specific primer amplification or cloning technology. In silico analytic tools were used to assess the functional effect of splice site variations.ResultsSix distinct variants in theABOgene splice sites were identified in nine individuals with ABO subtypes, including c.28 + 1_2delGT, c.28 + 5G > A, c.28 + 5G > C, c.155 + 5G > A, c.204-1G > A and c.374 + 5G > A. c.28 + 1_2delGT was detected in an Awindividual, while c.28 + 5G > A, c.28 + 5G > C, and c.204-1G > A were detected in Belindividuals. c.155 + 5G > A was detected in one B3and two AB3individuals, whereas c.374 + 5G > A was identified in two Aelindividuals. Three novel splice site variants (c.28 + 1_2delGT, c.28 + 5G > A and c.28 + 5G > C) in theABOgene were discovered, all of which resulted in low antigen expression. In silico analysis revealed that all variants had the potential to alter splice transcripts.ConclusionsThree novel splice site variations in theABOgene were identified in Chinese individuals, resulting in decreased A or B antigen expression and the formation of ABO subtypes.
Computer-assisted cannulated screw internal fixation versus conventional cannulated screw internal fixation for femoral neck fractures: a systematic review and meta-analysis
Authors: Cheng Qing-hao , Li Peng-biao , Lu Ting-ting , Guo Shi-fang , Di Wen-fei , Yang Ke-hu , Qian Yao-wen 
Published: November 2021

AbstractObjectiveTo compare the effects between computer-assisted and traditional cannulated screw internal fixation on treating femoral neck fracture.MethodsThe search was conducted in Embase, Pubmed, Web of Science, Cochrane Library, China National Knowledge Infrastructure (CNKI) and Wanfang Database from the beginning to August 2020. RevMan5.4 software, which was provided by the International Cochrane Group, was used for the meta-analysis comparing the differences in operation time, intraoperative bleeding volume, fluoroscopy frequency, fracture healing time, total drilling times, Harris score, fracture healing rate, and femoral head necrosis rate between computer-assisted and traditional methods groups.ResultsA total of 1028 patients were included in 16 studies. Primary outcome indicators: Compared with the traditional method group, the computer-assisted group had less operative time (2RCTs,P < 0.00001; 8 non-RCTs,P = 0.009; Overall,P < 0.00001), intraoperative bleeding (1 RCTs,P < 0.00001; 9non-RCTs,P < 0.00001; Overall,P < 0.00001), femoral head necrosis rate (1 RCT,P = 0.11;7 non-RCTs,P = 0.09; Overall,P = 0.02) and higher Harris scores (1 RCT,P < 0.0001; 9 non-RCTs,P = 0.0002; Overall,P < 0.0001), and there were no significant differences in fracture healing rate between the two groups (5 non-RCTs,P = 0.17). Secondary outcomes indicators: The computer-assisted group had a lower frequency of intraoperative fluoroscopy and total number of drills compared with the traditional method group, while there was no significant difference in fracture healing time.ConclusionCompared with the traditional hollow screw internal fixation on the treatment of femoral neck fracture, computer-assisted percutaneous cannulated screw fixation can shorten the operation time and improve the operation efficiency and reduce the X-ray injury of medical staff and help patients obtain a better prognosis. Therefore, computer-assisted percutaneous cannulated screw fixation is a better choice for the treatment of femoral neck fracture.Study registrationPROSPERO registration number CRD42020214493.
A network pharmacology approach to reveal the pharmacological targets and biological mechanism of compound kushen injection for treating pancreatic cancer based on WGCNA and in vitro experiment validation
Authors: Wu Chao , Huang Zhi-Hong , Meng Zi-Qi , Fan Xiao-Tian , Lu Shan , Tan Ying-Ying , You Lei-Ming , Huang Jia-Qi , Stalin Antony , Ye Pei-Zhi , Wu Zhi-Shan , Zhang Jing-Yuan , Liu Xin-Kui , Zhou Wei , Zhang Xiao-Meng , Wu Jia-Rui 
Published: November 2021

AbstractBackgroundCompound kushen injection (CKI), a Chinese patent drug, is widely used in the treatment of various cancers, especially neoplasms of the digestive system. However, the underlying mechanism of CKI in pancreatic cancer (PC) treatment has not been totally elucidated.MethodsHere, to overcome the limitation of conventional network pharmacology methods with a weak combination with clinical information, this study proposes a network pharmacology approach of integrated bioinformatics that applies a weighted gene co-expression network analysis (WGCNA) to conventional network pharmacology, and then integrates molecular docking technology and biological experiments to verify the results of this network pharmacology analysis.ResultsThe WGCNA analysis revealed 2 gene modules closely associated with classification, staging and survival status of PC. Further CytoHubba analysis revealed 10 hub genes (NCAPG, BUB1, CDK1, TPX2, DLGAP5, INAVA, MST1R, TMPRSS4, TMEM92andSFN) associated with the development of PC, and survival analysis found 5 genes (TSPOAP1, ADGRG6, GPR87, FAM111BandMMP28) associated with the prognosis and survival of PC. By integrating these results into the conventional network pharmacology study of CKI treating PC, we found that the mechanism of CKI for PC treatment was related to cell cycle, JAK-STAT, ErbB, PI3K-Akt and mTOR signalling pathways. Finally, we found thatCDK1,JAK1,EGFR,MAPK1andMAPK3served as core genes regulated by CKI in PC treatment, and were further verified by molecular docking, cell proliferation assay, RT-qPCR and western blot analysis.ConclusionsOverall, this study suggests that the optimized network pharmacology approach is suitable to explore the molecular mechanism of CKI in the treatment of PC, which provides a reference for further investigating biomarkers for diagnosis and prognosis of PC and even the clinical rational application of CKI.