bluuebunny/crossref_metadata_2025_split huggingface dataset:
Performance evaluation of case definitions of type 1 diabetes for health insurance claims data in Japan
Authors: Okui Tasuku , Nojiri Chinatsu , Kimura Shinichiro , Abe Kentaro , Maeno Sayaka , Minami Masae , Maeda Yasutaka , Tajima Naoko , Kawamura Tomoyuki , Nakashima Naoki 
Published: February 2021

Abstract
Background
No case definition of Type 1 diabetes (T1D) for the claims data has been proposed in Japan yet. This study aimed to evaluate the performance of candidate case definitions for T1D using Electronic health care records (EHR) and claims data in a University Hospital in Japan.

Methods
The EHR and claims data for all the visiting patients in a University Hospital were used. As the candidate case definitions for claims data, we constructed 11 definitions by combinations of International Statistical Classification of Diseases and Related Health Problems, Tenth Revision. (ICD 10) code of T1D, the claims code of insulin needles for T1D patients, basal insulin, and syringe pump for continuous subcutaneous insulin infusion (CSII). We constructed a predictive model for T1D patients using disease names, medical practices, and medications as explanatory variables. The predictive model was applied to patients of test group (validation data), and performances of candidate case definitions were evaluated.

Results
As a result of performance evaluation, the sensitivity of the confirmed disease name of T1D was 32.9 (95% CI: 28.4, 37.2), and positive predictive value (PPV) was 33.3 (95% CI: 38.0, 38.4). By using the case definition of both the confirmed diagnosis of T1D and either of the claims code of the two insulin treatment methods (i.e., syringe pump for CSII and insulin needles), PPV improved to 90.2 (95% CI: 85.2, 94.4).

Conclusions
We have established a case definition with high PPV, and the case definition can be used for precisely detecting T1D patients from claims data in Japan.
The CRK2-CYC13 complex functions as an S-phase cyclin-dependent kinase to promote DNA replication in Trypanosoma brucei
Authors: Lee Kyu Joon , Li Ziyin 
Published: February 2021

AbstractBackgroundFaithful DNA replication is essential to maintain genomic stability in all living organisms, and the regulatory pathway for DNA replication initiation is conserved from yeast to humans. The evolutionarily ancient human parasiteTrypanosoma brucei, however, lacks many of the conserved DNA replication factors and may employ unusual mechanisms for DNA replication. Neither the S-phase cyclin-dependent kinase (CDK) nor the regulatory pathway governing DNA replication has been previously identified inT. brucei.ResultsHere we report that CRK2 (Cdc2-related kinase 2) complexes with CYC13 (Cyclin13) and functions as an S-phase CDK to promote DNA replication inT. brucei. We further show that CRK2 phosphorylates Mcm3, a subunit of the Mcm2–7 sub-complex of the Cdc45-Mcm2–7-GINS complex, and demonstrate that Mcm3 phosphorylation by CRK2 facilitates interaction with Sld5, a subunit of the GINS sub-complex of the Cdc45-Mcm2–7-GINS complex.ConclusionsThese results identify the CRK2-CYC13 complex as an S-phase regulator inT. bruceiand reveal its role in regulating DNA replication through promoting the assembly of the Cdc45-Mcm2–7-GINS complex.
Cardiovascular surrogate markers and cardiometabolic therapeutics: a viewpoint learned from clinical trials on dipeptidyl peptidase-4 inhibitors
Authors: Tanaka Atsushi , Node Koichi 
Published: February 2021

AbstractClinical trials are often performed to investigate the effects of various types of cardiometabolic therapies on cardiovascular surrogate markers, including vascular function and biomarkers. This study platform has the potential to provide information on the suspected actions of drugs and mechanistic insights into their prognostic impact. However, despite using the same class of drugs and similar study designs we are often faced with inconsistent and even conflicting results, possibly leading to some confusion in the clinical setting. When interpreting these results, it is important to investigate what caused the differences and carefully assess the information, taking into account the research situation and the patient population investigated. Using this approach, assessment of the impact on cardiovascular surrogate markers observed in clinical studies from multiple perspectives should help to better understand the potential cardiovascular effects. In this commentary we discuss how we should interpret the effects of cardiometabolic therapeutics on vascular surrogate markers, based on viewpoints learned from the results of clinical trials on dipeptidyl peptidase-4 inhibitors. This learning strategy could also be helpful for appropriate selection of drugs for evidence-based, patient-centric, tailored medication.
SGLT-2 inhibitors and atrial fibrillation in the Food and Drug Administration adverse event reporting system
Authors: Bonora Benedetta Maria , Raschi Emanuel , Avogaro Angelo , Fadini Gian Paolo 
Published: February 2021

Abstract
Background
Sodium glucose cotransporter-2 inhibitors (SGLT2i) reduce the risk of heart failure and new data show they can prevent atrial fibrillation (AF). We examined the association between SGLT2i and AF in the Food and Drug Administration adverse event reporting system (FAERS).

Methods
We mined the FAERS from 2014q1 to 2019q4 to compare AF reporting for SGLT-2 i versus reports for other glucose lowering medications (ATC10 class). Several exclusions were sequentially applied for: concomitant medications; diabetes, cardiovascular or renal disease indication; reports for competing adverse events (genitourinary tract infections, ketoacidosis, Fournier’s gangrene, amputation). We provide descriptive statistics and calculated proportional reporting ratios (PRR).

Results
There were 62,098 adverse event reports for SGLT2i and 642,031 reports for other ATC10 drugs. The reporting of AF was significantly lower with SGLT2i than with other ATC10 drugs (4.8 versus 8.7/1000; p < 0.001) with a PRR of 0.55 (0.49–0.62). Results did not change substantially after excluding reports listing insulin (PRR 0.49) or anti-arrhythmics (PRR 0.59) as suspect or concomitant drugs, excluding reports with indications for cardiovascular disease (PRR 0.49) or renal disease (PRR 0.55), and those filed for competing adverse events (PRR 0.63). Results were always statistically significant whether the diabetes indication was specified. Negative and positive controls confirmed internal validity of the database.

Conclusions
In a large pharmacovigilance database, AF was robustly and consistently reported more frequently for diabetes medications other than SGLT2i. This finding complements available evidence from trials supporting a protective role of SGLT2i against the occurrence of AF.
Exposure to traffic-related air pollution and changes in exhaled nitric oxide and DNA methylation in arginase and nitric oxide synthase in children with asthma
Authors: Ji N. , Fang M. , Baptista A. , Cepeda C. , Greenberg M. , Mincey I. Colon , Ohman-Strickland P. , Haynes F. , Fiedler N. , Kipen H. M. , Laumbach R. J. 
Published: February 2021

Abstract
Background
Traffic-related air pollution (TRAP) has been associated with increased risk of airway inflammation in children with asthma. While epigenetic changes could potentially modulate TRAP-induced inflammatory responses, few studies have assessed the temporal pattern of exposure to TRAP, epigenetic changes and inflammation in children with asthma. Our goal was to test the time-lag patterns of personal exposure to TRAP, airway inflammation (measured as fractional exhaled nitric oxide, FeNO), and DNA methylation in the promoter regions of genes involved in nitric oxide synthesis among children with asthma.

Methods
We measured personal exposure to black carbon (BC) and FeNO for up to 30 days in a panel of children with asthma. We collected 90 buccal cell samples for DNA methylation analysis from 18 children (5 per child). Methylation in promoter regions of nitric oxide synthase (NOS1, NOS2A, NOS3) and arginase (ARG1, ARG2) was assessed by bisulfite pyrosequencing. Linear-mixed effect models were used to test the associations of BC at different lag periods, percent DNA methylation at each site and FeNO level.

Results
Exposure to BC was positively associated with FeNO, and negatively associated with DNA methylation in NOS3. We found strongest association between FeNO and BC at lag 0–6 h while strongest associations between methylation at positions 1 and 2 in NOS3 and BC were at lag 13–24 h and lag 0–24 h, respectively. The strengths of associations were attenuated at longer lag periods. No significant associations between exposure to TRAP and methylation levels in other NOS and ARG isoforms were observed.

Conclusions
Exposure to TRAP was associated with higher levels of FeNO and lower levels of DNA methylation in the promoter regions of the NOS3 gene, indicating that DNA methylation of the NOS3 gene could be an important epigenetic mechanism in physiological responses to TRAP in children with asthma.
The association of parameters of body composition and laboratory markers with the severity of hypertriglyceridemia-induced pancreatitis
Authors: Chen Lifang , Huang Yingbao , Yu Huajun , Pan Kehua , Zhang Zhao , Man Yi , Hu Dingyuan 
Published: February 2021

AbstractBackgroundHypertriglyceridemia has arisen as the third leading cause of acute pancreatitis. This study aimed at exploring the association between the severity of hypertriglyceridemia-induced pancreatitis (HTGP) and computed tomography (CT)-based body composition parameters and laboratory markers.MethodsLaboratory and clinical parameters were collected from 242 patients with HTGP between 2017 and 2020. Severity of HTGP was evaluated by original or modified CT severity index. Body composition parameters such as area and radiodensity of muscle, subcutaneous adipose tissue and visceral adipose tissue were calculated by CT at the level of third lumbar vertebra. Parameters were compared between mild and moderately severe to severe HTGP. Uni-variate and multi-variate Logistic regression analyses were employed to assess the risk factors of the severity of HTGP.ResultsSeventy patients (28.9%) presented with mild HTGP. Body mass index, waist circumference and all CT-based body composition parameters differed between male and female patients. None was associated with the severity of HTGP, neither in males nor in females. Receiver operating characteristic curves showed that areas under the curves of apolipoprotein A-I and albumin to predict the severity of HTGP were 0.786 and 0.759, respectively (allP < 0.001). Uni-variate and further multi-variate Logistic regression analysis confirmed that low serum albumin (< 35 g/L,P = 0.004, OR = 3.362, 95%CI = 1.492–8.823) and apolipoprotein A-I (< 1.1 g/L,P < 0.001, OR = 5.126, 95%CI = 2.348–11.195), as well as high C-reactive protein (> 90 mg/L,P = 0.005, OR = 3.061, 95%CI = 1.407–6.659) and lipase (P = 0.033, OR = 2.283, 95%CI = 1.070–4.873) were risk factors of moderately severe to severe HTGP. Levels of albumin, apolipoprotein A-I, C-reactive protein and lipase were also associated with the length of hospital stay (allP < 0.05). Besides, low serum albumin, low-density lipoprotein cholesterol and high radiodensity of subcutaneous adipose tissue were significant risk factors of pancreatic necrosis in patients with HTGP (allP < 0.05).ConclusionsLow serum albumin and apolipoprotein A-I, and high C-reactive protein and lipase upon admission were associated with a more severe type of HTGP and longer hospital stay for these patients. Albumin and apolipoprotein A-I may serve as novel biomarkers for the severity of HTGP. However, none of the body composition parameters was associated with the severity of HTGP.
The impact of thrombocytopenia on prognosis of HBV-related small hepatocellular carcinoma: a propensity score matching analysis
Authors: Peng Wei , Li Chuan , Zhang Xiaoyun , Wen Tianfu , Chen Zheyu 
Published: February 2021

AbstractBackgroundThrombocytopenia was reported both detrimental and advantageous to hepatocellular carcinoma (HCC). However, there is little evidence showing clearly the clinical value of preoperative thrombocytopenia on the surgical outcome of patients with small HCC. This retrospective study aimed at elucidating the correlation between preoperative thrombocytopenia and surgical outcome of small HCC patients within Milan criteria treated with liver resection.MethodsData of hepatitis B virus (HBV)-related small HCC patients were retrospectively analyzed, and we performed the propensity score matching (PSM) analysis to overcome the imbalance of clinicopathological features. Patients enrolled were subsequently categorized into two groups according to preoperative platelet counts: thrombocytopenia group and non-thrombocytopenia group. Survival outcomes of the patients in both groups were described with the Kaplan-Meier method, and the difference was compared with a log-rank test. Cox regression analysis was applied to identify the risk factors of surgical outcome.ResultsAfter PSM, the estimated 1-, 3-, and 5-year overall survival (OS) rates for small HCC patients in the thrombocytopenia group were 94.5%, 77.0%, and 57.6%, and 95.0%, 79.6%, and 68.0%, respectively, for small HCC patients in the non-thrombocytopenia group (P= 0.042). And the 1-, 3-, and 5-year estimated recurrence-free survival (RFS) rates for small HCC patients in the thrombocytopenia group were 70.4%, 51.0%, and 42.1%, and 83.8%, 63.7%, and 46.7%, respectively, for small HCC patients in the non-thrombocytopenia group (P= 0.035). Multivariate analysis indicated preoperative thrombocytopenia was a significant prognosticator of poor RFS (hazard ratio (HR) = 1.388, 95% confidence interval (CI) 1.028~1.874,P= 0.033).ConclusionPreoperative thrombocytopenia had an undesirable impact on the recurrence of small HCC patients treated with liver resection.
Icariside I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity
Authors: Gao Yuan , Xu Guang , Ma Li , Shi Wei , Wang Zhilei , Zhan Xiaoyan , Qin Nan , He Tingting , Guo Yuming , Niu Ming , Wang Jiabo , Bai Zhaofang , Xiao Xiaohe 
Published: February 2021

Abstract
Background
Epimedii Folium (EF) is commonly used for treating bone fractures and joint diseases, but the potential hepatotoxicity of EF limits its clinical application. Our previous study confirms that EF could lead to idiosyncratic drug-induced liver injury (IDILI) and hepatocyte apoptosis, but the mechanism remains unknown. Studies have shown that NLRP3 inflammasome plays an important role in the development of various inflammatory diseases such as IDILI. Specific stimulus-induced NLRP3 inflammasome activation may has been a key strategy for lead to liver injury. Therefore, main compounds derived from EF were chosen to test whether the ingredients in EF could activate the NLRP3 inflammasome and to induce IDILI.

Methods
Bone-marrow-derived macrophages (BMDMs) were treated with Icariside I, and then stimulated with inflammasome stimuli and assayed for the production of caspase-1 and interleukin 1β (IL-1β) and the release of lactate dehydrogenase (LDH). Determination of intracellular potassium, ASC oligomerization as well as reactive oxygen species (ROS) production were used to evaluate the stimulative mechanism of Icariside I on inflammasome activation. Mouse models of NLRP3 diseases were used to test whether Icariside I has hepatocyte apoptosis effects and promoted NLRP3 inflammasome activation in vivo.

Results
Icariside I specifically enhances NLRP3 inflammasome activation triggered by ATP or nigericin but not SiO2, poly(I:C) or cytosolic LPS. Additionally, Icariside I does not alter the activation of NLRC4 and AIM2 inflammasomes. Mechanically, Icariside I alone does not induce mitochondrial reactive oxygen species (mtROS), which is one of the critical upstream events of NLRP3 inflammasome activation; however, Icariside I increases mtROS production induced by ATP or nigericin but not SiO2. Importantly, Icariside I leads to liver injury and NLRP3 inflammasome activation in an LPS-mediated susceptibility mouse model of IDILI, but the effect of Icariside I is absent in the LPS-mediated mouse model pretreated with MCC950, which is used to mimic knockdown of NLRP3 inflammasome activation.

Conclusions
Our study reveals that Icariside I specifically facilitates ATP or nigericin-induced NLRP3 inflammasome activation and causes idiosyncratic hepatotoxicity. The findings suggest that Icariside I or EF should be avoided in patients with diseases related to ATP or nigericin-induced NLRP3 inflammasome activation, which may be risk factors for IDILI.
PSF functions as a repressor of hypoxia-induced angiogenesis by promoting mitochondrial function
Authors: Dong Lijie , Li Wenbo , Lin Tingting , Liu Boshi , Hong Yaru , Zhang Xiaomin , Li Xiaorong 
Published: February 2021

Abstract
Background
Abnormal neovascularization is the most common cause of blindness, and hypoxia alters tissue metabolism, function, and morphology. HIF-1α, the transcriptional activator of VEGF, has intricate mechanisms of nuclear translocation and activation, but its signal termination mechanisms remain unclear.

Methods
We investigated the role of polypyrimidine tract-binding protein-associated splicing factor (PSF) in cellular energy production, migration, and proliferation by targeting HIF-1α in vivo and in vitro PSF plasmids were transfected with liposome 2000 transfection reagent. Young C57/BL6J mice were kept in a hyperoxia environment, followed by indoor air, resulting in oxygen-induced retinopathy. Oxygen-induced retinopathy (OIR) animals were randomly divided into three groups: OIR group, OIR + vector group (OIR cubs treated with rAAV vector) and OIR + PSF group (OIR cubs treated with rAAV-PSF). Age-matched C57/BL6J mice were used as controls and exposed to constant normoxic conditions. The animals were executed and their pupils were subjected to subsequent experiments. The metabolic spectrum was analyzed by Seahorse XFe96 flux analyzer, and OCR and extracellular acidification rate were quantified at the same time.

Results
PSF ameliorated retinal neovascularization and corrected abnormal VEGF expression in mice with oxygen-induced retinopathy and reduced intra-retinal neovascularization in Vldlr − / − mice. PSF reprogrammed mitochondrial bioenergetics and inhibited the transition of endothelial cells after hypoxia, suggesting its involvement in pathological angiogenesis.Ectopic PSF expression inhibited hypoxia-induced HIF-1α activation in the nucleus by recruiting Hakai to the PSF/HIF-1α complex, causing HIF-1α inhibition. PSF knockdown increased hypoxia-stimulated HIF-1α reactions. These hypoxia-dependent processes may play a vital role in cell metabolism, migration, and proliferation. Thus, PSF is a potential treatment target in neovascularization-associated ophthalmopathy.

Conclusion
This is the first study showing that PSF inhibits HIF-1α via recruitment of Hakai, modulates mitochondrial oxidation and glycolysis, and downregulates VEGF expression under hypoxia. We propose a new HIF-1 α/Hakai regulatory mechanism that may play a vital role in the pathogenesis of neovascularization in ophthalmopathy.

PSF-Hakai–HIF-1α signaling pathway under hypoxia condition. Schematic diagram showing that the PSF-Hakai–HIF-1α signaling pathway. Under hypoxia condition, PSF-Hakai complex regulate HIF-1α signaling, thus inhibiting downstream target gene VEGF, cell metabolism and angiogenesis eventually.
Rosuvastatin exerts anti-atherosclerotic effects by improving macrophage-related foam cell formation and polarization conversion via mediating autophagic activities
Authors: Zhang Xinxin , Qin Yating , Wan Xiaoning , Liu Hao , Lv Chao , Ruan Weibin , He Lin , Lu Li , Guo Xiaomei 
Published: February 2021

Abstract
Background
Atherosclerosis is a chronic vascular disease posing a great threat to public health. We investigated whether rosuvastatin (RVS) enhanced autophagic activities to inhibit lipid accumulation and polarization conversion of macrophages and then attenuate atherosclerotic lesions.

Methods
All male Apolipoprotein E-deficient (ApoE−/−) mice were fed high-fat diet supplemented with RVS (10 mg/kg/day) or the same volume of normal saline gavage for 20 weeks. The burden of plaques in mice were determined by histopathological staining. Biochemical kits were used to examine the levels of lipid profiles and inflammatory cytokines. The potential mechanisms by which RVS mediated atherosclerosis were explored by western blot, real-time PCR assay, and immunofluorescence staining in mice and RAW264.7 macrophages.

Results
Our data showed that RVS treatment reduced plaque areas in the aorta inner surface and the aortic sinus of ApoE−/− mice with high-fat diet. RVS markedly improved lipid profiles and reduced contents of inflammatory cytokines in the circulation. Then, results of Western blot showed that RVS increased the ratio LC3II/I and level of Beclin 1 and decreased the expression of p62 in aortic tissues, which might be attributed to suppression of PI3K/Akt/mTOR pathway, hinting that autophagy cascades were activated by RVS. Moreover, RVS raised the contents of ABCA1, ABCG1, Arg-1, CD206 and reduced iNOS expression of arterial wall, indicating that RVS promoted cholesterol efflux and M2 macrophage polarization. Similarly, we observed that RVS decreased lipids contents and inflammatory factors expressions in RAW264.7 cells stimulated by ox-LDL, accompanied by levels elevation of ABCA1, ABCG1, Arg-1, CD206 and content reduction of iNOS. These anti-atherosclerotic effects of RVS were abolished by 3-methyladenine intervention. Moreover, RVS could reverse the impaired autophagy flux in macrophages insulted by chloroquine. We further found that PI3K inhibitor LY294002 enhanced and agonist 740 Y-P weakened the autophagy-promoting roles of RVS, respectively.

Conclusions
Our study indicated that RVS exhibits atheroprotective effects involving regulation lipid accumulation and polarization conversion by improving autophagy initiation and development via suppressing PI3K/Akt/mTOR axis and enhancing autophagic flux in macrophages.
Macrophage activation syndrome in a newborn: report of a case associated with neonatal lupus erythematosus and a summary of the literature
Authors: Heijstek Veerle , Habib Meelad , van der Palen Roel , van Doorn Remco , Muller Petra Hissink 
Published: February 2021

Abstract
Background
Macrophage activation syndrome (MAS) is a life-threatening hyperinflammatory syndrome and is caused by a severely dysregulated immune response. It has rarely been associated with neonatal lupus.

Case presentation
We present a female neonate with MAS born to a mother who had cutaneous lupus erythematosus with circulating anti-nuclear antibodies (ANA), anti-SSA, anti-SSB and anti-extractable nuclear antigen (anti-ENA) antibodies.
Because of neonatal lupus (NLE) with a total atrioventricular block, epicardial pacemaker implantation was required on the sixth day of life. Following surgery she developed non-remitting fever and disseminated erythematous skin lesions. A diagnosis of MAS was made based on these symptoms, with hyperferritinemia, elevated transaminases, hypertriglyceridemia, and a skin biopsy that showed hemophagocytosis. Our patient was treated with steroids for 3 months with good effect. No relapse has occurred.

Conclusions
MAS is a rare complication of neonatal lupus that may be difficult to diagnose, but needs to be treated promptly. In this article, pathogenesis and overlap of MAS and hemophagocytic lymphohistiocytosis (HLH) has been described.
Diagnosis of MAS can be difficult. Different diagnostic criteria are used in both diagnosing MAS and HLH. Validated criteria for diagnosis of MAS in other disease than systemic onset JIA have not been validated yet. In NLE, diagnosing MAS is even more difficult, since skin lesions are already common in NLE. We show the potential additional value of skin biopsy in diagnosing MAS.