A machine learning model for identifying systemic lupus erythematosus through laboratory information system and electronic medical record.

OBJECTIVES: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease. Its diagnosis poses significant challenges especially at early stages and in atypical cases. The aim of this study was to develop a machine learning model based on common laboratory tests that can aid SLE diagnosis. METHODS: A standard protocol was developed to collect data of SLE and control immune diseases. A 10-fold cross-validation was performed in the modeling dataset (n=862), and an external dataset (n=198) was used for model validation. Machine learning algorithms were applied to construct a diagnostic model. Performance was evaluated based on area under the curve (AUC) values, F1-score, negative predictive value, positive predictive value, accuracy, sensitivity, and specificity. RESULTS: The optimal model was based on a random forest algorithm with 10 clinical features. Thrombin time, prothrombin activity, and uric acid contributed most to the diagnostic model. The SLE diagnostic model showed sufficient predictive accuracy, with AUC values of 0.8286 in the validation dataset. CONCLUSIONS: Our diagnostic model based on 10 common laboratory tests identified the patients with SLE with high accuracy. An online version of the model can potentially be applied in clinical settings for the differential diagnosis of SLE.

Systematic Identification of Methyl Jasmonate-Responsive Long Noncoding RNAs and Their Nearby Coding Genes Unveils Their Potential Defence Roles in Tobacco BY-2 Cells.

Long noncoding RNAs (lncRNAs) are distributed in various species and play critical roles in plant growth, development, and defence against stimuli. However, the lncRNA response to methyl jasmonate (MeJA) treatment has not been well characterized in Nicotiana tabacum Bright Yellow-2 (BY-2) cells, and their roles in plant defence remain elusive. Here, 7848 reliably expressed lncRNAs were identified in BY-2 cells, of which 629 differentially expressed (DE) lncRNAs were characterized as MeJA-responsive lncRNAs. The lncRNAs in BY-2 cells had a strong genus specificity in Nicotiana. The combined analysis of the cis-regulated lncRNAs and their target genes revealed the potential up- and downregulated target genes that are responsible for different biological functions and metabolic patterns. In addition, some lncRNAs for response-associated target genes might be involved in plant defence and stress resistance via their MeJA- and defence-related cis-regulatory elements. Moreover, some MeJA-responsive lncRNA target genes were related to quinolinate phosphoribosyltransferase, lipoxygenases, and endopeptidase inhibitors, which may contribute to nicotine synthesis and disease and insect resistance, indicating that MeJA-responsive lncRNAs regulate nicotine biosynthesis and disease resistance by regulating their potential target genes in BY-2 cells. Therefore, our results provide more targets for genetically engineering the nicotine content and plant defence in tobacco plants.

Crk1/2 and CrkL play critical roles in maintaining podocyte morphology and function.

Podocytes are actin-rich epithelial cells whose effacement and detachment are the main cause of glomerular disease. Crk family proteins: Crk1/2 and CrkL are reported to be important intracellular signaling proteins that are involved in many biological processes. However, the roles of them in maintaining podocyte morphology and function remain poorly understood. In this study, specific knocking down of Crk1/2 and CrkL in podocytes caused abnormal cell morphology, actin cytoskeleton rearrangement and dysfunction in cell adhesion, spreading, migration, and viability. The p130Cas, focal adhesion kinase, phosphatidylinositol 3-kinase/Akt, p38 and JNK signaling pathways involved in these alterations. Furthermore, knocking down CrkL alone conferred a more modest phenotype than did the Crk1/2 knockdown and the double knockdown. Kidney biopsy specimens from patients with focal segmental glomerulosclerosis and minimal change nephropathy showed downregulation of Crk1/2 and CrkL in glomeruli. In zebrafish embryos, Crk1/2 and CrkL knockdown compromised the morphology and caused abnormal glomerular development. Thus, our results suggest that Crk1/2 and CrkL expression are important in podocytes; loss of either will cause podocyte dysfunction, leading to foot process effacement and podocyte detachment.

Clinical manifestation and genetic findings in three boys with low molecular Weight Proteinuria - three case reports for exploring Dent Disease and Fanconi syndrome.

BACKGROUND: Dent disease is an X-linked form of progressive renal disease. This rare disorder was characterized by hypercalciuria, low molecular weight (LMW) proteinuria and proximal tubular dysfunction, caused by pathogenic variants in CLCN5 (Dent disease 1) or OCRL (Dent disease 2) genes. Fanconi syndrome is a consequence of decreased water and solute resorption in the proximal tubule of the kidney. Fanconi syndrome caused by proximal tubular dysfunction such as Dent disease might occur in early stage of the disease. CASE PRESENTATION: Three cases reported in this study were 3-, 10- and 14-year-old boys, and proteinuria was the first impression in all the cases. All the boys presented with LMW proteinuria and elevated urine albumin-to-creatinine ratio (ACR). Case 1 revealed a pathogenic variant in exon 11 of CLCN5 gene [NM_001127899; c.1444delG] and a nonsense mutation at nucleotide 1509 [p.L503*], and he was diagnosed as Dent disease 1. Case 2 carried a deletion of exon 3 and 4 of OCRL1 gene [NM_000276.4; c.120-238delG…A] and a nonsense mutation at nucleotide 171 in exon 5 [p.E57*], and this boy was diagnosed as Dent disease 2. Genetic analysis of Case 3 showed a missense mutation located in exon 2 of HNF4A gene [EF591040.1; c.253C > T; p.R85W] which is responsible for Fanconi syndrome. All of three pathogenic variants were not registered in GenBank. CONCLUSIONS: Urine protein electrophoresis should be performed for patients with proteinuria. When patients have LMW proteinuria and/or hypercalciuria, definite diagnosis and identification of Dent disease and Fanconi syndrome requires further genetic analyses.

An Axin2 mutation and perinatal risk factors contribute to sagittal craniosynostosis: evidence from a Chinese female monochorionic diamniotic twin family.

BACKGROUND: Craniosynostosis, defined as premature fusion of one or more cranial sutures, affects approximately 1 in every 2000-2500 live births. Sagittal craniosynostosis (CS), the most prevalent form of isolated craniosynostosis, is caused by interplay between genetic and perinatal environmental insults. However, the underlying details remain largely unknown. METHODS: The proband (a female monochorionic twin diagnosed with CS), her healthy co-twin sister and parents were enrolled. Obstetric history was extracted from medical records. Genetic screening was performed by whole exome sequencing (WES) and confirmed by Sanger sequencing. Functional annotation, conservation and structural analysis were predicted in public database. Phenotype data of Axin2 knockout mice was downloaded from The International Mouse Phenotyping Consortium (IMPC, http://www.mousephenotype.org ). RESULTS: Obstetric medical records showed that, except for the shared perinatal risk factors by the twins, the proband suffered additional persistent breech presentation and intrauterine growth restriction. We identified a heterozygous mutation of Axin2 (c.1181G > A, p.R394H, rs200899695) in monochorionic twins and their father, but not in the mother. This mutation is not reported in Asian population and results in replacement of Arg at residue 394 by His (p.R394H). Arg 394 is located at the GSK3ß binding domain of Axin2 protein, which is highly conserved across species. The mutation was predicted to be potentially deleterious by in silico analysis. Incomplete penetrance of Axin2 haploinsufficiency was found in female mice. CONCLUSIONS: Axin2 (c.1181G > A, p.R394H, rs200899695) mutation confers susceptibility and perinatal risk factors trigger the occurrence of sagittal craniosynostosis. Our findings provide a new evidence for the gene-environment interplay in understanding pathogenesis of craniosynostosis in Chinese population.

Baseline Glycated Albumin Predicts the Renal Dysfunction in a Five-Year Prospective Population-Based Study.

BACKGROUND: Glycated albumin (GA) was reported to be associated with renal dysfunction in non-diabetic CKD population. This study assessed the correlation of GA and renal dysfunction and explored risk factors affecting renal progression in a general population-based study through a five-year follow-up. METHODS: Individuals who underwent a physical examination between September 2010 and September 2015 were enrolled. Multivariate linear regression was performed to assess the relationship between GA and eGFR change rate. The relationship between GA and renal progression was analyzed by multivariate logistic regression among 1,501 participants. Other risk factors were also explored and their predictive value was evaluated by ROC analysis, external validation was carried out in another 603 participants from the general population. RESULTS: The frequencies of subjects with renal progression increased obviously with the increment of baseline and mean GA according to quartile stratification (p for trend < 0.001). Baseline GA, age, and uric acid (p < 0.05) were identified as risk factors for renal dysfunction with a 30% or more decrease of eGFR. For every 1% increase of GA, the risk of deterioration of renal function increased to 1.585 in the population (95% CI, 1.299 - 1.935, p < 0.001). The predictive value of the model-building equation was confirmed by ROC analysis (AUC = 0.82, 95% CI: 0.773 - 0.832, p < 0.001) and in the validation group, predictive sensitivity and specificity were 85.7% and 73.5%. CONCLUSIONS: Baseline GA is independently associated with renal dysfunction. Uric acid and age are also considered risk factors. GA combining with age, serum creatinine and uric acid can serve as predictive indicators for the progression of renal dysfunction.

Associations between estimated glomerular filtration rate and cardiac biomarkers.

BACKGROUND: Chronic kidney disease (CKD) is associated with an increased cardiovascular disease (CVD) mortality risk. Elevation of cardiac biomarkers in patients with renal dysfunction is ambiguous in the diagnosis of CVD. The purpose of this study was to investigate the associations between estimated glomerular filtration rate (eGFR) and cardiac biomarkers, and the influence of renal dysfunction on the cardiac biomarkers. METHODS: We examined the cross-sectional associations of eGFR with cardiac troponin I (cTnI), creatine kinase (CK), CK-MB, lactic dehydrogenase (LDH), hydroxybutyrate dehydrogenase (HBDH), and brain natriuretic peptide (BNP) in 812 adults and 215 child. Spearman correlation and logistic regression analysis were performed to evaluate the associations. RESULTS: For adults, lower eGFR CKD-EPI had significantly higher cTnI, CK-MB, LDH, HBDH, and BNP. There were negative correlations between eGFRCKD-EPI and cTnI, CK-MB, LDH, HBDH, and BNP. After adjustment for potential confounders, as compared with eGFRCKD-EPI  ≥ 90 mL/min/1.73 m2 , eGFRCKD-EPI  < 60 mL/min/1.73 m2 remained associated with a 2.83 (1.08-7.41) [ratio (95% CI)] times higher cTnI and a 6.50 (2.32-18.22) [ratio (95% CI)] times higher HBDH. For child, lower eGFRSchwartz had significant higher CK and CK-MB. There were negative correlations between eGFRSchwartz and CK, and eGFRSchwartz and CK-MB. After adjustment for potential confounders, as compared with eGFRSchwartz  ≥ 90 mL/min/1.73 m2 , eGFRSchwartz  < 90 mL/min/1.73 m2 revealed no significant higher CVD biomarkers. CONCLUSION: Reduced eGFR is associated with elevated cTnI and HBDH among adults without clinically evident CVD, but not child.

Urine proteomics of primary membranous nephropathy using nanoscale liquid chromatography tandem mass spectrometry analysis.

BACKGROUND: Primary membranous nephropathy (PMN) is an important cause of nephrotic syndrome in adults. Urine proteome may provide important clues of pathophysiological mechanisms in PMN. In the current study, we analyzed and compared the proteome of urine from patients with PMN and normal controls. METHODS: We performed two technical replicates (TMT1 and TMT2) to analyze and compare the urine proteome from patients with PMN and normal controls by tandem mass tag (TMT) technology coupled with nanoscale liquid chromatography tandem mass spectrometry analysis (LC-MS/MS). Gene ontology (GO) enrichment analysis was performed to analyse general characterization of the proteins. The proteins were also matched against the database of Kyoto Encyclopedia of Genes and Genomes (KEGG). For validation, Western blot was used to analyze the selected proteins. RESULTS: A total of 509 proteins and 411 proteins were identified in TMT1 and TMT2, respectively. 249 proteins were both identified in two technical replicates. GO analysis and KEGG analysis revealed immunization and coagulation were predominantly involved. Among the differential protein, the overexcretion of alpha-1-antitrypsin (A1AT) and afamin (AFM) were validated by Western blot analysis. CONCLUSIONS: Our data showed the important role of immunologic mechanism in the development of PMN, and the value of urinary A1AT and AFM in biomarker discovery of patients with PMN. The discovery of the overexcretion of A1AT and AFM in the urine can help to further elucidate pathogenetic mechanisms involved in PMN.

LPE-1, an orally active pyrimidine derivative, inhibits growth and mobility of human esophageal cancers by targeting LSD1.

Histone lysine specific demethylase 1 (LSD1) plays an important role in epigenetic modifications, and aberrant expression of LSD1 predicts tumor progression and poor prognosis in human esophageal cancers. In this study, a series of LSD1 inhibitors were synthesized and proved to be highly potent against human esophageal squamous cell carcinoma (ESCC). Our data showed that these LSD1 inhibitors selectively suppressed the viability of esophageal cancer cell line (EC-109) bearing overexpressed LSD1. Among these, compound LPE-1 (LSD1 IC50=0.336±0.003µM) significantly suppressed proliferation, induced apoptosis, arrested cell cycle of EC109 cells at G2/M phase, and caused changes of the associated protein markers correspondingly. We also found that compound LPE-1 potently inhibited the migration and invasion of EC-109 cells. Docking studies showed that the cyano group formed hydrogen bonds with Val811 and Thr810. Additionally, the thiophene moiety formed arene-H interaction with Trp761 residue. In vivo studies showed that compound LPE-1 inhibited tumor growth of xenograft models bearing EC-109 without obvious toxicity. Collectively, our findings indicate that LSD1 may be a potential therapeutic target in ESCC, and compound LPE-1 could serve as a lead compound for further development for anti-ESCC drug discovery.

Detection of Hepatocellular Carcinoma Biomarker Golgi Protein 73 Based on Magnetic Enzyme-Linked Immunoassay.

The magnetic enzyme-linked immunoassay (MEIA) based on magnetic nanoparticles as the solid phase was reported in this work. Magnetic nanoparticles (MNPs) have represented perfectly suitable materials for a variety of biomedical and biotechnological applications. Therefore, we used MEIA based on magnetic nanoparticles to provide a screening method for fast analysis of serum Golgi protein 73 (GP73) in hepatocellular carcinoma (HCC) and healthy subjects and comparison was made with the enzyme-linked immunosorbent assay (ELISA) method. Several relevant conditions, including the concentration of anti-GP73 monoclonal antibody and HRP-anti-human GP73 monoclonal antibody, amount of immunomagnetic beads, and the incubation time, were determined and optimized. Finally, the MEIA was successfully established and validated by 79 HCC and 64 healthy subjects. The results showed this method achieved a detection limit of 0.78 ng/mL, which was more sensitive than ELISA. Furthermore, the sensitivity and specificity of the MEIA were 78.43% and 91.47%, respectively, which were higher than ELISA. The MEIA based on MNPs proved to be simple, sensitive, specific and time-saving, therefore holds great potential for development of a commercial kit in the future.

Promoted Electron Transfer along the Newly Formed Bi-O-S Bond in Bi2O(OH)2SO4.

Today, research is increasingly focused on surface control of semiconductors; however, very little is known about the effect of bulk chemical bonds on photoelectrochemistry properties. In this report, Bi2O(OH)2SO4 with and without specific Bi-O-S bonds (WB and WOB) is synthesized via hydrothermal and water bath methods, respectively, and we reveal the Bi-O-S bond-dependent photoelectrochemistry properties. Both WB and WOB belong to a monoclinic space group (P21/c), but the newly synthesized WB has different unit cell parameters of a = 8.062 Å, b = 8.384 Å, and c = 5.881 Å, compared with WOB (a = 7.692(3) Å, b = 13.87(1) Å, c = 5.688(2) Å). Compared with WOB (4.18 eV), WB has a narrower band gap (3.6 eV), higher electrical conductivity, and an increased charge separation efficiency. It is found that the electrons are easy to transfer along the newly formed Bi-O-S bond in bulk; thus, the Bi-O-S bonds in WB have efficiently improved the photoelectrochemistry properties. As a result, WB exhibits a 1.1 times higher photocatalytic activity than WOB for the degradation of RhB under ultraviolet light irradiation (<420 nm). This helps us to understand the photoelectrochemistry properties from crystal bulk, but not merely from the crystal surface; thus, this study provides a new idea for improved photoelectrochemistry properties of semiconductors.

[Expression and clinical significance of Dyrk1b in the specimens and cells of cervical lesions].

OBJECTIVE: To detect and explore the expression and clinical significance of dual specificity tyrosine phosphorylation regulated kinase1b (Dyrk1b) in the specimens and cells of cervical lesions. METHODS: (1) All the data were collected from 75 patients with cervical cancer and 52 cases with squamous intraepithelial lesion (SIL) admitted in the First Affiliated Hospital of Dalian Medical College during Jan. 2011 to Dec. 2013 and confirmed by pathological examination, included 60 cases of stage Ⅰ and 15 cases of stage Ⅱ, 12 cases with low-grade squamous intraepithelial lesion (LSIL) and 40 cases with high-grade squamous intraepithelial lesion (HSIL). While, 28 cases with chronic cervicitis were chosen as the control group. The protein expression of Dyrk1b was detected by immunohistochemistry among the four groups. (2) The expression of Dyrk1b in HeLa and SiHa cells were detected by western blot method and the expression of Dyrk1b protein were also detected after treatment of AZ191 (5, 10 µmol/L) for 48 hours in HeLa and SiHa cells. (3) The cellular survival and proliferation of HeLa and SiHa cells treated by different concentrations of AZ191 (2.5, 5, 10, 25, 50, 100 µmol/L) for 48 hours were detected by methyl thiazolyl tetrazolium (MTT) assay. (4) The rate of apoptosis of HeLa and SiHa cells was detected by flowcytometry after treatment of AZ191 (5, 10 µmol/L) for 48 hours. RESULTS: (1) The positive rates of Dyrk1b protein in chronic cervicitis, LSIL, HSIL and cervical squamous cancer by immunohistochemistry were 11%(3/28), 1/12, 42% (17/40) and 71% (53/75), respectively. The expression of Dyrk1b in cervical squamous cancer and HISL were higher than those in LSIL and chronic cervicitis (P<0.01), there were significant difference between cervical squamous cancer and HSIL, or between HSIL and LSIL (all P<0.05), while there were not significant difference between LSIL and chronic cervicitis (P>0.05). Expression of Dyrk1b was correlated with stromal invasion depth of cervical cancer (P<0.05), but not with age, clinical stage, lymph node metastasis, and serum squamous cell carcinom antigen (SCC-Ag) levels (all P>0.05). (2) Dyrk1b protein was expressed in different levels in HeLa and SiHa cells, and the expression of Dyrk1b was decreased gradually as the increased of the concentration of AZ191 in both HeLa and SiHa cells by treatment of AZ191 for 48 hours. (3) Different concentration of AZ191 treated on cervical cancer cells could inhibit the cellular proliferation and induce cell apoptosis in a concentration-dependent manner (P<0.01), concomitant to the decreased cell survival rate. The apoptosis rate of HeLa and SiHa were increased significantly after 10 µmol/L AZ191-treatment for 48 hours, but no any difference induced by 5 µmol/L AZ191-treatment compared to control group. Also,there was no any difference between Hela and SiHa cells in either inhibitory effect or apoptosis rate induced by AZ191. CONCLUSIONS: Dyrk1b is over-expressed in either specimens or cells of cervical cancer. The expression of Dyrk1b protein in cervical lesions is increased as the progression of disease. Dyrk1b inhibitor AZ191 could inhibit cellular proliferation and induce apoptosis in a concentration-dependent manner in cervical cancer cells.

Design and synthesis of novel 1,2,3-triazole-pyrimidine-urea hybrids as potential anticancer agents.

A series of novel 1,2,3-triazole-pyrimidine-urea hybrids were designed, synthesized and evaluated for anticancer activity against four selected cancer cell lines (MGC-803, EC-109, MCF-7 and B16-F10). Majority of the synthesized compounds exhibited moderate to potent activity against all the cancer cell lines assayed. Particularly, compounds 26, 30 and 38 exhibited excellent growth inhibition against B16-F10 with IC50 values of 32nM, 35nM and 42nM, respectively. Flow cytometry analysis demonstrated that compound 26 induced the cellular apoptosis in a concentration-dependent manner.

First-line drugs inhibiting the renin angiotensin system versus other first-line antihypertensive drug classes for hypertension.

BACKGROUND: Renin-angiotensin system (RAS) inhibitors are widely prescribed for treatment of hypertension, especially for diabetic patients on the basis of postulated advantages for the reduction of diabetic nephropathy and cardiovascular morbidity and mortality. Despite widespread use of angiotensin converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) for hypertension in both diabetic and non-diabetic patients, the efficacy and safety of RAS inhibitors compared to other antihypertensive drug classes remains unclear. OBJECTIVES: To evaluate the benefits and harms of first-line RAS inhibitors compared to other first-line antihypertensive drugs in patients with hypertension. SEARCH METHODS: We searched the Cochrane Hypertension Group's Specialised Register, MEDLINE, MEDLINE In-Process, EMBASE and ClinicalTrials.gov for randomized controlled trials up to November 19, 2014 and the Cochrane Central Register of Controlled Trials (CENTRAL) up to October 19, 2014. The WHO International Clinical Trials Registry Platform (ICTRP) is searched for inclusion in the Cochrane Hypertension Group's Specialised Register. SELECTION CRITERIA: We included randomized, active-controlled, double-blinded studies with at least six months follow-up in people with primary elevated blood pressure (≥130/85 mmHg), which compared first-line RAS inhibitors with other first-line antihypertensive drug classes and reported morbidity and mortality or blood pressure outcomes. Patients with proven secondary hypertension were excluded. DATA COLLECTION AND ANALYSIS: Two authors independently selected the included trials, evaluated the risk of bias and entered the data for analysis. MAIN RESULTS: We included 42 studies, involving 65,733 participants, with a mean age of 66 years. Much of the evidence for our key outcomes is dominated by a small number of large studies at a low risk of bias for most sources of bias. Imbalances in the added second-line antihypertensive drugs in some of the studies were important enough for us to downgrade the quality of the evidence.Primary outcomes were all-cause death, fatal and non-fatal stroke, fatal and non-fatal myocardial infarction (MI), fatal and non-fatal congestive heart failure (CHF) requiring hospitalization, total cardiovascular (CV) events (consisted of fatal and non-fatal stroke, fatal and non-fatal MI and fatal and non-fatal CHF requiring hospitalizations), and ESRF. Secondary outcomes were systolic blood pressure (SBP), diastolic blood pressure (DBP) and heart rate (HR).Compared with first-line calcium channel blockers (CCBs), we found moderate quality evidence that first-line RAS inhibitors decreased heart failure (HF) (35,143 participants in 5 RCTs, RR 0.83, 95% CI 0.77 to 0.90, ARR 1.2%), and moderate quality evidence that they increased stroke (34,673 participants in 4 RCTs, RR 1.19, 95% CI 1.08 to 1.32, ARI 0.7%). They had similar effects on all-cause death (35,226 participants in 5 RCTs, RR 1.03, 95% CI 0.98 to 1.09; moderate quality evidence), total CV events (35,223 participants in 6 RCTs, RR 0.98, 95% CI 0.93 to 1.02; moderate quality evidence), total MI (35,043 participants in 5 RCTs, RR 1.01, 95% CI 0.93 to 1.09; moderate quality evidence). The results for ESRF do not exclude potentially important differences (19,551 participants in 4 RCTs, RR 0.88, 95% CI 0.74 to 1.05; low quality evidence).Compared with first-line thiazides, we found moderate quality evidence that first-line RAS inhibitors increased HF (24,309 participants in 1 RCT, RR 1.19, 95% CI 1.07 to 1.31, ARI 1.0%), and increased stroke (24,309 participants in 1 RCT, RR 1.14, 95% CI 1.02 to 1.28, ARI 0.6%). They had similar effects on all-cause death (24,309 participants in 1 RCT, RR 1.00, 95% CI 0.94 to 1.07; moderate quality evidence), total CV events (24,379 participants in 2 RCTs, RR 1.05, 95% CI 1.00 to 1.11; moderate quality evidence), and total MI (24,379 participants in 2 RCTs, RR 0.93, 95% CI 0.86 to 1.01; moderate quality evidence). Results for ESRF do not exclude potentially important differences (24,309 participants in 1 RCT, RR 1.10, 95% CI 0.88 to 1.37; low quality evidence).Compared with first-line beta-blockers, we found low quality evidence that first-line RAS inhibitors decreased total CV events (9239 participants in 2 RCTs, RR 0.88, 95% CI 0.80 to 0.98, ARR 1.7%), and low quality evidence that they decreased stroke (9193 participants in 1 RCT, RR 0.75, 95% CI 0.63 to 0.88, ARR 1.7% ). Our analyses do not exclude potentially important differences between first-line RAS inhibitors and beta-blockers on all-cause death (9193 participants in 1 RCT, RR 0.89, 95% CI 0.78 to 1.01; low quality evidence), HF (9193 participants in 1 RCT, RR 0.95, 95% CI 0.76 to 1.18; low quality evidence), and total MI (9239 participants in 2 RCTs, RR 1.05, 95% CI 0.86 to 1.27; low quality evidence).Blood pressure comparisons between RAS inhibitors and other classes showed either no differences or small differences that did not necessarily correlate with the differences in the morbidity outcomes.In the protocol, we identified non-fatal serious adverse events (SAE) as a primary outcome. However, when we extracted the data from included studies, none of them reported total SAE in a manner that could be used in the review. Therefore, there is no information about SAE in the review. AUTHORS' CONCLUSIONS: We found predominantly moderate quality evidence that all-cause mortality is similar when first-line RAS inhibitors are compared to other first-line antihypertensive agents. First-line thiazides caused less HF and stroke than first-line RAS inhibitors. The quality of the evidence comparing first-line beta-blockers and first-line RAS inhibitors was low and the lower risk of total CV events and stroke seen with RAS inhibitors may change with the publication of additional trials. Compared with first-line CCBs, first-line RAS inhibitors reduced HF but increased stroke. The magnitude of the reduction in HF exceeded the increase in stroke. The small differences in effect on blood pressure between the different classes of drugs did not correlate with the differences in the primary outcomes.

Influence of buffer distance on environmental geological hazard susceptibility assessment.

Previous researches seldom studied the selection of buffer distance between geological hazards (positive samples) and non-geological hazards (negative samples), and its reasonable selection plays a very important role in improving the accuracy of susceptibility zoning, protecting the environment and reducing the cost of hazard management. Based on GIS technology and random forest (RF) and frequency-ratio random forest (FR-RF) models, this study innovatively explored the influence of randomly selected non-geological hazard samples outside different buffer distances on the susceptibility evaluation results, with buffer distances of 100 m, 500 m, 1000 m and 2000 m in sequence. The results show that through the confusion matrix and ROC curve test, the accuracy of the model increases first and then decreases with the increase of buffer distance. Both RF and FR-RF models have the highest accuracy when the buffer distance is 1000 m, and the accuracy of the RF model is generally higher than that of the FR-RF model under the same buffer distance. Similar attribute values of positive samples and randomly selected negative samples or "extreme" attribute values of negative samples are the main reasons for the differences in evaluation results of different buffer distances. According to the weight analysis of causative factors, the distance from road, the distance from river and the normalized vegetation index (NDVI) are the main factors affecting the occurrence of hazards. The high and very high susceptibility areas in the study area are mainly distributed on both sides of roads and water systems, which are the key areas for hazard prevention and reduction. The HMC of RF-1000m decreased by 3.55% on average compared with other models. The results of this study improve the accuracy of geological hazard susceptibility assessment, maintain the safety of ecological environment, and provide a scientific basis for the selection of buffer distance index in local and surrounding areas in the future.

Overview of blood-brain barrier dysfunction in methamphetamine abuse.

Methamphetamine (METH) is one of the psychostimulants most widely abused in the world. METH abuse can lead to severe neurotoxicity. The blood-brain barrier (BBB) is a natural barrier separating the central nervous system (CNS) from the peripheral blood circulation, which can limit or regulate the exchange of toxic substances, molecules, ions, etc., to maintain the homeostasis of CNS. Long-term or high dose abuse of METH can cause structural or functional abnormalities of the BBB and increase the risk of neurodegenerative diseases. In this review, we discussed the mechanisms of METH-induced BBB dysfunction, summarized the risk factors that could exacerbate METH-induced BBB dysfunction, and introduced some potential therapeutic agents. It would provide an important basis and direction for the prevention and treatment of BBB dysfunction induced by METH.

The relationship between social anxiety and self-injury of junior high school students: Mediation by intolerance of uncertainty and moderation by self-esteem.

Objective: The problem of adolescents' self-injury has gradually attracted social attention, however, a lack of research exists on the internal mechanism between social anxiety and self-injury. This study explored the relationship between social anxiety and self-injury in Chinese junior high school students. Method: An adolescent self-injury questionnaire, social anxiety scale, intolerance of uncertainty questionnaire and self-injury questionnaire were used to survey 614 junior high school students. Results: The results showed that: (1) social anxiety had a significant positive predictive effect on self-injury; (2) intolerance of uncertainty had a significant mediating effect between social anxiety and self-injury; and (3) self-esteem had a significant moderating effect on the mediating effect of intolerance of uncertainty. Conclusion: The study suggested that social anxiety in junior high school students has an impact on self-injury through mediation of intolerance of uncertainty and modulation of self-esteem.

Case report: Whole-exome sequencing for a hereditary elliptocytosis case with an unexpectedly low HbA1c.

Objectives: Hereditary elliptocytosis is a group of erythroid hereditary diseases characterized by elliptically shaped erythrocytes in peripheral blood. It is mainly inherited through autosomal dominant inheritance. This study aimed to conduct a genetic etiology analysis in a case with a clinical diagnosis of hereditary elliptocytosis and an unexpectedly low HbA1c. Methods: Whole-exome sequencing was performed to find the possible pathogenic mutations. At the same time, bioinformatics software was used to predict the mutation function. Sanger sequencing was performed to verify the suspected pathogenic mutations. Results: Whole-exome sequencing results showed that the proband with mild anemia had a heterozygous c.2303G>A (p.G768D) missense mutation in the 13th exon of the SPTB gene. The Sanger sequencing confirmed this heterozygous mutation. This mutation was extremely rare in the population, and multiple software's predictions were harmful. Conservative analysis revealed that this site was highly conserved in various species. Conclusion: The c.2303G>A mutation of the SPTB gene is the suspected cause of hereditary elliptocytosis in the patient. Our data show that microscopic examination of red blood cells on blood smears is an important means of diagnosing hereditary elliptocytosis. Whole-exome sequencing is an effective tool to determine the genetic etiology of erythrocyte membrane diseases, which can promote accurate diagnosis and genetic counseling.

Intelligent Big Information Retrieval of Smart Library Based on Graph Neural Network (GNN) Algorithm.

In order to provide users with more humanized and intelligent big data knowledge services, a research method of intelligent big information retrieval of Smart Library Based on graph neural network (GNN) algorithm is proposed. Through the key technical problems and solutions of information recommendation represented by graph neural network (GNN) algorithm, this method explores how the library can realize the management and value mining of big data knowledge services. The research shows that the intelligent information retrieval of Smart Library Based on graph neural network (GNN) algorithm is 80% higher than the previous general methods. Graph neural network is a more advantageous algorithm for node classification, link prediction, node clustering, or network visualization, which is of great help to improve the efficiency of information retrieval.

Case Report: A Rare Case of Thrombotic Microangiopathy Induced by Remethylation Disorders.

In this research, we described a very rare case of thrombotic microangiopathy induced by remethylation disorders. A 16-year-old boy presented to the emergency department with 5 months of weakness and fatigue. He was diagnosed with thrombotic microangiopathy based on clinical manifestation and laboratory information, which showed microangiopathic hemolytic anemia, renal impairment, and thrombocytopenia. After a complex diagnostic workup, the metabolite screening parameters and sequencing results guided us toward the diagnosis of remethylation disorders. The patient was diagnosed with thrombotic microangiopathy induced by remethylation disorders (cblC).