[Study on primary screening technique for children with autism spectrum disorder].

To explore screening tools for children with autism spectrum disorder (ASD), which are convenient for primary hospitals, it can provide basic data for formulating ASD prevention policies. This was a cross-sectional study by cluster sampling. Huyi District and Xincheng District were extracted for investigation in Xi'an City. From July 2021 to September 2022, all children aged from 3 months to 36 months who live in the two districts were subjected to primary screening. The child care physician used the routine screening tool "warning signs checklist for screening psychological, behavioral and developmental problems of children" and cartoon pictures of "early high-risk warning signs of autism", the children who were positive in the initial screening were referred to the district level maternal and child health hospital for re-screening, and those who were positive in the re-screening were referred to Xi 'an Children's Hospital for diagnosis. The results showed that a total of 17 905 children aged from 3 months to 36 months were initially screened in the two districts, including 10 588 children aged from 18 months to 36 months, 50 children who were positive in the initial screening and 50 children who were re-screened. 23 children (18 boys and 5 girls) were diagnosed with ASD. The prevalence rate of ASD in children was 2.17‰ (95% confidence interval:1.29‰-3.06‰). 42 children were positive for "warning signs checklist" at the preliminary screening, and 19 were confirmed as ASD. 27 children were positive for "cartoon pictures" in the preliminary screening, and 23 were confirmed with ASD. The "cartoon pictures" in the preliminary screening and diagnosis of consistent rate was higher than the "warning signs checklist", two kinds of screening methods comparison were statistically significant difference in the odds of consistent (χ2=11.01, P=0.001). In conclusion, relying on the three-level network of maternal and child health care, it is conducive to the whole process management of screening and diagnosis of children with ASD, and to guide the formulation of prevention policies. The cartoon pictures of "early high-risk warning signs of autism" can assist the identification of children with ASD based on the "warning signs checklist", which is simple, effective and suitable for promotion in the community health care.

A Novel Transdermal Application for Clearing Skin Colonization by Candida auris.

BACKGROUND. Candida auris has demonstrated the ability to colonize the skin of hospitalized patients, possibly contributing to nosocomial spread. OBJECTIVE. The objective was to determine whether two novel transdermal agents could clear skin colonization established by C. auris METHODS. A murine skin colonization model was first optimized and then used to test fungal burden reduction following treatment with 1% terbinafine or 1% clotrimazole in a proprietary Advanced Penetration Technology formulation (APT™). RESULTS. Both treatments significantly reduced fungal burden compared to control groups. CONCLUSION. These novel agents show promise as a topical means of preventing skin colonization by C. auris.

EBV-associated primary CNS lymphoma occurring after immunosuppression is a distinct immunobiological entity.

Primary central nervous system lymphoma (PCNSL) is confined to the brain, eyes, and cerebrospinal fluid without evidence of systemic spread. Rarely, PCNSL occurs in the context of immunosuppression (eg, posttransplant lymphoproliferative disorders or HIV [AIDS-related PCNSL]). These cases are poorly characterized, have dismal outcome, and are typically Epstein-Barr virus (EBV)-associated (ie, tissue-positive). We used targeted sequencing and digital multiplex gene expression to compare the genetic landscape and tumor microenvironment (TME) of 91 PCNSL tissues all with diffuse large B-cell lymphoma histology. Forty-seven were EBV tissue-negative: 45 EBV- HIV- PCNSL and 2 EBV- HIV+ PCNSL; and 44 were EBV tissue-positive: 23 EBV+ HIV+ PCNSL and 21 EBV+ HIV- PCNSL. As with prior studies, EBV- HIV- PCNSL had frequent MYD88, CD79B, and PIM1 mutations, and enrichment for the activated B-cell (ABC) cell-of-origin subtype. In contrast, these mutations were absent in all EBV tissue-positive cases and ABC frequency was low. Furthermore, copy number loss in HLA class I/II and antigen-presenting/processing genes were rarely observed, indicating retained antigen presentation. To counter this, EBV+ HIV- PCNSL had a tolerogenic TME with elevated macrophage and immune-checkpoint gene expression, whereas AIDS-related PCNSL had low CD4 gene counts. EBV-associated PCNSL in the immunosuppressed is immunobiologically distinct from EBV- HIV- PCNSL, and, despite expressing an immunogenic virus, retains the ability to present EBV antigens. Results provide a framework for targeted treatment.

Cost and outcomes of routine HIV care and treatment: public and private service delivery models covering low-income earners in South Africa.

BACKGROUND: While South Africa's national HIV program is the largest in the world, it has yet to reach the UNAIDS 95-95-95 targets. To reach these targets, the expansion of the HIV treatment program may be accelerated through the use private sector delivery models. This study identified three innovative non-governmental primary health care models (private sector) providing HIV treatment, as well as two government primary health clinics (public sector) that served similar populations. We estimated the resources used, and costs and outcomes of HIV treatment across these models to provide inputs to inform decisions around how these services might best be provided through National Health Insurance (NHI). METHODS: A review of potential private sector models for HIV treatment in a primary health care setting was conducted. Models actively offering HIV treatment (i.e. in 2019) were considered for inclusion in the evaluation, subject to data availability and location. These models were augmented by government primary health clinics offering HIV services in similar locations. We conducted a cost-outcomes analysis by collecting patient-level resource usage and treatment outcomes through retrospective medical record reviews and a bottom-up micro-costing from the provider perspective (public or private payer). Patient outcomes were based on whether the patient was still in care at the end of the follow up period and viral load (VL) status, to create the following outcome categories: in care and responding (VL suppressed), in care and not responding (VL unsuppressed), in care (VL unknown) and not in care (LTFU or deceased). Data collection was conducted in 2019 and reflects services provided during the 4 years prior to that (2016-2019). RESULTS: Three hundred seventy-six patients were included across the five HIV treatment models. Across the three private sector models there were differences in the costs and outcomes of HIV treatment delivery, two of the models had results similar to the public sector primary health clinics. The nurse-led model appears to have a cost-outcome profile distinct from the others. CONCLUSION: The results show that across the private sector models studied the costs and outcomes of HIV treatment delivery vary, yet there were models that provided costs and outcomes similar to those found with public sector delivery. Offering HIV treatment under NHI through private delivery models could therefore be an option to increase access beyond the current public sector capacity.

[Application of Padua prediction score and serum albumin level in evaluating venous thromboembolism in rheumatic inpatients].

OBJECTIVE: To investigate the status of venous thromboembolism (VTE) in rheumatic inpatients, and to explore the efficiency of Padua prediction score (PPS) in the patient population. In addition, to analyze the relationship between serum albumin and VTE in rheumatic inpatients. METHODS: Data of inpatients with rheumatology were retrospectively collected and analyzed at Sichuan Provincial People's Hospital from September 2018 to September 2019. Occurrence of VTE was compared between high (PPS≥4) and low (PPS < 4) risk groups. PPS were analyzed in the VTE and non-VTE patients. Multivariate Logistic regression model was used to analyze the risk factors in PPS and the relationship between serum albumin and VTE. RESULTS: A total of 1 547 patients were included in this study, and 27 (1.7%) had symptomatic VTE. Among the symptomatic VTE cases, 19 (1.2%) had deep vein thrombosis (DVT) only, 6 (0.4%) had pulmonary thromboembolism (PTE) only, and 2 (0.1%) were diagnosed with DVT and PTE. PPS in the VTE and non-VTE groups were 3.33±1.78 and 1.80±0.97 respectively (P < 0.05).The number of patients with PPS≥4 in the VTE group and non-VTE group was 37.0% and 4.3% respectively (P < 0.01). The average serum albumin level in the VTE group was lower than that in non-VTE group [(29.79±6.36) g/L vs. (35.17±6.31) g/L, P < 0.001]. Seventy-six cases was divided into high-risk group of VTE, while 1 471 cases were in the low-risk group, and the incidence of VTE was 13.2% and 1.2% respectively (P < 0.001). Logistic regression analysis showed that ongoing hormonal treatment, age≥70 years, trauma and/or surgery ≤30 d, reduced mobility and previous VTE were risk factors of VTE in the rheumatology patients, OR values were 7.11, 7.07, 3.40, 2.40 and 2.00, respectively. Lower serum albumin level was the risk factor of VTE in the rheumatology patients [OR=0.88 (95%CI: 0.82-0.94)]. CONCLUSION: The incidence of VTE was relatively higher in the hospitalized patients in Department of Rheumatology and Immunology. Glucocorticoid therapy was the highest risk factor of VTE and lower serum albumin level also was the risk factor. Although the PPS can reflect the risk of VTE in rheumatic inpatients to some extent, its effectiveness is limited. PPS can be optimized for quantitative VTE risk assessment of rheumatic inpatients in the future.

Evaluation of the Efficiency of TIMP-2 as a Biomarker for Acute Kidney Injury in Sepsis.

The aim of this study was to evaluate the biomarker potential of TIMP-2 in septic-induced acute kidney injury (AKI). Healthy male rats (n=56, age 8-10 weeks, body weight 250-300 g) were randomized into 3 groups: controls (intact rats, n=6), sham-operated (SO, n=24), and sepsis model (cecum ligation and perforation, CLP, n=24). Thirty minutes before and 6, 12, 24, and 48 h after surgery, blood samples were collected to measure serum creatinine, blood urea nitrogen (BUN), and TIMP-2 and the kidneys were isolated for histopathological analysis and Western blotting. The key sepsis-related genes were screened through bioinformatics analysis. In 24 and 48 h after surgery, 2 rats in the SO group reached the diagnostic criteria of AKI (increased levels of serum creatinine and BUN). In the CLP group, serum creatinine in 6 h after the surgery was slightly higher than 30 min before the surgery, but this change did not meet the diagnostic criteria for AKI. In the CLP group, BUN was normal 6 h after the surgery, but increased after 12 h. In more than 50% rats of the CLP group, serum creatinine and BUN significantly increased 12 h after operation, so this can be diagnosed as AKI. In rats of the CLP group, plasma TIMP-2 was elevated 6 h after surgery and increased with time, suggesting that plasma TIMP-2 can be used as an early marker of AKI. Histological examination of the kidneys in this group revealed destruction of the renal tubular structure, swelling of renal tubular epithelium, the disappearance of brush edge and collapse of necrotic epithelial cells, etc., and the degree of damage increased with time. Immunohistochemistry showed that TIMP-2 was expressed in rats of the CLP group at all terms of the experiment. The expression of TIMP-2 and pyroptosis-related proteins (NLRP3, IL-1ß, caspase-1, and GSDMD) in the CLP group was higher than in the SO group (p<0.05) and increased with time, suggesting that pyroptosis is involved in AKI. Thus, plasma TIMP-2 is sensitive indicator for the early detection of kidney injury and can be used as an early biomarker of AKI.

Low-dose Ketamine Infusion for Pediatric Hematology/Oncology Patients: Case Series and Literature Review.

Management of refractory pain in pediatric sickle cell disease (SCD) and oncology is reliant on opioids though high opioid dosing increases side effects and tachyphylaxis. We introduced low-dose ketamine infusion (LDKI) to our inpatient unit to determine if LDKI was tolerable. We subsequently hypothesized that LDKI would improve pain scores. We reviewed inpatients from LDKI initiation in March 2014 through October 2017, with the day before LDKI initiation compared with the day of LDKI initiation and 2 subsequent days. For patients with SCD, the LDKI admission was compared with up to 3 admissions in the prior year for a vaso-occlusive event. Nineteen patients (12 oncology, 7 SCD) with a median age of 14.6 years received LDKI for a median of 6 days at a median initial dose of 0.06 mg/kg/h (1.1 µg/kg/min). There was no change in pain scores or opioid utilization when comparing the day before LDKI initiation with subsequent days. No patient discontinued LDKI because of intolerability. For patients with SCD, there was a median 32% reduction in cumulative pain scores when comparing the LDKI admission with prior admissions. LDKI is well tolerated for refractory pediatric cancer-related and sickle cell-related pain.

[A multicenter study on the tolerance of intravenous low-dose cyclophosphamide in systemic lupus erythematosus].

OBJECTIVE: To compare the safety of low-dose cyclophosphamide and high-dose cyclophosphamide in the treatment of systemic lupus erythematosus (SLE). METHODS: A total of 1 022 patients with systemic lupus erythematosus from 24 hospitals in China between March 2017 to July 2018 were enrolled. Their clinical manifestations, laboratory tests, adverse events, reasons for stopping receiving intravenous cyclophosphamide and comorbidities were collected. Among them, 506 SLE patients received short-interval low-dose intravenous cyclophosphamide therapy (SILD IV-CYC, 400 mg every two weeks), and 256 patients underwent high-dose cyclophosphamide therapy (HD IV-CYC, 500 mg/m2 of body surface area every month), the side effects between the two groups were compared, the remaining 260 SLE patients were treated with IV-CYC irregularly. Moreover, a total of 377 patients in SILD IV-CYC group and 214 patients in HD IV-CYC group had medical records of the reasons for stopping recei-ving IV-CYC. The reasons for stopping receiving IV-CYC in these two groups were analyzed. RESULTS: In this study, only 40.27%(238/591)of the SLE patients stopped receiving intravenous cyclophosphamide for the causes of disease improvement, however, up to 33.67% (199/591) of the patients for the reason of drug-related side effects. There were 83 patients out of 214 (38.79%) with high-dose intravenous cyclophosphamide treatment who stopped receiving IV-CYC for the drug-related side effects, which was significantly higher than that in the low-dose cyclophosphamide group (30.77%, 116/337, P=0.048). Of theses 506 patients in SILD IV-CYC group, 88 (17.39%) patients experienced gastrointestinal reactions, 66 (13.04%) suffered from infections, 49 (9.68%) had myelosuppression and 68 (13.44%) had alopecia, respectively. Among the 256 patients in the HD IV-CYC group, 80 (31.25%) experienced gastrointestinal reactions, 57 (22.27%) suffered from infections, 51 (19.92%) had myelosuppression and 49 (19.14%) had alopecia. Moreover, 71 (25.18%) of 282 female patients with age between 16 to 45 years in SILD IV-CYC group had abnormal menstruation, while menstrual disorder occurred in 39.72% (56/141) patients of HD IV-CYC group. There was no difference of drug-induced hepatic injury, hemorrhagic cystitis and fatigue between the two groups. CONCLUSION: Low-dose cyclophosphamide showed a lower prevalence of adverse events than high-dose cyclophosphamide in systemic lupus erythematosus patients.

[Observation of PD-1+CXCR5+CD4+T lymphocyte and sPD-1 levels in HBeAg positive chronic hepatitis B virus carriers treated with entecavir].

Objective: To dynamically observe the clinical efficacy of entecavir and the changes of PD-1+CXCR5+CD4+T lymphocytes and sPD-1 levels in peripheral blood of HBeAg-positive chronic hepatitis B virus carriers treated with entecavir, and further explore its clinical significance. Methods: There were 31 cases of chronic hepatitis B virus carriers in the treatment group (A), 32 cases of chronic hepatitis B virus carriers in the treatment group (B), and 15 cases of chronic hepatitis B virus carriers in the non-treatment group (C).Three groups peripheral blood samples and clinical data at 0, 24 and 48 weeks were collected and compared. PD-1+CXCR5+CD4+T lymphocytes were detected by flow cytometry, and the level of sPD-1 was detected by enzyme-linked immunosorbent assay. ANOVA and Spearman correlation analysis were performed on the measurement data among the three groups. Results: At week 0, the serum levels of HBsAg, HBeAg and HBV DNA were significantly higher in groups A and C than group B. PD-1+CXCR5+CD4+T lymphocytes in peripheral blood were significantly higher in group B (4.70%±1.58%) than group A (3.25%±1.01%) and group C (2.77%±0.67%) (F=16.65, P<0.05). There was no significant difference between group A and group C (P>0.05). Peripheral blood sPD-1 in group B [(1 866.62±1 472.70) pg/ml] was significantly higher than group A [(824.86±538.66) pg/ml] and group C [(618.19±602.62) pg/ml] (F=10.95, P<0.05). There was no significant difference between group A and group C (P>0.05). At 48 weeks, the serum HBsAg did not decrease significantly in groups A and C than baseline (P>0.05), but were significantly higher than group B (P<0.05). Serum HBeAg levels were decreased significantly in groups A and B than baseline (P<0.05). <0.05), but group A was significantly higher than group B (P<0.05), and there was no significant difference between group A and group C (P>0.05). Serum HBV DNA level was significantly lower in groups A and B than group C (P<0.05), and there was no significant difference between group A and group B (P>0.05). Peripheral blood PD-1+CXCR5+CD4+T lymphocytes were significantly lower in Group A (1.56%±0.73%) and group B (1.32%±0.43%) than group C (2.64%±0.85%) (P<0.05). Peripheral blood sPD-1 were significantly lower in group A [(289.05±215.86) pg/ml] and group B [(236.01±173.92) pg/ml] than group C [(650.34±598.46) pg/ml] (P<0.05). There was no significant difference between group A and group B. Correlation analysis results: In group A at 48 weeks, the decreased level of PD-1+CXCR5+CD4+T lymphocyte ratio had no correlation with the decreased level of HBsAg and HBV DNA, but was positively correlated with the decreased level of HBeAg (r=0.376, P<0.05). The decreased level of sPD-1 had no correlation with the changes of HBsAg, but was positively correlated with the decreased levels of HBeAg and HBV DNA (r=0.598 and 0.384, P<0.05). In group B at 48 weeks, the decreased levels of PD-1+CXCR5+CD4+T lymphocytes and sPD-1 were positively correlated with the decreased levels of HBsAg, HBeAg, and HBV DNA (P<0.05). Conclusion: Hepatitis B virus replication and expressions in HBeAg-positive chronic hepatitis B virus carriers were significantly inhibited after 48 weeks of antiviral treatment, which is related not only to entecavir treatment, but also to the immunological mechanism involved in sPD-1. Moreover, the inhibition of HBeAg expression is associated with a decrease in the number and/or activity of PD-1+CXCR5+CD4+T lymphocytes.

[Analysis of the diagnostic performance of MRI Liver Imaging Reporting and Data System version 2018 for intrahepatic parenchymal substantial lesions ≤3.0 cm].

Objective: To investigate the diagnostic performance of MRI Liver Imaging Reporting and Data System version 2018 in high-risk hepatocellular carcinoma (HCC) patients with intrahepatic parenchymal substantial lesions ≤3.0 cm. Methods: A retrospective analysis was conducted in hospitals between September 2014 to April 2020. 131 pathologically confirmed non-HCC cases with lesions ≤3.0 cm in diameter were randomly matched with 131 cases with lesions ≤3.0 cm in diameter and divided into benign (56 cases), other hepatic malignant tumor (OM, 75 cases), and HCC group (131 cases) in a 1:1 ratio. MRI features of the lesions were analyzed and classified according to LI-RADS v2018 criteria (tie-break rule was applied to lesions with both HCC and LR-M features). Taking the pathological results as the gold standard, the sensitivity and specificity of the LI-RADS v2018 classification criteria and the more stringent LR-5 criteria (with three main signs of HCC at the same time) were calculated for HCC, OM or benign lesions diagnosis. Mann -Whitney U test was used to compare the classification results. Results: The number of cases classified as LR-M, LR-1, LR-2, LR-3, LR-4, and LR-5 in HCC group after applying the tie-break rule were 14, 0, 0, 12, 28, and 77, respectively. There were 40, 0, 0, 4, 17, 14 and 8, 5, 1, 26, 13, 3 cases in benign and OM group, respectively. There were 41 (41/77), 4 (4/14) and 1 (1/3) lesion case in the HCC, OM and benign group, respectively, that met the more stringent LR-5 criteria. The sensitivity of LR-4 combined with LR-5 (LR-4/5) criteria, LR-5 criteria and more stringent LR-5 criteria for HCC diagnosis were 80.2% (105/131), 58.8% (77/131) and 31.3% (41/131), respectively, and the specificity were 64.1% (84/131), 87.0% (114/131) and 96.2% (126/131), respectively. The sensitivity and specificity of LR-M were 53.3% (40/75) and 88.2% (165/187), respectively. The sensitivity and specificity using LR-1 combined with LR-2 (LR-1/2) criteria for the diagnosis of benign liver lesions were 10.7% (6/56) and 100% (206/206), respectively. Conclusions: LR-1/2, LR-5, and LR-M criteria have high diagnostic specificity for intrahepatic lesions with a diameter of ≤3.0 cm. Lesions classified as LR-3 are more likely to be benign. The specificity of LR-4/5 criteria is low, while the more stringent LR-5 criteria has a high specificity for HCC diagnosis.

BMPRII deficiency impairs apoptosis via the BMPRII-ALK1-BclX-mediated pathway in pulmonary arterial hypertension.

Pulmonary arterial hypertension (PAH) is a devastating cardiovascular disorder characterized by the remodelling of pre-capillary pulmonary arteries. The vascular remodelling observed in PAH patients results from excessive proliferation and apoptosis resistance of pulmonary arterial smooth muscle cells (PASMCs) and pulmonary arterial endothelial cells (PAECs). We have previously demonstrated that mutations in the type II receptor for bone morphogenetic protein (BMPRII) underlie the majority of the familial and inherited forms of the disease. We have further demonstrated that BMPRII deficiency promotes excessive proliferation and attenuates apoptosis in PASMCs, but the underlying mechanisms remain unclear. The major objective of this study is to investigate how BMPRII deficiency impairs apoptosis in PAH. Using multidisciplinary approaches, we demonstrate that deficiency in the expression of BMPRII impairs apoptosis by modulating the alternative splicing of the apoptotic regulator, B-cell lymphoma X (Bcl-x) transcripts: a finding observed in circulating leukocytes and lungs of PAH subjects, hypoxia-induced PAH rat lungs as well as in PASMCs and PAECs. BMPRII deficiency elicits cell specific effects: promoting the expression of Bcl-xL transcripts in PASMCs while inhibiting it in ECs, thus exerting differential apoptotic effects in these cells. The pro-survival effect of BMPRII receptor is mediated through the activin receptor-like kinase 1 (ALK1) but not the ALK3 receptor. Finally, we show that BMPRII interacts with the ALK1 receptor and pathogenic mutations in the BMPR2 gene abolish this interaction. Taken together, dysfunctional BMPRII responsiveness impairs apoptosis via the BMPRII-ALK1-Bcl-xL pathway in PAH. We suggest Bcl-xL as a potential biomarker and druggable target.

[Analysis of the clinical efficacy and safety of bronchial thermoplasty in the treatment of patients with severe asthma and asthma-chronic obstructive pulmonary disease overlap].

Objective: To investigate the clinical efficacy and safety analysis of bronchial thermoplasty (BT) in the treatment of severe asthma and asthma-chronic obstructive pulmonary disease overlap. Methods: The clinical data of 49 patients with asthma-COPD overlap who received BT in the University of Chinese Academy of Sciences Shenzhen Hospital from January 2016 to December 2018 and 50 patients with severe asthma who received BT in the same period were retrospectively analyzed. Patients were divided into overlap group and asthma group, and the baseline data of two groups were recorded. The pulmonary function before and after treatment (including forced vital capacity (FVC), forced expiratory volume in the first second (FEV1), FEV1 as a percentage of predicted value (FEV1% pred)), hormone consumption, asthma control test (ACT) score, asthma quality of life questionnaire (AQLQ) score, asthma control questionnaire (ACQ) score, the overlap group before and after treatment COPD assessment test (CAT) score, modified British Medical Research Council (mMRC) score and postoperative respiratory adverse events in the next 3 weeks were comparatively analyzed. Results: The general baseline characteristics of the two groups are compared. The patients in the overlap group were older than those in the asthma group, and the course of disease and smoking history were longer than those in the asthma group. The inhaled hormone dosage in asthma group was greater than those in the overlap group ((64±11) years vs (48±11) years; 10.00 (10.00, 25.00) years vs 9.00 (1.75, 20.00) years; 20.00(2.00, 40.00) years vs 0 (0, 10.00) years; 320 (320, 640) µg/d vs 960 (320, 960) µg/d) (all P<0.05). The predicted values of lung function indexes FVC, FEV1, FEV1% pred in the overlap group before treatment were all lower than those in the asthma group (1.98 (1.43, 2.43) L vs 2.54 (2.02, 3.15) L; 0.92 (0.61, 1.26) L vs 1.69(1.17, 2.16) L; (50±16) L vs (65±14) L) (all P<0.05). There were no significant differences in ACT, ACQ, and AQLQ scores between the two groups before treatment (all P>0.05). Within 3 months after treatment, except for no significant improvement in FEV1% predicted value and inhaled hormone dosage in the overlap group (all P>0.05), other indexes in both groups were improved compared with those before treatment (all P<0.05). After 1 year of treatment, all indexes of the two groups were significantly improved than those before treatment, and all indexes of the asthma group were better than those of the overlap group (all P<0.05). In terms of respiratory adverse events occurring within 3 weeks after the operation, the incidence of cough and bloody sputum in the overlap group was higher than that in the asthma group, while the incidence of sputum and short-term wheezing was lower than that in the asthma group (all P<0.05). There were no statistically significant differences in the incidence of chest tightness, chest pain, segmental atelectasis and pneumonia between the two groups (all P>0.05), and the postoperative adverse reactions could be effectively controlled in a short period of time. Conclusion: BT treatment could not only improve the lung function, clinical symptoms and quality of life of asthmatic patients, but was also effective for asthma-COPD overlap patients. However, BT treatment had more benefits for asthmatic patients without serious adverse events occurred.

Efficacy of Ibrexafungerp (SCY-078) against Candida auris in an In Vivo Guinea Pig Cutaneous Infection Model.

Candida auris has been shown to have a high risk of skin colonization in hospitalized patients, possibly contributing to nosocomial spread. In a guinea pig skin model, animals were evaluated for clinical appearance, tissue fungal burden, histology, and pharmacokinetics. Oral dosing with 10 mg/kg ibrexafungerp (IBX) reduced the severity of lesions and significantly reduced the C. auris fungal burden in infected animals compared with untreated controls. This indicates promise for use of IBX in controlling skin infection and colonization of hospitalized patients.

[Interaction between PSF and cytokeratin 18 mediates PSF relocation to cell membrane and maintains chemosensitivity of myeloid leukemia].

OBJECTIVE: To identify the chaperone of polypyrimidine tractor-binding protein-associated splicing factor (PSF) in myeloid leukemia cells, and to explore the mechanism and redistributive pattern to cell surface of PSF in chemo-sensitive HL60 cells and resistant HL60/DOX cells. METHODS: The eukaryotic expression vector of PSF was transfected with liposomes transiently, then flow cytometry was used to detect the expression level of PSF on the cell surface 24 h, 48 h and 72 h after vector transfections. We constructed a chimeric expression vector, streptavidin binding peptide (SBP)-PSF, meanwhile this vector was transfected and made SBP-PSF fusion protein overexpress. In addition, we used streptavidin magnetic beads to precipitate the cellular chaperonin of PSF and then identified its chaperonin by mass spectrometry (MS). Lentiviral vectors containing cytokeratin18 (K18) interference sequences were transfected into 293T cells to prepare lentivirus. HL60 and HL60/DOX cells were infected with lentivirus to obtain stable interfering K18 cell lines. Next, flow cytometry was used to test the membrane relocation level of PSF. Together, these methods confirmed the similar or different mechanisms of the PSF redistributing to membrane synergistically mediated by K18 in HL60 and HL60/DOX cells. RESULTS: The expression of membrane relocated PSF was detected every day for three days (at the end of 24 h, 48 h and 72 h) after transient overexpression. The expressing rate of PSF on the cell surface was 22.4%±3.5%, 37.9%±6.0%, 58.3%±8.8%, respectively in sensitive HL60 cells, while that was 4.7%±0.5%, 3.9%±0.6%, 2.9%±0.6% , respectively in resistant HL60/DOX cells. The difference of expressing rate on each day was significant, P<0.01. We identified K18 detected by co-immunoprecipitation and mass spectrum assay which was the cellular chaperone of PSF. We found that K18 knockdown decreased the PSF expression level which redistributed on cell surface from 48.9%±5.4% to 6.2%±1.0% in sensitive HL60 cells, and from 9.11%±1.2% to 2.21%±0.51% in resistant HL60/DOX cells, respectively. CONCLUSION: K18 is the intracellular chaperonin of PSF. The interaction of PSF and K18 mediates its redistribution to cell membrane in sensitive cells. While in resistant cells, PSF failed to relocate at the cell surface and accumulated in cells, which mediated resistance to chemotherapeutics.

[Clinical characteristics and related factors of rheumatoid arthritis complicated with tuberculosis infection].

OBJECTIVE: To investigate the clinical characteristics and high risk factors of Rheumatoid arthritis (RA) complicated with tuberculosis infection. METHODS: Patients with rheumatoid arthritis diagnosed in the hospital of Sichuan Provincial People's Hospital from January 2007 to January 2017 was retrospectively collected, who were enrolled in the study group. A control group was randomly selected from the RA patients hospitalized in the same period without co-infection at a ratio of 1 :2. The general data, clinical data, laboratory test data, treatment plan, etc. of the two groups were collected in detail for single factor statistical analysis. Then multivariate Logistic regression was used to analyze the independent risk factors of RA complicated with tuberculosis infection with statistical significance in univariate analysis. RESULTS: The clinical manifestations of fever (83.3%) were most common, followed by cough (69%) and body mass loss (45.2%). In the infected group, pulmonary tuberculosis accounted for 73.3%. In the infected group the chest CT showed two or more cases, accounting for 59%. There were 9 cases (33.3%) occurring in the typical tuberculosis occurrence site. Compared with the control group, the erythrocyte sedimentation rate (ESR), C-reaction protein (CRP) levels, and the daily average dose of glucocorticoid in 1 year in the infected group were higher than those in the control group. And those differences were statistically significant(P < 0.05). There were no significant differences in gender, age, disease duration, disease activity score, white blood cell (WBC), platelet (PLT), hemoglobin (Hb), immunoglobulin G (IgG), complement (C), Anti cyclic citrullinated peptide antibody (anti-CCP), CD4+T cell count, and immunosuppressant use (P > 0.05). Multivariate Logistic regression analysis showed that CRP levels(OR=1.016, 95%CI:1.002-1.031) and the daily average dose of glucocorticoid in 1 year(OR=1.229, 95%CI:1.066-1.418)were the independent risk factors of RA complica-ted with tuberculosis infection. CONCLUSION: RA patients with tuberculosis infection are mainly phthisis. The clinical manifestations of RA combined with tuberculosis infection are lack of specificity, and the chest imaging features of pulmonary tuberculosis are diverse, which are easy to be misdiagnosed. CRP levels and the daily average dose level of glucocorticoid in 1 year were risk factors for RA and tuberculosis infection.

[Analysis of the safety and efficacy of bronchial thermoplasty for severe asthma with the first second forced expiratory volume (FEV(1)) as a percentage of the predicted value (FEV(1)%pred)<60].

Objective: To investigate the efficacy and safety of bronchial thermoplasty (BT) in severe asthma patients with the first second forced expiratory volume (FEV(1)) as a percentage of the predicted value (FEV(1)%pred) <60%. Methods: A retrospective analysis was performed on 75 patients with asthma who were treated with BT at Shenzhen University Hospital of the Chinese Academy of Sciences from January 2016 to January 2018. The patients were divided into two groups based on the FEV(1)%pred before treatment: FEV(1)%pred <60% group (39 cases) and FEV(1)%pred ≥60% group (36 cases). Comparative analysis of glucocorticoid consumption, times of acute attack, asthma control test (ACT) score, changes in lung function, and adverse reactions at 3 weeks after treatment were performed between the two groups of patients. Results: Before BT treatment, the consumption of oral prednisone, the amount of budesonide inhaled, and the times of acute attack [M (Q(1), Q(3))] in the FEV(1)%pred <60% group were significantly greater than those in the FEV(1)%pred ≥60% group, and the ACT score was significantly lower than the FEV(1)%pred ≥60% group [10.00 (0, 20.00) vs 0(0, 3.75) mg/d, 960 (320, 960) vs 320 (320, 640) µg/d, 5(4, 8) vs 4 (4, 5) times/year, 13 (9, 15) vs 17 (13, 19) scores] (all P<0.05). Except that the oral prednisone dosage in the FEV(1)%pred<60% group was still higher 1 year after treatment [0 (0, 5.00) vs 0 (0, 0) mg/d] (P=0.009), there was no significant difference in the remaining indicators between the two groups 1 year after treatment and 2 years after treatment (all P>0.05). After 1 year and 2 years of treatment, all indicators in the two groups were better than before treatment (all P<0.05). The inhaled budesonide amount and the times of acute exacerbation in the FEV(1)%pred <60% group 2 years after treatment were less than those 1 year after treatment [320 (320, 320) vs 320 (320, 640) µg/d, 0 (0, 0) vs 0(0, 1) times/year] (all P<0.05), and there was no significant difference in the remaining indicators. In the FEV(1)%pred ≥60% group, there was no significant difference between 2 years after treatment and 1 year after treatment in the above indicators except the amount of inhaled budesonide (all P>0.05). In the FEV(1)%pred <60% group, FEV(1) and the FEV(1)%pred were significantly lower than the FEV(1)%pred ≥60% group before treatment, 1 year after treatment and 2 years after treatment [FEV(1):(1.21±0.41) vs (2.26±0.80)L, (1.84±0.73) vs (2.30±0.78)L, (1.70±0.66) vs (2.38±0.76)L; FEV(1)%pred:46.2 (38.5, 53.7)% vs 80.8(66.5, 93.6)%, 60.1 (48.2, 71.6)% vs 87.4 (68.5, 96.5)%, 58.5 (48.6, 74.8)% vs 86.6 (73.0, 97.3)%] (all P<0.05). In the FEV(1)%pred <60% group, FEV(1) and FEV(1)%pred 1 year after treatment and 2 years after treatment were all increased compared with before treatment (all P<0.05). In the FEV(1)%pred ≥60% group, there was no statistical difference in FEV(1) at each time point before and after treatment (all P>0.05), but the FEV(1)%pred at 2 years after treatment was higher than before treatment (P<0.05). There were no significant differences in adverse events between the two groups (all P>0.05). Conclusion: BT can significantly improve the lung function, reduce the times of acute attack and the dosage of glucocorticoids in severe asthma patients with FEV(1)% pred<60%, which is safe and effective.

Activity of a novel 1,3-beta-D-glucan Synthase Inhibitor, Ibrexafungerp (formerly SCY-078), Against Candida glabrata.

Ibrexafungerp (formerly SCY-078), a novel glucan synthase inhibitor with oral availability, was evaluated for activity against Candida glabrata Susceptibility of clinical strains to Ibrexafungerp was determined by microdilution and time kill assays. The MIC range against wild type strains was 1-2 µg/mL. IBX was also active against the majority of echinocandin-resistant strains. Time kill studies showed a 4 to 6-log reduction in growth at concentrations of 0.25 to 4 µg/ml at 24 and 48 hr.

A Novel 1,3-Beta-d-Glucan Inhibitor, Ibrexafungerp (Formerly SCY-078), Shows Potent Activity in the Lower pH Environment of Vulvovaginitis.

Ibrexafungerp (IBX) (formerly SCY-078) is a novel glucan synthase inhibitor whose oral availability is being evaluated for efficacy against vulvovaginal candidiasis (VVC). Bioavailability and in vitro activity are important efficacy indicators, but accepted susceptibility methods do not always accurately predict activity in an acidic environment, such as the vagina. Studies were 3-fold, as follows: (i) pharmacokinetic study following oral administration in a murine model; (ii) susceptibility testing of isolates from a phase 2 VVC clinical trial by CLSI M27-A4 methodology; and (iii) susceptibility testing of Candida albicans and Candida glabrata isolates obtained from this trial group in RPMI 1640 adjusted to 3 different pH values, 7.0, 5.72, and 4.5, compared to susceptibility testing for micafungin and fluconazole. IBX readily accumulated in vaginal tissues and secretions following oral administration. Potent in vitro activity was demonstrated against Candida strains obtained at baseline and end of study visits. Moreover, the geometric mean (GM) values for IBX at pH 4.5 were dramatically lower than those at pH 7.0 and 5.72. The MIC90 values of micafungin remained the same regardless of pH value, while those of fluconazole tended to increase with lower pH values. IBX is able to reach target tissues following oral administration at pharmacologically meaningful levels. IBX demonstrated potent in vitro activity, with no development of resistance, following repeated exposure over the course of the clinical trial. Importantly, activity of IBX in an acidic medium suggests a therapeutic advantage of this novel antifungal in the treatment of vaginal Candida infections.

Spontaneous Magnetic Superdomain Wall Fluctuations in an Artificial Antiferromagnet.

Collective dynamics often play an important role in determining the stability of ground states for both naturally occurring materials and metamaterials. We studied the temperature dependent dynamics of antiferromagnetically ordered superdomains in a square artificial spin lattice using soft x-ray photon correlation spectroscopy. We observed an exponential slowing down of superdomain wall motion below the antiferromagnetic onset temperature, similar to the behavior of typical bulk antiferromagnets. Using a continuous time random walk model we show that these superdomain walls undergo low-temperature ballistic and high-temperature diffusive motions.

Gene deficiency and pharmacological inhibition of caspase-1 confers resilience to chronic social defeat stress via regulating the stability of surface AMPARs.

Both inflammatory processes and glutamatergic systems have been implicated in the pathophysiology of mood-related disorders. However, the role of caspase-1, a classic inflammatory caspase, in behavioral responses to chronic stress remains largely unknown. To address this issue, we examined the effects and underlying mechanisms of caspase-1 on preclinical murine models of depression. We found that loss of caspase-1 expression in Caspase-1-/- knockout mice alleviated chronic stress-induced depression-like behaviors, whereas overexpression of caspase-1 in the hippocampus of wild-type (WT) mice was sufficient to induce depression- and anxiety-like behaviors. Furthermore, chronic stress reduced glutamatergic neurotransmission and decreased surface expression of glutamate receptors in hippocampal pyramidal neurons of WT mice, but not Caspase-1-/- mice. Importantly, pharmacological inhibition of caspase-1-interleukin-1ß (IL-1ß) signaling pathway prevented the depression-like behaviors and the decrease in surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) in stressed WT mice. Finally, the effects of chronic stress on both depression- and anxiety-like behaviors can be mimicked by exogenous intracerebroventricular (i.c.v.) administration of IL-1ß in both WT and Caspase-1-/- mice. Taken together, our findings demonstrate that an increase in the caspase-1/IL-1ß axis facilitates AMPAR internalization in the hippocampus, which dysregulates glutamatergic synaptic transmission, eventually resulting in depression-like behaviors. These results may represent an endophenotype for chronic stress-induced depression.