[The association between frontotemporal connecting fibers and seizure severity in patients with temporal lobe epilepsy].

The patients with temporal lobe epilepsy (TLE) admitted in the Department of Neurology, Zhongshan Hospital, Fudan University from June 2009 to February 2012 were prospectively enrolled. The diffusion tensor imaing was performed on the patients at the time of enrollment and 3 years later. The fractional anisotropy (FA) values of the white matter connecting fibers(bilateral hooked, arcuate, cingulate, and superior longitudinal tracts), the connecting fibers of both hemispheres(anterior union, anterior callosal forceps, posterior forceps, and bilateral fornix), and fibers of perirhinal cortices system(bilateral radiating crown and anterior limb of the internal capsule) were measured by the region of interest method. The severity of epilepsy was evaluated using the Veterans Administration Seizure Type and Frequency Rating Scale(VA-2) and National Hospital Seizure Severity Scale (NHS3). A total of 51 patients with TLE were screened, with 27 patients completing the 3-year follow-up. There were 13 males and 14 females with an age of (32±11) years and a follow-up duration of (39.1±1.1) months. During the follow-up, 6 patients had increased/unchanged NHS3 or VA-2 scores, while 21 patients had decreased scores. Three years later, the FA values of the bilateral arcuate fasciculus, the right superior longitudinal fasciculus, the right radial coronal and corpus callosum anterior forceps in TLE patients decreased compared to baseline(P<0.05). However, compared to the patients with decreased VA-2 scores during the follow-up, the degree of increase in FA values (ΔFA, follow-up FA value-baseline FA value) of the ipsilateral hook bundle caused by epilepsy was more significant in the group with increased/unchanged VA-2 scores (decreased score group vs increased/unchanged score group:-0.032±0.063 vs 0.018±0.043, t=2.305, P=0.035). The value of ΔFA in epileptic patients with increased/unchanged NHS3 scores (0.075±0.113) was higher compared to those with decreased scores (-0.079±0.099, t=2.804, P=0.010). Correlation analysis also showed the changes in FA values of epileptic lateral fasciculus (r=0.503, P=0.009) and arcuate fasciculus (r=0.602, P=0.001)were positively correlated with the changes in VA-2 and HNS3 scores, respectively. The seizure severity in patients with TLE was closely associated with the microstructure changes in the frontal and temporal white matter, especially the arcuate and uncinate tracts, on the same side that caused seizures, which may indicate the white matter remodeling and abnormal network reformation associated with seizures.

[Transperineal targeted prostate puncture combined with rapid pathological examination in the diagnosis of prostate cancer].

Exploring the clinical value of multiparametric magnetic resonance (Mp-MRI)-cognitive fusion method of targeted transperineal prostate puncture combined with rapid pathological diagnosis. Patients with suspected prostate cancer admitted to our hospital from 2022.01 to 2023.05 were selected as the study subjects, and Mp-MRI was performed and the suspected lesions were scored by the Prostate Imaging Reporting and Data System (PI-RADS). The enrolled patients were randomly divided into the transperineal prostate targeted puncture plus rapid pathology group (experimental group) and the transperineal prostate systematic combined targeted puncture plus conventional pathology group (control group), and the positive puncture rate, pathological findings, and complications were analyzed to compare the differences between the two groups. A total of 100 patients were enrolled, 53 in the experimental group [age 55-89 years, (73.17±7.79) years; tPSA 7.01-100 µg/L, mean 21.34 (12.38, 44.42) µg/L]and 47 in the control group [age 60-87 years, (71.96±7.07) years; tPSA 6.11-98.82 µg/L, mean 18.77 (9.04, 38.09) µg/L], and there was no significant difference between the two groups in the diagnostic positivity rate of overall PCa and clinically significant PCa (P>0.05); there was no significant difference in the highest Gleason score of pathological tissues between the two groups (P>0.05); the number of cases of medically induced sarcoid hematuria in the experimental group were significantly reduced compared with the control group (P<0.05). In terms of biopsy pain score (VAS), patients in the experimental group experienced less pain than those in the control group (P<0.05). The Mp-MRI-cognitive fusion method of transperineal targeted prostate puncture combined with rapid frozen section pathological examination can provide rapid and accurate pathological results, reduce the chance of post-puncture complications, and alleviate the pain caused by puncture sampling, which has high clinical value.

Minimizing thermal damage using self-cooling jaws for radiofrequency intestinal tissue fusion.

INTRODUCTION: Radiofrequency (RF)-induced tissue fusion shows great potential in sealing intestinal tissue without foreign materials. To improve the performance of RF-induced tissue fusion, a novel self-cooling jaw has been designed to minimize thermal damage during the fusion. MATERIAL AND METHODS: The prototype of self-cooling jaws was developed and manufactured. A total number of 60 mucosa-to-mucosa fusions were conducted using ex-vivo porcine intestinal segments with the proposed design and conventional bipolar jaws. The effects of intestinal fusion were evaluated based on temperature curves, burst pressure, thermal damage, and histological appearances. RESULTS: The self-cooling jaws showed significant decrease in temperature during the fusion process. An optimal burst pressure (5.7 ± 0.5 kPa) and thermal damage range (0.9 ± 0.1 mm) were observed when the applied RF power was 100 W. The thermal damage range of the prototype has almost decreased 36% in comparison with the conventional bipolar jaws (1.4 ± 0.1 mm). The histological observation revealed that a decrease of thermal damage was achieved through the application of self-cooling jaws. CONCLUSIONS: The self-cooling jaws were proved to be effective for reducing the thermal damage during RF-induced tissue fusion, which could potentially promote the clinical application of tissue fusion techniques in the future.

Toripalimab (anti-PD-1) versus high-dose interferon-α2b as adjuvant therapy in resected mucosal melanoma: a phase II randomized trial.

BACKGROUND: No standard of care for mucosal melanoma (MM) in the adjuvant setting has been established. Meanwhile, relapse-free survival (RFS) is only ∼5 months after surgery alone. This phase II trial aimed to compare toripalimab versus high-dose interferon-α2b (HDI) as an adjuvant therapy for resected MM. PATIENTS AND METHODS: From July 2017 to May 2019, 145 patients with resected MM were randomized (1 : 1) to receive HDI (n = 72) or toripalimab (n = 73) for 1 year until disease relapse/distant metastasis, unacceptable toxicity, or withdrawal of consent. The primary endpoint was RFS. The secondary endpoints included distant metastasis-free survival (DMFS), overall survival (OS), and safety. RESULTS: After a median follow-up of 26.3 months, the number of RFS, OS, and DMFS events was 51 versus 46, 33 versus 29, and 49 versus 44 in the toripalimab arm and the HDI arm, respectively. The median RFS was 13.6 [95% confidence interval (CI) 8.31-19.02] months and 13.9 (95% CI 8.28-19.61) months in the toripalimab arm and the HDI arm, respectively. The DMFS was not significantly different between the two arms [hazard ratio (HR) 1.00; 95% CI 0.65-1.54]. The median OS was 35.1 months (95% CI 27.93 months-not reached) in the toripalimab arm, with no significant difference in all-cause death (HR 1.11, 95% CI 0.66-1.84) for the two arms. The median sums of the patients' actual infusion doses were 3672 mg and 1054.5 MIU in the toripalimab arm and the HDI arm, respectively. The incidence of treatment-emergent adverse events with a grade ≥3 was much higher in the HDI arm than in the toripalimab arm (87.5% versus 27.4%). CONCLUSIONS: Toripalimab showed a similar RFS and a more favorable safety profile than HDI, both better than historical data, suggesting that toripalimab might be the better treatment option. However, additional translational studies and better treatment regimens are still warranted to improve the clinical outcome of MM.

[Value of radiomics model based on dynamic contrast-enhanced magnetic resonance imaging in differentiation fat-poor angiomyolipoma from alpha-fetoprotein-negative hepatocellular carcinoma in the background of non-cirrhotic liver].

Objective: To explore the value of radiomics model based on dynamic contrast-enhanced magnetic resonance imaging (MRI) in differentiation fat-poor angiomyolipoma (fp-AML) from alpha-fetoprotein-negative hepatocellular carcinoma (n-HCC) in the background of non-cirrhotic liver. Methods: The complete data of 121 patients from Guangdong Provincial People's Hospital, Zhongshan Hospital Affiliated to Fudan University and Sun Yat-sen University Cancer Center with hepatic fp-AML and n-HCC confirmed by pathology from October 2010 to July 2020 were retrospectively analyzed. Among them, 75 were males and 46 were females, aged from 23 to 80 (55±12) years. A total of 93 patients from Zhongshan Hospital Affiliated to Fudan University were divided into the training cohort (n=75) and internal test cohort (n=18) according to entry time, and the patients of other 2 hospitals were divided into external test cohort (n=28). The radiomics features were extracted from the preoperative triple-phase contrast-enhanced images. The feature selection algorithm based on Joint Mutual Information Maximisation (JMIM) was used to extract the optimal feature subset, and support vector machine (SVM) was used to build the radiomics model. The diagnostic performance of radiomics model was evaluated using the receiver operating characteristic (ROC) curve, and was compared with that of two radiologists. Results: In the internal cohort, the area under the curve (AUC) for the differential diagnosis between fp-AML and n-HCC of the radiomics model was 0.819 (with an accuracy of 72.2%), outperforming than radiologist 1 with 10 years of diagnostic experience (AUC=0.542, P=0.029) and radiologist 2 with 2 years of diagnostic experience (AUC=0.375, P=0.004). In the external cohort, the AUC of the radiomics model was 0.772 (with and accuracy of 71.4%), which was comparable to that of radiologist 1 (AUC=0.661, P=0.442) and better than that of radiologist 2 (AUC=0.400, P=0.008). Conclusion: The radiomics model based on dynamic contrast-enhanced MRI is of high accuracy for preoperatively differentiating hepatic fp-AML from n-HCC in the noncirrhotic liver.

[Risk factors of newly developed nonalcoholic fatty liver disease after pancreaticoduodenectomy].

Objective: To identify the risk factors of newly developed nonalcoholic fatty liver disease(NAFLD) after pancreaticoduodenectomy(PD). Methods: The clinical data of 130 patients who had undergone PD at Department of Hepatopancreatobiliary Surgery, Nanjing Drum Tower Hospital, the Affiliated Hospital of Medical School of Nanjing University from June 2018 to December 2020 were collected retrospectively. There were 74 males and 56 females, with age(M(IQR)) of 62(16) years (range: 22 to 84 years). Twenty-nine patients who developed NAFLD were divided into NAFLD group and 101 patients who did not suffer NAFLD were divided into no NAFLD group. Observation indications included:(1)preoperative demographics,intraoperative and postoperative characteristics; (2)the risk factors of newly developed NAFLD after PD. Count data were analyzed using χ2 test or Fisher's exact test. Measurement data were analyzed by student t test or Mann-Whitney U test. Multivariate analysis was performed using Logistic regression model with a stepwise forward approach. Results: All 130 patients successfully underwent PD and 29 cases(22.3%) developed NAFLD in 6 months after PD. The results of univariate analysis showed that gender,diabetic mellitus,the level of triglyceride preoperatively,and pancreatic ductal adenocarcinoma were the related factors of the development of NAFLD after PD(t=-2.655, χ²=4.563,U=-2.192,χ²=7.044;all P<0.05).Multivariate analysis revealed that gender,body mass index and pancreatic ductal adenocarcinoma were independent risk factors for the development of NAFLD after PD(OR=2.849,1.214,4.165,all P<0.05). Conclusion: Gender, body mass index and pancreatic ductal adenocarcinoma were independent risk factors for the development of NAFLD after PD.

[Investigation of newly diagnosed pneumoconiosis from artificial quartz stone manufacturers].

Artificial quartz dust exposure may cause associated pneumoconiosis. From November 2019 to July 2020, a total of 27 cases of silicosis associated with artificial quartz stone manufacturers were diagnosed and treated in the Occupational disease Department of Suzhou Fifth People's Hospital. The average age of onset was (46.8±6.6) years, and the average working age of dust exposure was (5.7±1.7) years.The main feature of high KV chest radiography is P/S shadow with strip shadow. CT imaging findings showed diffuse small nodules and ground glass shadows with band shadows. The lesions were mainly distributed in the upper lung, accompanied by pleural thickening, lymphadenopathy and calcification. The pulmonary function impairment was mainly mild restrictive ventilation disorder, and the bronchial mucosa longitudinal plica was the main manifestation under tracheoscopy. The age of silicosis of workers in artificial quartz stone production enterprises is younger, the working age of dust exposure is short, the lung function and bronchial mucosa have a certain degree of damage, and effective preventive measures should be taken in time.

Cognitive ageing is premature among a community sample of optimally treated people living with HIV.

OBJECTIVES: Evidence of premature cognitive ageing amongst people living with HIV (PLHIV) remains controversial due to previous research limitations including underpowered studies, samples with suboptimal antiretroviral access, varying rate of virological control, high rate of AIDS, over-representation of non-community samples, and inclusion of inappropriate controls. The current study addresses these limitations, while also considering mental health and non-HIV comorbidity burden to determine whether PLHIV showed premature cognitive ageing compared with closely comparable HIV-negative controls. METHODS: This study enrolled 254 PLHIV [92% on antiretroviral therapy; 84% with HIV RNA < 50 copies/mL; 15% with AIDS) and 72 HIV-negative gay and bisexual men [mean (SD) age = 49 (10.2) years] from a single primary care clinic in Sydney, Australia. Neurocognitive function was evaluated with the Cogstate Computerized Battery (CCB) at baseline and 6 months after. Linear mixed-effects (LME) models examined main and interaction effects of HIV status and chronological age on the CCB demographically uncorrected global neurocognitive z-score (GZS), adjusting for repeated testing, and then adjusting sequentially for HIV disease markers, mental health and comorbidities. RESULTS: HIV status and age interacted with a lower GZS (ß = -0.43, P < 0.05). Higher level of anxiety symptoms (ß = -0.11, P < 0.01), historical AIDS (ß = -0.12, P < 0.05) and historical HIV brain involvement (ß = -0.12, P < 0.05) were associated with lower GZS. CONCLUSIONS: We found a robust medium-sized premature ageing effect on cognition in a community sample with optimal HIV care. Our study supports routine screening of cognitive and mental health among PLHIV aged ≥ 50 years.

[Source investigation on a familiar cluster of coronavirus disease 2019 in Dandong city of Liaoning Province].

To Track the source of the infection through an investigation of a clustering of coronavirus disease 2019(COVID-19), and provide scientific basis and Strategy for the effective control of the aggregated epidemic situation of COVID-19. Field epidemiological method was used to survey the cases and related close contacts in a family clustering epidemic of COVID-19 in Dandong city of Liaoning Province. We obtained survey data for a descriptive analysis.Real time RT-PCR technique was used to detect 2019-nCoV nucleic acid in samples collected from cases and related close contacts combined with serum specific antibody detection. A total of 3 confirmed cases and 2 asymptomatic infection cases were discovered in the clustering epidemic, with 34 close contacts.Of eight close family contacts visiting from other province, one patient was on the same flight as the confirmed case, and her antibody IgG was positive. The family clustering was caused by past infection case who visited her friend through Wuhan from other provinces to local area.

[Surgical treatment of Stanford type A aortic dissection after thoracic endovascular aortic repair].

Objective: To examine the surgical treatment of Stanford type A aortic dissection (type A dissection) after thoracic endovascular aortic repair (TEVAR). Methods: The data of 58 patients with reoccurrence of type A dissection after TEVAR admitted into the Department of Cardiovascular Surgery, Henan Chest Hospital from February 2012 to January 2020 were analyzed retrospectively. There were 40 males and 18 females, aged (57.0±6.7) years (range: 31 to 71 years). The time between recurrence of type A dissection and TEVAR (M(QR)) was 37 days (72.8 months) (range: 1 h to 14 years). Forty-eight cases underwent emergency operation, 9 cases underwent sub-emergency operation, and 1 case died of dissection rupture on the way to the operating room. All 57 patients underwent radical treatment. Fifty-four cases underwent the frozen elephant trunk technique under deep hypothermia circulatory arrest and selective cerebral perfusion, and 3 cases (>65 years old) underwent arch debranch anastomosis+ascending aorta replacement+descending arch covered stent implantation under mild hypothermia. Results: The operation time was (445±32) minutes (range: 382 to 485 minutes), the aortic crossclamp time was (103±19) minutes (range: 89 to 133 minutes), the cardiopulmonary bypass time was (189±27) minutes (range: 162 to 221 minutes), and the intraoperative blood loss was (665±343) ml (range: 450 to 1 750 ml). Postoperative ICU stay time was 5 (6) days (range: 2 to 27 days), and postoperative hospital stay was 14.0 (4.5) days (range: 2 to 36 days). Three cases died, including 2 cases with severe brain complications and 1 case with systemic multiple organ failure caused by severe liver insufficiency and gastrointestinal hemorrhage. Postoperative follow-up was 0.5 to 7.0 years, which showed that 1 case had left coronary artery anastomotic stoma fistula 3 months after operation and underwent reoperation, 2 cases underwent thoracoabdominal aortic replacement again, and the rest of patients had no anastomotic stoma fistula and incomplete stent distortion and expansion on CT angiography. Four cases died during follow-up, and 1 case died of sudden cerebral infarction 2 years after operation. Conclusion: The recurrent type A dissection after TEVAR is mostly related to stent graft, and the patients can undergo operation actively with good prognosis.

[Analysis of the detection of metals and metalloids in the bronchoalveolar lavage fluid for the etiological diagnosis value of pneumoconiosis].

Objective: To analyze the differences of the concentrations of metals and metalloids in bronchoalveolar lavage fluid (BALF) of patients with pneumoconiosis, so as to provide reference for the etiological diagnosis of pneumoconiosis. Methods: From September 2019 to August 2020, 47 pneumoconiosis patients hospitalized in Chongqing Prevention and Treatment Center for Occupational Diseases and undergoing bronchoalveolar lavage were selected as the research objects using cluster sampling method. The general situation and occupational history of patients were investigated by questionnaire, The BALF of 47 pneumoconiosis patients was collected, and the concentrations of metals and metalloids in BALF were detected by inductively coupled plasma mass spectrometry (ICP-MS) , the differences among patients with different types of pneumoconiosis, different stages of silicosis and different occupational history were analyzed by one-way ANOVA. Results: The concentrations of 50 metals and metalloids in BALF were detected, and 21 of them were analyzed. Compared with different types of pneumoconiosis, the concentrations of Zn, Mn and Sn in BALF were statistically significant (F=9.959, 3.635, 9.488, P<0.05) . The concentrations of K, Mg, Fe, Zn, Cu and Ni in BALF were significantly different in different stages of silicosis (F=4.271, 4.334, 3.588, 5.120, 7.340, 3.905, P<0.05) . The concentrations of Zn and Sn in pneumoconiosis patients with different types of work and types of exposed dust were significantly different (P<0.05) . Conclusion: The detection of Zn, Mn, Sn, and other metals in BALF can provide reference basis for the etiological diagnosis of pneumoconiosis and provide a new idea for the diagnostic method of pneumoconiosis.

Using IL-2R/lymphocytes for predicting the clinical progression of patients with COVID-19.

Effective laboratory markers for the estimation of disease severity and predicting the clinical progression of coronavirus disease-2019 (COVID-19) is urgently needed. Laboratory tests, including blood routine, cytokine profiles and infection markers, were collected from 389 confirmed COVID-19 patients. The included patients were classified into mild (n = 168), severe (n = 169) and critical groups (n = 52). The leukocytes, neutrophils, infection biomarkers [such as C-reactive protein (CRP), procalcitonin (PCT) and ferritin] and the concentrations of cytokines [interleukin (IL)-2R, IL-6, IL-8, IL-10 and tumor necrosis factor (TNF)-α] were significantly increased, while lymphocytes were significantly decreased with increased severity of illness. The amount of IL-2R was positively correlated with the other cytokines and negatively correlated with lymphocyte number. The ratio of IL-2R to lymphocytes was found to be remarkably increased in severe and critical patients. IL-2R/lymphocytes were superior compared with other markers for the identification of COVID-19 with critical illness, not only from mild but also from severe illness. Moreover, the cytokine profiles and IL-2R/lymphocytes were significantly decreased in recovered patients, but further increased in disease-deteriorated patients, which might be correlated with the outcome of COVID-19. Lymphopenia and increased levels of cytokines were closely associated with disease severity. The IL-2R/lymphocyte was a prominent biomarker for early identification of severe COVID-19 and predicting the clinical progression of the disease.

CCL18 overexpression predicts a worse prognosis in oral squamous cell carcinoma (OSCC).

Oral squamous cell carcinoma (OSCC) presents severe morbidity and high mortality owing to local recurrence or remote metastasis. Molecular markers, including chemokines, might provide more efficient prognostic information or even therapeutic targets for the treatment of OSCC. Using quantitative RT-qPCR, we found that CCL18 was dramatically overexpressed in 30 OSCC tissues at the mRNA level in comparison with their adjacent non-cancerous oral mucosa tissues and 15 oral mucosa tissues from non-malignant patients. We then analyzed the relationship between CCL18 overexpression and patient clinical characters and outcomes using immunohistochemistry staining (IHC) in 102 paired OSCC cancerous and adjacent non-cancerous tissues; the increase in CCL18 expression was significantly higher in male patients (p=0.047), tumors of the palate and floor of the mouth (p=0.014), patients with positive lymph node metastasis (p=0.007), and patients with poor tumor differentiation (p=0.029). The median overall survival time and time-to-recurrence were 80.6 and 61.4 months in patients with high CCL18 expression, respectively, as against 93.4 and 81.6 months in patients with comparatively lower CCL18 expression, respectively (p=0.033 and 0.012, respectively; log-rank test). Multivariate analyses indicated age, poor differentiation, and CCL18 levels to be independent prognostic factors for predicting both overall and disease-free survival time. Our study suggests that CCL18 is a novel candidate marker for the OSCC malignancy and prognosis, including lymph node metastasis, time-to-recurrence, and disease-free survival time.

[Abnormalities of white matter differentiate the Parkinson variant of multiple system atrophy from Parkinson's disease].

Objective: To identify objective markers between the Parkinson variant of multiple system atrophy (MSA-P) and Parkinson's disease (PD). Methods: Retrospective analysis was performed on 10 patients with MSA-P, 15 patients with PD, and 15 healthy control group during the period from August 2016 to February 2019 in Baoshan Branch of Shanghai First People's Hospital.We combined the novel tract based spatial statistics (TBSS) and region of interest (ROI) analyses for the first time to investigate three groups with diffusion tensor imaging. By TBSS, we performed pairwise comparisons of mean diffusivity and fractional anisotropy (FA) maps. The clusters with significant differences between MSA-P and PD were used as ROIs for further analyses. Results: FA values in the left anterior thalamic radiation(ATR) (ROI values were 0.371(0.287-0.535), 0.472(0.390-0.594), 0.473(0.388-0.555); P values were 0.008, 0.008) and left superior longitudinal fasciculus (SLF)(ROI values were 0.397(0.291-0.469), 0.456(0.338-0.560), 0.473(0.427-0.530); P values were 0.013,<0.001) were significantly decreased in MSA-P compared with PD or controls, and significantly correlated with clinical data((r =-0.807, P =0.005),(r =-0.455, P =0.022)). Conclusion: Our findings indicate the abnormalities of left ATR and left SLF as specific biomarkers for differential diagnosis.

[Evaluation of drug-drug interactions between yimitasvir phosphate capsules with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets].

Objective: To evaluate the drug-drug interactions and the tolerability of combined medication between yimitasvir phosphate capsules with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets in healthy volunteers. Methods: A randomized, open, and continuous administration design was used in trial 1 (yimitasvir phosphate capsules with sofosbuvir tablets). 28 subjects were randomly divided into two groups. A non-randomized, open design was used in trial 2 (yimitasvir phosphate capsules with omeprazole magnesium enteric-coated tablets), and included 42 subjects divided into three groups. The open design method was used in trial 3 (yimitasvir phosphate capsules with rosuvastatin calcium tablets), and included 14 subjects. The plasma concentrations of yimitasvir phosphate, sofosbuvir and their main metabolites GS-331007, omeprazole and rosuvastatin were validated by a liquid chromatography/tandem mass spectrometry (LC-MS/MS). The pharmacokinetic parameters were calculated by Phoenix winNonlin software. Results: (1) in trial 1, after single and co-administration, the 90% CI of sofosbuvir C(max) and AUC(0-tau) geometric mean ratio (GMR) were 152.0% (118.0% ~ 197.0%) and 230.0% (184.0% ~ 287.0%), with an increase of 52.0% and 130.0% compared to single dose of sofosbuvir, respectively. The 90% CI of GS-331007 C(max) GMR was 74.0% (67.5% ~ 81.2%) and reduced by 26% compared to single dose of sofosbuvir. (2) in trial 2, the 90% CI of C(max) GMR after yimitasvir single or co-administration at the same time, with a 4-hours interval, or with a 12- hours interval were 68.9% (44.5% ~ 106.7%) , 64.0% (43.8% ~ 93.6%) and 56.4%(38.9% ~ 81.9%), and the 90% CI of AUC(0-t) GMR were 68.6% (46.5% ~ 101.2%), 68.3% (47.6% ~ 98.0%) and 60.5% (41.8% ~ 87.5%), respectively. Compared with single dose of yimitasvir, the C(max) and AUC(0-t) were decreased by 31.1% and 31.4%, 36.0% and 31.7%, 43.6% and 39.5%, respectively. (3) In trial 3, after single and co-administration, the 90% CI of rosuvastatin C(max) and AUC(0-72) GMR were 172.4% (153.6% ~ 193.5%) and 158.0% (144.3% ~ 172.9%), respectively, with an increase of 74.9% and 60.5% compared to single dose of rosuvastatin. There were no serious adverse events and adverse events leading to withdrawal from the trial. Conclusion: Yimitasvir phosphate capsules have drug-drug interactions with sofosbuvir tablets, omeprazole magnesium enteric-coated tablets, and rosuvastatin calcium tablets.

[The value of adenosine triphosphate in CD4(+)T lymphocytes in predicting repeated respiratory tract infections in silicosis patients].

Objective: To explore the value of the concentration of adenosine triphosphate (ATP) in CD4(+)T lymphocytes in predicting repeated respiratory tract infections (RRTI) in silicosis patients. Methods: In April 2020, 614 silicosis patients admitted from March 2016 to March 2018 were included in the study, and they were divided into the RRTI group (n=105) and the non RRTI group (n=509) according to whether the occurrence of RRTI, another 30 healthy cases taken from body check were served as control group, and the concentrations of ATP produced by CD4(+)T lymphocytes was measured by ImmuKnow assay, and were compared between the three groups. And drawed the receiver operating characteristic (ROC) curve, and the Logistic regression analysis was used to explore the risk factors of RRTI. Results: The incidence of RRTI in silicosis patients was 17.10% (105/614) . The concentration of ATP produced by CD4(+)T lymphocytes in the RRTI group [ (260.42±90.36) mg/L] was significantly lower than that in the non RRTI group [ (413.66±138.74) mg/L] (t=-10.849, P<0.01) . The area under the ROC curve was 0.834, the cutoff value was 284 mg/L, the sensitivity was 0.88, and the specificity was 0.83. Logistic regression analysis showed that the concentration of ATP produced by CD4(+)T lymphocytes≤284 mg/L, impaired pulmonary ventilation function, serum albumin<40 g/L and diabetes were the risk factors of RRTI in silicosis patients (OR=2.126, 1.217, 1.164, 1.125, P<0.05) . Conclusion: Low CD4(+)T lymphocyte ATP value was a risk factor of RRTI in silicosis patients, and can predict the risk of RRTI in patients with silicosis.

[Analysis on characteristic of patients with stage I coal worker's pneumoconiosis].

Objective: To compare the clinical and imaging characteristics of patients with stage I coal worker's pneumoconiosis (CWP) . Methods: All 347 cases of coal workers' pneumoconiosis diagnosed in the Third Hospital of Peking University from January 2014 to December 2018 were included in the study. According to different working posts, the subjects were divided into three categories: mining, tunneling and mixing workers. Dust exposure duration, initial dust exposure age, diagnosis age, latency, small shadow shape and lung regions distribution in X-ray chest film of different categories of CWP patients were analyzed. Results: Among the 347 patients, 216 were mining workers (62.2%) , 77 were tunneling workers (22.2%) and 54 were mixing workers (15.6%) . The dust exposure duration of mining, tunneling and mixing workers were (14.5±7.0) , (16.3±8.2) and (19.0±8.8) years, respectively. There are statistically significant differences in dust exposure duration between different categories of workers (P<0.05) . There were no significant difference in the age of diagnosis, initial dust exposure age and the latency between different categories of workers (P>0.05) . The X-ray films of mining, tunneling and mixing workers showed small round shadow, accounting for 50.9% (110/216) , 96.1% (74/77) and 96.3% (52/54) respectively. 48.1% (104/216) of the mining workers and 38.9% (21/54) of mixing workers, the distribution of small shadow in chest X-ray films reached middle and lower lung regions, while in the 48.1% (37/77) of the tunneling workers, the distribution of small shadow in chest X-ray films reached lower lung regions. There were differences in above indicators among workers with different categories (P<0.05) . Conclusion: The dust exposure duration, the shape and the distribution of lung area on chest X-ray films are different in stage I CWP patients of different occupational categories.

[The study on the role of extracellular histones in the pathogenesis of coal worker's pneumoconiosis].

Objective: To explore the role of extracellular histones in the pathogenesis of coal worker's pneumoconiosis (CWP) , the relationship of extracellular histones in plasma with pulmonary fibrosis caused by coal mine dust was analyzed, and the stimulating effect of extracellular histones on fibroblast proliferation was studied. Methods: In May 2019, a total of 220 coal mine dust exposure workers (including coal miners and CWP patients) who visited the occupational disease outpatient department of Peking University Third Hospital from 2012 to 2015 were enrolled in the study. According to the classification of small opacity profusion (SOP) in chest radiograph for pneumoconiosis diagnosis (category 0, 1, 2, 3) , 61 coal miners were in category 0 SOP, 65 coal miners were in category 1 SOP, 56 coal miners were in category 2 SOP and 38 coal miners were in category 3 SOP. The plasma levels of extracellular histone H4 and platelet-derived growth factor (PDGF) were measured by enzyme-linked immunosorbent assay (ELISA) kit. The stimulating effects of CWP patients' plasma and calf thymus histones (CTHs) on fibroblast and the antagonizing effect of anti-H4 antibody were investigated by fibroblast proliferation experiment in vitro. Results: Among the study subjects, there were 195 males (88.6%, 195/220) and 25 females (11.4%, 25/220) , age (55.1±7.2) years, coal mine dust exposure time (16.3±4.4) years. The plasma concentrations of histone H4 in the coal miners with category 0, 1, 2 and 3 SOP were (3.92±1.75) 、(9.84±4.17) 、(14.35±5.52) and (17.83±7.69) µg/ml, respectively. There were significant differences among the four groups (P<0.01) . The plasma level of histone H4 was positively correlated with the plasma level of PDGF in the coal miners (r=0.769, P<0.01) . Compared with healthy control plasma group, the cell proliferation percentages of patients' plasma group (272%±87%) and CTH group (283%±84%) were significantly increased (P<0.05) . Compared with patients' plasma group, the cell proliferation percentage of patients' plasma+anti-H4 antibody group (185%±66%) was significantly decreased (P<0.05) . Compared with CTH group, the cell proliferation percentage of CTH+anti-H4 antibody group (167%±59%) was significantly decreased (P<0.05) . Conclusion: Extracellular histones in plasma are associated with pulmonary fibrosis in patients with CWP. Studies in vitro have shown that extracellular histones can promote proliferation of pulmonary fibroblasts. It is suggested that extracellular histones can be important biomarkers for pulmonary fibrosis caused by coal mine dust.

Novel small molecule IL-6 inhibitor suppresses autoreactive Th17 development and promotes Treg development.

Multiple sclerosis (MS) is the leading cause of non-traumatic neurological disability in the United States in young adults, but current treatments are only partially effective, making it necessary to develop new, innovative therapeutic strategies. Myelin-specific interleukin (IL)-17-producing T helper type 17 (Th17) cells are a major subset of CD4 T effector cells (Teff ) that play a critical role in mediating the development and progression of MS and its mouse model, experimental autoimmune encephalomyelitis (EAE), while regulatory T cells (Treg ) CD4 T cells are beneficial for suppressing disease. The IL-6/signal transducer and activator of transcription 3 (STAT-3) signaling pathway is a key regulator of Th17 and Treg cells by promoting Th17 development and suppressing Treg development. Here we show that three novel small molecule IL-6 inhibitors, madindoline-5 (MDL-5), MDL-16 and MDL-101, significantly suppress IL-17 production in myelin-specific CD4 T cells in a dose-dependent manner in vitro. MDL-101 showed superior potency in suppressing IL-17 production compared to MDL-5 and MDL-16. Treatment of myelin-specific CD4 T cells with MDL-101 in vitro reduced their encephalitogenic potential following their subsequent adoptive transfer. Furthermore, MDL-101 significantly suppressed proliferation and IL-17 production of anti-CD3-activated effector/memory CD45RO+ CD4+ human CD4 T cells and promoted human Treg development. Together, these data demonstrate that these novel small molecule IL-6 inhibitors have the potential to shift the Teff  : Treg balance, which may provide a novel therapeutic strategy for ameliorating disease progression in MS.

Calhm2 governs astrocytic ATP releasing in the development of depression-like behaviors.

Extracellular ATP is a widespread cell-to-cell signaling molecule in the brain, where it functions as a neuromodulator by activating glia and neurons. Although ATP exerts multiple effects on synaptic plasticity and neuro-glia interactions, as well as in mood disorders, the source and regulation of ATP release remain to be elaborated. Here, we define Calhm2 as an ATP-releasing channel protein based on in vitro and in vivo models. Conventional knockout and conditional astrocyte knockout of Calhm2 both lead to significantly reduced ATP concentrations, loss of hippocampal spine number, neural dysfunction and depression-like behaviors in mice, which can be significantly rescued by ATP replenishment. Our findings identify Calhm2 as a critical ATP-releasing channel that modulates neural activity and as a potential risk factor of depression.