The PA-PB1 interface of the influenza polymerase is an attractive site for antiviral drug design. In this study, we designed and synthesized a mini-library of indazole-containing compounds based on rational structure-based design to target the PB1-binding interface on PA. Biological evaluation of these compounds through a viral yield reduction assay revealed that compounds 27 and 31 both had a low micromolar range of the half maximal effective concentration (EC₅₀) values against A/WSN/33 (H1N1) (8.03 μmol/L for 27; 14.6 μmol/L for 31), while the most potent candidate 24 had an EC₅₀ value of 690 nM. Compound 24 was effective against different influenza strains including a pandemic H1N1 strain and an influenza B strain. Mechanistic studies confirmed that compound 24 bound PA with a K _d which equals to 1.88 μmol/L and disrupted the binding of PB1 to PA. The compound also decreased the lung viral titre in mice. In summary, we have identified a potent anti-influenza candidate with potency comparable to existing drugs and is effective against different viral strains. The therapeutic options for influenza infection have been limited by the occurrence of antiviral resistance, owing to the high mutation rate of viral proteins targeted by available drugs. To alleviate the public health burden of this issue, novel anti-influenza drugs are desired. In this study, we present our discovery of a novel class of indazole-containing compounds which exhibited favourable potency against both influenza A and B viruses. The EC₅₀ of the most potent compounds were within low micromolar to nanomolar concentrations. Furthermore, we show that the mouse lung viral titre decreased due to treatment with compound 24. Thus our findings identify promising candidates for further development of anti-influenza drugs suitable for clinical use.

Lung cancer is the top cause of cancer deaths globally.Advances in immune checkpoint inhibitors(ICIs)have transformed cancer treatment,but their use in lung cancer has led to more side effects.This study examined if past pulmonary tuberculosis(TB)affects ICIs'effectiveness and safety in lung cancer treatment.We reviewed lung cancer patients treated with ICIs at Beijing Chest Hospital from January 2019 to August 2022.We compared outcomes and side effects between patients with and without prior TB.Of 116 patients(40 with TB history,76 without),prior TB didn't reduce treatment effectiveness but did increase severe side effects.Notably,older patients(≥65 years)faced a higher risk of severe side effects.Detailed cases of two patients with severe side effects underscored TB as a risk factor in lung cancer patients receiving ICIs,stressing the need for careful monitoring and personalized care.

Objectives: The primary aim of this study is to discern the association between specific clinical parameters and low muscle mass (LMM). We endeavor to elucidate the determinants of LMM and the predictive potency of individual factors. Methods: In this retrospective cross-sectional study, we encompassed 450 older adult Chinese participants (252 males and 198 females). Muscle mass quantifications were performed using bioelectrical impedance analysis.Comprehensive data encompassing demographic details (age, sex, height, and weight) and laboratory results (complete blood count, thyroid function, liver function, and renal function) were systematically recorded. Lo gistic regression models, coupled with receiver operating characteristic curve analytics, were employed to ascertain the variables influencing LMM and to evaluate the predictive validity of each parameter on LMM. Results: Upon confounding adjustment for age, gender, body mass index (BMI), and free thyroxine (FT4) persisted as a determinant of LMM. Specifically, individuals with an FT4 exceeding 1.105 ng/dL exhibited a 1.803-fold increased propensity for LMM relative to those with FT4 values below the specified threshold. Incorporating age, gender, BMI, and FT4 in the diagnostic algorithm enhanced the precision of LMM. The results differ between men and women. In the male population, we can still observe that FT4 has a certain value in the diagnosis of LMM, but this phenomenon is not found in the female population. Conclusions Elevated FT4 concentrations, albeit within clinically accepted limits, are inversely associated with muscle mass. As such, FT4 could be postulated as a potential biomarker for LMM in geriatric individuals, especially in the male group.

Objective To observe the application effect of magnetic resonance imaging technology in evaluating the brain structure and function of patients with type 2 diabetic painful neuropathy (PDN). Methods Forty patients with type 2 diabetes mellitus hospitalized in our hospital were selected as the study objects, and were divided into diabetes mellitus (DM) group (n=12), peripheral neuropathy (DPN) group (n=14) and PDN group (n=14). General clinical biochemical indexes of three groups were analyzed. The structural brain and function of brain area in three groups were compared. Results Age, duration of diabetes, systolic blood pressure, diastolic blood pressure, fasting blood glucose (FBG), glycosylated hemoglobin (HbA1c), free fatty acid (FFA), albumin (ALB), creatinine (Cr), uric acid (UA), estimated glomerular filtration rate (eGFR), cystatin C (Cys-C), total cholesterol (TC), triglyceride (TG) of the three groups were compared, high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C), triiodothyronine (T3), thyroxine (T4), thyroid stimulating hormone (TSH), thyroglobulin antibody (TGAb), thyroid peroxidase antibody (TPO-Ab) and serum calcium (Ca) in the three groups showed no significant differences (P > 0.05). Compared with the DM group, the gray matter volume (GMV) in the DPN group was significantly decreased (P < 0.05). Compared with the DM group, amplitude of low frequency fluctuation (ALFF) and fractional amplitude of low frequency fluctuation (fALFF) of left medial superiorfrontal gyrus in the PDN group were significantly decreased (P < 0.05). Conclusion Abnormal GMV in the left angular gyrus in DPN patients may be associated with a higher risk of concomitant cognitive impairment. The decrease of ALFF in the right cerebellar vermis and fALFF in the left medial superior frontal gyrus in PDN patients may be related to the pathogenesis of pain.

Objective: To investigate the changes of ambient dose equivalent rate in 99mTcO4- single photon emission computed tomography (SPECT) of the thyroid among patients with hyperthyroidism, so as to provide insights into radiation protection guidance. Methods: Patients with hyperthyroidism who underwent 99mTcO4- SPECT of the thyroid in a tertiary hospital were enrolled. The ambient dose equivalent rate was measured at different time points following 99mTcO4- infection and at sites with different distances from patients' neck, and the effects of time post-injection, distance from patients' neck, 24-hour thyroidal radioiodine uptake and thyroid weight on the ambient dose equivalent rate were examined using a generalized linear mixed model. Results: Totally 100 patients with hyperthyroidism were enrolled, including 24 men and 76 women and with a mean age of (38.5±14.0) years. The generalized linear mixed model was statistically significant (F=6 610.165, P<0.001), and patients' thyroid weight, time post-injection and distance from patients' neck significantly affected the ambient dose equivalent rate (F=57.967, 15 988.574, 11 200.645, all P<0.001), and the ambient dose equivalent rate positively correlated with patients' thyroid weight and negatively correlated with time post-injection and distance from patients' neck. Conclusions The ambient dose equivalent rate is affected by patients' thyroid weight, time post-injection and distance from patients' neck among patients with hyperthyroidism undergoing 99mTcO4- SPECT of the thyroid. Delay in contact with patients or keeping distance from patients may be effective for radiation protection.

Objective : To explore the association of time in range(TIR) and glucose management indicator ( GMI) with the risk of type 2 diabetic nephropathy (DN) ． Methods : The clinical data of 215 patients with type 2 diabetes mellitus (T2DM) were collected and analyzed．According to the results of estimated glomerular filtration rate (eGFR) and urinary albumin to creatinine ratio( UACR) ，they were divided into 117 patients with T2DM and 98 patients with DN．The clinical data，biochemical indicators and continuous glucose monitoring ( CGM) indicators of the two groups were compared．Logistic regression was used to analyze the influencing factors of DN risk．The predictive value of TIR and GMI on the risk of DN was evaluated by receiver operating characteristic (ROC) curve. Results: There were significant differences in age，duration of diabetes，systolic blood pressure，glycosylated hemoglobin ( HbA1c) ，fasting plasma glucose (FPG) ，2 hour postprandial plasma glucose (2hPG) ，creatinine( Cr) ，UACR, eGFR between the two groups(P＜0. 05) ．There were statistically significant differences between the two groups in the CGM indexes of GMI，mean absolute difference of mean of daily differences ( MODD) ，glucose above target range time(TAR) and TIR(P＜0. 05) ．The results of logistic regression analysis showed that TIR was a protective factor of DN．In the ROC curve analysis of TIR prediction DN，the area under the ROC curve was 0. 718 (95% CI = 0. 648 ～0. 789，P＜0. 001) ，and the Yoden index was 0. 38．At this time，the sensitivity was 66. 7% ，and the specificity was 71. 3%．In the ROC curve analysis of GMI prediction DN，the area under the ROC curve was 0. 701 (95% CI = 0. 629 ～0. 774，P＜0. 001) ，and the Yoden index was 0. 368．At this time，the sensitivity was 63. 3% ， and the specificity was 73. 5%． Conclusion Specifically，lower TIR and higher GMI increase the risk of DN.

Objective:In general, patients with seropositive rheumatoid arthritis (RA) are considered to show an aggressive disease course. However, the relationship between the two subgroups in disease severity is controversial. Our study is aimed to compare the clinical characteristics and prognosis of double-seropositive and seronegative RA in China through a real-world large scale study.Methods:RA patients who met the 1987 American College of Rheumatology (ACR) classification criteria or the 2010 ACR/European Anti-Rheumatism Alliance RA classification criteria, and who attended the 10 hospitals across the country from September 2015 to January 2020, were enrolled. According to the serological status, patients were divided into 4 subgroups [rheumatoid factor (RF)(-) anti-cyclic citrullinated peptide (CCP) antibody (-), RF(+), RF(+) anti-CCP antibody(+), anti-CCP antibody(+)] and compared the disease characteristics and treatment response. One-way analysis of variance was used for measurement data that conformed to normal distribution, Kruskal-Wallis H test was used for measurement data that did not conform to normal distribution; paired t test was used for comparison before and after treatment within the group if the data was normally distributed else paired rank sum test was used; χ2 test was used for count data. Results:① A total of 2 461 patients were included, including 1 813 RF(+) anti-CCP antibody(+) patients (73.67%), 129 RF(+) patients (5.24%), 245 RF(-) anti-CCP antibody(-) patients (9.96%), 74 anti-CCP antibody(+) patients (11.13%). ② Regardless of the CCP status, RF(+) patients had an early age of onset [RF(-) anti-CCP antibody(-) (51±14) years old, anti-CCP antibody(+) (50±15) years old, RF(+) anti-CCP antibody(+) (48±14) years old, RF(+)(48±13) years old, F=3.003, P=0.029], longer disease duration [RF(-) anti-CCP antibody(-) 50 (20, 126) months, anti-CCP antibody(+) 60(24, 150) months, RF(+) anti-CCP antibody(+) 89(35, 179) months, RF(+) 83(25, 160) months, H=22.001, P<0.01], more joint swelling counts (SJC) [RF(-) anti-CCP antibody(-) 2(0, 6), Anti-CCP antibody(+) 2(0, 5), RF(+) anti-CCP antibody(+) 2(0, 7), RF(+) 2(0, 6), H=8.939, P=0.03] and tender joint counts (TJC) [RF(-) anti-CCP antibody(-) 3(0, 8), anti-CCP antibody(+) 2(0, 6), RF(+) anti-CCP antibody(+) 3(1, 9), RF(+) 2(0, 8), H=11.341, P=0.01] and the morning stiff time was longer [RF(-) anti-CCP antibody(-) 30(0, 60) min, anti-CCP antibody(+) 20(0, 60) min, RF(+) anti-CCP antibody(+) 30(10, 60) min, RF(+) 30(10, 60) min, H=13.32, P<0.01]; ESR [RF(-) anti-CCP antibody(-) 17(9, 38) mm/1 h, anti-CCP antibody(+) 20(10, 35) mm/1 h, RF(+) anti-CCP antibody(+) 26(14, 45) mm/1 h, RF(+) 28(14, 50) mm/1 h, H=37.084, P<0.01] and CRP [RF(-) anti-CCP antibody(-) 2.3 (0.8, 15.9) mm/L, Anti-CCP antibody(+) 2.7(0.7, 12.1) mm/L, RF(+) anti-CCP antibody(+) 5.2(1.3, 17.2) mm/L, RF (+) 5.2(0.9, 16.2) mm/L, H=22.141, P<0.01] of the RF(+)patients were significantly higher than RF(-) patients, and RF(+) patients had higher disease severity(DAS28-ESR) [RF(-) anti-CCP antibody(-) (4.0±1.8), anti-CCP antibody(+) (3.8±1.6), RF(+) anti-CCP antibody(+) (4.3±1.8), RF(+) (4.1±1.7), F=7.269, P<0.01]. ③ The RF(+) anti-CCP antibody(+) patients were divided into 4 subgroups, and it was found that RF-H anti-CCP antibody-L patients had higher disease severity [RF-H anti-CCP antibody-H 4.3(2.9, 5.6), RF-L anti-CCP antibody-L 4.5(3.0, 5.7), RF-H anti-CCP antibody-L 4.9(3.1, 6.2), RF-L anti-CCP antibody-H 2.8(1.8, 3.9), H=20.374, P<0.01]. ④ After 3-month follow up, the clinical characteristics of the four groups were improved, but there was no significant difference in the improvement of the four groups, indicating that the RF and anti-CCP antibody status did not affect the remission within 3 months. Conclusion:Among RA patients, the disease activity of RA patients is closely related to RF and the RF(+) patients have more severe disease than RF(-) patients. Patients with higher RF titer also have more severe disease than that of patients with low RF titer. After 3 months of medication treatment, the antibody status does not affect the disease remission rate.

Objective:To explore the value of different machine learning models based on Gd-EOB-DTPA enhanced MRI hepatobiliary phase radiomics features in preoperative prediction of microvascular invasion (MVI) of hepatocellular carcinoma (HCC).Methods:The data of 132 patients with HCC confirmed by pathology in the First Affiliated Hospital of Soochow University from January 2015 to May 2020 were retrospectively analyzed, including 72 cases of positive MVI and 60 cases of negative MVI. According to the proportion of 7∶3, the cases were randomly divided into training set and validation set. The radiomics features of hepatobiliary phase images for HCC were extracted by PyRadiomics software. The clinical and radiomics features of the training set were screened by the least absolute shrinkage and selection operator (LASSO) regression with 5 fold cross-validation, and then the optimal feature subset was obtained. Six machine learning algorithms, including decision tree, extreme gradient boosting, random forest, support vector machine (SVM), generalized linear model (GLM) and neural network, were used to build the prediction models, and the ROC curves were used to evaluate the prediction ability of the models. DeLong test was used to compare the differences of area under the curve (AUC) for 6 machine learning algorithms.Results:Totally 14 features selected by LASSO regression were obtained to form the optimal feature subset, including 2 clinical features (maximum tumor diameter and alpha-fetoprotein) and 12 radiomics features. The AUCs of decision tree, extreme gradient boosting, random forest, SVM, GLM and neural network based on the optimal feature subset were 0.969, 1.000, 1.000, 0.991, 0.966, 1.000 in the training set and 0.781, 0.890, 0.920, 0.806, 0.684, 0.703 in the validation set, respectively. There were significant differences in the AUCs between extreme gradient boosting and GLM or neural network ( Z=2.857, 3.220, P=0.004, 0.001). The differences in AUCs between random forest and SVM, GLM, or neural network were significant ( Z=2.371, 3.190, 3.967, P=0.018, 0.001,<0.001). The difference in AUCs between SVM and GLM was statistically significant ( Z=2.621 , P=0.009). There were no significant differences in the AUCs among the other machine learning models ( P>0.05). Conclusion:Machine learning models based on Gd-EOB-DTPA enhanced MRI hepatobiliary phase radiomics features can be used to preoperatively predict MVI of HCC, particularly the extreme gradient boosting and random forest models have high prediction efficiency.

Objective:To evaluate associations of psoriasis with adverse pregnancy outcomes.Methods:Databases, including CNKI, Wanfang, VIP, PubMed, Embase and Cohrane Library databases, were searched for published articles on associations between psoriasis and adverse pregnancy outcomes between January 1980 and December 2018. Quality of included articles was assessed by using MOOSE checklist. Statistical analysis was carried out with Review Manager 5.3 software.Results:One cohort study, 4 case-control studies and 2 cross-sectional studies meet the inclusion criteria. After heterogeneity test, meta-analysis was carried out by using a random effect model. The risks of cesarean ( OR= 1.17, 95% CI: 1.01- 1.37) , eclampsia or preeclampsia ( OR= 1.34, 95% CI: 1.00- 1.79) and premature birth ( OR= 1.09, 95% CI: 1.00- 1.19) were significantly higher in patients with psoriasis than in individuals without psoriasis (all P < 0.05) . There was no significant difference between patients with psoriasis and individuals without psoriasis in the risks of spontaneous abortion, low birth weight, high birth weight, stillbirth, congenital malformation, placental abruption, overdue delivery, low Apgar score (< 7) , polyhydramnios and oligohydramnios. Conclusion:The risks of cesarean, eclampsia or preeclampsia, and premature birth are higher in patients with psoriasis than in individuals without psoriasis.

Objective:To determine the expression of microRNA-188-5p (miR-188-5p) in cutaneous squamous cell carcinoma (CSCC) tissues and cells, and to assess the effect of its downregulation on the proliferation and invasion of CSCC cells.Methods:From November 2012 to October 2018, 50 surgically resected CSCC tissue specimens and 50 paracancerous normal skin tissue specimens were collected from the First Affiliated Hospital of Xinxiang Medical College in Henan Province. Real-time fluorescence-based quantitative PCR (qPCR) was employed to determine the expression of miR-188-5p in CSCC tissues, paracancerous normal skin tissues, CSCC cell lines SCL-1, A431 and HSC-5, and a human immortalized keratinocyte line HaCaT. Cultured A431 and HSC-5 cells were both divided into 2 groups: miR-188-5p inhibitor group and negative control group, which were transfected with a miR-188-5p inhibitor and its negative control respectively. Then, qPCR was performed to determine the relative expression level of miR-188-5p (expressed as 2 -△△Ct), and cell counting kit-8 (CCK8) and Transwell assays were conducted to assess cellular proliferative activity and invasive ability respectively in the above groups. Dual-luciferase reporter assay was performed to investigate interactions between miR-188-5p and phosphatase and tensin homologue deleted on chromosome 10 (PTEN), and Western blot analysis to determine the protein expression of PTEN, total Akt (t-Akt) and phosphorylated Akt (p-Akt). Two independent samples were compared by using t test. Results:The relative expression level of miR-188-5p was significantly higher in the CSCC tissues (5.213 ± 3.138) than in the paracancerous normal skin tissues (1.010 ± 0.364, t = 9.187, P < 0.001), and significantly higher in the SCL-1, A431 and HSC-5 cells (3.858 ± 0.163, 7.068 ± 0.262 and 4.572 ± 0.413, respectively) than in the HaCaT cells (1.079 ± 0.300, t = 17.890, 21.110 and 8.737, respectively, all P < 0.05). Compared with the negative control group, the miR-188-5p inhibitor group showed significantly decreased miR-188-5p expression in both A431 and HSC-5 cells (both P < 0.01), and decreased proliferative activity and invasive ability of both A431 and HSC-5 cells (all P < 0.05). Dual-luciferase reporter assay showed that the downregulation of miR-188-5p significantly increased the expression of PTEN, but inhibited the expression of p-Akt in A431 and HSC-5 cells. Conclusion:MiR-188-5p is highly expressed in CSCC tissues and cells, and the downregulation of miR-188-5p may inhibit the proliferative activity and invasive ability of CSCC cells by regulating the PTEN/Akt pathway.