A network meta-analysis to evaluate the efficacy and safety of different dosages of new drugs in the treatment of psoriatic arthritis / 中华风湿病学杂志

Objective:To compare the efficacy and safety of different dosages of new drugs in the treatment of PsA by using network meta-analysis.Methods:Three medical databases (PubMed, Web of Science, Cochrane Library) were searched for the studies that compared the efficacy and safety of 4 new drugs (secukinumab, ixekizumab, apremilast, tofacitinib) with different dosages in the treatment of PsA. Data from included studies were analyzed by Stata 15.0.Results:A total of 16 RCTs were included. The results of the network meta-analysis showed that: (1) Among the overall patients, in terms of ACR20 response rate, the larger the surface under the cumulative ranking (SUCRA), the more effective it is. Secukinumab 300 mg Q4W(96.1%) had the best efficacy, followed by ixekizumab 80 mg Q4W(79.0%), ixekizumab 80 mg Q2W(75.1%), secukinumab 150 mg Q4W(73.2%), apremilast 30 mg BID(50.6%), apremilast 20 mg BID(38.6%), tofacitinib 5 mg BID(18.1%), tofacitinib 10 mg BID(17.7%) and placebo(2.0%). (2) In terms of PASI75 response rate, the larger the area under the SUCRA curve, the more effective it is. Ixekizumab 80 mg Q4W(96.1%) had the best efficacy, followed by ixekizumab 80 mg Q2W(88.7%), secukinumab 300 mg Q4W(75.6%), secukinumab 150 mg Q4W(63.3%), apremilast 30 mg BID(44.5%), apremilast 20 mg BID(38.4%), tofacitinib 10 mg BID(30.0%), tofacitinib 5 mg BID(12.5%) and placebo(1.0%). (3) Among the overall patients, in terms of safety, the smaller the area under the SUCRA curve, the higher the safety it is. Secukinumab 300 mg Q4W (17.3%) has the best safety. (4) The results of subgroup analysis showed that in terms of ACR20 response rate, ixekizumab 80 mg Q2W(85.3%) had the best efficacy in bDMARDs-na?ve patients, while in bDMARDs-IR patients, secukinumab 300 mg Q4W(83.9%) had the best efficacy.Conclusion:Among all patients, secukinumab 300 mg Q4W is the best in terms of ACR20 response rate and safety, but ixekizumab 80 mg Q4W is more effective in improving PsA lesions comparing yo other drugs.

Large clones of pre-existing T cells drive early immunity against SARS-COV-2 and LCMV infection.

We analyzed the dynamics of the earliest T cell response to SARS-COV-2. A wave of TCRs strongly but transiently expand during infection, frequently peaking the same week as the first positive PCR test. These expanding TCR CDR3s were enriched for sequences functionally annotated as SARS-COV-2 specific. Most epitopes recognized by the expanding TCRs were highly conserved between SARS-COV-2 strains, but not with circulating human coronaviruses. Many expanding CDR3s were also present at high precursor frequency in pre-pandemic TCR repertoires. A similar set of early response TCRs specific for lymphocytic choriomeningitis virus epitopes were also found at high frequency in the pre-infection naive repertoire. High frequency naive precursors may allow the T cell response to respond rapidly during the crucial early phases of acute viral infection. One-Sentence SummaryHigh frequency naive precursors underly the rapid T cell response during the crucial early phases of acute viral infection.

SARS-CoV-2 mutations affect proteasome processing to alter CD8+ T cell responses

Viral CD8+ epitopes are generated by the cellular turnover of viral proteins, predominantly by the proteasome. Mutations located within viral epitopes can result in escape from memory T cells but the contribution of mutations in flanking regions of epitopes in SARS-CoV-2 has not been investigated. Focusing on two of the most dominant SARS-CoV-2 nucleoprotein CD8+ epitopes, we identified mutations in epitope flanking regions and investigated the contribution of these mutations to antigen processing and T cell activation using SARS-CoV-2 nucleoprotein transduced B cell lines and in vitro proteasomal processing of peptides. We found that decreased NP9-17-B*27:05 CD8+ T cell responses to the NP-Q7K mutation correlated with lower epitope surface expression, likely due to a lack of efficient epitope production by the proteasome, suggesting immune escape caused by this mutation. In contrast, NP-P6L and NP-D103N/Y mutations flanking the NP9-17-B*27:05 and NP105-113-B*07:02 epitopes, respectively, increased CD8+ T cell responses associated with enhanced epitope production by the proteasome. Our results provide evidence that SARS-CoV-2 mutations outside the epitope could have a significant impact on antigen processing and presentation, thereby contributing to escape from immunodominant T cell responses. Alternatively, mutations could enhance antigen processing and efficacy of T cell recognition, opening new avenues for improving future vaccine designs. One Sentence SummaryNatural mutations in the flanking regions of known immunodominant SARS-CoV-2 nucleoprotein epitopes can decrease CD8+ T cell responses leading to partial escape.

The impact of viral mutations on recognition by SARS-CoV-2 specific T-cells

We identify amino acid variants within dominant SARS-CoV-2 T-cell epitopes by interrogating global sequence data. Several variants within nucleocapsid and ORF3a epitopes have arisen independently in multiple lineages and result in loss of recognition by epitope-specific T-cells assessed by IFN-{gamma} and cytotoxic killing assays. These data demonstrate the potential for T-cell evasion and highlight the need for ongoing surveillance for variants capable of escaping T-cell as well as humoral immunity.

Broad and strong memory CD4+ and CD8+ T cells induced by SARS-CoV-2 in UK convalescent COVID-19 patients.

COVID-19 is an ongoing global crisis in which the development of effective vaccines and therapeutics will depend critically on understanding the natural immunity to the virus, including the role of SARS-CoV-2-specific T cells. We have conducted a study of 42 patients following recovery from COVID-19, including 28 mild and 14 severe cases, comparing their T cell responses to those of 16 control donors. We assessed the immune memory of T cell responses using IFN{gamma} based assays with overlapping peptides spanning SARS-CoV-2 apart from ORF1. We found the breadth, magnitude and frequency of memory T cell responses from COVID-19 were significantly higher in severe compared to mild COVID-19 cases, and this effect was most marked in response to spike, membrane, and ORF3a proteins. Total and spike-specific T cell responses correlated with the anti-Spike, anti-Receptor Binding Domain (RBD) as well as anti-Nucleoprotein (NP) endpoint antibody titre (p<0.001, <0.001 and =0.002). We identified 39 separate peptides containing CD4+ and/or CD8+ epitopes, which strikingly included six immunodominant epitope clusters targeted by T cells in many donors, including 3 clusters in spike (recognised by 29%, 24%, 18% donors), two in the membrane protein (M, 32%, 47%) and one in the nucleoprotein (Np, 35%). CD8+ responses were further defined for their HLA restriction, including B*4001-restricted T cells showing central memory and effector memory phenotype. In mild cases, higher frequencies of multi-cytokine producing M- and NP-specific CD8+ T cells than spike-specific CD8+ T cells were observed. They furthermore showed a higher ratio of SARS-CoV-2-specific CD8+ to CD4+ T cell responses. Immunodominant epitope clusters and peptides containing T cell epitopes identified in this study will provide critical tools to study the role of virus-specific T cells in control and resolution of SARS-CoV-2 infections. The identification of T cell specificity and functionality associated with milder disease, highlights the potential importance of including non-spike proteins within future COVID-19 vaccine design.

Analysis of drug clinical trials for rheumatic diseases in China / 中华风湿病学杂志

Objective:To analyze and summarize the drug registration clinical trial for rheumatic diseases in China from January 2013 to November 2019.Methods:The website of CDE was searched to obtain the data and statistical analysis was conducted.Results:①The number of drug clinical trials for rheumatic diseases in China increased year by year and the total was 525. The registered indications mainly included diffuse connective tissue disease, spondylo arthritis, metabolic diseases and degenerative diseases, including rheumatoid arthritis (RA) (189), gout (122), osteoarthritis (OA) (89), ankylosing spondylitis (AS) (60) and systemic lupus erythematosus (SLE) (39). ② The phaseⅡ-Ⅲ clinical trials were mainly for biological disease-modifying antirheumatic drugs (bDMARDs). Most of the bioequivalence test (BE) were chemical drugs.③ The domestically developed chemicals and biological included BLyS/APRIL, CD22, JAK1, S1P1 and BTK. ④ Adalimumab and tocilizumab accounted for the largest proportion of biosimilar drugs. The indications were mainly RA. ⑤ The number of international multi-center clinical trials increased year by year, with the indications mainly for RA and SLE.Conclusion:① The overall number of drugs trials for rheumatic diseases in China has been increasing rapidly in recent years. ② The research and development of chemicals and biologics is the trend. ③ Significant achievements have been made in the research and development of biosimilars in China and it is expected to benefit more patients by broaden the indications.

Frequency of HLA gene in MSM cohort and correlation with AIDS disease pro-gression / 中国免疫学杂志

Objective:HIV-1 infection was associated with a variety of host genetic factors ,and HLA was one of the factors that contribute to the progression of disease .We analyze the frequency of HLA-A, HLA-B, HLA-C in MSM cohort , and the relationship between HLA gene with disease progression .Methods:PCR-sequence specific primer typing HLA typing was used to detect the allele frequency of HLA gene in 310 patients.HIV Molecular Immunology Database ( HLA Analysis Tools ) to analysis the frequency of HLA.Results:In MSM cohort,HLA-A*1101(34.52%) gene was the highest,followed by HLA-A*0201(31.94%),HLA-C*0102 (27.10%) and HLA-A*2402(26.45%).According to the CD4 cell count of HIV infected patients ,the results showed that there were low levels of HLA-B*4403(1.12%,P=0.0276),HLA-B*1511(2.25%,P=0.0282) and HLA-B*5701(0.37%,P=0.0491) in rapid progressors,while the HLA-C*0304(8.96%,P=0.0319) was higher than that of nonprogressors (4.56%).Conclusion: We obtained the distribution frequency data of HLA-A,HLA-B and HLA-C in MSM cohort.Our data presented here may offer potential cor-relation between dominant effect of HLA alleles and HIV-1 disease progression.And found that the HLA-B*4403,HLA-B*1511, HLA-B*5701 related to slow HIV disease progression and HLA-C*0304 related to accelerate HIV disease progression .

Effects of HIV infection on the disease progression of hepatitis C in patients with HIV/HCV coinfec-tion / 中华微生物学和免疫学杂志

Objective To analyze the differentiation status of CTL and to evaluate its clinical val-ue in patients with HIV/HCV coinfection .Methods Twenty-eight patients with HIV/HCV coinfection and twelve patients with single HCV infection were enrolled in this study .The technique of Fibro-Scan was used to evaluate liver fibrosis .The viral load of HCV was detected by real-time quantitative PCR .Flow cytometry analysis was performed to measure the differentiation status of CTL .Results Both of the levels of alanine transaminase ( ALT) and alkaline phosphatase ( ALP) in patients with HIV/HCV coinfection were signifi-cantly higher than those in patients with single HCV infection [(53.7464±48.1180) U/L vs (27.4750± 13.9850) U/L, P=0.012;(24.5071±8.1940) g/L vs (16.9667±7.1890) g/L, P=0.009].The liver stiffness of patients with HIV/HCV coinfection was higher than that of patients with single HIV infection [(5.9500, 5.8250) Kpa vs (5.1500, 1.0500) Kpa, P=0.117].Compared with the patients with single HCV infection, the patients with HIV/HCV coinfection showed higher viral loads of HCV [( 6.4768, 5.3434) lg copy/ml vs (2.6815, 1.6990) lg copy/ml, P=0.012], but lower clearance rate of HCV [32.14%vs 75%, P=0.032].Compared with the patients with single HCV infection , the patients with HIV/HCV coinfection showed lower percentages of CD 27+CD28+CTL [(28.265±15.095)%vs (18.068±10.263)%, P=0.017), but higher percentages of CD27+/-CD28+CTL [(62.449 ±14.561)% vs (71.111±12.681)%, P=0.066].A trend toward negative correlation was observed between the percent -age of CD27+CD28+CTL and the degree of liver stiffness (r=-0.310, P=0.058).Conclusion HIV in-fection could accelerate the progression of liver disease in patients with HIV /HCV coinfection by affecting the differentiation of CTL .

Postoperative defectography as a function evaluation in children of Hirschsprung′s disease / 中国普通外科杂志

Objective KG1This study is to evaluate defectography in postoperative defecation function of Hirschsprung′s disease (HD). KG2MethodsKG1 Between 1979 and 1993, 30 HD cases were treated operatively and followed-up by defectography. KG2ResultsKG1 Thirty cases were classified into 3 groups, according to the standard quantitative clinical scoring systems with the stooling score from 0 to 14. There were 4 cases (13%) graded as excellent (maximum score of 14) with normal bowel habit, 21 cases (70%) as good (score between 10～13) with minor continence problems, 5 cases (16 7%) as fair (score between 5～9) with marked limitations in social life. Anorectal manometry study showed that the anal resting pressure and voluntary sphincter force (maximal queeze pressure minus resting pressure) in fair group were significantly lower than that in control group( P