Search

Spontaneous renal hemorrhage (SRH) in ANCA-associated vasculitis (AAV) is rare but fatal. We aimed to characterize clinical manifestations and managements of AAV patients with SRH.Hospitalized AAV patients were screened from January 2000 to April 2021, at Peking Union Medical College Hospital (PUMCH). Also, a systematic review was based on retrieving all the relevant literature from PubMed, MedlinePlus, and Web of Science until April 2021. Clinical features, management, and prognosis of the patients were collected and concluded.In PUMCH, four out of 1640 AAV patients with SRH were included in our study; three had granulomatosis with polyangiitis (GPA) and one had microscopic polyangiitis (MPA). The ratio of men to women was 3 to 1, and the average age of onset was 55 years. The Birmingham Vasculitis Activity Score (BVAS) ranged from 21 to 23. Combining with documented reports, 13 patients were diagnosed as AAV complicated with SRH (including four from PUMCH), 7 with GPA, and 6 with MPA. Mean BVAS was 25.2 ± 6.6. The symptoms of SRH presented as severe back or abdominal pain. Patients with SRH to age- and gender-matched patients without SRH were compared, and we found that in the SRH group, the duration of disease was shorter, and BVAS, renal function, and inflammatory markers (WBC and ESR) were significantly greater, whereas Hb, Alb, and renal function greatly reduced.This is the first summary of clinical features and treatments of SRH in AAV. Patients with AAV in early stage and with high disease activity appeared to be more likely to develop SRH. Key Points • This is the first summary of clinical features and treatments of SRH in AAV. • SRH more likely occurs in AAV patients in the early stage (≤ 3 months) and with high disease activity. • Clinicians should be aware of the possibility of SRH when AAV patients complain of back or abdominal pain.

The novel inflammatory markers C-reactive protein to albumin ratio (CAR), neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR) were associated with the disease activity of many autoimmune diseases. The aim of this study was to evaluate the association of these new inflammatory indexes with relapsing polychondritis disease activity index (RPDAI). The data of relapsing polychondritis (RP) patients hospitalized between 2004 and 2020 at Peking Union Medical College Hospital were collected. One of the exclusive criteria was that RP patients overlapped with other diseases. Another was the RP patients with incomplete data. A total of 170 RP patients and 170 healthy controls (HCs) were included. The association of new inflammatory makers with RPDAI was assessed by Spearman’s correlation analysis. Compared to HCs, the CAR, NLR, and PLR were significantly higher in RP patients (both p

Background: NLRP3-associated autoinflammatory disease (NLRP3-AID) is a spectrum of autosomal dominant inherited diseases associated with NLRP3 gene mutations. Reports of Chinese NLRP3-AID cases are limited to date. In the present study, we aim to describe the phenotype and genotype of a cohort of Chinese adult NLRP3-AID patients.Methods: This single-center study included sixteen adult patients diagnosed with NLRP3-AID at Department of Rheumatology, Peking Union Medical College Hospital between July 2015 to September 2021. Whole-exome sequencing using next-generation sequencing was performed in each patient. Clinical data and mutational information were compared with a European cohort.Results: The median age of disease onset was 16 (0-46) years old, and adult-onset was observed in 4 patients (25%). The median time of diagnosis delay was 20 (0–39) years. Five patients (31.3%) had family history of similar symptoms. The most common clinical manifestations were recurrent fever (93.8%), arthralgia/arthritis (81.3%), skin rash (75%), myalgia (62.5%), and central nervous system manifestations (50%). Heterozygous NLRP3 variants detected in these patients were p.T348M (n=4, 25%), Q703K, V70M, K131R, M116I, P38S, V442I, D303G, G328E, A439V, K829T, L632F and V198M (n=1, separately). All the variants were missense mutations.Conclusions: We reported the largest case series of Chinese adult NLRP3-AID patients. The distinct symptoms of NLRP3-AID patients suggest the heterogeneity of disease. P38S, M116I, K131R, V442I and K829T were identified as novel NLRP3 variants. These data expand the clinical phenotypic and genotypic profiles of NLRP3-AID.

It has been over 20 years since the introduction of evidence-based medicine (EBM) into the research of traditional Chinese medicine (TCM). The development of evidence-based TCM research has profoundly influenced the process of clinical research and decision-making, impelling researchers to pay attention to raise evidence quality, accumulate data, and explore appropriate evaluation methods adaptive to TCM original theories and knowledge. In this paper, the authors aim to summarize and review the existing work and seek promising research interests in this field, expecting to inspire more thoughts leading to breakthroughs in the near future.

Atherosclerosis is the primary cause of many cardiovascular diseases, and an increasing number of studies have shown that berberine could delay plaque formation and development. Therefore, we aimed to evaluate its effects and explore its mechanisms in this meta-analysis. We searched PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure, Wanfang, and VIP databases for original preclinical studies to conduct meta-analysis. Twelve articles (16 studies; 312 ApoE -/- mice) were included, and all the studies scored 3-5 points according to SYRCLE's risk of bias tool. Berberine could significantly decrease plaque area and plaque macrophage content (plaque area, SMD = -2.02, 95% CI: -2.80 to -1.24, P = 0.000; plaque macrophage content, SMD = -4.28, 95% CI: -7.67 to -0.88, P = 0.013); lower the levels of TC, triglyceride, and low-density lipoprotein (TC, SMD = -1.47, 95% CI: -2.20 to -0.74, P = 0.000; triglyceride, SMD = -0.77, 95% CI: -1.21 to -0.33, P = 0.000; low-density lipoprotein, SMD = -0.61, 95% CI: -1.11 to -0.11, P = 0.000), and change the secretion of inflammatory cytokines (IL-1β, SMD = -2.29, 95% CI: -3.40 to -1.18, P = 0.000; interleukin-6, SMD = -1.48, 95% CI: -2.11 to -0.85, P = 0.008; tumor necrosis factor-α, SMD = -1.98, 95% CI: -3.01 to -0.94, P = 0.000; interleukin-10, SMD = 1.78, 95% CI: 0.76 to 2.80, P = 0.015), but there were no significant differences in high-density lipoprotein levels and plaque lipid content (high-density lipoprotein, SMD = 0.02, 95% CI: -0.35 to 0.40, P = 0.021; plaque lipid content, SMD = -6.85, 95% CI: -21.09 to 7.39, P = 0.007). The results were robust across a range of sensitivity analyses. Therefore, the results indicate that berberine is a promising drug for the treatment of atherosclerosis through regulating lipid metabolism, inflammation, and plaque composition. However, some potential mechanisms remain to be further elucidated.

Background MicroRNAs (miRNAs) are endogenous noncoding single-stranded small RNAs. Numerous studies have shown that miRNAs have pivotal roles in the occurrence and development of myocardial fibrosis (MF). However, miRNA expression profile in rats with MF after myocardial infarction (MI) is not well understood. The present study aimed to find the potential miRNA for MF post MI. Methods SPF male Sprague-Dawley (SD) rat models of acute myocardial infarction (AMI) were established by ligating the anterior descending branch of the left coronary artery, while sham-operated rats were only threaded without ligation as a control group. Hematoxylin-eosin and Masson trichrome staining were used to detect myocardial histopathological changes for model evaluation. The differentially expressed miRNAs were detected by using the Agilent Rat miRNA gene chip in the myocardial tissue of the infarct marginal zone. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were performed by DAVID. The expression of miR-199a-5p was verified by real-time fluorescence quantitative PCR (qRT-PCR). Transfected miR-199a-5p mimics into cardiac fibroblasts (CFs) to construct cell models of miR-199a-5p overexpression. Dual-luciferase reporter assay was employed to validate the target gene of miR-199a-5p. The protein expression of the target gene in CFs transfected with miR-199a-5p mimics were detected by Western blot. Results Myocardial fibrosis was exacerbated in the model group compared with the control group. Thirteen differentially expressed miRNAs between the two groups were screened and their expression levels in the model group were all higher than those in the control group. The expression of miR-199a-5p was significantly increased in the model group in qRT-PCR, which was consistent with the results of the gene chip. KEGG enrichment analysis showed that the target genes of miR-199a-5p were enriched in the insulin signaling pathway. Furthermore, dual-luciferase reporter assay indicated that miR-199a-5p could negatively regulate the expression of GSK-3β. After transfection, the expression of miR-199a-5p was increased in the miR-199a-5p mimics group. The protein expression of GSK-3β was decreased in CFs transfected with miR-199a-5p mimics. Conclusion Our study identified miR-199a-5p could promote the progression of myocardial fibrosis after myocardial infarction by targeting GSK-3β, which provides novel targets for diagnosis and treatment of MF.

This paper proposes an investment strategy based on a regression linear model to predict sector rotation and a multi-factor scoring model to select stocks to achieve excess returns. The strategy uses January 2006 December 2020 as the model construction period and January 2021 June 2021 as the model validation and backtesting period. Using Shenyin & wanguo’s industry classification as a standard, the cyclicality of industries is classified by β value and the existence of sector rotation is verified using the difference in rate of return between cyclical and non-cyclical industry. The factors associated with the annualized rate of return are selected and the fitted formula for the annualized rate of return is obtained by regressing linear equation and neural network multidimensional correlation to select the dominant board. Valid factors for each board were selected for fitting, and the factors were assigned weights for scoring, resulting in 32 stocks. The backtest results significantly outperformed the CSI 300 Index, and the model performance is stable and can achieve better returns.

Objectives TNF receptor-associated periodic fever syndrome (TRAPS) is an autosomal dominant systemic autoinflammatory disease caused by mutations of TNF receptor superfamily member 1 A (TNFRSF1A) gene. TRAPS has hardly been reported in the Chinese population. We aimed to characterize the clinical and genetic features of Chinese adult patients with TRAPS. Methods Nine adult patients (≥16 years) were diagnosed during April 2015 to June 2019, at the Department of Rheumatology, Peking Union Medical College Hospital. Clinical and genetic features of these patients were evaluated and compared with those from Japan and Europe. Results The median age of disease onset was 3 (0.5–38.5) years old, and adult-onset was observed in two (22.2%) patients. The median time of diagnosis delay was 16.5 (1.5–50.5) years. One patient had a family history of TRAPS. The frequent symptoms were fever (nine, 100%), rash (seven, 77.8%), arthralgia/arthritis (five, 55.6%) and abdominal pain (five, 55.6%). Only two (22.2%) patients had periorbital oedema. Nine TNFRSF1A gene variants were detected, including C58R, G65E, F89L, C99G, V202G, V202D, c.769-23T>C, S290I and c.*64T>C. Rash was more frequently seen in Chinese than in Japanese and European patients, while chest pain and amyloidosis occurred less frequently. Conclusion This is the first and largest case series of TRAPS in Chinese adult patients. Two novel TNFRSF1A variants, S290I and V202G, have been identified. The different clinical manifestations of our patients compared with those from Japan and Europe might be related to their TNFRSF1A variants.

Zhou et al. identify the mechanism of autophagosome (AP) closure. They show that Rab5 GTPase regulates an interaction between the ESCRT subunit Snf7 and Atg17 to bring ESCRT to APs where it catalyzes AP closure. These findings highlight the convergence of the endocytic and autophagic pathways at this step., In the conserved autophagy pathway, autophagosomes (APs) engulf cellular components and deliver them to the lysosome for degradation. Before fusing with the lysosome, APs have to close via an unknown mechanism. We have previously shown that the endocytic Rab5-GTPase regulates AP closure. Therefore, we asked whether ESCRT, which catalyzes scission of vesicles into late endosomes, mediates the topologically similar process of AP sealing. Here, we show that depletion of representative subunits from all ESCRT complexes causes late autophagy defects and accumulation of APs. Focusing on two subunits, we show that Snf7 and the Vps4 ATPase localize to APs and their depletion results in accumulation of open APs. Moreover, Snf7 and Vps4 proteins complement their corresponding mutant defects in vivo and in vitro. Finally, a Rab5-controlled Atg17–Snf7 interaction is important for Snf7 localization to APs. Thus, we unravel a mechanism in which a Rab5-dependent Atg17–Snf7 interaction leads to recruitment of ESCRT to open APs where ESCRT catalyzes AP closure.

Protein-protein interactions are important for physiology performance. Green fluorescent protein (GFP) is a widely used protein tag to show protein localization in vivo. GFP binding protein (GBP) is a specific domain with high affinity to GFP. A novel technique with GBP fused protein X tagged with red fluorescence protein binding to GFP of GFP fused protein Y to establish a close association for proteins X and Y independently from other proteins has recently been developed. It is found that the interaction and colocalization between Snf7 and Atg17 is impaired in Saccharomyces cerevisiae vps21Δ cells, which are defective in autophagy. In order to determine whether the interaction between Snf7 and Atg17 is important for autophagy, we forced the interaction between Snf7 and Atg17 through GBP-GFP binding. Snf7-GBP-mCherry and/or GFP-Atg17 tagged wild-type and vps21Δ cells were compared for autophagy process under starvation by determining the maturation of proprotein of Ape1 (prApe1). Our results showed that the defective autophagy in vps21Δ cells was significantly suppressed when both Snf7-GBP-mCherry and GFP-Atg17 were installed. Our results indicate that the GBP-GFP nanotrap technique is a powerful tool to restore colocalization/interaction in vivo and the Snf7-Atg17 interaction is important for yeast autophagy.

NLRP3-associated autoinflammatory disease (NLRP3-AID) is a rare autosomal dominant disorder involving multiple systems. We aim to assess the ocular manifestations of Chinese adult patients with NLRP3-AID. Twelve adult patients (> 18 years old) were diagnosed as NLRP3-AID at the Department of Rheumatology, Peking Union Medical College Hospital. All patients underwent ophthalmologic evaluation by an ophthalmologist. Clinical and genetic features of these patients were collected and compared with those from Caucasian population. A total of 7 NLRP3-AID patients (58%) 14 eyes had ocular manifestations. Five NLRP3 variants were identified, and 3 patients (43%) with severe ocular damages were all found to have the NLRP3 T348M variant. The incidences of papilledema and optic atrophy in the Chinese adult NLRP3-AID patients of moderate type were similar to those in the Caucasian NLRP3-AID patients of severe type. This is the first cohort of Chinese adult NLRP3-AID patients with ocular involvement. Ocular manifestations were diverse and even severe in NLRP3-AID, particularly in patients with the moderate phenotype, and may have relationship with genotypes. Awareness of these manifestations by rheumatologists and ophthalmologists could help to avoid the irreversible ocular damages.

The novel inflammatory markers C-reactive protein to albumin ratio (CAR), neutrophil to lymphocyte ratio (NLR), and platelet to lymphocyte ratio (PLR) were associated with the disease activity of many autoimmune diseases. The aim of this study was to evaluate the association of these new inflammatory indexes with relapsing polychondritis disease activity index (RPDAI).The data of relapsing polychondritis (RP) patients hospitalized between 2004 and 2020 at Peking Union Medical College Hospital were collected. One of the exclusive criteria was that RP patients overlapped with other diseases. Another was the RP patients with incomplete data. A total of 170 RP patients and 170 healthy controls (HCs) were included. The association of new inflammatory makers with RPDAI was assessed by Spearman's correlation analysis.Compared to HCs, the CAR, NLR, and PLR were significantly higher in RP patients (both p 0.001). The CAR, NLR, PLR, erythrocyte sedimentation rate and neutrophil counts in peripheral blood positively correlated with RPDAI. Blood albumin, lymphocyte count, hemoglobin (Hb) negatively correlated with RPDAI. The association of CAR, NLR, and PLR with RPDAI was demonstrated by Spearman's correlation analysis.The novel inflammatory markers CAR, NLR and PLR were associated with RPDAI. Key Points • This is the first research to explore the association of CAR, NLR, and PLR with disease activity in patients with RP • CAR, NLR, and PLR are positively correlated with RPDAI • CAR, NLR, and PLR might be the potential predictors of disease activity in RP.

Background The therapeutic evidence collected from well-designed studies is needed to help manage the global pandemic of the coronavirus disease 2019 (COVID-19). Evaluating the quality of therapeutic data collected during this most recent pandemic is important for improving future clinical research under similar circumstances. Objective To assess the methodological quality and variability in implementation of randomized controlled trials (RCTs) for treating COVID-19, and to analyze the support that should be provided to improve data collected during an urgent pandemic situation. Search strategy PubMed, Excerpta Medica Database, China National Knowledge Infrastructure, Wanfang, and Chongqing VIP, and the preprint repositories including Social Science Research Network and MedRxiv were systematically searched, up to September 30, 2020, using the keywords “coronavirus disease 2019 (COVID-19),” “2019 novel coronavirus (2019-nCoV),” “severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2),” “novel coronavirus pneumonia (NCP),” “randomized controlled trial (RCT)” and “random.” Inclusion criteria RCTs studying the treatment of COVID-19 were eligible for inclusion. Data extraction and analysis Screening of published RCTs for inclusion and data extraction were each conducted by two researchers. Analysis of general information on COVID-19 RCTs was done using descriptive statistics. Methodological quality was assessed using the risk-of-bias tools in the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.1.0). Variability in implementation was assessed by comparing consistency between RCT reports and registration information. Results A total of 5886 COVID-19 RCTs were identified. Eighty-one RCTs were finally included, of which, 45 had registration information. Methodological quality of the RTCs was not optimal due to deficiencies in five main domains: allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, and selective reporting. Comparisons of consistency between published protocols and registration information showed that the 45 RCTs with registration information had common deviations in seven items: inclusion and exclusion criteria, sample size, outcomes, research sites of recruitment, interventions, and blinding. Conclusion The methodological quality of COVID-19 RCTs conducted in early to mid 2020 was consistently low and variability in implementation was common. More support for implementing high-quality methodology is needed to obtain the quality of therapeutic evidence needed to provide positive guidance for clinical care. We make an urgent appeal for accelerating the construction of a collaborative sharing platform and preparing multidisciplinary talent and professional teams to conduct excellent clinical research when faced with epidemic diseases of the future. Further, variability in RCT implementation should be clearly reported and interpreted to improve the utility of data resulting from those trials. Please cite this article as: Zhao MZ, Zhao C, Tu SS, Wei XX, Shang HC. Evaluating the methodology of studies conducted during the global COVID-19 pandemic: A systematic review of randomized controlled trials. J Integr Med. 2021; Epub ahead of print.

Protein-protein interactions are important for physiology performance. Green fluorescent protein (GFP) is a widely used protein tag to show protein localization in vivo. GFP binding protein (GBP) is a specific domain with high affinity to GFP. A novel technique with GBP fused protein X tagged with red fluorescence protein binding to GFP of GFP fused protein Y to establish a close association for proteins X and Y independently from other proteins has recently been developed. It is found that the interaction and colocalization between Snf7 and Atg17 is impaired in Saccharomyces cerevisiae vps21Δ cells, which are defective in autophagy. In order to determine whether the interaction between Snf7 and Atg17 is important for autophagy, we forced the interaction between Snf7 and Atg17 through GBP-GFP binding. Snf7-GBP-mCherry and/or GFP-Atg17 tagged wild-type and vps21Δ cells were compared for autophagy process under starvation by determining the maturation of proprotein of Ape1 (prApe1). Our results showed that the defective autophagy in vps21Δ cells was significantly suppressed when both Snf7-GBP-mCherry and GFP-Atg17 were installed. Our results indicate that the GBP-GFP nanotrap technique is a powerful tool to restore colocalization/interaction in vivo and the Snf7-Atg17 interaction is important for yeast autophagy.

Objectives Adult-onset Still’s disease (AOSD) is a multifactorial systemic autoinflammatory disease. Neurological damage has been rarely reported in AOSD. We aimed to characterize the clinical features of AOSD patients with neurological involvement. Methods A total of 187 AOSD patients were admitted to Peking Union Medical College Hospital from January 2015 to August 2019. The complete medical records were reviewed in this retrospective study. Clinical features of 14 AOSD patients with neurological involvement were collected and compared with those without. Results The prevalence of neurological involvement in AOSD inpatients was 7.5%. The median disease duration was 4.5 months, with a range of 1–15 months. The frequent symptoms were fever [14 (100%)], rash [13 (92.9%)], liver dysfunction [11 (78.6%)], arthralgia/arthritis [10 (71.4%)] and lymphadenopathy [10 (71.4%)]. Four (28.6%) patients had macrophage activation syndrome (MAS). Aseptic meningitis was the most common presentation (64.3%) when the nervous system was involved. Other rare manifestations included cranial nerve palsy, encephalitis and cerebral infarction. The rate of MAS, serum levels of lactate dehydrogenase and ferritin were significantly higher in AOSD patients with neurological involvement than in those without. All patients received high-dose corticosteroid therapy and immunosuppressive agents and two were given tocilizumab. Clinical remission was achieved in all 14 AOSD patients with neurological involvement. Conclusion Neurological involvement, particularly aseptic meningitis, is not a rare complication of AOSD. It is frequently complicated by MAS. There may be a potential relationship between the neurological damage of AOSD and MAS.

Background: Development of a core outcome set (COS) for clinical trials for COVID-19 is urgent because of the pandemic wreaking havoc worldwide and the heterogeneity of outcomes in clinical trials. Methods: A preliminary list of outcomes was developed after a systematic review of protocols of clinical trials for COVID-19. Then, two rounds of the Delphi survey were conducted. Stakeholders were traditional Chinese medicine (TCM) experts, Western medicine (WM) experts, nurses and the public. Patients with confirmed COVID-19 were also invited to participate in a questionnaire written in understandable language. Then different stakeholders participated a consensus meeting by video conference to vote. Results: Ninety-seven eligible study protocols were identified from 160 clinical trials. Seventy-six outcomes were identified from TCM clinical trials and 126 outcomes were identified from WM clinical trials. Finally, 145 outcomes were included in the first round of the Delphi survey. Then, a COS for clinical trials of TCM and WM was developed. The COS include clinical outcomes (recovery/improvement/progression/death), etiology (SARS-CoV-2 nucleic-acid tests, viral load), inflammatory factor (C-reactive protein), vital signs (temperature, respiration), blood and lymphatic-system parameters (lymphocytes, virus antibody), respiratory outcomes (Pulmonary imaging, blood oxygen saturation, PaO2/FiO2 ratio, arterial blood gas analysis, mechanical ventilation, oxygen intake, pneumonia severity index), clinical efficacy (prevalence of preventing patients with mild-to-moderate disease progressing to severe disease), symptoms (clinical symptom score). Outcomes were recommended according to different types of disease. Outcome measurement instrument/definition were also recommended. Conclusion: Though there are some limitations for the research, such as insufficient patients and the public involvement, the unbalanced stakeholders’ region, the COS for COVID-19 may improve consistency of outcome reporting in clinical trials. It also should be updated with research progression. Key words: COVID-19; core outcome set; traditional Chinese medicine; Western medicine; methodology.

BackgroundDevelopment of a core outcome set (COS) for clinical trials for COVID-19 is urgent because of the pandemic wreaking havoc worldwide and the heterogeneity of outcomes in clinical trials.MethodsA preliminary list of outcomes were developed after a systematic review of protocols of clinical trials for COVID-19. Then, two rounds of the Delphi survey were conducted. Stakeholders were traditional Chinese medicine (TCM) experts, Western medicine (WM) experts, nurses and the public. Patients with confirmed COVID-19 were also invited to participate in a questionnaire written in understandable language. Frontline clinicians, as well as nurse, methodologist, evidence based-medicine researcher, and staff from the Chinese Clinical Trials Registry participated by video conference to vote.ResultsNinety-seven eligible study protocols were identified from 160 clinical trials. Seventy-six outcomes were identified from TCM clinical trials and 126 outcomes were identified from WM clinical trials. Finally, 145 outcomes were included in the first round of the Delphi survey. Then, a COS for clinical trials of TCM and WM was developed. The COS include clinical outcomes (recovery/improvement/progression/death), etiology (SARS-CoV-2 nucleic-acid tests, viral load), inflammatory factor (C-reactive protein), vital signs (temperature, respiration), blood and lymphatic-system parameters (lymphocytes, virus antibody), respiratory outcomes (Pulmonary imaging, blood oxygen saturation, PaO2/FiO2 ratio, arterial blood gas analysis, mechanical ventilation, oxygen intake, pneumonia severity index), clinical efficacy (prevalence of preventing patients with mild-to-moderate disease progressing to severe disease), symptoms (clinical symptom score). Outcomes were recommended according to different types of disease. Outcome measurement instrument/definition were also recommended.ConclusionA COS for COVID-19 may improve consistency of outcome reporting in clinical trials.

ObjectivesTo examine heterogeneity of outcomes in protocols of clinical trials of Coronavirus Disease 2019 (COVID-19) and to identify outcomes for prioritization in developing a core outcome set (COS) in this field.DesignThis study is a review.Data sourcesDatabases of ICMJE-accepted clinical trial registry platform were searched on February 14, 2020.Eligibility CriteriaRandomized controlled trials (RCTs) and non-RCTs of COVID-19 were considered. Conditions of patients include common type, severe type or critical type. Interventions include traditional Chinese medicine (TCM) and Western medicine. We excluded trials that for discharged patients, psychological intervention and complications of COVID-19.Data extraction and synthesisThe general information and outcomes, outcome measurement instruments and measurement times were extracted. The results were analysed by descriptive analysis.Results19 registry platforms were searched. A total of 97 protocols were included from 160 protocols. For protocols of TCM clinical trials, 76 outcomes from 16 outcome domains were reported, and almost half (34/76, 44.74%) of outcomes were reported only once; the most frequently reported outcome was time of SARS-CoV-2 RNA turns to negative. 27 (27/76, 35.53%) outcomes were provided one or more outcome measurement instruments. 10 outcomes were provided one or more measurement time frame. For protocols of western medicine clinical trials, 126 outcomes from 17 outcome domains were reported; almost half (62/126, 49.21%) of outcomes were reported only once; the most frequently reported outcome was proportion of patients with negative SARS-CoV-2. 27 outcomes were provided one or more outcome measurement instruments. 40 (40/126, 31.75%) outcomes were provided one or more measurement time frame.ConclusionOutcome reporting in protocols of clinical trials of COVID-19 is inconsistent. Thus, developing a core outcome set is necessary.Strengths and limitations of this study1.This review is the first to describe variation in outcomes, outcome measurement instruments and outcome measurement time reporting in clinical trials for Coronavirus Disease 2019 (COVID-19).2.All the database of ICMJE-accepted clinical trial registry platform were searched, and randomized controlled trials and observational studies were considered.4.The aim of this review was to provide a list of outcomes for clinical trials of COVID-19, both interventions of Traditional Chinese Medicine and western medicine were considered.5.When the searching was conducted, no clinical trials were registered by countries out of China, so all of included protocols were from China.

Objectives Blau syndrome (BS) is a rare dominantly inherited autoinflammatory disorder associated with mutations in the nucleotide-binding oligomerization domain containing 2 (NOD2) gene. Biologic therapy of BS yielded diverse results. We aimed to evaluate clinical features and outcomes of Chinese patients with BS who were treated with tumor necrosis factor (TNF)α inhibitors. Methods A total of four patients with BS were diagnosed and treated with infliximab (IFX) at the Peking Union Medical College Hospital during 2015 to 2018 and were followed up for 18 months. All patients were systematically studied for treatment outcomes including the clinical manifestations and inflammatory markers. We also conducted a comprehensive literature review about TNFα inhibitor therapy in BS. Results Four BS patients were all Chinese Han, and three were women. The mean age of disease onset was 4 ± 3.5 years, and the mean time of diagnosis delay was 19 ± 11 years. All patients received IFX plus methotrexate, and all achieved clinical remission of skin lesions and polyarthritis rapidly, as well as normalization of erythrocyte sedimentation rate and C-reactive protein and improvements in inflammatory cytokines, patient visual analogue scale, physician global assessment, and Short Form (SF)-36, at the first follow-up of 6 months. The disease relapsed in two patients after they lengthened the interval of IFX and discontinued methotrexate. According to the 38 English-language publications, 62 patients with BS were reported who underwent TNFα inhibitor therapy, including IFX used in 31, adalimumab in 24, and etanercept in 7. IFX was well tolerated in 27 patients, while 2 still had uveitis, and the other 2 experienced an adverse drug reaction. Conclusions Early recognition and effective treatment of BS are very important to avoid irreversible organ damage. TNFα inhibitors such as IFX may be a promising approach for BS patients who have unsatisfactory response to corticosteroids and traditional disease-modifying antirheumatic drugs.

Objective Systemic autoinflammatory diseases (SAIDs) are a group of disorders characterized by a dysregulation of innate immune system leading to multi-systemic inflammation. We aim to assess the neurological manifestations of Chinese adult patients with SAIDs. Methods Eighty adult patients (≥16 years) were diagnosed as SAIDs from April 2015 to June 2019, at the center of adult autoinflammatory diseases, Department of Rheumatology, Peking Union Medical College Hospital. Clinical and genetic features of these patients were collected. All patients underwent neurologic, ophthalmologic and otolaryngologic evaluation. Results Totally 31 out of 80 (38.8%) patients had neurological manifestations, including 14 familial Mediterranean fever (45.2%), 6 NLRP3-associated autoinflammatory disease (19.4%), 5 tumor necrosis factor receptor-associated periodic fever syndrome (16.1%), 5 NLRP12-associated autoinflammatory disease (16.1%), and 1 Yao syndrome (3.2%). Twenty patients (64.5%) were adult-onset. The median time of diagnosis delay was 11.7 years (0.5–50 years). The common neurological damage included headache (28 patients, 90.3%), sensorineural hearing loss (6, 19.4%), dizziness (4, 12.9%), cerebral infarction/hemorrhage (4, 12.9%), chronic aseptic meningitis (3, 9.7%), intracranial hypertension (3, 9.7%), papilledema (3, 9.7%), optic neuritis (2, 6.5%), and hydrocephalus (1, 3.2%). Severe neurological damage was observed in 8 patients (25.8%), including brain atrophy, hydrocephalus, complete hearing loss, chronic aseptic meningitis and optic neuritis. Conclusion Neurological damage was diverse in SAIDs patients. Neurological symptoms should be fully realized by physicians, in not only pediatric but also adult patients with SAIDs. CSF analysis and brain images should be performed promptly. Early diagnosis and appropriate treatment are essential to avoid irreversible neurological complications.

Background: Tumor Necrosis Factor Receptor-Associated Periodic Syndrome (TRAPS) is an autosomal dominant autoinflammatory disase, associated with the mutation of tumor necrosis receptor superfamily member 1A (TNFRSF1A) gene, located on chromosome12p13. TRAPS is usually diagnosed during pediatric age. However, adult-onset disease or diagnosis during adulthood has been occasionally described. Moreover, TRAPS has been hardly reported in the Chinese population. Herein, we aimed to characterize the clinical and genetic features of Chinese adult patients with TRAPS. Objectives: Adult patients (≥16 years) suspected monogenic autoinflammatory diseases during the period April 2015 to October 2018, at the adult autoinflammatory disease center, Department of Rheumatology, Peking Union Medical College Hospital (PUMCH). Methods: Clinical data were evaluated. Gene sequencing was performed in each patient to support the diagnosis and exclude other monogenic autoinflammatory diseases. Finally we compared the data with those from Japan and Europe. Results: During the study period, 8 patients with TRAPS were diagnosed and follow-up. The ratio of male to female was 3: 1. The median age of disease onset was 4 (0.5–38.5), and adult-onset was observed in 2 (25%) patients. The median time of diagnosis delay was 17.8 (1.5-50.5) years. There were seven Chinese Han and one Manchu patients. One patient had a family history of TRAPS. The most frequent symptom was fever (8, 100%). The attacks of 5 (62.5%) patients lasted more than 1 week, and the intervals of 7 (87.5%) patients were longer than 2 weeks. Skin involvement occurred in 6 (75%) patients, with maculopapular mentioned in 6 and erythema annulare presented in 3. Four (50%) patients had arthralgia, while one had polyarthritis. 4 (50%) patients complained respectively of myalgia or headache. 4 (50%) patients experienced abdominal pain and one (12.5%) had vomiting. One (12.5%) patient had periorbital edema, while 3 (37.5%) had conjunctivitis. Up to 5 (62.5%) patients got nonspecific pharyngitis. No patient suffered from chest pain or amyloidosis. Eight gene variants were detected in TNFRSF1A gene. Heterozygous gene variants were found in 7 Chinese Han patients, and homozygous (c.769-23, T>C) happened to the Manchu patient. The variants included C58 (exon 2), G65E (exon 3), F89L (exon 3), C99G (exon 3), V202G (exon 6), c.769-23T>C (IVS8), S290I (exon 9) and m.1735A>G (non-coding region). NSAIDs were given to 2 patients, glucocorticoid or immunosuppressive agents given to 3 patients respectively, and etanercept to 5 patients. A complete response was found in all the 5 patients received etanercept. The effectiveness of other drugs were 50% in NSAIDs, 66.7% in glucocorticoid and immunosuppressive agents. Conclusion: This is the first and largest case series of TRAPS in Chinese adult patients. It highlights the importance of screening TNFRSF1A gene in patients with unexplained periodic fever syndrome. Four novel TNFRSF1A variants, S290I, F89L, V202G and m.1735A>G in non-coding region, have been identified. The atypical clinical manifestations of our patients compared to those from Europe might be related to their low-penetrance TNFRSF1A variants. Further studies are needed to explore the more accurate phenotypes and genotypes of the Chinese patients with TRAPS. References: [1] Lachmann HJ, et al. The phenotype of TNF receptor-associated autoinflammatory syndrome (TRAPS) at presentation: a series of 158 cases from the Eurofever/EUROTRAPS international registry. Ann Rheum Dis2014, 73: 2160-2167. [2] Ueda N, et al. Clinical and Genetic Features of Patients With TNFRSF1A Variants in Japan: Findings of a Nationwide Survey. Arthritis Rheumatol 2016, 68: 2760-2771. Disclosure of Interests: None declared

The macroautophagy/autophagy pathway includes successive steps of phagophore assembly structure formation, phagophore expansion, autophagosome (AP) closure and AP fusion with the lysosome/v...

We isolated a gene encoding a putative MADS-box protein designated RcAGL15 from a protocorm-like body (PLB), a somatic embryogenetic structure) of Rosa canina L. RcAGL15 encodes a predicted protein of 251 amino acid residues with a molecular weight of 28 kDa and a theoretical isoelectric point of 7.5. Reverse-transcription polymerase chain reaction shows that RcAGL15 is mainly expressed in PLB and regenerated PLB, but not in leaves of aseptic seedlings, incubated leaflets before callus formation, calli, rhizoids, or leaves of regenerated shoots. Transgenic, ectopic expression of RcAGL15 in Arabidopsis changes numbers of floral organs and reduces content of indole-3-acetic acid, but increases levels of abscisic acid. Thus, RcAGL15 appears to be a new MADS-box gene that plays regulatory roles in morphological development and the number of flower organs, as well as somatic embryogenesis.

Survey data describing land cover information such as type and diversity over several decades are scarce. Therefore, our capacity to reconstruct historical land cover using field data and archived remotely sensed data over large areas and long periods of time is somewhat limited. This study explores the relationship between CORONA texture—a surrogate for actual land cover type and complexity—with spectral vegetation indices and texture variables derived from Landsat MSS under the Spectral Variation Hypothesis (SVH) such as to reconstruct historical continuous land cover type and complexity. Image texture of CORONA was calculated using a mean occurrence measure while image textures of Landsat MSS were calculated by occurrence and co-occurrence measures. The relationship between these variables was evaluated using correlation and regression techniques. The reconstruction procedure was undertaken through regression kriging. The results showed that, as expected, texture based on the visible bands and corresponding indices indicated larger correlation with CORONA texture, a surrogate of land cover (correlation >0.65). In terms of prediction, the combination of the first-order mean of band green, second-order measure of tasseled cap brightness, second-order mean of Normalized Visible Index (NVI) and second-order entropy of NIR yielded the best model with respect to Akaike’s Information Criterion (AIC), r-square, and variance inflation factors (VIF). The regression model was then used in regression kriging to map historical continuous land cover. The resultant maps indicated the type and degree of complexity in land cover. Moreover, the proposed methodology minimized the impacts of topographic shadow in the region. The performance of this approach was compared with two conventional classification methods: hard classifiers and continuous classifiers. In contrast to conventional techniques, the technique could clearly quantify land cover complexity and type. Future applications of CORONA datasets such as this one could include: improved quality of CORONA imagery, studies of the CORONA texture measures for extracting ecological parameters (e.g., species distributions), change detection and super resolution mapping using CORONA and Landsat MSS.

Superparamagnetic iron oxide nanoparticles (SPIONs) as a contrast agent have been widely used in magnetic resonance imaging for tumor diagnosis and theranostics. However, there has been safety concern of SPIONs with cirrhosis related to excess iron-induced oxidative stress. In this study, the impact of iron overload by SPIONs was assessed on a mouse cirrhosis model. A single dose of SPION injection at 0.5 or 5 mg Fe/kg in the cirrhosis group induced a septic shock response at 24 h with elevated serum levels of liver and kidney function markers and extended impacts over 14 days including high levels of serum cholesterols and persistent low serum iron level. In contrast, full restoration of liver functions was found in the normal group with the same dosages over time. Analysis with PCR array of the toxicity pathways revealed the high dose of SPIONs induced significant expression changes of a distinct subset of genes in the cirrhosis liver. All these results suggested that excess iron of the high dose of SPIONs might be a risk factor for cirrhosis because of the marked impacts of elevated lipid metabolism, disruption of iron homeostasis and possibly, aggravated loss of liver functions.