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Zhuoran Li,1,* Yirui Zhai,1,* Fan Wu,2,* Dayong Cao,2,* Feng Ye,3,* Yan Song,4 Shulian Wang,1 Yueping Liu,1 Yongwen Song,1 Yuan Tang,1 Hao Jing,1 Hui Fang,1 Shunan Qi,1 Ningning Lu,1 Ye-Xiong Li,1 Jianxiong Wu,2 Bo Chen1 1State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, People’s Republic of China; 2Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, People’s Republic of China; 3Department of Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, People’s Republic of China; 4Department of Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Bo Chen, State Key Laboratory of Molecular Oncology, Department of Radiation Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, People’s Republic of China, Tel +86-10-87788280, Email chenboo@outlook.com Jianxiong Wu, Department of Hepatobiliary Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences (CAMS) and Peking Union Medical College (PUMC), Beijing, People’s Republic of China, Tel +86-10-87781700, Email Dr_wujx@163.comPurpose: This study evaluated the clinical outcomes of patients with hepatocellular carcinoma (HCC) with hepatic vein tumor thrombus (HVTT) and/or inferior vena cava tumor thrombus (IVCTT) receiving radiotherapy (RT) combined with systemic therapies.Patients and Methods: Patients with HCC with HVTT and/or IVCTT who received RT were identified at our institution. The prescription doses were 30– 65 Gy for planning target volume and 40– 65 Gy for the gross tumor volume. Targeted therapy and immune checkpoint inhibitors were used concurrently if patients were at a high risk of or already had distant metastasis. After RT completion, follow-up was performed at 1, 3, 6, and 12 months, and 3 to 6 months thereafter. The objective response rate (ORR), overall survival (OS), progression-free survival (PFS) and toxicity were recorded.Results: Thirty-four patients were retrospectively enrolled between January 2016 and September 2021. Most patients received concurrent targeted therapy (70.6%) and/or post-RT (79.4%). The in-field ORR and disease control rates were 79.4% and 97.1%, respectively. The OS rates were 77.6% at 1 year and 36.3% at 2 years (median OS, 15.8 months). The median PFS and median in-field PFS were 4.2 months and not reached, respectively. The PFS and in-field PFS rates were 24.6% and 79.2% at 1 year, 19.7% and 72.0% at 2 years, respectively. An alpha-fetoprotein level > 1000 ng/mL was a significant prognostic factor for worse OS (HR, 5.674; 95% CI, 1.588– 20.276; p=0.008); in-field complete/partial response was a significant prognostic factor for better OS (HR, 0.116; 95% CI, 0.027– 0.499; p=0.004). The most common site of first failure was the lungs (13/34 patients, 38.2%), followed by the liver (7/34 patients, 20.6%). No patients developed radiation-induced liver disease or pulmonary embolism during follow-up.Conclusion: Combining RT and systemic therapy was safe and effective in treating patients with HCC with HVTT and IVCTT.Keywords: liver cancer, immunotherapy, systemic therapy, radiation therapy

Minli Hu,1,* Hao Fang,2,* Yibing Hu,1 Chong Lu,1 Yuan Chen,1 Zhifeng Zhong,3 Hongqi Shi,4 Qunying Wang1 1Department of Gastroenterology, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, People’s Republic of China; 2Department of Traumatology, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, People’s Republic of China; 3Department of Anus & Intestine Surgery, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, People’s Republic of China; 4Department of Pathology, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, People’s Republic of China*These authors contributed equally to this workCorrespondence: Qunying Wang, Department of Gastroenterology, Jinhua Municipal Central Hospital, Jinhua, Zhejiang, People’s Republic of China, Email wqy616717@126.comBackground: Allied disorders of Hirschsprung’s disease (ADHD) exhibit symptoms akin to those of Hirschsprung’s disease, primarily characterized by intestinal obstruction, bowel dilatation, and chronic constipation. The occurrence of amyloid complications in patients with ADHD is infrequent. In this report, we present a case of ADHD with intestinal ulcers as the initial gastrointestinal manifestation, and subsequent pathological examination revealed the presence of amyloid deposits in the colonic mucosa.Case Report: A male patient, aged 20, exhibited recurring abdominal distension and intestinal obstruction for a duration of three years. Multiple colonoscopies revealed the presence of recurrent colonic ulcers, with pathological examination indicating the existence of amyloid deposits within the mucosal layer of the colon. Abdominal CT scans suggested colonic dilatation. Following a multidisciplinary consultation, a subtotal resection of the colon was performed, and subsequent postoperative pathology confirmed a decrease and absence of myenteric plexus ganglion cells. Considering the patient’s symptoms and the findings from the postoperative pathology, a diagnosis of ADHD was made. The patient’s symptoms resolved postoperatively and he was discharged from the hospital and followed up for 1 year in stable condition.Conclusion: Our study highlights the potential association between ADHD and the initial presentation of recurrent colonic ulcers, accompanied by amyloid deposition in the intestinal mucosa. This finding suggests a possible pathogenic mechanism for ADHD and offers a novel perspective on its diagnosis.Keywords: allied disorders of Hirschsprung’s disease, colonic ulcer, amyloid, intestinal obstruction, colonoscopy biopsy colonic

Lujian Zhu,1,* Jing Zhou,1,* Chen Yu,2 Lei Gu,3 Qin Wang,1 Hanglu Xu,1 Yin Zhu,4 Maodong Guo,5 Minli Hu,5 Wei Peng,6 Hao Fang,7 Haizhen Wang8 1Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China; 3Department of Respiratory and Critical Care Medicine, the First Affiliated Hospital of Soochow University, Suzhou, People’s Republic of China; 4Department of Infectious Diseases, Taizhou Enze Medical Center (Group), Enze Hospital, Taizhou, People’s Republic of China; 5Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China; 6Department of Intensive Care Unit, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China; 7Department of Trauma Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China; 8Department of Health Management Center, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haizhen Wang, Department of Health Management Center, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China, Email whz002012@sina.comAbstract: Ferroptosis, a type of programmed cell death that relies on iron, is distinct in terms of its morphological, biochemical and genetic features. Unlike other forms of cell death, such as autophagy, apoptosis, necrosis, and pyroptosis, ferroptosis is primarily caused by lipid peroxidation. Cells that die due to iron can potentially trigger an immune response which intensifies inflammation and causes severe inflammatory reactions that eventually lead to multiple organ failure. In recent years, ferroptosis has been identified in an increasing number of medical fields, including neurological pathologies, chronic liver diseases and sepsis. Ferroptosis has the potential to cause an inflammatory tempest, with many of the catalysts and pathological indications of respiratory ailments being linked to inflammatory reactions. The growing investigation into ferroptosis in respiratory disorders has also garnered significant interest to better understand the mechanism of ferroptosis in these diseases. In this review, the recent progress in understanding the molecular control of ferroptosis and its mechanism in different respiratory disorders is examined. In addition, this review discusses current challenges and prospects for understanding the link between respiratory diseases and ferroptosis.Keywords: respiratory system, ferroptosis, iron metabolism, oxidative stress, treatment

Chenhua Yang,1 Fengling Huang,2 Huiqin Fang,3 Yunhua Zang1 1General Medicine, Bao’an Authentic TCM Therapy Hospital, Shenzhen, Guangdong, People’s Republic of China; 2College of Traditional Chinese Medicine, Henan University of Chinese Medicine, Zhengzhou, Henan, People’s Republic of China; 3The First Clinical Medical College, Shandong University of Traditional Chinese Medicine, Jinan, Shandong, People’s Republic of ChinaCorrespondence: Yunhua Zang, Bao’an Authentic TCM Therapy Hospital, No. 99, Lai’an Road, Xixiang Street, Bao’an District, Shenzhen, Guangdong, 518101, People’s Republic of China, Email 2209162836@qq.comPurpose: This study aimed to investigate the intervention mechanism of Jiawei Shengjiangsan (JWSJS) on kidney injury in diabetic nephropathy mice.Methods: Thirty 8-week-old db/db mice were randomly divided into five groups: model group, Perindopril group, and JWSJS low-, medium-, and high-dose groups (n=6 per group) based on body weight. Additionally, a blank control group was established consisting of 6 db/m mice aged 8 weeks. The blank and model groups received daily intragastric administration of 7g/kg/d pure water. The remaining groups were assigned to JWSJS low (3.5g/kg/d), medium (7g/kg/d), high (14g/kg/d) dosage groups, and perindopril positive control group (0.48mg/kg/d) for 12 weeks. Post-experiment, serum creatinine (SCr) and blood urea nitrogen (BUN) were analyzed using an automatic biochemical analyzer. Enzyme-linked immunosorbent assay (ELISA) measured 24-hour urinary albumin, neutrophil gelatinase-associated lipocalin (NGAL), TNF-α, IL-1β, VCAM-1, MCP-1, and HbA1c. Western blot assessed the protein expressions of p-PI3K, p-Akt, and p-NF-κB p65, while pathological kidney changes were observed.Results: Compared to the blank group, the model group exhibited increased SCr, BUN, 24-hour urinary albumin, serum NGAL, TNF-α, IL-1β, VCAM-1, MCP-1, HbA1c, p-PI3K, and p-Akt, alongside increased p-NF-κB p65 expression, indicating significant kidney pathology. After treatment, the JWSJS group showed decreased SCr, BUN, 24-hour urinary microalbumin, NGAL, HbA1c, TNF-α, IL-1β, VCAM-1, MCP-1 levels, increased p-PI3K and p-Akt expression (P< 0.05), and reduced p-NF-κB p65 content (P< 0.05). Histopathological analysis revealed that JWSJS ameliorated renal tubular epithelial cell damage, glomerular capillary and basement membrane injuries, and facilitated the repair of damaged podocytes in diabetic nephropathy mice.Conclusion: JWSJS demonstrated efficacy in reducing renal inflammation in diabetic nephropathy mice, with its mechanism likely associated with the inhibition of the PI3K/Akt/NF-κB signaling pathway.Keywords: Jiawei Shengjiangsan, diabetic nephropathy, PI3K/Akt/NF-κB signaling pathway, db/db mice, inflammation

Jie Li,1,2 Xinyu Nan,1 Yixuan Ma,3 Zhen Wang,4 Hui Fang1,2 1Department of Internal Medicine, Hebei Medical University, Shijiazhuang, 050000, People’s Republic of China; 2Department of Endocrinology, Tangshan Gongren Hospital, Tangshan, 063000, People’s Republic of China; 3Graduate School, Hebei North University, Zhangjiakou, 075000, People’s Republic of China; 4Department of Orthopedics, Handan First Hospital, Handan, 056000, People’s Republic of ChinaCorrespondence: Hui Fang, Department of Endocrinology, Tangshan Gongren Hospital, Tangshan, 063000, People’s Republic of China, Tel +86 13831581838, Email fanghui2818@126.comAbstract: Diabetes mellitus is a metabolic disease characterized by elevated blood glucose due to a deficiency of insulin secretion and/or action. Long-term poor blood glucose control may lead to chronic damage and dysfunction of the heart, kidneys, eyes, and other organs. Therefore, it is important to develop treatments for diabetes and its chronic complications. Fingolimod is a structural sphingosine analogue and sphingosine-1-phosphate receptor modulator currently used for the treatment of relapsing-remitting multiple sclerosis. Several studies have shown that it has beneficial effects on the improvement of diabetes and its chronic complications. This paper reviews the therapeutic potential of Fingolimod in diabetes and its chronic complications, aiming to further guide future treatment strategies.Keywords: fingolimod, diabetes mellitus, diabetes-related complications, treatment

Lujian Zhu,1,&ast; Qin Wang,1,&ast; Maodong Guo,2 Hao Fang,3 Ting Li,4 Yin Zhu,5 Huimian Jiang,6 Peiguang Xiao,2 Minli Hu2 1Department of Infectious Diseases, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China; 2Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China; 3Department of Traumatology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China; 4Department of Emergency Medicine, the First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of China; 5Department of Infectious Diseases, Taizhou Enze Medical Center (Group), Enze Hospital, Taizhou, People’s Republic of China; 6Department of Infectious Diseases, the First Affiliated Hospital of Ningbo University, Ningbo, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Minli Hu, Department of Gastroenterology, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, People’s Republic of China, Email huminlignmc@126.comAbstract: Chronic liver conditions are associated with high mortality rates and have a large adverse effect on human well-being as well as a significant financial burden. Currently, the only effective treatment available for the effects of liver failure and cirrhosis resulting from the progression of several chronic liver diseases is liver transplantation carried out at the original location. This implies that developing novel and effective treatments is imperative. Regenerative medicine has long been associated with stem cell therapy. Mesenchymal stem cells (MSCs), a type of cell with great differentiation potential, have become the preferred source for stem cell therapy. According to recent studies, MSCs’ paracrine products—rather than their capacity for differentiation—play a significant therapeutic effect. MSC exosomes, a type of extracellular vesicle (MSC-EV), came into view as the paracrine substances of MSCs. According to research, MSC exosomes can maintain tissue homeostasis, which is necessary for healthy tissue function. All tissues contain them, and they take part in a variety of biological activities that support cellular activity and tissue regeneration in order to preserve tissue homeostasis. The outcomes support the use of MSCs and the exosomes they produce as a therapeutic option for a range of diseases. This review provides a brief overview of the source of MSC-EVs and outlines their physiological roles and biochemical capabilities. The elucidation of the role of MSC-EVs in the recovery and repair of hepatic tissues, as well as their contribution to maintaining tissue homeostasis, is discussed in relation to different chronic liver diseases. This review aims to provide new insights into the unique roles that MSC-EVs play in the treatment of chronic liver diseases.Keywords: mesenchymal stem cells, exosomes, liver disease, immunomodulation, tissue homeostasis

Hanyu Fang,1,2 Tairan Dong,1 Shanlin Li,1 Yihan Zhang,1 Zhuojun Han,1 Mingfei Liu,1,2 Wenjun Dong,1,2 Zheng Hong,1,2 Min Fu,3 Hongchun Zhang1,2 1Graduate School, Beijing University of Chinese Medicine, Beijing, People’s Republic of China, 100029; 2Department of Traditional Chinese Medicine for Pulmonary Diseases, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China; 3Department of Infectious Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100029, People’s Republic of ChinaCorrespondence: Hongchun Zhang, Department of Traditional Chinese Medicine for Pulmonary Diseases, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China, Tel +86 13701226664, Email 13701226664@139.com Min Fu, Department of Infectious Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100029, People’s Republic of China, Tel +86 13366093706, Email bdfumin@126.comObjective: Although studies on the association between COPD and lung cancer are of great significance, no bibliometric analysis has been conducted in the field of their comorbidity. This bibliometric analysis explores the current situation and frontier trends in the field of COPD and lung cancer comorbidity, and to lay a new direction for subsequent research.Methods: Articles in the field of COPD and cancer comorbidity were retrieved from Web of Science Core Collections (WoSCC) from 2004 to 2023, and analyzed by VOSviewer, CiteSpace, Biblimatrix and WPS Office.Results: In total, 3330 publications were included. The USA was the leading country with the most publications and great influence. The University of Groningen was the most productive institution. Edwin Kepner Silverman was the most influential scholar in this field. PLOS One was found to be the most prolific journal. Mechanisms and risk factors were of vital importance in this research field. Environmental pollution and pulmonary fibrosis may be future research prospects.Conclusion: This bibliometric analysis provided new guidance for the development of the field of COPD and lung cancer comorbidity by visualizing current research hotspots, and predicting possible hot research directions in the future.Keywords: COPD, lung cancer, bibliometric analysis, VOSviewer, CiteSpace

Hanyu Fang,1,2,&ast; Tairan Dong,1,&ast; Zhuojun Han,1 Shanlin Li,1 Mingfei Liu,1 Ying Liu,3 Qiwen Yang,1 Min Fu,4 Hongchun Zhang1,2 1Graduate School, Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 2Department of Traditional Chinese Medicine for Pulmonary Diseases, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China; 3The Second Health and Medical Department, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China; 4Department of Infectious Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100029, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongchun Zhang, Department of Traditional Chinese Medicine for Pulmonary Diseases, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China, Tel +86 13701226664, Email 13701226664@139.com Min Fu, Department of Infectious Diseases, Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, 100029, People’s Republic of China, Tel +86 13366093706, Email bdfumin@126.comObjective: The comorbidity of pulmonary fibrosis and COPD/emphysema has garnered increasing attention. However, no bibliometric analysis of this comorbidity has been conducted thus far. This study aims to perform a bibliometric analysis to explore the current status and cutting-edge trends in the field, and to establish new directions for future research.Methods: Statistical computing, graphics, and data visualization tools such as VOSviewer, CiteSpace, Biblimatrix, and WPS Office were employed.Results: We identified a total of 1827 original articles and reviews on the comorbidity of pulmonary fibrosis and COPD/emphysema published between 2004 and 2023. There was an observed increasing trend in publications related to this comorbidity. The United States, Japan, and the United Kingdom were the countries with the highest contributions. Professor Athol Wells and the University of Groningen had the highest h-index and the most articles, respectively. Through cluster analysis of co-cited documents, we identified the top 17 major clusters. Keyword analysis predicted that NF-κB, oxidative stress, physical activity, and air pollution might be hot spots in this field in the future.Conclusion: This bibliometric analysis demonstrates a continuous increasing trend in literature related to the comorbidity of pulmonary fibrosis and COPD/emphysema. The research hotspots and trends identified in this study provide a reference for in-depth research in this field, aiming to promote the development of the comorbidity of pulmonary fibrosis and COPD/emphysema.Keywords: COPD, pulmonary fibrosis, bibliometric analysis, VOSviewer, CiteSpace

Jianfeng Hong,1 Xindong Chen,2 Lingli Chen,2 Yigang Wang,2 Biao Huang,2 Hongming Fang1 1Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, People’s Republic of China; 2Immunological Analysis Laboratory of Academy of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, People’s Republic of ChinaCorrespondence: Hongming Fang, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, 310016, People’s Republic of China, Tel + 86 0571-83865858, Email 3295988078@qq.com Biao Huang, Immunological Analysis Laboratory of Academy of Life Sciences, Zhejiang Sci-Tech University, Hangzhou, 310016, People’s Republic of China, Tel +86 0571-86843187, Email jswxhb@163.comPurpose: The present study aimed to evaluate the clinical value of Combined Detection of serum soluble T-cell immunoglobulin 3 (sTim-3) with carcinoembryonic antigen (CEA) or glycotype antigen 19– 9 (CA19-9) for Postoperative Recurrence of Colorectal Cancer (CRC) Diagnosis.Patients and Methods: The serum sTim-3 was measured by highly sensitivity TRFIA, and serum CEA and CA19-9 were obtained through the collection of clinical data. Quantitative detection of serum sTim-3, CEA, CA19-9 in 90 patients after the CRC surgery (52 postoperative recurrence and 38 no-postoperative recurrence), 21 patients with colorectal benign tumors, and 67 healthy controls. To analyze the clinical diagnostic value of combined detection of sTim-3 with CEA or CA19-9 to test whether patients have recurrence after CRC surgery.Results: The sTim-3 (15.94± 11.24ng/mL) in patients after CRC surgery was significantly higher than in healthy controls (8.95± 3.34ng/mL) and colorectal benign tumors (8.39± 2.28ng/mL) (P < 0.05), and sTim-3 (20.33± 13.04ng/mL) in CRC postoperative recurrent group was significantly higher than in the group without recurrence after CRC surgery (9.94± 2.36ng/mL) (P < 0.05). In terms of detecting postoperative recurrence after CRC surgery, combined detection of sTim-3 and CEA (AUC: 0.819, sensitivity: 80.77%, specificity: 65.79%), sTim-3 and CA19-9 test (AUC: 0.813, sensitivity: 69.23%, specificity: 97.30%) was significantly better than the CEA single test (AUC: 0.547, sensitivity: 63.16%, specificity: 48.08%) and CA19-9 single test (AUC: 0.675 sensitivity: 65.38%, specificity: 67.57%), Delong test P < 0.05.Conclusion: The efficacy of CEA and CA19-9 single test was not optimal, and the combination of sTim-3 in serum could significantly improve the sensitivity and specificity of detecting patient recurrence after CRC surgery.Keywords: serum tumor markers, Tim-3, time-resolved fluorescence immunoassay, colorectal cancer recurrence

Jin-Hu Shi,1,&ast; Jian Ding,2,&ast; Hu Cheng,1,&ast; Huang Fang,3 Jian Zhu4 1Department of Cardiology, General Hospital of Central Theater Command of the People’s Liberation Army, Wuhan, People’s Republic of China; 2Department of Disinfection and Supply, General Hospital of Central Theater Command of the People’s Liberation Army, Wuhan, People’s Republic of China; 3Department of Neurology, General Hospital of Central Theater Command of the People’s Liberation Army, Wuhan, Hubei Province, People’s Republic of China; 4Department of Thoracic Cardiovascular Surgery, General Hospital of Central Theater Command of the People’s Liberation Army, Wuhan, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Huang Fang, Department of Neurology, General Hospital of Central Theater Command of the People’s Liberation Army, 627&num;, Wuluo Road, Wuchang District, Wuhan, Hubei Province, 430070, People’s Republic of China, Email mhdytfine@163.com Jian Zhu, Department of Thoracic Cardiovascular Surgery, General Hospital of Central Theater Command of the People’s Liberation Army, 627&num;, Wuluo Road, Wuchang District, Wuhan, Hubei Province, 430070, People’s Republic of China, Fax +86-27-50772388, Email zhujian0718@163.comObjective: To evaluate the effect of sleep duration on blood pressure in patients with hypertension urgencies combined with SARS-CoV-2 infection in a Fangcang shelter hospital.Methods: From April 10, 2020 to May 20, 2022, we statistically analyzed the blood pressure and sleep conditions of 52 patients with combined hypertension urgencies and SARS-CoV-2 infection admitted in Shanghai National Convention and Exhibition Center Fangcang shelter hospital. They were divided into the short-term (daily sleep duration: < 7 h) and normal sleep group (7– 9 h). We performed a comparison of the control effects of basic antihypertensive drugs. Additionally, patients in the short-term sleep group underwent drug therapy for sleep regulation and continuous monitoring of blood pressure.Results: Among these patients, the blood pressure was higher in the short-term sleep group than that of the normal sleep group, and also more difficult to control (p < 0.05). Furthermore, the blood pressure of the patients in the short-term sleep group was more easily controlled after treatment with drugs for sleep regulation and basic antihypertensive drugs (p < 0.05).Conclusion: The blood pressure level in patients with combined SARS-CoV-2 infection and hypertension urgencies was higher in those with a shorter duration of daily sleep, and also more difficult to control in Fangcang shelter hospital. Drug therapy for sleep regulation should be administered early to obtain sufficient blood pressure control effects.Keywords: hypertension urgencies, shelter hospital, sleep regulation, Fangcang hospital, blood pressure, short-term sleep, SARS-CoV-2, COVID-19

Hanyu Fang,1,&ast; Ying Liu,2,&ast; Qiwen Yang,1 Siyu Han,1 Hongchun Zhang1– 3 1Beijing University of Chinese Medicine, Beijing, 100029, People’s Republic of China; 2The Second Health and Medical Department, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China; 3Department of Traditional Chinese Medicine for Pulmonary Diseases, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hongchun Zhang, Department of Traditional Chinese Medicine for Pulmonary Diseases, Center of Respiratory Medicine, China-Japan Friendship Hospital, Beijing, 100029, People’s Republic of China, Tel +86 13701226664, Email 13701226664@139.comAbstract: Chronic obstructive pulmonary disease (COPD) is a common heterogeneous respiratory disease which is characterized by persistent and incompletely reversible airflow limitation. Due to the heterogeneity and phenotypic complexity of COPD, traditional diagnostic methods provide limited information and pose a great challenge to clinical management. In recent years, with the development of omics technologies, proteomics, metabolomics, transcriptomics, etc., have been widely used in the study of COPD, providing great help to discover new biomarkers and elucidate the complex mechanisms of COPD. In this review, we summarize the prognostic biomarkers of COPD based on proteomic studies in recent years and evaluate their association with COPD prognosis. Finally, we present the prospects and challenges of COPD prognostic-related studies. This review is expected to provide cutting-edge evidence in prognostic evaluation of clinical patients with COPD and to inform future proteomic studies on prognostic biomarkers of COPD.Keywords: chronic obstructive pulmonary disease, omics, proteome, biomarker, prognosis

Xiaoxia Wang, Haining Fang Department of Pediatrics, Maternal and Child Health Hospital of Hubei Province, Wuhan, 430070, People’s Republic of ChinaCorrespondence: Haining Fang, Department of Pediatrics, Maternal and Child Health Hospital of Hubei Province, No. 745, Wuluo Road, Hongshan District, Wuhan, 430070, People’s Republic of China, Tel +86 27 87169085, Email fanghaining2022@126.comObjective: To investigate the clinical and gene mutation characteristics of fatty acid oxidative metabolic diseases found in neonatal screening.Methods: A retrospective analysis was performed on 29,948 neonatal blood tandem mass spectrometry screening samples from January 2018 to December 2021 in our neonatal screening centre. For screening positive, recall review is still suspected of fatty acid oxidation metabolic disorders in children as soon as possible to improve the genetic metabolic disease-related gene detection package to confirm the diagnosis. All diagnosed children were followed up to the deadline.Results: Among 29,948 neonates screened by tandem mass spectrometry, 14 cases of primary carnitine deficiency, six cases of short-chain acyl coenzyme A dehydrogenase deficiency, two cases of carnitine palmitoyltransferase-I deficiency and one case of multiple acyl coenzyme A dehydrogenase deficiency were recalled. Except for two cases of multiple acyl coenzyme A dehydrogenase deficiency that exhibited [manifestations], the other 21 cases were diagnosed pre-symptomatically. Eight mutations of SLC22A 5 gene were detected, including c.51C>G, c.403G>A, c.506G>A, c.1400C>G, c.1085C>T, c.706C>T, c.1540G>C and c.338G>A. Compound heterozygous mutation of CPT1A gene c.2201T>C, c.1318G>A, c.2246G>A, c.2125G>A and ETFA gene c.365G>A and c.699_701delGTT were detected, and new mutation sites were found.Conclusion: Neonatal tandem mass spectrometry screening is an effective method for identifying fatty acid oxidative metabolic diseases, but it should be combined with urine gas chromatography-mass spectrometry and gene sequencing technology. Our findings enrich the gene mutation profile of fatty acid oxidative metabolic disease and provide evidence for genetic counselling and prenatal diagnosis in families.Keywords: fatty acid oxidative metabolic disorder, primary carnitine deficiency, multiple acyl coenzyme A dehydrogenase deficiency, carnitine palmitoyltransferase-I deficiency, short-chain acyl-coenzyme A dehydrogenase deficiency

Liangjie Lu,1 Haiming Fang,1 Mengchao Gu,1 Huihan Wang,2 Qiuxia Yu,3 Aqiong Chen,3 Kai-feng Gan1 1Department of Orthopaedics, Li Huili Hospital Affiliated to Ningbo University, Ningbo, 315040, People’s Republic of China; 2Department of Orthopaedics, Zhengzhou Central Hospital Affiliated to Zhengzhou University, Zhengzhou, 450007, People’s Republic of China; 3Department of Rheumatology, Li Huili Hospital Affiliated to Ningbo University, Ningbo, 315040, People’s Republic of ChinaCorrespondence: Kai-feng Gan, Tel +86-15724288924, Email gankaifeng1982@163.comPurpose: This study aimed to compare the changes in the expression of microRNA Let-7i in peripheral blood mononuclear cells (PBMCs) of patients with ankylosing spondylitis (AS) and the correlation between Let-7i and innate pro-inflammatory factors. It is necessary to search for a new biomarker to guide the prognosis of AS.Methods: A total of 10 patients with AS and 10 healthy volunteers were selected as AS and control groups, respectively. The expression levels of Let-7i, Toll-like receptor 4 (TLR4), nuclear factor-κB (NF-κB), and interferon-gamma (IFN-γ) in PBMCs were detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blotting (WB) to explore the relationship between Let-7i and pro-inflammatory factors. Furthermore, the relationship between Let-7i and TLR4 was determined by the luciferase reporter technology.Results: The expression level of Let-7i in PBMCs of patients with AS was significantly lower than that of healthy control. The expression levels of TLR4, NF-κB, and IFN-γ in PBMCs derived from patients with AS were significantly higher than those of healthy control. The results show that Let-7i manipulation can regulate lipopolysaccharide (LPS)-induced TLR4 and IFN-γ expression in CD4+ T cells of patients with AS. The overexpression of Let-7i in T cells of patients with AS can suppress TLR4 and IFN-γ LPS-induced expression levels of cellular mRNA and protein. Let-7i can directly interfere TLR4-3’untranslated region (UTR) sequence and regulate the expression of the TLR4 gene in Jurkat T cells.Conclusion: Let-7i may be involved in the pathogenesis of AS, and Let-7i expression in PBMCs may be helpful for the diagnosis and treatment of AS in the future.Keywords: ankylosing spondylitis, Let-7i, TLR4, innate inflammatory

Yali Li,1 Jialing Xiao,2 Yi Sun,3 Hong Fang,1 Jianjun Qiao1 1Department of Dermatology, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2Department of Stomatology, Zhejiang Hospital, Hangzhou, People’s Republic of China; 3Department of Dermatology, Jingzhou Central Hospital, The Second Clinical Medical College, Yangtze University, Jingzhou, People’s Republic of ChinaCorrespondence: Jianjun Qiao, Department of Dermatology, The First Affiliated Hospital, School of Medicine, Zhejiang University, 79# Qingchun Road, Shangcheng District, Hangzhou, 310003, People’s Republic of China, Tel +86-571-87235857, Email qiaojianjun@zju.edu.cnAbstract: Previously case reports showed dupilumab may benefit for hand eczema treatment, but relatively comprehensive assessments are lacking. A 45-year-old male with multiple severe vesicles, bullae and pustule on the palmar aspects of both hand and foot diagnosed dyshidrotic eczema by pathology was treated with dupilumab at an initial dose of 600 mg subcutaneously, followed by 300 mg every 2 weeks. The physician’s assessment of the patient revealed an excellent response to the treatment with dupilumab; the lesions and symptoms achieved dramatic improvement on the third day, and at 6 weeks, the hands and feet became completely normal without relapse in the past 1.5 years of discontinuation. Systematic literature searches were performed, and 6 case reports, 5 case series, 2 prospective observational studies and 1 retrospective review with a total of 150 patients were identified to describing the evaluation of efficacy and safety of dupilumab treatment for hand and foot eczema. Dupilumab appears to be safe and well tolerated with clinical benefit in recalcitrant hand and foot eczema. Larger randomized controlled trials using validated outcome measures and detailed hand eczema type and population classification are needed before dupilumab can be applied in clinical settings.Keywords: dupilumab, hand eczema, dyshidrotic eczema, treatment, quick

Yuqi Chu, Taoming Liu, Juan Bai, Hong Fang, Jianjun Qiao Department of Dermatology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Jianjun Qiao, Department of Dermatology, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, 310003, People’s Republic of China, Tel +86 13735542393, Email qiaojianjun@zju.edu.cnAbstract: Pyoderma gangrenosum (PG) is a rare autoinflammatory skin disorder, which is characterised by rapidly developing and tender cutaneous ulcers. The treatment of PG is challenging. Palmoplantar pustulosis (PPP) is also an autoinflammatory dermatosis with sterile pustules on the palms and/or the soles. We demonstrated a 68-year-old patient with coexisting autoinflammatory diseases including PG, 1-year history of plaque psoriasis and PPP, recovered after treatment with adalimumab. We also reviewed published reports of PG-associated autoinflammatory syndromes with adalimumab.Keywords: adalimumab, autoinflammatory syndrome, palmoplantar pustulosis, plaque psoriasis, pyoderma gangrenosum

Jeffrey M Cochran,1 Hui Fang,1 John G Sonnenberg,2,3 Elan A Cohen,4 Jean-Pierre Lindenmayer,5 J Corey Reuteman-Fowler1 1Otsuka Pharmaceutical Development & Commercialization, Inc, Princeton, NJ, USA; 2Uptown Research Institute, Chicago, IL, USA; 3Department of Psychiatry and Behavioral Sciences, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA; 4Hassman Research Institute, Marlton, NJ, USA; 5Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USACorrespondence: Jeffrey M Cochran, Otsuka Pharmaceutical Development & Commercialization, Inc, Princeton, NJ, USA, Tel +1 609 535 9035, Email Jeffrey.Cochran@otsuka-us.comPurpose: Schizophrenia is a severe, chronic condition accounting for disproportionate healthcare utilization. Antipsychotics can reduce relapse rates, but the characteristics of schizophrenia may hinder medication adherence. A phase 3b open-label clinical trial used aripiprazole tablets with sensor (AS; includes pills with ingestible event-marker, wearable sensor patches and smartphone application) in adults with schizophrenia. This post hoc analysis explored how healthcare providers’ (HCPs) usage of a dashboard that provided medication ingestion information impacted treatment decisions and clinical assessments.Patients and Methods: Participants used AS for 3– 6 months. HCPs were instructed to check the dashboard regularly, identify features used, and report impact on treatment decisions. After stratifying HCPs by frequency of dashboard checks and resulting treatment decisions, changes from baseline were calculated for Positive and Negative Syndrome Scale (PANSS), Clinical Global Impression (CGI)–Severity of Illness and CGI-Improvement (CGI-I), and Personal and Social Performance (PSP), and compared using Mann–Whitney U-tests and rank-biserial correlation coefficient (r) effect sizes.Results: To ensure sufficient opportunity for AS engagement, 113 participants who completed ≥ 3 months on study were analyzed. HCPs most often accessed dashboard data regarding medication ingestion and missed doses. HCPs recommended adherence counseling and participant education most often. Participants whose HCPs used the dashboard more and recommended adherence counseling and participant education (n=61) improved significantly more than participants with less dashboard-active HCPs (n=49) in CGI-I mean score (2.9 versus 3.4 [p=0.004]), total PANSS (mean change: − 9.2 versus − 3.1 [p=0.0002]), PANSS positive subscale (− 3.2 versus − 1.5 [p=0.003]), PANSS general subscale (− 4.3 versus − 1.2 [p=0.02]), and Marder factor for negative symptoms (− 1.9 versus 0.0 [p=0.03]). Most HCPs found the dashboard easy to use (74%) and helpful for improving conversations with participants about their treatment plan and progress (78%).Conclusion: This provider dashboard may facilitate discussions with patients about regular medication-taking, which can improve patient outcomes.Keywords: digital medicine system, clinical decision-making, clinical decision support, patient–provider communication, schizophrenia

Jeffrey M Cochran,1 Hui Fang,2 Christophe Le Gallo,3 Timothy Peters-Strickland,4 Jean-Pierre Lindenmayer,5 J Corey Reuteman-Fowler6 1Medical & Real World Data Analytics, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USA; 2Biostatistics, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USA; 3Clinical Programming, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USA; 4PPD, Inc., Wilmington, NC, USA; 5Department of Psychiatry, New York University Grossman School of Medicine, New York, NY, USA; 6Global Clinical Development, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, USACorrespondence: Jeffrey M Cochran, Medical & Real World Data Analytics, Otsuka Pharmaceutical Development & Commercialization, Inc., 508 Carnegie Center, Princeton, NJ, 08540, USA, Tel +1 609 535 9035, Email Jeffrey.Cochran@otsuka-us.comPurpose: A recent, phase 3b, mirror-image clinical trial of outpatients with schizophrenia found that use of aripiprazole tablets with sensor (AS; Abilify MyCite®, comprising an ingestible event-marker sensor embedded in aripiprazole tablets, wearable sensor patches, and a smartphone application) reduced the incidence of psychiatric hospitalizations relative to oral standard-of-care antipsychotics. This analysis explored the relationship between AS engagement by participants and changes in participant performance and symptom-severity measures assessed by clinical raters.Participants and Methods: This post hoc analysis used prospectively collected clinical data from a phase 3b clinical trial (NCT03892889). Outpatients had schizophrenia, were aged 18– 65 years, and had ≥ 1 psychiatric hospitalization in the previous 48 months. Participants were grouped by study completion status and a k-means clustering algorithm based on AS utilization, resulting in 3 groups: discontinued (discontinued AS before month 3 of the study); moderate engagement (completed 3 months, used AS intermittently); and high engagement (completed 3 months, used AS regularly). Baseline to end-of-study differences for the Clinical Global Impression Scale (Severity of Illness and Improvement of Illness scales), Personal and Social Performance Scale, and Positive and Negative Syndrome Scale were calculated.Results: A total of 277 outpatients were enrolled (discontinued, n = 164; moderate engagement, n = 63; high engagement, n = 50). All groups experienced symptom improvement from baseline to end-of-study, with significant changes in the more-engaged groups. Highly engaged participants showed significant improvement for all clinical scores and subscores (all P < 0.05) and demonstrated significantly more improvement in symptoms than participants with less engagement.Conclusion: Participants who completed 3 months of the study and had higher AS engagement experienced significantly greater improvement in their end-of-study clinical assessments versus participants who did not complete 3 months. Improvement may be related to more-consistent medication intake and better engagement with a digital health system.Keywords: digital medicine, medication ingestion, treatment utilization, Positive and Negative Syndrome Scale

Huankun Fang,1,2,&ast; Zhiqin Deng,1,&ast; Jianquan Liu,1,&ast; Siyu Chen,3 Zhenhan Deng,3 Wencui Li1 1Hand and Foot Surgery Department, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, Guangdong, 518035, People’s Republic of China; 2Medical College, Shantou University, Shantou, Guangdong, 515041, People’s Republic of China; 3Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, Shenzhen, Guangdong, 518035, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Zhenhan Deng, Department of Sports Medicine, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, 3002 Sungang West Road, Shenzhen City, 518025, People’s Republic of China, Tel +86 13928440786, Fax +86 755-83366388, Email dengzhenhan@email.szu.edu.cn Wencui Li, Department of Hand and Foot Surgery, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People’s Hospital, 3002 Sungang West Road, Shenzhen City, 518025, People’s Republic of China, Tel +86 13923750767, Email wencuilisz@126.comAbstract: Senescence mainly manifests as a series of degenerative changes in the morphological structure and function of the body. Osteoporosis is a systemic bone metabolic disease characterized by destruction of bone microstructure, low bone mineral content, decreased bone strength, and increased brittleness and fracture susceptibility. Osteoblasts, osteoclasts and osteocytes are the main cellular components of bones. However, in the process of aging, due to various self or environmental factors, the body’s function and metabolism are disordered, and osteoporosis will appear in the bones. Here, we summarize the mechanism of aging, and focus on the impact of aging on bone remodeling homeostasis, including the mechanism of ion channels on bone remodeling. Finally, we summarized the current clinical medications, targets and defects for the treatment of osteoporosis.Keywords: aging, osteoporosis, bone formation, epigenetics, autophagy, chlorine channel

Huidan Zhang,1– 3,&ast; Jing Xu,1,2,4,&ast; Qingrui Wu,3,&ast; Heng Fang,1,2,4 Xin Shao,1,2 Xin Ouyang,1 Zhimei He,2 Yiyu Deng,2– 4 Chunbo Chen1,3,4 1Department of Intensive Care Unit of Cardiovascular Surgery, Guangdong Cardiovascular Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People’s Republic of China; 2Department of Critical Care Medicine, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People’s Republic of China; 3School of Medicine, South China University of Technology, Guangzhou, 510006, People’s Republic of China; 4The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, Guangdong, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yiyu Deng; Chunbo Chen, Tel +86-20-83827812 ext. 61526, Fax +86-20-83827712, Email yiyudeng666@163.com; gghccm@163.comPurpose: Neuroinflammation plays an important part in the pathophysiology of sepsis-associated encephalopathy (SAE). Gut microbiota and gut brain axis are considered as important mediators in the development of neurological diseases. The aim of this study was to investigate the role of intestinal microbiota in sepsis-related brain injury and to explore the underlying mechanisms.Methods: Mouse model of SAE was established using cecal ligation and puncture (CLP). Based on the mouse mortality and the associated time of death, light SAE (LSAE) and severe SAE (SSAE) were classified. Fecal microbiota transplantation (FMT) was performed to verify the role of intestinal microbiota. Feces of mice in the two groups which collected before operation were sequenced for 16S and targeted short chain fatty acids.Results: Intestinal microbiota from SSAE and LSAE mice displayed diverse functions. Interestingly, LSAE mice produced more butyric acid compared with SSAE mice. In the in vivo experiments, sodium butyrate (NaB) reduced the high oxidative stress levels in mice hippocampus and conferred a marked survival superiority to sepsis mice. In addition, NaB prevented the increase in intracellular reactive oxygen species (ROS) generation and inducible nitric-oxide synthase expression in LPS-stimulated primary microglia. The GPR109A/Nrf2/HO-1 signaling pathway was found to be involved in the activation of antioxidant response of primary microglia induced by sodium butyrate.Conclusion: Our findings indicate a crucial role of gut microbiota in the susceptibility to SAE. Butyrate, a metabolite of intestinal microbiota, may have a neuroprotective effect in the process of sepsis by GPR109A/Nrf2/HO-1 pathway.Keywords: gut microbiome, butyrate, sepsis-related brain injury, primary microglia, oxidative stress

Serena Scarpelli,1 Michael R Nadorff,2,3 Bjørn Bjorvatn,4 Frances Chung,5 Yves Dauvilliers,6 Colin A Espie,7 Yuichi Inoue,8 Kentaro Matsui,9,10 Ilona Merikanto,11,12 Charles M Morin,13 Thomas Penzel,14 Mariusz Sieminski,15 Han Fang,16 Tainá Macêdo,17 Sérgio A Mota-Rolim,18 Damien Leger,19 Giuseppe Plazzi,20,21 Ngan Yin Chan,22 Markku Partinen,23 Courtney J Bolstad,2 Brigitte Holzinger,24,25 Luigi De Gennaro1,26 1Department of Psychology, Sapienza University of Rome, Rome, Italy; 2Mississippi State University, Mississippi State, MS, USA; 3Department of Psychiatry and Behavioral Sciences, Baylor College of Medicine, Houston, TX, USA; 4Department of Public Health and Primary Care, University of Bergen and Norwegian Competence Center for Sleep Disorders, Haukeland University Hospital, Bergen, Norway; 5Department of Anesthesiology and Pain Medicine, University Health Network, University of Toronto, Toronto, Canada; 6Sleep-Wake Disorders Unit, Department of Neurology, Gui-de-Chauliac Hospital, CHU Montpellier, INM, Univ Montpellier, INSERM, Montpellier, France; 7Sleep and Circadian Neuroscience Institute, Nuffield Department of Clinical Neurosciences, University of Oxford, Oxford, UK; 8Tokyo Medical University, Tokyo, Japan; 9Department of Laboratory Medicine, National Center Hospital, National Center of Neurology and Psychiatry, Kodaira, Japan; 10Department of Psychiatry, Tokyo Women’s Medical University, Tokyo, Japan; 11SleepWell Research Program, Faculty of Medicine, University of Helsinki, Helsinki, Finland; 12Department of Public Health Solutions, Finnish Institute for Health and Welfare, Helsinki, Finland; 13École de Psychologie, Centre d’étude des troubles du sommeil, Centre de recherche CERVO/Brain Research Center, Université Laval, Québec, Canada; 14Sleep Medicine Center, Charité Universitätsmedizin Berlin, Berlin, Germany; 15Department of Emergency Medicine, Medical University of Gdansk, Gdansk, Poland; 16Department of Pulmonary and Critical Care Medicine, Peking University People’s Hospital, Beijing, People’s Republic of China; 17Department of Psychology, Federal University of Rio Grande do Norte, Natal, Brazil; 18Brain Institute, Physiology and Behavior Department, and Onofre Lopes University Hospital - Federal University of Rio Grande do Norte, Natal, Brazil; 19Université de Paris, APHP, Hôtel-Dieu, Centre du Sommeil et de la Vigilance, Paris, France; 20IRCCS, Istituto delle Scienze Neurologiche di Bologna, Bologna, Italy; 21Department of Biomedical, Metabolic and Neural Sciences, University of Modena and Reggio Emilia, Modena, Italy; 22Li Chiu Kong Family Sleep Assessment Unit, Department of Psychiatry, Faculty of Medicine, The Chinese University of Hong Kong, Shatin, Hong Kong, Special Administrative Regions, People’s Republic of China; 23Helsinki Sleep Clinic, Terveystalo Healthcare, and Department of Neurosciences, Clinicum, University of Helsinki, Helsinki, Finland; 24Institute for Consciousness and Dream Research, Vienna, Austria; 25Medical University Vienna, Postgraduate Master Program Medical Sleep Coaching, ZK-Schlafcoaching, Vienna, Austria; 26IRCCS Fondazione Santa Lucia, Rome, ItalyCorrespondence: Luigi De Gennaro, Tel +39-06-49917647, Fax +39-06-49917711, Email luigi.degennaro@uniroma1.itIntroduction: A growing number of studies have demonstrated that the coronavirus disease-19 (COVID-19) pandemic has severely affected sleep and dream activity in healthy people. To date, no investigation has examined dream activity specifically in COVID-19 patients.Methods: As part of the International COVID-19 Sleep Study (ICOSS), we compared 544 COVID-19 participants with 544 matched-controls. A within-subjects comparison between pre-pandemic and pandemic periods computed separately for controls and COVID-19 participants were performed on dream recall and nightmare frequency (DRF; NF). Also, non-parametric comparisons between controls and COVID-19 participants were carried out. Further, we compared psychological measures between the groups collected during pandemic. Ordinal logistic regression to detect the best predictors of NF was performed.Results: We found that people reported greater dream activity during the pandemic. Comparisons between controls and COVID-19 participants revealed a) no difference between groups concerning DRF in the pre-pandemic period and during the pandemic; b) no difference between groups concerning nightmare frequency in the pre-pandemic period; and c) COVID-19 participants reported significantly higher NF than controls during pandemic (p = 0.003). Additionally, we showed that a) anxiety, depression, post-traumatic stress-disorder (PTSD) symptom scores were higher in COVID-19 participants than controls; and b) quality of life and health as well as wellbeing (WHO-5) scores were significantly higher in controls than COVID-19 participants. Finally, ordinal logistic regression indicates that DRF (p < 0.001), PTSD (p < 0.001), anxiety (p = 0.018), insomnia (p = 0.039), COVID-19 severity (p = 0.014), sleep duration (p = 0.003) and age (p = 0.001) predicted NF.Discussion: Our work shows strong associations between increased nightmares in those reporting having had COVID-19. This suggests that the more that people were affected by COVID-19, the greater the impact upon dream activity and quality of life.Keywords: dreaming, pandemic, sleep, PTSD, anxiety, COVID-19 severity

Free-standing nanoribbons of InAs quantum membranes (QMs) transferred onto a (Si/Mo) multilayer mirror substrate are characterized by hard x-ray photoemission spectroscopy (HXPS) and by standing-wave HXPS (SW-HXPS). Information on the chemical composition and on the chemical states of the elements within the nanoribbons was obtained by HXPS and on the quantitative depth profiles by SW-HXPS. By comparing the experimental SW-HXPS rocking curves to x-ray optical calculations, the chemical depth profile of the InAs(QM) and its interfaces were quantitatively derived with ångström precision. We determined that (i) the exposure to air induced the formation of an InAsO4 layer on top of the stoichiometric InAs(QM); (ii) the top interface between the air-side InAsO4 and the InAs(QM) is not sharp, indicating that interdiffusion occurs between these two layers; (iii) the bottom interface between the InAs(QM) and the native oxide SiO2 on top of the (Si/Mo) substrate is abrupt. In addition, the valence band offset (VBO) between the InAs(QM) and the SiO2/(Si/Mo) substrate was determined by HXPS. The value of VBO = 0.2 ± 0.04 eV is in good agreement with literature results obtained by electrical characterization, giving a clear indication of the formation of a well-defined and abrupt InAs/SiO2 heterojunction. We have demonstrated that HXPS and SW-HXPS are non-destructive, powerful methods for characterizing interfaces and for providing chemical depth profiles of nanostructures, quantum membranes, and 2D layered materials.

Lingli Chen,1,&ast; Jianfeng Hong,2,&ast; Renjing Hu,3,&ast; Xiaomei Yu,1 Xindong Chen,1 Shaoxiong Zheng,1 Yuan Qin,1 Xiumei Zhou,1 Yigang Wang,1 Liping Zheng,2 Hongming Fang,2 Pengfei Liu,4 Biao Huang1 1Department of Immunoassay Laboratory, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, People’s Republic of China; 2Department of Laboratory, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, People’s Republic of China; 3Department of Laboratory, The Affiliated Wuxi No.2 People’s Hospital of Nanjing Medical University, Wuxi, People’s Republic of China; 4Department of Gastroenterology, The Jiangyin Clinical College of Xuzhou Medical University, Wuxi, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Biao HuangImmunoassay Laboratory, College of Life Sciences and Medicine, Zhejiang Sci-Tech University, Hangzhou, 310016, People’s Republic of ChinaTel +86 571-86843187Email jswxhb@163.comHongming FangDepartment of Laboratory, Affiliated Xiaoshan Hospital, Hangzhou Normal University, Hangzhou, 310016, People’s Republic of ChinaTel +86 571 83865858Email 3295988078@qq.comPurpose: The present study aimed to evaluate the clinical value of the combined detection of soluble T cell immunoglobulinand mucin domain molecule 3 (sTim-3) and pepsinogen (PG) in sera for gastric cancer (GC) diagnosis.Patients and Methods: The double antibody sandwich method was used to establish a highly sensitive time-resolved fluorescence immunoassay for the detection of sTim-3. Serum sTim-3, PGI, and PGII levels in 149 GC patients (123 first-diagnosis GC patients and 26 post-GC patients), 81 patients with benign gastric disease (BGD), and 73 healthy controls were quantitatively detected. The clinical diagnostic value of the combined detection of sTim-3 and PG in GC was analyzed.Results: Serum sTim-3 levels in GC (20.41 ± 9.55 ng/mL) and BGD (16.50 ± 9.76 ng/mL) patients were significantly higher (P < 0.001) than those in healthy controls (9.22 ± 3.40 ng/mL). Combined detection of sTim-3 and PGI/PGII (AUC: 0.9330, sensitivity: 86.44%, and specificity: 91.78%) showed a high diagnostic value for GC. When the level of PGI/PGII was less than 12.11 and that of sTim-3 was greater than 14.30 ng/mL, the positive rate of the control group was reduced to 0%, and the positive detection rate of GC was 54.47%. In addition, in post-operative patients, serum sTim-3 levels in the recurrence group (33.56 ± 4.91 ng/mL) were significantly higher than those in the no recurrence group (11.95 ± 5.16 ng/mL).Conclusion: sTim-3 levels in BGD and GC sera were significantly higher than those in the control group sera. Additionally, sTim-3 serum levels can predict recurrence in post-operative patients. Compared with PG alone, the combined detection of serum PG and sTim-3 can significantly improve the detection sensitivity and specificity of BGD and GC.Keywords: T cell immunoglobulin and mucin domain molecule 3, time-resolved fluorescence immunoassay, biomarker, gastric cancer

Xiaonan Zhang,1,&ast; Huimin Fang,1,&ast; Zhigang Zeng,1 Kaijun Zhang,1 Zhanyi Lin,1,2 Gang Deng,1 Weiping Deng,1 Lichang Guan,1 Xuebiao Wei,1 Xinyi Li,2 Lei Jiang,1– 3 Lishu Xu1– 3 1Guangdong Provincial Geriatrics Institute, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, 510080, People’s Republic of China; 2School of Medicine, South China University of Technology, Guangzhou, 510641, People’s Republic of China; 3The Second School of Clinical Medicine, Southern Medical University, Guangzhou, 510515, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Lei Jiang; Lishu Xu Tel +86-20-83827812; +86-20-13660032429Email jianglei@smu.edu.cn; xulishu70@163.comPurpose: Gastric cancer is a common tumor type associated with nutritional and immune status. The aim of the current study was to investigate the prognostic value of a preoperative prognostic nutritional index (PNI), composed of nutritional factors and immune factors in elderly patients undergoing gastric cancer surgery.Patients and Methods: A total of 454 patients undergoing gastric cancer surgery were divided into two groups based on preoperative PNI scores: ≤ 45.1 (n = 307) and > 45.1 (n = 147). Survival analysis was performed using the Kaplan–Meier method and Log rank tests. Univariate and multivariate analyses were conducted to identify independent prognostic factors using a Cox proportional hazards model.Results: According to the X-tile program, the optimal cutoff value for predicting overall survival (OS) with the PNI was 45.1. The receiver operating characteristic analysis revealed that PNI exhibited 70.6% sensitivity and 56.5% speci&filig;city for predicting death during long-term follow-up. The cumulative incidence of postoperative 4-year mortality indicated that the risk of death increased significantly for PNI ≤ 45.1. In multivariate analysis, preoperative PNI was a significant independent predictor of mortality. In the age-stratified subgroup analysis, preoperative PNI was more sensitive for the old elderly subgroup than for the young elderly subgroup.Conclusion: Preoperative PNI is a sensitive and specific prognostic predictor among elderly patients undergoing gastric cancer surgery.Keywords: elderly patients, gastric cancer, prognostic nutritional index, radical gastrectomy

Taoming Liu, Juan Bai, Shuni Ying, Sheng Li, Yunlei Pan, Deren Fang, Jianjun Qiao, Hong Fang Department of Dermatology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Jianjun Qiao; Hong FangDepartment of Dermatology, The First Affiliated Hospital, Zhejiang University School of Medicine, No.79 Qingchun Road, Hangzhou, People’s Republic of ChinaTel/Fax +86-571-87236706Email qiaojianjun@zju.edu.cn; fanghongzy@zju.edu.cnBackground: Urticarial vasculitis is a small vessel vasculitis characterized by long-lasting wheals. It was suggested omalizumab is well tolerated and effective in patients with hypocomplementaemic urticarial vasculitis.Objective: To evaluate the clinical response and safety of omalizumab for treating patients with normocomplementaemic urticarial vasculitis (NUV) in real-world setting.Methods: We collected data from a single-center. This study included patients with NUV who was received omalizumab therapy. During a 24-week study period, the clinical efficacy was evaluated by patient’s self-assessment instrument urticarial vasculitis activity score and Dermatology Life Quality Index.Results: Five patients with NUV were enrolled. Three patients received 6 doses of 150 or 300 mg omalizumab subcutaneously every 4 weeks. At 24-week follow-up, it was revealed improvement of clinical manifestations and reduction of urticarial vasculitis activity score and Dermatology Life Quality Index. At 24-week visit, mild wheals recurred in one patient who was only administrated with omalizumab for 4 times. One patient did not response to omalizumab therapy. No adverse events were recorded in the 5 patients.Conclusion: Omalizumab may be a potential choice in the treatment of patients with NUV in the real-world life.Keywords: normocomplementemic urticarial vasculitis, omalizumab, real-world, targeted therapy, IgE

Min Zhou,1,* Yadi Zhang,2,* Rui Tang,1 Haiyan Liu,1 Min Du,1 Zhi Gao,1 Zongshu Ji,1 Haoshu Fang3 1Neurocritical Care Unit, The First Affiliated Hospital of USTC, Division of Life Sciences and Medicine, University of Science and Technology of China, Hefei, Anhui, 230001, People’s Republic of China; 2Department of Respiratory Medicine, The Second People’s Hospital of Hefei and Hefei Hospital Affiliated with Anhui Medical University, Hefei, Anhui, 230011, People’s Republic of China; 3Department of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, Hefei, Anhui, 230032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Haoshu FangDepartment of Pathophysiology, School of Basic Medical Sciences, Anhui Medical University, 81 Meishan Road, Hefei, Anhui, 230032, People’s Republic of ChinaTel +86 551-65161129Email fang.haoshu@hotmail.comBackground: High-mobility group box-1 protein (HMGB1) serves as the prototypic damage-associated molecular pattern molecule, and TLR4 is considered a receptor for HMGB1. Regulatory T cells (Tregs) play a crucial role in infectious diseases. The role of HMGB1 in the modulation of Tregs is of great interest.Methods: Serum HMGB1 and Treg proportions were detected in 58 patients with acute lung injury (ALI) and 36 healthy volunteers. The correlations of these parameters with disease severity were analyzed. The WT and TLR4-/- mice were administered HMGB1 by intratracheal injection. After 48 h, the mice were sacrificed. The morphological changes and wet/dry ratio of the lung were measured. Spleen CD4+CD25+ Tregs were sorted from spleen cells, the expression of FOXP3 and CTLA-4, and releasing of cytokines was detected. CD4+CD25+ Tregs were cocultured with effector T cells, the inhibitory effect, and release of cytokines was detected.Results: Significantly increased plasma levels of HMGB1 and reduced CD4+CD25+CD127low Tregs were detected in ALI patients. In the mouse model, lung injury was significantly increased after HMGB1 instillation in the WT and TLR4-/- groups compared with control group. The lung wet/dry ratio and the TNF-α and IL-1β contents in BALF were significantly increased, and the severity of WT mice was higher than that of TLR4-/- mice. The expression of FOXP3 and CTLA-4 in TLR4-/- mice was significantly increased compared with that in WT mice and was associated with a similar trend of IL-10 and TGF-β levels (p< 0.05). In coculture with effector T cells, Tregs isolated from TLR4-/- mice exhibited decreased IL-2 and IFN-γ and increased IL-4 levels compared with Tregs from WT mice. Increased polarization of TLR4-/- CD4+CD25+ Treg cells to Th2 cells was observed.Conclusion: In HMGB1-induced lung injury, HMGB1 affects the expression of FOXP3 and CTLA-4 through TLR4, thus reducing the immunosuppressive function of Treg cells.Keywords: HMGB1, TLR4, Treg, acute lung injury

Taoming Liu, Juan Bai, Su Wang, Shuni Ying, Sheng Li, Jianjun Qiao, Hong Fang Department of Dermatology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, People’s Republic of ChinaCorrespondence: Jianjun Qiao; Hong FangDepartment of Dermatology, The First Affiliated Hospital, Zhejiang University School of Medicine, No. 79 Qingchun Road, Hangzhou, People’s Republic of ChinaTel/Fax +86-571-87236706Email qiaojianjun@zju.edu.cn; fanghongzy@zju.edu.cnAbstract: Prurigo nodularis (PN) is an intense pruritic skin condition. Treatment of PN is challenging. We described an elderly patient with PN who had contradictions of cyclosporine or methotrexate and achieved significant improvement after treatment with dupilumab. We also reviewed published cases of elderly patients with PN who were refractory to traditional therapy.Keywords: prurigo nodularis, dupilumab, elderly patient, targeted therapy

Limin Luo,1,* Jun Li,2,* Yuran Wu,3 Jianjun Qiao,1 Hong Fang1 1Department of Dermatology, The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou, 310003, People’s Republic of China; 2Department of Cardiology, The First Affiliated Hospital of Zhejiang University, Hangzhou, 310003, People’s Republic of China; 3Department of Dermatology, Dongfeng General Hospital, Hubei University of Medicine, Shiyan, 442000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hong Fang Tel +86-571-87235857Email fanghongzy@zju.edu.cnIntroduction: Numerous studies have elucidated adiponectin as a negative impact on inflammation and tissue fibrosis. However, little is known about the relevance between adiponectin and inflammatory factors in keloid.Methods: To clarify whether adiponectin plays a role in the inflammation and fibrosis of keloid, 50 patients with keloid and 50 healthy subjects were enrolled, We examined the serum and mRNA expression levels of adiponectin, TGF-β 1, CTGF, IL-6 and TNF-α in normal skin tissues and keloid tissues by ELISA and qPCR, respectively. Correlation analysis between serum concentration of adiponectin with Vancouver Scar Scale (VSS) scores and the age of patients with keloid was evaluated, and the adiponectin concentrations in patients with keloid between different genders were measured. We further examined the effects of adiponectin on TGF-β 1 mediated expression of collagen I, FN and MMP-1 in normal fibroblasts (NFs) and keloid fibroblasts (KFs).Results: We discovered that lower serum concentration and mRNA expression of adiponectin, but higher TGF-β 1, CTGF, IL-6 and TNF-α levels were measured in patients with keloid compared with those in normal controls. Furthermore, there was a strong inverse correlation between the serum adiponectin levels and VSS scores in patients with keloid, but not in ages, and there was no statistically difference between different genders. Moreover, adiponectin attenuated TGF-β 1 mediated expression of collagen I and FN, and upregulated the expression level of MMP-1 in KFs, but not in NFs. In addition, the inhibitory effect of adiponectin on TGF-β 1 was attenuated by AMPK inhibitor Compound C, but not PI3K/Akt inhibitor LY294002.Discussion: Adiponectin may exert an anti-inflammation and anti-fibrosis role in the development of keloid. One of the underlying mechanisms may be the activation of the AMPK signaling pathway.Keywords: keloid, adiponectin, inflammatory factors, fibrosis, Vancouver Scar Scale scores