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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

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.

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

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

J Corey Fowler,1 Nathan Cope,2 Jonathan Knights,3 Hui Fang,4 Taisa Skubiak,5 Sukhi S Shergill,6 Peter Phiri,7 Shanaya Rathod,7 Timothy Peters-Strickland1 1Global Clinical Development, CNS and Digital Medicine, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA; 2Program Management, Otsuka Pharmaceutical Europe Ltd., Wexham, SL3 6PJ, UK; 3Data Insights and Analytics, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA; 4Biostatistics, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA; 5Clinical Management, Otsuka Pharmaceutical Development & Commercialization, Inc., Princeton, NJ, 08540, USA; 6Institute of Psychiatry, Psychology and Neuroscience, King’s College London and South London and Maudsley NHS Foundation Trust, London, SE5 8AF, UK; 7Southern Health NHS Foundation Trust, Moorgreen Hospital, Clinical Trials Facility, Research Department, Southampton, SO30 3JB, UKCorrespondence: J Corey FowlerOtsuka Pharmaceutical Development & Commercialization, Inc., 508 Carnegie Center, Princeton, NJ, 08540, USATel +1 919 475 4823Email corey.fowler@otsuka-us.comPurpose: Symptoms of psychotic disorders can complicate efforts to accurately evaluate patients’ medication ingestion. The digital medicine system (DMS), composed of antipsychotic medication co-encapsulated with an ingestible sensor, wearable sensor patches, and a smartphone application, was developed to objectively measure medication ingestion. We assessed performance and acceptance of the DMS in subjects with psychotic disorders.Methods: This was an 8-week open-label, single-arm, multicenter, Phase 4 pragmatic study (NCT 03568500; EudraCT #2017-004602-17). Eligible adults were diagnosed with schizophrenia, schizoaffective disorder, or first-episode psychosis; were receiving aripiprazole, quetiapine, olanzapine, or risperidone; and could use the DMS with the application downloaded on a personal smartphone. The primary endpoint was good patch coverage, defined as the proportion of days over the assessment period where ≥ 80.0% of patch data was available, or an ingestion was detected. Exploratory endpoints included a survey on user satisfaction, used to assess acceptance of the DMS. Safety analyses included the incidence of treatment-emergent adverse events (TEAEs).Results: From May 25, 2018 to March 22, 2019, 55 subjects were screened and 44 were enrolled. Good patch coverage was achieved on 63.4% of days assessed and the DMS generated an adherence metric of ≥ 80.0%, reflecting the percentage of ingestion events expected when good patch coverage was reported. Most subjects (53.5%) were satisfied with the DMS. Medical device skin irritations were the only TEAEs reported.Conclusion: The DMS had sufficient performance in, and acceptance from, subjects with psychotic disorders and was generally well tolerated.Keywords: digital medicine, antipsychotic, digital health, medication adherence

We have investigated the chemical bonding interaction of S in a CTAB (cetyltrimethylammonium bromide, CH3(CH2)15N+(CH3)3Br-)-modified sulfur-graphene oxide (S-GO) nanocomposite used as the cathode material for Li/S cells by S K-edge X-ray absorption spectroscopy (XAS). The results show that the introduction of CTAB to the S-GO nanocomposite and changes in the synthesis recipe including alteration of the S precursor ratios and the sequence of mixing ingredients lead to the formation of different S species. CTAB modifies the cathode materials through bonding with Na2Sx in the precursor solution, which is subsequently converted to C-S bonds during the heat treatment at 155 °C. Moreover, GO bonds with CTAB and acts as the nucleation center for S precipitation. All these interactions among S, CTAB, and GO help to immobilize the sulfur in the cathode and may be responsible for the enhanced cell cycle life of CTAB-S-GO nanocomposite-based Li/S cells.