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Wenzhen Ge,1 Ning Wu,1 Chieh-I Chen,1 Timothy J Inocencio,1 Patrick R LaFontaine,2 Frank Seebach,3 Matthew Fury,4 James Harnett,1 Emily S Ruiz5 1Department of Health Economics and Outcomes Research, Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA; 2Department of Global Health Economics & Outcomes Research, Sanofi, Cambridge, MA, USA; 3Department of Regulatory Affairs, Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA; 4Department of Clinical Sciences, Oncology, Regeneron Pharmaceuticals, Inc, Tarrytown, NY, USA; 5Department of Dermatology, Dana-Farber Cancer Institute, Boston, MA, USACorrespondence: Wenzhen Ge, Regeneron Pharmaceuticals, Inc, 1 Rockwood Road, Sleepy Hollow, NY, 10591, Tel +1 914-847-7000, Email wenzhen.ge@regeneron.comBackground: Prior to the Food and Drug Administration approval of cemiplimab in 2018, the median overall survival (OS) for adult patients with advanced CSCC receiving systemic therapy was approximately 8 to 15 months. Limited real-world data are available on cemiplimab for this indication in the US.Patients and Methods: This retrospective cohort study included US patients with advanced CSCC initiating cemiplimab monotherapy in a real-world database (2018– 2021). A clinical trial–like sub-cohort was identified using select criteria. Time to treatment discontinuation (TTD), time to next treatment (TTNT), and OS were estimated using Kaplan–Meier methods. Cox proportional hazard models were used to examine prognostic factors associated with OS in the main cohort.Results: The main cohort included 622 patients (n = 240 in the trial-like cohort). In the main cohort, the median age was 78 years, 77.8% were male, 21.4% were immunocompromised/immunosuppressed, and 63.8% had metastatic CSCC. Median (95% CI) TTD and TTNT were 8.0 (6.6– 9.0) months and 16.4 (13.3– 21.0) months, respectively, in the main cohort. Median (95% CI) OS was 24.8 (21.8– 29.1) months in the main cohort (not reached in the trial-like cohort). In multivariable analyses, age < 60 years (hazard ratio [HR], 0.37), Eastern Cooperative Oncology Group performance status < 3– 4 (HR range, 0.13– 0.57), and primary CSCC location in the head and neck only versus extremities only (HR, 0.59) were associated with better OS. Similar OS was observed between patients who had immunosuppressing/immunocompromising conditions and those without.Conclusion: These findings confirm the effectiveness of cemiplimab among a heterogenous, real-world advanced CSCC patient population and substantiate the efficacy of cemiplimab observed in clinical trials.Keywords: cutaneous squamous cell carcinoma, cemiplimab, immune checkpoint inhibitor, real-world study, skin cancer

Guang Chen,1,&ast; Caohua Lv,2,&ast; Qing Nie,3 Xin Li,1 Yinyi Lv,1 Guoyan Liao,1 Shuangchun Liu,4 Weiwei Ge,2 Jinguang Chen,1 Yunting Du5 1Taizhou Central Hospital (Taizhou University Hospital), Taizhou University, Taizhou, 318000, People’s Republic of China; 2Department of Dermatology, Taizhou Second People’s Hospital, Taizhou, 317200, People’s Republic of China; 3Weifang Centers for Disease Control and Prevention, Weifang, 261061, People’s Republic of China; 4Municipal Hospital Affiliated to Medical School of Taizhou University, Taizhou, 318000, People’s Republic of China; 5Department of Laboratory Medicine, Cancer Hospital of China Medical University, Liaoning Cancer Hospital & Institute, Shenyang, 110042, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Jinguang Chen; Yunting Du, Tel/Fax +86 576 88661988, Email tongly0422@126.com; m15840557769@163.comBackground: The traditional Matricaria chamomilla L. has been used to treat dermatitis for thousands of years. Due to emerging trends in alternative medicine, patients prefer natural remedies to relieve their symptoms. Therefore, finding safe and effective plant medicines for topical applications on the skin is an important treatment strategy for dermatologists. German chamomile (Matricaria chamomilla L.) from the Compositae family is a famous medicinal plant, often known as the “star of medicinal species.”However, the function of Matricaria chamomilla essential oil on skin inflammation has not been thoroughly examined in earlier research.Methods: GC-MS analyzed the components of MCEO, and this study explored the anti-inflammation effects of MCEO on psoriasis with network pharmacological pathway prediction. Following this, we used clinical samples of psoriasis patients to confirm the secretory characteristic of relative inflammatory markers. The therapeutic effect of MCEO on skin inflammation was detected by examination of human keratinocytes HaCaT. At the same time, we prepared imiquimod-induced psoriatic-like skin inflammation in mice to investigate thoroughly the potential inhibition functions of MCEO on psoriatic skin injury and inflammation.Results: MCEO significantly reduced interleukin-22/tumor necrosis factor α/lipopolysaccharide-stimulated elevation of HaCaT cell inflammation, which was correlated with downregulating PI3K/Akt/mTOR and p38MAPK pathways activation mediated by MCEO in HaCaT cells treated with IL-22/TNF-α/LPS. Skin inflammation was evaluated based on the PASI score, HE staining, and relative inflammatory cytokine levels. The results showed that MCEO could significantly contribute to inflammatory skin disease treatment.Conclusion: MCEO inhibited inflammation in HaCaT keratinocytes induced by IL-22/TNF-α/LPS, the potential mechanisms associated with inhibiting excessive activation and crosstalk between PI3K/Akt/mTOR and p38MAPK pathways. MCEO ameliorated skin injury in IMQ-induced psoriatic-like skin inflammation of mice by downregulating the levels of inflammatory cytokines but not IL-17A. Thus, anti-inflammatory plant drugs with different targets with combined applications were a potential therapeutic strategy in psoriasis.Keywords: Matricaria chamomilla, essential oil, psoriasis, HaCaT, IMQ, mouse

Wei Ge,1 Li-Hua Shao,1 Hai-Yan Gong,2 Gang Chen1 1Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, People’s Republic of China; 2Physical Examination Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, People’s Republic of ChinaCorrespondence: Hai-Yan Gong, Physical Examination Center, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, People’s Republic of China, Email haiyangong666@126.com Gang Chen, Department of General Surgery, Nanjing Drum Tower Hospital, The Affiliated Hospital of Nanjing University Medical School, Nanjing, Jiangsu Province, 210008, People’s Republic of China, Email 331812195@qq.comBackground: Lead poisoning is a rare but serious disease. The clinical manifestations of lead poisoning are various and nonspecific, such as abdominal pain, headache, dizziness, nightmare, fatigue and so on. Rapid diagnosis of lead poisoning is challenging because it does not have special symptoms and the morbidity is very low.Case Presentation: A 31-year-old woman presented with epigastric discomfort without any obvious cause. The patient was diagnosed with lead poisoning, as the blood levels of heavy metals were detected and the lead was 463.17 μg/L, which was very high (normal value was less than 100 μg/L). The patient was treated with intravenous drip of calcium sodium edentate and got better. The patient achieved good recovery and there was no recurrence.Conclusion: Lead poisoning is a rare disease and easy to be misdiagnosed as acute abdomen disease when present with abdominal pain. Lead poisoning should be considered when common causes of abdominal pain are excluded, especially patients with anemia and abnormal liver function. The diagnosis of lead poisoning is mainly replied on the blood or urine lead concentrations. Then we should firstly cut off the contact with lead and use metal complexing agent to facilitate lead excretion.Keywords: lead poisoning, abdominal pain, acute abdomen, calcium sodium edentate

Ge W, Wang D, Chuang CC, et al. Clinicoecon Outcomes Res. 2022;14:691–697. Following a review of the paper post-publication, the authors realized there were a few errors that were missed when the paper was revised before publication. Page 691, Abstract, Results section, line one, the text “Of 6311 patients” should read “Of 6113 patients”. Page 691, Abstract, Results section, line two, the text “and 37.1% had asthma” should read “and 37.2% had asthma”. Page 693, Results section, line one, the text “A total of 6311 eligible patients” should read “A total of 6113 eligible patients”. Page 693, Results, Demographic and Clinical Characteristics section, line three, the text “37.1% of patients” should read “37.2% of patients”. Page 693, Figure 2, the sample size has been corrected, the correct Figure is as follows. Figure 2 Patient selection. Page 694, Table 1, Key comorbidities at baseline, n (%) section, Asthma/All Patients with NP Surgery (N=6113) data point, the text “2271 (37.1)” should be “2271 (37.2)”. See updated Table 1 below. Page 694, Costs and Outcomes section, line four, the text “were $15,174 (10,998) for first surgery and $15,511 (16,767) for repeat surgery” should read “were $15,361 (11,133) for first surgery and $15,703 (16,974) for repeat surgery”. Page 694, Costs and Outcomes section, line seven, the text “and 14/719 (2.0%) with repeat surgery” should read “and 14/719 (1.9%) with repeat surgery”. Page 695, Table 2, Complications within 30 days after index, n (%) section, Any major complication/NP Surgery within Previous 3 Years – Yes data point “14 (2.0)” should read “14 (1.9)”. See updated Table 2 below. Page 695, Table 3, the section heading “Total medical costs (including cost of NP surgery) within 10 days after” should read “Total medical costs (including cost of NP surgery) within 10 days after index”. See updated Table 3 below. Page 696, second paragraph, lines three and four, the text “in patients receiving revision surgery [2.0%]” should read “in patients receiving revision surgery [1.9%]”. The authors affirm that these errors do not affect the results, discussion, and conclusions of the reported study and apologize for any inconvenience caused to the readers. Table 1 Demographic and Clinical Characteristics of Patients with NP Surgery Table 2 Costs and Rate of Major Complications After Index NP Surgery* Table 3 Costs After Index NP Surgery in Patients with and without Major Complications

Wenzhen Ge,1 Ning Wu,1 Jessica J Jalbert,1 Ruben GW Quek,1 Jinjie Liu,2 Petra Rietschel,1 Jean-Francois Pouliot,1 James Harnett,1 Melinda Laine Hsu,3 Josephine L Feliciano4 1Regeneron Pharmaceuticals, Inc., Tarrytown, NY, USA; 2Genesis Research, LLC, Hoboken, NJ, USA; 3University Hospitals, Cleveland Medical Center, Cleveland, OH, USA; 4Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USACorrespondence: Josephine L Feliciano, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA, Tel +1 410 550 1711, Email jfelici4@jhmi.eduBackground: Immune checkpoint inhibitors (ICIs) are standard-of-care for patients with advanced non-small cell lung cancer (aNSCLC) and programmed cell death-ligand 1 (PD-L1) expression ≥ 50%.Methods: A retrospective cohort study was conducted using the US de-identified electronic health record-derived Flatiron Health aNSCLC database (January 1, 2018, to July 31, 2021) among patients with PD-L1 ≥ 50% initiating first-line ICIs with or without chemotherapy. A clinical trial-like sub-cohort was also identified with Eastern Cooperative Oncology Group performance status 0– 1, adequate organ function, and no brain metastases or other primary cancers. Kaplan–Meier methods were used to estimate time to treatment discontinuation, time to next treatment, progression-free survival and overall survival (OS) by ICI regimen (ICI+chemotherapy, ICI monotherapy) and PD-L1 expression (50– 69%, 70– 89%, 90– 100%). Cox proportional hazard models were used to examine associations between ICI regimen, PD-L1 level, and OS, adjusting for baseline demographic and clinical variables.Results: A total of 2631 patients with aNSCLC initiating ICI+chemotherapy (n = 992) or ICI monotherapy (n = 1639) were included; median (Q1, Q3) age was 71 (63– 78) years and 51.6% were male. The trial-like sub-cohort (n = 1029) generally had better outcomes vs. the overall cohort. Patients receiving ICI+chemotherapy generally had longer median OS vs. ICI monotherapy. Multivariable analyses showed no association between ICI regimen and OS among patients with PD-L1 70– 89% (hazard ratio [HR]: 0.90, 95% confidence interval [CI]: 0.73– 1.09) or 90– 100% (HR: 0.91, 95% CI: 0.77– 1.08), but patients with PD-L1 50– 69% receiving ICI+chemotherapy had longer OS (HR: 0.80, 95% CI: 0.64– 0.99).Conclusion: Outcomes in real-world clinical trial-like patients with aNSCLC approached those reported in pivotal ICI trials in high PD-L1 expressers. ICI monotherapy offers a potential alternative in patients with PD-L1 ≥ 70% while avoiding potential chemotherapy toxicity exposure; the benefits are less clear in patients with PD-L1 50– 69%. Future studies should confirm these findings.Keywords: immune checkpoint inhibitors, non-small cell lung cancer, PD-L1 expression, real-world data, overall survival, progression-free survival

Wenzhen Ge,1 Degang Wang,1 Chien-Chia Chuang,2 Yongtao Li,3 Raj Rout,4 Shahid Siddiqui,1 Siddhesh Kamat1 1Health Economics and Outcomes Research, Medical Affairs, Regeneron, Tarrytown, NY, USA; 2Global Health Economics and Value Assessment, Sanofi, Cambridge, MA, USA; 3Global Medical Affairs, Sanofi, Bridgewater, NJ, USA; 4Global Medical Affairs, Sanofi, Reading, UKCorrespondence: Siddhesh Kamat, Email siddhesh.kamat@regeneron.comBackground: Endoscopic nasal polyp (NP) surgery is a treatment option for patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Previous studies report NP surgery costs of &dollar;8000– 13,000 and risk of major complications of NP surgery of ~0.1– 1%. Limited contemporary data for costs and complications associated with NP surgery in US clinical practice are available.Methods: IQVIA PharMetrics Plus claims data were used to identify patients with NP surgery in 2019 with ≥ 3 years continuous baseline health-plan enrollment prior to index date (date of first eligible NP surgery) and ≥ 30 days continuous enrollment after index (follow-up). In this descriptive analysis, total costs of NP surgery were estimated as all medical costs on the index date (or during the entire hospital stay for patients who received surgery in the inpatient setting). Total medical costs (all-cause) were estimated for all medical services occurring from the index date to the index date +9 or +29 days (10-day and 30-day). Major complication was defined as cerebrospinal fluid (CSF) leak, orbital injury, or major hemorrhage within 30 days of index.Results: Of 6311 patients, median age was 46 years (interquartile range: 34– 56); 59.7% were male; 88.2% had no NP surgery in the prior 3 years; 63.7% had allergic rhinitis, and 37.1% had asthma. Mean (SD) total medical cost of surgery was &dollar;14,697 (11,679) and mean (SD) 10-day total medical cost was &dollar;15,401 (11,968). Major complications occurred in 102 (1.7%) patients. Total medical costs and 10-day costs were higher in patients with major complications than those without (&dollar;23,605 [19,264] vs &dollar;15,251 [11,741]).Conclusion: In this descriptive analysis, NP surgery costs and rates of major surgical complications were updated using recent real-world data in the US. Results indicated that NP surgery complication rates were numerically higher than previously reported.Keywords: chronic rhinosinusitis with nasal polyps, nasal polyp surgery, real-world, complications, costs

Changchang Kong, Shijunyin Chen, Wenhao Ge, Yang Zhao, Xiaodong Xu, Shiming Wang, Jianfa Zhang Center for Molecular Metabolism, Nanjing University of Science & Technology, Nanjing, Jiangsu, 210094, People’s Republic of ChinaCorrespondence: Jianfa Zhang, Center for Molecular Metabolism, Nanjing University of Science & Technology, 200 Xiaolingwei, Nanjing, 210094, People’s Republic of China, Tel/Fax +86 25 84318533, Email jfzhang@njust.edu.cnPurpose: In order to overcome the inflammatory response to bacterial infection during wound healing, we have fabricated an antibacterial and anti-inflammatory wound dressing based on polysaccharide riclin and silver nanoparticles (AgNPs).Methods: The riclin-AgNPs nanocomposite was developed by borohydride method and was characterized by UV-Vis, TEM, XRD, Zeta potential, DLS. In vitro, we assessed the cumulative release, antibacterial activities and cytotoxicity. In vivo, we examined the wound healing in mice wound infection experiment and inflammatory mediators using histological observations and gene expression analysis.Results: The riclin/AgNPs nanocomposite hydrogel exhibited nanosized orbicular particles with high purity and stability. In vitro, the riclin/AgNPs showed sustained release of AgNPs, effective suppression in pathogen growth and negligible toxicity toward mammalian fibroblasts and macrophage cells. In vivo, the riclin/AgNPs treatment leads to faster and smoother growth of fresh skin with suppressed expression of inflammatory mediators.Conclusion: The reported Riclin-AgNPs nanocomposite hydrogel showed both antibacterial and anti-inflammatory functions, which induce significantly accelerated wound healing, indicating great potential as a novel attractive wound dressing material.Keywords: nanocomposite hydrogels, wound healing, riclin, silver nanoparticles

Mengxin Yao,1 Yue Xiao,1 Zhuoqiao Yang,1 Wenxin Ge,1 Fei Liang,1 Haoyue Teng,1 Yingjie Gu,2 Jieyun Yin1 1Department of Epidemiology and Health Statistics, Medical College of Soochow University, Suzhou, People’s Republic of China; 2Department of Obstetrics and Gynecology, International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, People’s Republic of ChinaCorrespondence: Jieyun Yin, School of Public Health, Medical College of Soochow University, 199 Renai Road, Suzhou, Jiangsu, People’s Republic of China, Tel/Fax +86 0512 6588036, Email jyyin@suda.edu.cnBackground: Preeclampsia (PE) is a significant cause of maternal and neonatal morbidity and mortality worldwide. However, the pathogenesis of PE is unclear and reliable early diagnostic methods are still lacking. The purpose of this review is to summarize potential metabolic biomarkers and pathways of PE, which might facilitate risk prediction and clinical diagnosis, and obtain a better understanding of specific metabolic mechanisms of PE.Methods: This review included human metabolomics studies related to PE in the PubMed, Google Scholar, and Web of Science databases from January 2000 to November 2021. The reported metabolic biomarkers were systematically examined and compared. Pathway analysis was conducted through the online software MetaboAnalyst 5.0.Results: Forty-one human studies were included in this systematic review. Several metabolites, such as creatinine, glycine, L-isoleucine, and glucose and biomarkers with consistent trends (decanoylcarnitine, 3-hydroxyisovaleric acid, and octenoylcarnitine), were frequently reported. In addition, eight amino acid metabolism-related, three carbohydrate metabolism-related, one translation-related and one lipid metabolism-related pathways were identified. These biomarkers and pathways, closely related to renal dysfunction, insulin resistance, lipid metabolism disorder, activated inflammation, and impaired nitric oxide production, were very likely to contribute to the progression of PE.Conclusion: This study summarized several metabolites and metabolic pathways, which may be associated with PE. These high-frequency differential metabolites are promising to be biomarkers of PE for early diagnosis, and the prominent metabolic pathway may provide new insights for the understanding of the pathogenesis of PE.Keywords: gestational hypertension, metabolite, biomarker, prediction

Lan Xia,1,&ast; Ping Zhang,2,&ast; Jing-Wen Niu,2 Wei Ge,2 Jun-Tao Chen,2 Shuai Yang,2 Ai-Xi Su,2 Yi-Zhou Feng,2 Fang Wang,3 Gong Chen,4 Gui-Hai Chen2 1Department of Neurology, The Second Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Department of Neurology (Sleep Disorders), The Affiliated Chaohu Hospital of Anhui Medical University, Hefei (Chaohu), People’s Republic of China; 3Department of Neurology, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 4Hefei Technology College, Hefei (Chaohu), People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Gui-Hai ChenDepartment of Neurology (Sleep Disorders), The Affiliated Chaohu Hospital of Anhui Medical University, Hefei (Chaohu), People’s Republic of ChinaTel/Fax +86-551-82321571Email doctorcgh@163.comGong ChenHefei Technology College, Hefei (Chaohu), People’s Republic of ChinaTel +86-551-82367072Fax +86-551-82351650Email ch_gong@163.comPurpose: To examine whether associations exist between chronic insomnia disorder (CID) and overlooked inflammatory factors (Serum amyloid protein A [SAA]), tumor necrosis factor [TNF]-α, granulocyte-macrophage colony-stimulating factor [GM-CSF], and regulated on activation and normal T cell expressed and presumably secreted [RANTES]).Patients and Methods: A total of 65 CID patients and 39 sex- and age-matched good sleeper (GS) controls participated in this study. They completed a baseline survey to collect data on demographics, and were elevated sleep and mood by Pittsburgh Sleep Quality Index (PSQI), Athens Insomnia Scale (AIS), 17-item Hamilton Depression Rating Scale (HAMD-17) and 14-item Hamilton Anxiety Rating Scale (HAMA-14), respectively. The blood samples were collected and tested the serum levels of SAA, TNF-α, GM-CSF and RANTES.Results: The CID group had higher serum levels of SAA, TNF-α, and GM-CSF and a lower level of RANTES than the GS group. In the Spearman correlation analysis, SAA and GM-CSF positively correlated with the PSQI and AIS scores. After controlling for sex, HAMD-17 score, and HAMA-14 score, the partial correlation analysis showed that GM-CSF was positively correlated with PSQI score. Further stepwise linear regression analyses showed that GM-CSF was positively associated with the PSQI and AIS scores, while RANTES was negatively associated with them, and SAA was positively associated with just the AIS score.Conclusion: The serum levels of inflammatory mediators (SAA, TNF-α, and GM-CSF) were significantly elevated and the level of RANTES was significantly decreased in CID patients and, to some extent, the changes are related to the severity of insomnia. These findings may help us to improve interventions to prevent the biological consequences of CID by inhibiting inflammation, thereby promoting health.Keywords: chronic insomnia disorder, serum amyloid protein A; tumor necrosis factor (TNF)-α, granulocyte-macrophage colony-stimulating factor, regulated on activation and normal T cell expressed and presumably secreted

Qing Shu,1,* Qingqing Fan,1,* Bingzhu Hua,2 Hang Liu,1 Shiying Wang,2 Yunxing Liu,1 Yao Yao,1 Han Xie,1 Weihong Ge1 1Department of Pharmacy, Nanjing Drum Tower Hospital, Nanjing, 210008, People’s Republic of China; 2Department of Rheumatology and Immunology, Nanjing Drum Tower Hospital, Nanjing, 210008, People’s Republic of China*These authors contributed equally to this workCorrespondence: Weihong GeDepartment of Pharmacy, Nanjing Drum Tower Hospital, Nanjing, 210008, People’s Republic of ChinaEmail 6221230@sina.comIntroduction: Mycophenolate mofetil (MMF), a new type of immunosuppressant, has emerged as a frontline agent for treating autoimmune diseases. Mycophenolic acid (MPA) is an active metabolite of MMF. MPA exposure varies greatly among individuals, which may lead to adverse drug reactions such as gastrointestinal side effects, infection, and leukopenia. Genetic factors play an important role in the variation of MPA levels and its side effects. Although many published studies have focused on MMF use in patients after organ transplant, studies that examine the use of MMF in patients with autoimmune diseases are still lacking.Methods: This study will not only explore the genetic factors affecting MPA levels and adverse reactions but also investigate the relationships between UGT1A9 − 118(dT)9/10, UGT1A9 - 1818T>C, UGT2B7 802C>T, SLCO1B1 521T>C, SLCO1B3 334T>G, IMPDH1 − 106G>A and MPA trough concentration (MPA C0), along with adverse reactions among Chinese patients with autoimmune diseases. A total of 120 patients with autoimmune diseases were recruited. The MPA trough concentration was detected using the enzyme multiplied immunoassay technique (EMIT). Genotyping was performed using a real-time polymerase chain reaction (PCR) system and validated allelic discrimination assays. Clinical data were collected for the determination of side effects.Results: SLCO1B1 521T>C demonstrated a significant association with MPA C0/d (p=0.003), in which patients with the CC type showed a higher MPA C0/d than patients with the TT type (p=0.001) or the CT type (p=0.000). No significant differences were found in MPA C0/d among the other SNPs. IMPDH1 − 106G>A was found to be significantly related to infections (p=0.006). Subgroup analysis revealed that UGT2B7 802C>T was significantly related to Pneumocystis carinii pneumonia infection (p=0.036), while SLCO1B1 521T>C was associated with anemia (p=0.029).Conclusion: For Chinese autoimmune disease patients, SLCO1B1 521T>C was correlated with MPA C0/d and anemia. IMPDH1 − 106G>A was significantly related to infections. UGT2B7 802C>T was significantly related to Pneumocystis carinii pneumonia infection.Keywords: mycophenolic acid, gene polymorphisms, adverse drug reactions, infections, anemia, autoimmune diseases

Chen-miao Huang,1,2 Jia-jing Cai,1,2 Shao-wu Jin,1,2 Qi-cheng Lin,1,2 Qian-juan Fang,1,2 Ke Nan,1,2 Yuan Han,1,2 Wen-wei Ge,1,2 Yu Liu,1,2 Yuan-xiang Tao,1,3 Hong Cao,1,2 Jun Li1,2 1Department of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People’s Republic of China; 2Zhejiang Province Key Laboratory of Anesthesiology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People’s Republic of China; 3Department of Anesthesiology, New Jersey Medical School, Rutgers, The State University of New Jersey, Newark, NJ, 07103, USACorrespondence: Jun Li; Hong CaoDepartment of Anesthesiology and Perioperative Medicine, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, Zhejiang, 325027, People’s Republic of ChinaTel/Fax +86 577-88002925 Email lijun0068@163.com; caohong1955@21cn.comObjective: Perioperative neurocognitive disorders (PND) are a common complication in the elderly. Histone deacetylases (HDACs) are a class of enzymes that control the acetylation status of intracellular proteins. Thus, we explored whether HDACs trigger the release of high mobility group box 1 (HMGB1) through altering the acetylation status in the hippocampi of aged mice.Materials and Methods: The effect of the Class IIa HDAC in PND was explored using an in vivo form of splenectomy. Sixteen-month-old healthy male C57BL/6J mice were randomly divided into five groups: control, anesthesia plus sham surgery, anesthesia plus splenectomy, LMK235 treatment, and PBS treatment. The hippocampi were harvested on either first, third, or seventh postoperative day. Cognitive function was assessed via a Morris water maze (MWM) test. Quantitative RT-PCR, Western blots and ELISAs were carried out to assess the targeted gene expression at transcriptional and translational levels.Results: Splenectomy led to a significant deficiency in spatial memory acquisition, marked decreases in mRNA and protein levels of HDAC4 and HDAC5 in the hippocampus, and increases in the levels of total HMGB1 and acetylated HMGB1. In a similar fashion to splenectomy, treatment with the HDAC4/5 inhibitor LMK235 produced impaired spatial memory and an increase in the expression of HMGB1 and its acetylated counterpart in the hippocampus.Conclusion: These results suggest that surgery leads to PND through class IIa HDAC downregulation-triggered HMGB1 release in hippocampus of aged mice. HDACs may be a potential therapeutic target for postoperative cognitive dysfunction.Keywords: postoperative cognitive dysfunction, hippocampus, HDAC4, HDAC5, HMGB1, neuroinflammation

Composited p-type electrodes with high reflectivity have been investigated in AlGaN-based ultraviolet light emitting diodes (UV-LEDs) to improve the light extraction efficiency, which are composed of a patterned ITO layer and an Al reflector. It is verified that the patterned ITO with a thickness of 30 nm can not only well form Ohmic contact with p-GaN capping layer, but also be nearly 90% transparent to ultraviolet light, and thus presenting a reflectivity of 73% at 280 nm when combined with an Al reflector. Further experimental efforts confirm that the performance of the UV-LEDs is dramatically improved with such p-type electrodes. The maximum light output power and wall plug efficiency in the current range of 0–100 mA are severally increased by 49.8% and 54.2% compared to the device with traditional Ni/Au electrodes. [ABSTRACT FROM AUTHOR]

A full-spectrum k-distribution (FSK) look-up table has been constructed for gas mixtures within a certain range of thermodynamic states for three species, i.e., CO2, H2O and CO. The k-distribution of a mixture is assembled directly from the summation of the linear absorption coefficients of three species. The systematic approach to generate the table, including the generation of the pressure-based absorption coefficient and the generation of the k-distribution, is discussed. To efficiently obtain accurate k-values for arbitrary thermodynamic states from tabulated values, a 6-D linear interpolation method is employed. A large number of radiative heat transfer calculations have been carried out to test the accuracy of the FSK look-up table. Results show that, using the FSK look-up table can provide excellent accuracy compared to the exact results. Without the time-consuming process of assembling k-distribution from individual species plus mixing, using the FSK look-up table can save considerable computational cost. To evaluate the accuracy as well as the efficiency of the FSK look-up table, radiative heat transfer via a scaled Sandia D Flame is calculated to compare the CPU execution time using the FSK method based on the narrow-band database, correlations, and the look-up table. Results show that the FSK look-up table can provide a computationally cheap alternative without much sacrifice in accuracy.

Zhi Li,1,* Wen Ge,2,* Chunyan Han,3,* Mengwei Lv,4,5,* Yanzhong He,5 Juntao Su,6 Ban Liu,3 Yangyang Zhang5 1Department of Cardiovascular Surgery, Jiangsu Province Hospital, The First Affiliated Hospital of Nanjing Medical University, Nanjing, People’s Republic of China; 2Department of Thoracic and Cardiovascular Surgery, Shuguang Hospital, Shanghai University of TCM, Shanghai, People’s Republic of China; 3Department of Cardiology, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 4Shanghai East Hospital of Clinical Medicine College, Nanjing Medical University, Shanghai, People’s Republic of China; 5Department of Cardiovascular Surgery, Shanghai East Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China; 6Tongji University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yangyang Zhang; Ban Liu Email zhangyangyang_wy@tongji.edu.cn; 2013liuban@tongji.edu.cnBackground: Renal dysfunction is independently associated with both short-term and long-term mortality after coronary artery bypass grafting (CABG). The estimated glomerular filtration rate (eGFR) is a convenient and effective indicator of renal function. However, the ability of eGFR calculated by various equations to predict the outcomes of patients undergoing off-pump CABG (OPCABG) is still unclear. This study was aimed to compare the predictive ability of in-hospital and long-term mortality in three equations of estimating renal functions after OPCABG.Methods: Totally, 1362 patients undergoing OPCABG were retrospectively reviewed. Preoperative and postoperative serum creatinine (Scr) levels were detected. The renal function was evaluated by the Cockcroft-Gault (CG) equation, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation, and the full-age spectrum (FAS) equation. The endpoints were in-hospital and long-term all-cause mortality rates. Receiver operating characteristic curves, net reclassification index, decision curve analysis (DCA), multivariable logistic model, and Cox regression model were used for comparisons.Results: The CG equation had the significantly highest discriminatory power to predict in-hospital mortality (area under the curve=0.815). Valuable clinical net benefits of the CG equation were greater than the other two equations regardless of before or after operation by DCA. Multivariable logistic and Cox regression analysis illustrated that the eGFR calculated by the CG equation was a significant independent risk factor of both in-hospital mortality (odds ratio=3.390) and long-term mortality (hazard ratio=1.553).Conclusion: The CG equation outperformed the FAS and CKD-EPI equations in predicting the mortality of patients after OPCABG. Postoperative renal function was more efficiently predicted compared with the preoperative one.Keywords: coronary artery bypass grafting, off-pump, estimated glomerular filtration rate, mortality

Yifan Liu,1,2,* Haotian Liu,3,* Chunyuan Li,3 Chao Ma,1,2 Wei Ge3 1Institute of Basic Medical Sciences, Neuroscience Center, National Human Brain Bank for Development and Function, Chinese Academy of Medical Sciences, Beijing 100005, People’s Republic of China; 2Department of Human Anatomy, Histology and Embryology, School of Basic Medicine, Peking Union Medical College, Beijing 100005, People’s Republic of China; 3State Key Laboratory of Medical Molecular Biology & Department of Immunology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing 100005, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wei Ge; Chao Ma Email wei.ge@chem.ox.ac.uk; machao@ibms.cams.cnPurpose: Chronic obstructive pulmonary disease (COPD) is a worldwide public health challenge due to its high prevalence and related disability and mortality; however, the pathogenesis of COPD remains unclear. In this study, we aimed to identify key proteins involved in the pathogenesis of COPD.Patients and Methods: We collected lung tissue from three patients with COPD who required thoracic surgery for lung transplantation in the China–Japan Friendship Hospital. Lung tissue from three donors who had no history of lung disease was collected as healthy controls through a whole-body donation program of Peking Union Medical College (China). We conducted a proteomic analysis of the protein expression profiles in the two groups using a combination of high-resolution liquid chromatography coupled with tandem mass spectrometry (LC-MS/MS) and quantitative 6-plex tandem mass tag-labeling; these data were validated by Western blot analysis.Results: A total of 4976 proteins were identified and analyzed, of which 173 were significantly changed (118 downregulated and 55 upregulated). Gene ontology analysis and protein–protein interaction networks demonstrated that the significantly changed proteins, especially downregulated proteins, were involved in platelet and macrophage activation. The mass spectrometry proteomics data have been deposited to the ProteomeXchange Consortium (http://proteomecentral.proteomexchange.org) via the iProX partner repository with the dataset identifier PXD017158.Conclusion: In our study, GP6, PF4, and THBS1, which are associated with platelet activation and wound healing, were significantly downregulated in COPD patients. These results indicate that patients with COPD are more likely to develop hemostasis disorders, which could impede the repair process of the lung tissues. Moreover, downregulation of CD163, MARCO and VSIG4, which are involved in dysfunction of alveolar macrophages in efferocytosis, may inhibit the resolution of inflammation and contribute to the pathogenesis of COPD.Keywords: chronic obstructive pulmonary disease, proteomics, macrophage, platelet

Qingqing Zong,1,* Jing Deng,1,* Wanli Ge,2,* Jie Chen,1 Di Xu3 1Department of Ultrasonography, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of China; 2Department of General Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of China; 3Department of Geriatric Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of China*These authors contributed equally to this workCorrespondence: Di XuDepartment of Geriatric Medicine, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of ChinaTel/Fax +86 25 8371 4511Email 13951805973@126.comPurpose: Axillary lymph node (ALN) involvement is an important prognostic factor of early invasive breast cancer. The objective of this study was to establish simple nomograms for predicting ALN involvement based on ultrasound (US) characteristics and evaluate the predictive value of US in the detection of ALN involvement.Patients and Methods: A total of 1328 patients with cT1-2N0 breast cancer by physical exam were retrospectively analyzed. Univariate analysis was used for the comparison of variables, and multivariate analysis was performed by binary logistic regression analysis. The R software was used to establish simple nomograms based on the US characteristics alone. The receiver operating characteristic (ROC) curves of the prediction model and the verification group were drawn, and the area under the curve (AUC) was calculated to evaluate the discrimination of the prediction model. A calibration curve was plotted to assess the nomogram predictions vs the actual observations of the ALN metastasis rate and axillary tumor burden rate.Results: The ALN metastasis rates of the training group and the validation group were 35.1% and 34.1%, respectively. Multivariate analysis showed that molecular subtype, lymphovascular invasion, mass descriptors (size, margin, microcalcification and blood flow signal) and LN descriptors (shape, cortical thickness and long-to-short ratio) were independent impact factors in early breast cancer. The AUC of ALN metastasis rate of prediction model based on US features was 0.802, the AUC of high tumor burden rate was 0.873, and the AUC of external validation group was 0.731 and 0.802, respectively. The calibration curve of the nomogram showed that the nomogram predictions are consistent with the actual metastasis rate and the high tumor burden rate. The results showed that preoperative US had a sensitivity of 59.4% and a specificity of 88.9% for predicting the ALN metastasis rate.Conclusion: The successfully established nomograms based on US characteristics to predict ALN metastasis rate and high axillary tumor burden rate in early breast cancer can achieve individual prediction. Compared with other nomogram predictions, it is more intuitive, and can help clinical decision-making; thus, it should be promoted. However, at this time US features alone are insufficient to replace sentinel lymph node biopsy.Keywords: axillary lymph node involvement, early breast cancer, ultrasound, nomogram

The spherical harmonics (PN) method is a radiative transfer equation solver, which approximates the radiative intensity as a truncated series of spherical harmonics. For general 3-D configurations, N(N+1)/2 intensity coefficients must be solved from a system of coupled second-order elliptic PDEs. In 2-D axisymmetric applications, the number of equations and intensity coefficients reduces to (N+1)2/4 if the geometric relations of the intensity coefficients are taken into account. This paper presents the mathematical details for the transformation and its implementation on the OpenFOAM finite volume based CFD software platform. The transformation and implementation are applicable to any arbitrary axisymmetric geometry, but the examples to test the new formulation are based on a wedge grid, which is the most common axisymmetric geometry in CFD simulations, because OpenFOAM and most other platforms do not have true axisymmetric solvers. Two example problems for the new axisymmetric PN formulation are presented, and the results are verified with that of the general 3-D PN solver, a Photon Monte Carlo solver and exact solutions.

Weiting Ge,1 Wen Cai,1,2 Rui Bai,1 Wangxiong Hu,1 Dehao Wu,1,2 Shu Zheng,1 Hanguang Hu1,2 1Cancer Institute (Key Laboratory of Cancer Prevention and Intervention, China National Ministry of Education), The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China; 2Department of Medical Oncology, The Second Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou, Zhejiang, China Background: Hypermutated colorectal cancer (CRC) reportedly accounts for 15%–17% of all cases of CRC. However, the proportion and number of patients with hypermutated CRC cannot be unappreciated. Additionally, therapy options for these patients differ from those for CRC patients, with a greater potential benefit from immunotherapy. Materials and methods: We sequenced the tumor mucosa of CRC patients with >24 months of follow-up data at our center and identified mutation profiles of hypermutated CRC as a training data set (Zhejiang University [ZJU]); we then collected patients from The Cancer Genome Atlas (TCGA) as a validation data set. Recurrently mutated genes were combined to calculate a compound score via Cox proportional hazards model. Patients with higher-than-median scores were segregated as the high-risk group. Outcomes were analyzed by Kaplan–Meier and Cox regression analyses using Python (3.6.0) and R (3.4.0). Results: We constructed a 4-gene signature (ACVR2A, APC, DOCK2, and POLE), with training in 45 hypermutated patients at ZJU and validation in 24 hypermutated patients from TCGA. Patients in the high-risk group showed poor survival (adjusted HR =9.85, 95% CI: 2.07–46.81, P=0.004). Further subgroup analysis was performed for stage II and III colon cancer (HR =10.91, 95% CI: 1.36–87.5, P=0.005) and high microsatellite instability (MSI-H) CRC (HR =12.57, 95% CI: 1.57–100.69, P=0.002) subgroups, which verified that our signature is universal. We then compared our prognostic signature with other risk factors (including MSI status, POLE driver mutation, BRAF-p.V600E, tumor mutational burden, and TNM staging). The results proved that our 4-gene signature is better than the other risk factor for prognosis in hypermutated CRC.Conclusion: Our 4-gene signature is a good predictor of survival for hypermutated CRC, and this signature is powerful in stage II and III colon cancer and MSI-H CRC. Future prospective studies are needed to confirm the power of the 4-gene signature in patients receiving immunotherapy. Keywords: colorectal cancer, hypermutation, gene signature, prognosis

Wenzhang Ge,1,* Jianli Xie,2,* Lianzhen Chang3 1Department of Special Clinic, Jinan Stomatological Hospital, Jinan, Shandong, People’s Republic of China; 2Department of Periodontics and Oral Medicine, Jinan Stomatological Hospital, Jinan, Shandong, People’s Republic of China; 3Medical Department, Jinan Stomatological Hospital, Jinan, Shandong, People’s Republic of China *These authors contributed equally to this work Introduction: Although red blood cell distribution width (RDW) has been reported to reflect inflammation and nutritional status and to predict prognosis in several different types of cancer, little is known about how RDW might be related to oral squamous cell carcinoma (OSCC). The present study aimed to investigate the prognostic value of preoperative RDW in OSCC patients.Materials and methods: We included 236 OSCC patients from Jinan Stomatological Hospital (Shandong, People’s Republic of China) in this retrospective study. All enrolled patients were divided into 2 groups: high RDW (≥15%) and low RDW (

Hai-lin Ruan,1,* Wen-han Ge,2,* Jian-ping Chen,1 Yuan-qun Zhu,3 Wei Huang1 1Department of Emergency, Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, 2Department of Emergency, Huai’an Hospital Affiliated with Xuzhou Medical University, Huai’an, Jiangsu, 3Department of Neurology, Fourth Affiliated Hospital of Guangxi Medical University, Liuzhou, Guangxi, China *These authors contributed equally to this work Objective: To evaluate the prognostic value of the Prehospital Index (PHI) for hospitalized patients with acute trauma. Materials and methods: PHI score and the Injury Severity Score (ISS) were determined in 1,802 hospitalized patients with acute trauma. Receiver-operator characteristic (ROC) curves were used to compare the PHI and ISS in subgroups, and corresponding prediction indicators were calculated. Results: There were significant differences in PHI score and ISS between the survival group and the death group (Z=2.674, P=0.007). The area under the ROC curve was 0.871 (95% CI 0.855–0.886) for PHI score and 0.792 (95% CI 0.773–0.811) for ISS. Optimal cutoff points to determine the risk of critical illness were PHI ≥4 and ISS ≥22. The sensitivity of the PHI was superior to the ISS (χ2=6.975, P=0.008), but the specificity and the accuracy of the PHI and ISS showed no significant difference (P>0.05). Conclusion: The PHI is valuable in prognostic prediction of hospitalized patients with acute trauma, and it is superior to the ISS. The PHI has such advantages as being simple in operation, easy to learn, capable of reflecting conditions timely and reliably, and suitable for dynamic evaluation and screening for critical patients with trauma. Keywords: Prehospital Index, trauma, hospitalized patient, Injury Severity Score

DNA methylation is a major epigenetic factor that has been postulated to regulate cell lineage differentiation. We report here that conditional gene deletion of the maintenance DNA methyltransferase I (Dnmt1) in neural progenitor cells (NPCs) results in DNA hypomethylation and precocious astroglial differentiation. The developmentally regulated demethylation of astrocyte marker genes as well as genes encoding the crucial components of the gliogenic JAK-STAT pathway is accelerated in Dnmt1(-/-) NPCs. Through a chromatin remodeling process, demethylation of genes in the JAK-STAT pathway leads to an enhanced activation of STATs, which in turn triggers astrocyte differentiation. Our study suggests that during the neurogenic period, DNA methylation inhibits not only astroglial marker genes but also genes that are essential for JAK-STAT signaling. Thus, demethylation of these two groups of genes and subsequent elevation of STAT activity are key mechanisms that control the timing and magnitude of astroglial differentiation.

Wei Ge,* Qi Sun,* Gen Li, Guanghua Lu, Ming Cai, ShaoHua Li Department of Orthopedics, Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai, People’s Republic of China *These authors contributed equally to this work Purpose: The incidence of proximal humeral fractures is high in the elderly, and the superior management of these fractures remains a controversy. The study aims to compare clinical outcomes of intramedullary nails, locking plates and conservative treatment for the management of displaced proximal humeral fractures in the elderly. Patients and methods: In this prospective study, a total of 198 patients with 2- or 3-part proximal humeral fractures who received fixation of locking plates or intramedullary nails or conservative treatment were included. The primary outcome was the 24-month Constant–Murley score. The secondary outcomes included the American Shoulder and Elbow Surgeons (ASES) scores, the visual analog scale (VAS) pain scores, shoulder range of motion and complication rate. Results: There were no statistically significant differences in the Constant–Murley scores and ASES scores among the plate group, the nail group and the conservative group for 2-part fractures. For 3-part fractures, Constant–Murley scores and ASES scores were lower in the conservative group compared with those in the plate group and the nail group. Besides, the conservative group showed a significantly lower external rotation during follow-ups. The complication rate was comparable among the plate group, the nail group and the conservative group for both 2-part and 3-part fractures. Conclusion: Similar satisfactory functional outcomes can be achieved with the locking plates, intramedullary nails or conservative treatment for 2-part proximal humeral fractures in the elderly. The advantages in functional outcomes favor locking plates and intramedullary nails in the management of 3-part proximal humeral fractures. Keywords: proximal humeral fractures, intramedullary nails, locking plates, conservative treatment, the elderly