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Kunrong Yan, Yingjian Wang, Peng Xin Department of Anaesthesia, Chaoyang Second Hospital, Chaoyang, Liaoning, People’s Republic of ChinaCorrespondence: Peng Xin, Email cy08xp@163.comObjective: Observational studies have indicated that immune cells and circulating inflammatory proteins may play a dual role in the progression of COPD; however, the precise mechanisms remain uncertain. The objective of this study was to ascertain the causal relationship between immune cells and COPD and to quantify the potential role of circulating inflammatory proteins as mediators.Methods: A two-sample Mendelian randomisation analysis was conducted involving 731 immune cells, 91 inflammatory proteins and COPD, utilising summary-level data from genome-wide association studies. The causal relationships between immune cells, inflammatory proteins and COPD were sequentially analysed by multivariate Mendelian randomisation and validated using Bayesian weighted Mendelian randomisation. Subsequently, sensitivity analyses were conducted, employing Cochran’s Q test to assess heterogeneity, MR-PRESSO and MR-Egger tests to assess pleiotropy, and reverse MR and Steiger directionality tests to rule out reverse causality. Lastly, a two-step approach was employed to ascertain the proportion of inflammatory proteins that mediate immune cell-mediated effects in COPD.Results: The combination of the inverse variance weighting method and the Bayesian weighting algorithm identified 30 immune cells that were found to be causally associated with COPD, as well as eight inflammatory proteins that were associated with COPD. By two-step analysis, six inflammatory proteins were found to mediate the effects of eight immune cell phenotypes on COPD, with CXCL10 having the highest percentage of mediation at 14.49%, followed by IL20RA at 11.47%.Conclusion: This study provides a comprehensive investigation of the causal relationship between immune cells and COPD, as well as an estimation of the proportion of the effect of inflammatory proteins as mediators. These findings facilitate the identification of individuals at high risk of COPD and offer novel insights for early prevention and clinical intervention.Keywords: Mendelian randomization, Bayesian weighted Mendelian randomization, immune cells, circulating inflammatory proteins, COPD, mediation analysis

Desheng Yan,1 Gehang Ju,2 Xin Liu,2 Qing Shao,1 Yan Zhang,3 Na Wang,1 Keyu Yan1 1Department of Pharmacy, Xi’an Mental Health Center, Xi’an, Shaanxi, 710100, People’s Republic of China; 2Department of Clinical Pharmacology, Xiangya Hospital, Central South University, Changsha, Hunan, 410000, People’s Republic of China; 3Xi’an Key Laboratory of Pharmacy (Mental Health), Xi’an Mental Health Center, Xi’an, Shaanxi, 710100, People’s Republic of ChinaCorrespondence: Keyu Yan, Xi’an Mental Health Center, Xi’an, Shaanxi, 710100, People’s Republic of China, Tel/Fax +86-18198010730, Email 614591931@qq.comObjective: This study aimed to evaluate the predictive performance of published amisulpride population pharmacokinetic (PopPK) models in schizophrenia patients with an external data set and establish remedial dosing regimens for nonadherent amisulpride-treated patients.Methods: A systematic search was conducted on PubMed, Embase, and Web of Science to identify PopPK models for evaluation. The evaluation process involved analyzing 390 serum concentration samples obtained from 361 Chinese adult inpatients diagnosed with schizophrenia. Model predictability was evaluated by prediction-based and simulation-based diagnostics. Based on validation results, a modified PopPK model was constructed to characterize amisulpride pharmacokinetic in our patients. Monte Carlo simulation was employed to investigate non-adherence scenarios and the impact of subsequently administered remedial regimens.Results: In the five assessed published models, four included trough concentrations from schizophrenia patients, and one combined single-dose data from healthy older adults and trough concentrations from older adults with Alzheimer’s disease. The PE for population and individual predictions ranged from − 92.89% to 27.02% and − 24.82% to 4.04%, respectively. In the simulation-based diagnostics, the NPDE results indicated noticeable bias in all models. Therefore, a modified one-compartment model, with estimated creatinine clearance(eCLcr) as covariates on the apparent clearance (CL/F) of amisulpride, was developed. For delays in medication dosing, if the delay is within 12 hours, take half the missed dose right away, then resume the normal schedule; if the delay is up to 24 hours, just continue with the regular dosing schedule.Conclusion: Existing published models lack the necessary reliability for cross-center application. Future prospective studies are required to assess our model before integrating it into clinical practice. Model-based simulations provided a rational approach to propose remedial strategies for delayed or missed doses.Keywords: population pharmacokinetics, amisulpride, schizophrenia, external validation, adherence

Haoyi Xu,1 Yan Ma,2 Huiling Li,1 Xinyu Song,1 Yuanjing Liu,1 Zuliyaer Mierzhakenmu,1 Kang Yan,1 Rui Xu,1 Ziqian Zhao,1 Hongyi Yuan,1 Chao Dong1 1Department of Breast and Thyroid Surgery, the Third Clinical Medical College of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, 830000, People’s Republic of China; 2Department of Gynecological Surgery, the Third Clinical Medical College of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, 830000, People’s Republic of ChinaCorrespondence: Chao Dong, Department of Breast and Thyroid Surgery, the Third Clinical Medical College of Xinjiang Medical University, Urumqi, Xinjiang Uygur Autonomous Region, 830000, People’s Republic of China, Tel +86 139 9911 1211, Email dc_dongchao@outlook.comObjective: Triple-negative breast cancer (TNBC) lacks effective targeted, endocrine therapeutic agents and the development of novel agents is costly and time-consuming. The objective of this study was to identify pharmaceuticals and natural products utilized in clinical practice that have the potential to inhibit the expression of Cellular-myelocytomatosis oncogene (c-Myc), based on a review of the current literature. The aim was to assess the effect of the specified drugs on c-Myc expression in TNBC cells, determine the most potent inhibitor, and evaluate its impact on TNBC cell proliferation, invasive migration, and apoptosis, as well as the expression of estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER-2) at both the gene and protein levels. Explore its potential for treatment or adjuvant therapy for triple-negative breast cancer.Methods: Quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot were used to quantify gene and protein expression levels. Flow cytometry was employed to measure cell proliferation and apoptosis, while the Transwell assay was utilized to assess cell invasion and migration.Results: Harmaline emerged as the strongest inhibitor, significantly decreasing the expression of c-Myc at both the gene and protein levels in TNBC cells. It also inhibited cell proliferation, invasion, and migration while promoting apoptosis in TNBC cells. Additionally, there was a varying increase in the expression of ER and PR genes and proteins. While the expression of the HER-2 gene was elevated, there was no significant change in HER-2 protein levels. Notably, the expression of the phosphorylated HER-2 protein increased.Conclusion: Harmaline was found to promote apoptosis and inhibit cell proliferation, invasion, and migration in TNBC cells by targeting the inhibition of c-Myc. It also induced the re-expression of the ER, PR, and HER-2 genes, as well as the ER and PR proteins.Keywords: c-Myc, harmaline, molecular typing, triple-negative breast cancer

Hui Zeng,1,* Rong Liu,1,2,* Chuanli Cheng,2,* Nana Yang,2 Luwen Luo,1,2 Shengshuang Long,3 Renjia Zhou,4 Kai Yan,1 Huantao Huang1 1Nursing Department of the Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, People’s Republic of China; 2School of Nursing of Zunyi Medical University, Zunyi, Guizhou, 563000, People’s Republic of China; 3Infection Department of the Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, People’s Republic of China; 4ICU of the Second Affiliated Hospital of Zunyi Medical University, Zunyi, Guizhou, 563000, People’s Republic of China*These authors contributed equally to this workCorrespondence: Hui Zeng, Email zenghui.1221@163.comObjective: This study investigated the distribution and resistance patterns of pathogens in the intensive care unit of a newly established hospital in Guizhou Province to promote the rational use of antibiotics to reduce multidrug resistance.Methods: A retrospective analysis was conducted on the distribution of pathogens and changes in drug resistance in the ICU of a newly built hospital in Guizhou Province from March 2019 to December 2023. WHONET 5.6 was used to analyze the results.Results: A total of 2444 culture samples were received, predominantly sputum (34.66%) and blood (23.36%) samples, with a steady annual increase in specimen types. A total of 572 pathogenic strains were isolated, predominantly from respiratory specimens (54.02%), including 345 Gram-negative bacteria (60.31%), 135 Gram-positive cocci (23.60%), and 92 fungi (16.08%). The most frequent pathogens included Acinetobacter baumannii (30.77%), Candida albicans (11.71%), and Klebsiella pneumoniae (9.97%). Drug sensitivity tests indicated a fluctuating resistance rate of Acinetobacter baumannii over the past five years. Staphylococcus aureus displayed strong in vitro activity against vancomycin, tigecycline, and linezolid, with no resistant strains identified. The detection rates of carbapenem-resistant Acinetobacter baumannii (CR-AB), carbapenem-resistant Pseudomonas aeruginosa (CR-PA), methicillin-resistant Staphylococcus aureus (MRSA), and strains producing extended-spectrum beta-lactamases (ESBL) were 86.78%, 26.79%, 32.45%, 70.27%, and 23.54%, respectively.Conclusion: Compared with other countries in the world, China has increased its data on the prevalence of MDR pathogens and antibiotic resistance.The high resistance rate of Acinetobacter baumannii in the ICU underscores the need for effective infection control measures. Enhanced monitoring of CR-AB, ESBL-producing bacteria, and MRSA is essential, along with improved management of antibacterial drugs and the pursuit of new therapeutic options.Keywords: new-built hospital, intensive care unit, pathogens, multidrug-resistant bacteria, antimicrobial resistance

Dan Ye,1,2 Yuanyuan Li,2 Kangkang Yan,1 Wenzhong Peng2 1Department of Pharmacy, Xi’an No.3 Hospital, the Affiliated Hospital of Northwest University, Xi’an, People’s Republic of China; 2Department of Respiratory Medicine, Xiangya Hospital, Central South University, Changsha, Hunan, People’s Republic of ChinaCorrespondence: Wenzhong Peng, Department of Respiratory Medicine, Xiangya Hospital, Central South University, Xiangya Road No. 87, Kaifu District, Changsha, Hunan, 410008, People’s Republic of China, Tel +86-0731-89753287, Fax +86-89753287, Email pengwenzhong@csu.edu.cnBackground: Chlamydia abortus is a zoonotic pathogen that causes miscarriage, stillbirth, and sepsis of pregnancy in pregnant women when it infects humans. However, it rarely causes pneumonia in humans.Case Presentation: This case reports a case of severe pneumonia characterized by high fever and cough, and the disease rapidly progressed to dyspnea. The patient was treated with moxifloxacin and doxycycline. Chlamydia abortus was detected in bronchoscopy examination and bronchoalveolar lavage fluid (BALF) through metagenomic next-generation sequencing (mNGS)-DNA. A weak positive for influenza A (H1N1) antigen was also found in the throat swab tested. Subsequently, we added mabaloxavir and replaced doxycycline with an intravenous infusion of omadacycline. After effective treatment, the patient developed a urinary tract infection, and the treatment plan was adjusted to meropenem combined with omadacycline. The patient’s condition improved, and she was discharged on the 14th day of admission.Conclusion: This is the first report of cases of non-pregnant female patients with Chlamydia abortus infection pneumonia. Consequently, infections with Chlamydia abortus can result in severe respiratory distress, disturbance of water and electrolyte balance, and abnormal liver function, which requires timely diagnosis and correct use of antibiotics by clinicians. Consequently, the mixed infection of H1N1 and Chlamydia abortus aggravated the complexity of the condition and treatment. Combining tetracycline and quinolone is effective for treating severe pneumonia with Chlamydia abortus infection.Keywords: chlamydia abortus, severe pneumonia, metagenomics next-generation sequencing, case report

Lijuan Liang,1,* Ming Jia,2,3,* Min Zhao,4,* Yiping Deng,5,* Jun Tang,5 Xinghui He,2 Yilin Liu,2 Kexin Yan,2 Xin Yu,6 Hong Yang,7 Chunhong Li,2 Yao Li,2,8 Tao Li4 1Department of Pharmacy, Hejiang County People’s Hospital, Luzhou, Sichuan, People’s Republic of China; 2Department of Pharmaceutical Sciences, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 3Nanchong Institute for Food and Drug Control, Nanchong, Sichuan, People’s Republic of China; 4Key Laboratory of Medical Electrophysiology of Ministry of Education, Institute of Cardiovascular Research, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 5Analysis and Testing Center, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 6Chinese Pharmacy Laboratory, School of Pharmacy, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 7Department of Pediatrics, The Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, People’s Republic of China; 8Science and Technology department, Southwest Medical University, Luzhou, Sichuan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yao Li; Tao Li, Email lnetyao@163.com; leta49@swmu.edu.cnAbstract: As a pivotal transition metal oxide, manganese dioxide (MnO2) has garnered significant attention owing to its abundant reserves, diverse crystal structures and exceptional performance. Nanosizing MnO2 results in smaller particle sizes, larger specific surface areas, optimized material characteristics, and expanded application possibilities. With the burgeoning research efforts in this field, MnO2 has emerged as a promising nanomaterial for tumor diagnosis and therapy. The distinctive properties of MnO2 in regulating the tumor microenvironment (TME) have attracted considerable interest, leading to a rapid growth in research on MnO2-based nanomaterials for tumor diagnosis and treatment. Additionally, MnO2 nanomaterials are also gradually showing up in the regulation of chronic inflammatory diseases. In this review, we mainly summarized the recent advancements in various MnO2 nanomaterials for tumor diagnosis and therapy. Furthermore, we discuss the current challenges and future directions in the development of MnO2 nanomaterials, while also envisaging their potential for clinical translation.Keywords: manganese dioxide nanoparticles, tumors, inflammation, biomedicine, research progress

Kailun Yan, Jiawen Li, Pei Zhu, Xiaofang Tang, Yulong Li, Yuejin Yang, Runlin Gao, Jinqing Yuan, Xueyan Zhao National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People’s Republic of ChinaCorrespondence: Xueyan Zhao; Jinqing Yuan, National Clinical Research Center for Cardiovascular Diseases, State Key Laboratory of Cardiovascular Disease, Fu Wai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100037, People’s Republic of China, Tel +86-10-88322451, Fax +86-10-68351786, Email zhao_xueyan@sina.com; jqyuanfw@163.comPurpose: The association between high-density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (ApoA-I) and cardiovascular risk in patients with coronary artery disease remains inconsistent. Recent investigations indicated potential dysfunctionality of HDL under inflammation. This study endeavors to explore whether the inflammatory status modifies the effects of HDL-C and ApoA-I on cardiovascular risk in individuals with percutaneous coronary intervention (PCI).Patients and Methods: Consecutive 10,724 PCI patients at Fuwai hospital in 2013 were enrolled. Inflammation status was defined by high-sensitivity C-reactive proteins (hsCRP) ≥ 2 mg/L. The study endpoint was cardiac mortality.Results: Among 9569 PCI patients eventually included, 225 (2.4%) cardiac mortality happened during 5 years. In hsCRP ≥ 2 mg/L group, an U-shaped curve was observed for HDL-C and multivariate Cox regression showed that elevated risks of cardiac mortality correlated to both the lowest quintile (hazard ratio [HR], 2.50; 95% confidence interval [CI], 1.32– 4.71) and the highest quintile of HDL-C (HR, 2.28; 95% CI, 1.23– 4.25). However, an L-shaped curve existed in ApoA-I, indicating only the lowest quintile level of ApoA-I was associated with an increased cardiac mortality risk (HR, 2.19; 95% CI, 1.28– 3.75). Nevertheless, in hsCRP < 2 mg/L group, no significant correlations between HDL-C and ApoA-I and cardiac mortality risk were identified (both P > 0.05).Conclusion: In PCI patients with hsCRP ≥ 2 mg/L. both low and high HDL-C levels correlated with higher cardiac mortality risk (U-shaped), while only low ApoA-I levels were linked to elevated risk (L-shaped). However, in patients with hsCRP < 2 mg/L, neither HDL-C nor ApoA-I levels were associated with higher cardiac mortality risk. These findings shed light on the importance of considering inflammation status, particularly hsCRP levels, in managing HDL-C and ApoA-I levels, and suggest targeting elevated ApoA-I levels as a potential therapeutic approach for PCI patients with hsCRP ≥ 2 mg/L. Keywords: apolipoprotein A-I, high-density lipoprotein-cholesterol, inflammation, mortality, percutaneous coronary intervention

Kuocheng Yan,1,&ast; Xiaohui Wang,2,&ast; Yao Han,1,&ast; Yuan Tian,1 Mengwei Niu,1 Xue Dong,1 Xiaowei Li,2 Hao Li,1 Yansong Sun1 1State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, People’s Republic of China; 2Department of Gastroenterology, the Sixth Medical Center of Chinese People’s Liberation Army General Hospital, Beijing, 100080, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Hao Li, State Key Laboratory of Pathogen and Biosecurity, Beijing Institute of Microbiology and Epidemiology, Beijing, 100071, People’s Republic of China, Email lihao88663239@126.com Xiaowei Li, Department of Gastroenterology, the Sixth Medical Center of Chinese People’s Liberation Army General Hospital, Beijing, 100080, People’s Republic of China, Email lixwei12@126.comBackground: Infection caused by Helicobacter pylori (H. pylori) affects approximately 50% of the global population. It is a major pathogenic factor for chronic gastritis and gastric cancer. Besides, the resistance to antibiotics such as clarithromycin could reduce the eradication rate. Currently, there is an urgent need for a swift, easy to perform, and highly sensitive detection method for H. pylori and clarithromycin resistance.Methods: We used FAM/Digoxin labeled primers to amplify specific H. pylori 23S rRNA fragments by Recombinase Aided Amplification (RAA), and resistance mutations were distinguished using CRISPR/Cas13a system combined with lateral flow strip. Twenty-eight saliva samples were analyzed using qPCR, gene sequencing and this method to evaluate the detection efficiency.Results: We developed a simultaneous detection method for H. pylori and clarithromycin resistance mutations named sensitive H. pylori easy-read dual detection (SHIELD). The results showed both A2142G and A2143G mutant DNAs causing clarithromycin resistance could be distinguished from the wild type with a concentration of 50 copies/μL, and no cross-reaction with other 5 common gastrointestinal bacteria was observed. For the detection of H. pylori in 28 saliva samples, the positive predictive value of this method was 100% (19/19) in comparison with qPCR. For detecting clarithromycin resistance, the positive predictive value of this method was 84.6% (11/13) compared with gene sequencing.Conclusion: SHIELD assay showed high sensitivity and specificity in detecting H. pylori and clarithromycin resistance mutations. It could be a potential measure in the rapid detection of H. pylori, large-scale screening and guiding clinical medication.Keywords: Helicobacter pylori, clarithromycin resistance mutation, recombinase aided amplification, CRISPR/Cas13a, nucleic acid detection

Wenli Hui, Wenhua Mu, Cong Zhao, Dan Xue, Zihua Zhong, Yani Fang, Ming Gao, Xiao Li, Shihao Gao, Kaiyue Liu, Kunping Yan College of Life Science, Northwest University, Xi’an City, Shaanxi Province, 710069, People’s Republic of ChinaCorrespondence: Kunping Yan, Email kpyan@nwu.edu.cnIntroduction: A limitation of hemoglobin-based oxygen carriers (HBOCs) as oxygen therapeutics is unpolymerized hemoglobin, which induces vasoconstriction leading to hypertension. The removal of unpolymerized hemoglobin from polymerized hemoglobin (PolyHb) is complex, expensive, and time-consuming.Methods: Herein, we developed a method to completely polymerize hemoglobin almost without unpolymerized hemoglobin. Hemoglobin was adsorbed on the anion-exchange resin Q Sepharose Fast Flow or DEAE Sepharose Fast Flow, and acetal, a crosslinker prepared from glutaraldehyde and ethylene glycol, was employed to polymerize the hemoglobin. The polymerization conditions, including reaction time, pH, resin type, and molar ratios of glutaraldehyde to ethylene glycol and hemoglobin to acetal, were optimized. The blood pressure and blood gas of mice injected with PolyHb were monitored as well.Results: The optimal polymerization condition of PolyHb was when the molar ratio of glutaraldehyde to ethylene glycol was 1:20, and the molar ratio of 10 mg/mL hemoglobin adsorbed on anion-exchange resin to glutaraldehyde was 1:300 for 60 min. Under optimized reactive conditions, hemoglobin was almost completely polymerized, with < 1% hemoglobin remaining unpolymerized, and the molecular weight of PolyHb was more centrally distributed. Furthermore, hypertension was not induced in mice by PolyHb, and there were also no pathological changes observed in arterial oxygen, blood gas, electrolytes, and some metabolic indicators.Conclusion: The findings of this study indicate that the use of solid-phase polymerization and acetal is a highly effective and innovative approach to HBOCs, resulting in the almost completely polymerized hemoglobin. These results offer promising implications for the development of new methods for preparing HBOCs.Graphical Abstract: Keywords: polymerized hemoglobin, glutaraldehyde, acetal, solid-phase adsorption, hemoglobin-based oxygen carriers, HBOCs

Inorganic perovskite (CsPbX 3 , X = Cl, Br and I) nanocrystals (NCs) have received great attention for their fascinating optoelectronic properties. However, their potential applications are primarily limited by the instability arising from their mobile ionic nature. Herein, we demonstrate extremely stable CsPbX 3 nanocomposites (denoted as CsPbX 3 @CA-SiO 2 ) using a facile and effective templated synthetic strategy, by the in situ anchoring of CsPbX 3 NCs onto octadecyl-/propylamine-capped silica particles (SiO 2 NPs). The two-step synthesis involves first the preparation of amino-group-capped silica NPs from a mixed 3-aminopropyltriethoxysilane (APTES) and trimethoxy(octadecyl)silane (TMODS) precursor, which were utilized to induce the nucleation and growth of CsPbX 3 nanocrystals to produce CsPbX 3 @CA-SiO 2 composites with monodispersed CsPbX 3 NCs (∼6 nm). The emission wavelength of the resulting composite can be tuned between 400 nm and 650 nm by controlling the halide composition, while maintaining a high photoluminescence quantum yield (PLQY = 76%). The as-fabricated composites exhibited remarkable photostability and water stability, both uncommon in these materials. The CsPbX 3 @CA-SiO 2 composite can also be used to create an anti-counterfeit ink and down-converting white light emitting diode (WLED). This work provides a valuable approach for the production of future optoelectronic devices, catalysts and sensors based on perovskite NCs.

Xiang Li,1,* Guodong Wang,2,* Kun Yan,1 Shanshan Yin,1 Hongzhi Wang,2 Yanjie Wang,1 Xiumei Bai,1 Yanfen Shen2 1Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Ultrasound, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China; 2Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), ICU, Peking University Cancer Hospital & Institute, Beijing, People’s Republic of China*These authors contributed equally to this workCorrespondence: Kun YanKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Ultrasound, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100042, People’s Republic of ChinaTel + 86 13611176073Fax +86 10-88196195Email ydbz@vip.sina.comHongzhi WangKey Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), ICU, Peking University Cancer Hospital & Institute, No. 52 Fucheng Road, Haidian District, Beijing, 100142, People’s Republic of ChinaTel/Fax +86 10-88196112Email doctorwhz@163.comPurpose: A peripherally inserted central catheter (PICC) is associated with venous thromboembolism (VTE) especially in patients suffering from cancer. We analyzed the incidence, risk factors, and patterns of PICC-related VTE in cancer patients.Patients and Methods: Patients with cancer who underwent PICC placement were evaluated retrospectively. Routine, prospective ultrasound post-PICC placement was used for asymptomatic and symptomatic patients to identify VTE. Multivariable logistic regression models with odds ratios (ORs) were used to examine VTE risk factors.Results: Of 2353 PICCs placed, 165 patients (7.01%) developed PICC-related VTE with a median thrombosis time of 12 days. After adjustment of multivariable analysis, patients with PICC-related VTE were more likely to have a ratio of PICC diameter:vein diameter > 0.35 (adjusted OR, 1.689; 95% CI, 1.023– 2.789) and high level of triglycerides (1.561; 1.096– 2.223). The prevalence of A (adjusted OR, 1.680; 95% CI, 1.009– 2.798), B (1.835; 1.137– 2.961), and AB (3.275; 1.840– 5.829) blood group was significantly higher than that of the O blood group in VTE patients. Venous recanalization was observed in 44.8% (74/165) patients after anticoagulation therapy, and more often in patients with combined deep VTE than in patients with isolated superficial VTE (OR, 17.942; 95% CI, 5.427– 59.316). The recanalization time was 20± 5 (range, 10– 31) days.Conclusion: The non-O blood group, larger ratio of PICC diameter:vein diameter, and high level of triglycerides were significantly associated with PICC-related VTE. Almost half of cases of PICC-related deep VTE could be reversed by anticoagulation treatment.Keywords: recanalization, ultrasound, venous thromboembolism

Zhengbo Wei,1 Mengwei Yao,2 Sisi Ning,2 Yuan Wu,2 Xunzhao Zhou,2 Changtao Zhong,2 Kui Yan,2 Ying Xie3,4 1Department of Head and Neck Tumor Surgery, Cancer Hospital of Guangxi Medical University, Nanning, People’s Republic of China; 2Graduate School of Guangxi Medical University, Nanning, People’s Republic of China; 3Life Science Institute of Guangxi Medical University, Nanning, People’s Republic of China; 4Key Laboratory of High-Incident-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, 530021, People’s Republic of ChinaCorrespondence: Ying XieKey Laboratory of High-Incident-Tumor Prevention & Treatment (Guangxi Medical University), Ministry of Education, Nanning, Guangxi, 530021, People’s Republic of ChinaEmail xieying@gxmu.edu.cnObjective: We examined whether the single-nucleotide polymorphism (SNP) rs13181 in the gene encoding excision repair cross complementation group 2 (ERCC2) is associated with the risk and prognosis of nasopharyngeal carcinoma (NPC).Methods: SNPs at rs13181 were genotyped in 439 NPC patients (NPC group) and 431 age- and gender-matched cancer-free controls (control group) from a region of China where NPC is endemic, and frequencies of GG, GT and TT genotypes were compared between the two groups in the case–control study. In a subset of 365 NPC cases, SNPs were examined for potential correlation with tumor-free survival time (TFS) and overall survival (OS).Results: Relative to NPC risk with a TT genotype, NPC risk was similar with GT + GG genotypes (OR 1.052, 95% CI 0.656– 1.688), after adjusting for gender, age, smoking history, and immunoglobin A against Epstein-Barr virus capsid antigen (EBV-VCA-IgA) status. Univariate analysis showed that the GG or GT genotype was associated with significantly worse TFS (p< 0.001) and OS (p=0.010) than the TT genotype. Prognosis was significantly worse for men than for women (TFS, p=0.045; OS, p=0.031), for T3–T4 classification than for T1–T2 (TFS, p=0.009; OS, p=0.007), for N3 than for N0+N1+N2 (TFS, p< 0.001; OS, p< 0.001). Based on multivariate analysis, independent risk factors for poor TFS were GG or GT genotype (HR 2.629, 95% CI 1.625– 4.254, p< 0.001), T3–T4 classification (HR 2.146, 95% CI 1.244– 3.701, p=0.006) and N3 (HR 2.527, 95% CI 1.574– 4.059, p< 0.001). GG or GT genotype (HR 2.217, 95% CI 1.283– 3.832, p=0.004), gender (HR 1.989, 95% CI 1.046– 3.785, p=0.036), T3–T4 (HR 2.431, 95% CI 1.306– 4.526, p=0.005) and N3 (HR 2.693, 95% CI 1.637– 4.432, p< 0.001) were independent risk factors for poor OS.Conclusion: The rs13181 SNP in ERCC2 does not appear to be associated with NPC risk, but it may serve as an independent prognostic factor for NPC recurrence and death.Keywords: single nucleotide polymorphism, rs13181, nasopharyngeal carcinoma, excision repair cross complementation group 2, tumor-free survival, overall survival

The electrolyte, a key component for the successful operation of energy materials, is greatly affected by its solvents. The influence of solvents on the electrochemical performance of a LiFePO4/C composite cathode was investigated at various operating temperatures. The reaction kinetics of the LiFePO4/C composite electrode, including changes of rate capability, redox potential, polarization degree, electrode reaction process, exchange current densities, and activation energies, were evaluated using various techniques. The composition and volume ratio of solvents greatly affect the electrode kinetics. In the mixed solvents of ethylene carbonate (EC), dimethyl carbonate (DMC) and ethyl methyl carbonate (EMC), EMC is beneficial for the room temperature performance, while the substitution of 20 vol % of EMC by ethyl acetate (EA) is good for the low temperature performance. When 30 vol % of DMC is substituted by 10 vol % of EMC and 20 vol % of EA, the exchange current density increases from 0.022 to 0.038 mA cm−2 at −20 °C, while the activation energy of the charge-transfer process decreases from 48.36 to 33.01 kJ mol−1. Possible mechanisms for improving the electrochemical performance using different solvents have been analyzed. These results are significant for the exploration of appropriate electrolytes for the extensive applications of LiFePO4/C composite electrodes.

Sb distribution in the phases of SiO2 saturated Sb-Fe-O-SiO2-CaO system was determined for the first time through hightemperature experiment and quenching techniques, followed by Electron probe X-ray microanalysis (EPMA) in air (Ptot = 1 atm, PO2 = 0.21 atm). The phases were quantified in the temperature range of 900°C-1200°C and the effects of Fe/SiO2 (mass fraction) and CaO/SiO2 (mass fraction) on Sb2O3 content in the Sb-Fe-O-SiO2-CaO system were investigated at 1200°C. The results indicated that the Sb-containing phase primarily existed in the solid solution phase at 1200°C. With the increase of temperature from 1100°C to 1200°C, the Sb2O3 content in the solid solution phase increased drastically from 7.52 wt% to 17.36 wt%. Lowering the values of CaO/SiO2 and Fe/SiO2 in the smelting process effectively reduced Sb2O3 content in the slag. The verification of the experiment results suggested that the antimony content in slag was 0.57 wt%, the crude antimony yield rate was lower than 4%, and the crude antimony grade was beyond 94 wt%, which meant that the reduction of antimony content in the slag could be achieved.

Chakrapani Balijepalli,1 Lakshmi Gullapalli,1 Eric Druyts,1 Kevin Yan,1 Kamal Desai,1 Stephane Barakat,2 Jason Locklin2 1Pharmalytics Group, Vancouver, British Columbia, Canada; 2Alexion Pharmaceuticals, Vaughan, Ontario, CanadaCorrespondence: Chakrapani Balijepalli Email chak.balijepalli@pharmalyticsgroup.comAbstract: Orphan drugs have high acquisition costs and when standard health technology assessment (HTA) approaches are used to assess their cost-effectiveness, they often appear not cost-effective. The Canadian Patented Medicine Review Board (PMPRB), through new regulations, will apply HTA assessment results from the Canadian Agency for Drugs and Technologies in Health (CADTH) and Institut national d’excellence en santé et en services sociaux (INESSS) when setting the maximum price that can be charged for Category I patented medicines (treatments with an annual cost exceeding 150% of GDP per capita of Canada or with expected annual market size >$50M). Through these regulations, PMPRB has also established a willingness-to-pay threshold of CAD$200,000 or CAD$150,000 per quality adjusted life year (QALY) for medications with a prevalence of no more than 1 in 2000 across all approved indications. We reviewed the orphan drug submissions made to CADTH’s Common Drug Review (CDR) January 2015–May 2020 to understand how the methodology of assessing cost-effectiveness of orphan drugs has guided pricing in Canada. A total of 35 orphan drug submissions were assessed by CDR in this period, none of which met the willingness-to-pay threshold of CAD$50,000 per QALY. Only one drug met the CAD$200,000 per QALY for Therapeutic Criteria Level I, and two drugs met CAD$150,000 per QALY for other Therapeutic Criteria Levels proposed by PMPRB. Price reductions of 32– 99% were recommended for treatments that were approved in order to be listed for reimbursement. This review showed that the new PMPRB regulations could be creating challenges for manufacturers of rare disease treatments to meet Canadian pricing regulations. These regulations may jeopardize the launch of new medicines and limit opportunities to add to the development of real-world evidence of orphan drugs, which can be used in reimbursement approaches such as pay-for-performance.Keywords: orphan drugs, rare diseases, CADTH, QALY, HTA

Meijuan Liu, Kun Zhang, Linjie Wang, Hongbo Yang, Kemin Yan, Hui Pan, Huijuan Zhu, Fengying Gong Key Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, Beijing 100730, People’s Republic of ChinaCorrespondence: Fengying Gong; Huijuan ZhuKey Laboratory of Endocrinology of National Health Commission, Department of Endocrinology, Peking Union Medical College Hospital, Chinese Academy of Medical Science and Peking Union Medical College, 1# Shuaifuyuan, Wangfujing, Beijing 100730, People’s Republic of ChinaTel +86 10 69155100Fax +86 10 69155073Email fygong@sina.com; shengxin2004@163.comIntroduction: To explore serum zinc-α 2-glycoprotein (ZAG) and adiponectin in metabolically healthy non-obese (MHNO), metabolically healthy obesity (MHO), metabolically abnormal obesity (MAO) and metabolically abnormal diabetic obese (MADO) subjects and the relationship with metabolically phenotypes of obesity.Methods: Two hundred twenty-five subjects including 32 with MHNO, 40 with MHO, 104 with MAO and 49 with MADO were enrolled. Baseline clinical data and biochemical variables were collected. Serum ZAG and adiponectin levels were measured by enzyme-linked immunosorbent assay (ELISA) kits. Metabolically healthy (< 3 metabolic abnormalities) or abnormal (≥ 3 metabolic abnormalities) subjects were classified based on the National Cholesterol Education Program–Adult Treatment Panel III (NCEP/ATP III) criteria. Obesity (body mass index ≥ 28 kg/m2) was recommended by China Obesity Task Force.Results: Serum ZAG levels were higher in the MHO group, but were progressively lower in MAO and MADO groups (P all< 0.05). In all subjects, total cholesterol, 2-hour postprandial blood glucose and homeostasis model assessment of adiponectin were independent variables to serum ZAG levels. Compared with subjects in the highest tertile of ZAG, the odds ratio (OR) of metabolically abnormal risks of subjects in the lowest and median tertiles of ZAG were higher both in a univariate and three adjustment models (P all< 0.05). Serum ZAG could discriminate the metabolically abnormal phenotype with receiver operating characteristic (ROC) curve area of 0.622 (95% CI, 0.539– 0.706, P< 0.05). Combination of ZAG and adiponectin had improved diagnosis value accuracy, with ROC curve area of 0.703 (95% CI, 0.629– 0.776, P< 0.05), and 62.7% sensitivity and 73.6% specificity.Conclusion: Serum ZAG levels were higher in MHO subjects, but lower in MAO and MADO subjects. The decreased serum ZAG levels were closely related to the metabolically abnormal phenotype of obese patients. Serum ZAG, especially the combination with adiponectin might be the potential diagnostic biomarkers for metabolically abnormal obese patients.Keywords: zinc-α 2-glycoprotein, ZAG, metabolically healthy non-obese, MHNO, metabolically healthy obese, MHO, metabolically abnormal obese, MAO, metabolically abnormal diabetic obese, MADO

Gehang Ju,1 Keyu Yan,1 Youwei Xu,2 Shilin Chen,3 Zhonghui Zheng,2 Wen Qiu4 1School of Pharmacy Lanzhou University, Lanzhou University, Lanzhou, People’s Republic of China; 2Research Institute, Shandong Xinhua Pharmaceutical Company Limited, Shandong, People’s Republic of China; 3The Department of Analysis, Chengdu Fanweixi Pharmaceutical Technology Company, Limited, Chengdu, People’s Republic of China; 4Phase I Clinical Unit, Lanzhou University Second Hospital, Lanzhou, People’s Republic of ChinaCorrespondence: Wen Qiu Tel/ Fax +86-931-8487117Email qiuwenmm@sina.comPurpose: Glimepiride, an FDA-approved oral hypoglycemic drug, is a long-acting sulfonylurea (SU), used for treating type 2 diabetes. The study aimed to evaluate the bioequivalence and safety profiles of two different formulations of glimepiride 1 mg from two different manufactures in healthy Chinese subjects in the fasting and fed state in order to acquire adequate pharmacokinetic evidence for registration approval of the test formulation.Patients and Methods: This study is an open-label, two-period, two-sequence, randomized, two-way crossover pharmacokinetic study in healthy Chinese subjects in the fasting and fed state. Seventy-two subjects were randomly assigned to the fasting group and the fed group (n=36 each). We collected blood samples, 24-h post drug administration. The plasma concentration of glimepiride was assessed using HPLC coupled with mass spectrometry. The following parameters were evaluated: AUC0-inf, AUC0-last, Cmax, t1⁄ 2, Tmax, and λz. Safety was determined based on the occurrence of adverse events (AEs) and laboratory examinations (biochemistry, hematology, and urinalysis) throughout the entire study period.Results: The geometric mean ratios (GMR) amongst the two glimepiride formulations for the primary pharmacokinetic parameters, ie, AUC0-inf, AUC0-last, and Cmax as well as the corresponding 90% CIs, were all within the range of 80.00– 125.00% in the fasting and fed state. The safety profile for both treatments was comparable.Conclusion: PK analysis revealed that the test and reference formulations of glimepiride were bioequivalent and well tolerated in healthy Chinese subjects. Chinese Clinical Trials Registry identifier: CTR20171121.Clinical Trial Registration Number: CTR20171121.Keywords: glimepiride, bioequivalence, pharmacokinetics, HPLC-MS/MS, adverse event

Kevin Yan,1,2 Kamal Desai,1 Lakshmi Gullapalli,1 Eric Druyts,1 Chakrapani Balijepalli1 1Pharmalytics Group, Vancouver, British Columbia, Canada; 2Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, CanadaCorrespondence: Chakrapani Balijepalli 637 East 15th Ave, Vancouver, British Columbia V5T 3K5, CanadaTel +1 604-398-4025Email chak.balijepalli@pharmalyticsgroup.comAbstract: Atypical hemolytic uremic syndrome (aHUS) is a rare but severe disorder that frequently has a genetic component and results from the overactivation of the alternative complement pathway. As research moves toward improved diagnosis and therapy of aHUS, it will be important to better understand its epidemiology. Our objective was to conduct a systematic literature review to assess the incidence and prevalence estimates of aHUS globally. A comprehensive literature search was conducted in Embase and MEDLINE. Additionally, practice guidelines, databases of national/international organizations, and regulatory agencies were searched. From 2960 publications identified via MEDLINE and Embase, 105 publications were eligible for full-text screening, and a total of eight full-text articles met eligibility criteria for inclusion. Regional epidemiologic estimates were obtained for Europe and Oceania. Country-specific data were available for France, Norway, Australia, and Italy. Four of the identified studies reported on the prevalence of aHUS, prevalence in the age group of 20 years or younger was ranging from 2.2 to 9.4 per million population, while the only study that reported prevalence in all ages showed a prevalence of 4.9 per million population. Six studies reported on the incidence of aHUS, annual incidence in the age group of 20 years or younger was ranging from 0.26 to 0.75 per million population, and for all ages, annual incidence was ranging from 0.23 to 1.9 per million population. To our knowledge, this is the first systematic review conducted to provide a comprehensive overview of global incidence and prevalence estimates of aHUS. In general, incidence estimates were similar across all the studies; however, prevalence data were found to be more variable. Study limitations were related to inconsistencies in the definitions of aHUS between studies and also a dearth of epidemiological studies assessing incidence and prevalence of aHUS outside of Europe.Keywords: incidence, prevalence, aHUS, rare, orphan, kidney

Lithium-oxygen (Li-O2) cells are a promising power source, and carbons are an attractive non-metal catalyst for air electrodes. To improve the electrochemical performance, various carbons are heated in an inert atmosphere. It is found that heat treatment at 900 C can differently improve the electrochemical performance of multiwalled carbon nanotubes (CNTs), acetylene carbon black (AB) and activated carbon (AC), but the improvement of CNTs is the most obvious. After heat treatment, the peak current density of the oxygen reduction reaction (ORR) and the 1st discharge capacity of CNTs increase ∼30% and ∼125%, respectively, while the charge transfer reaction resistance and the Warburg diffusion resistance decrease ∼7.0% and ∼11.1%, respectively. AC has the highest charge capacities and capacity retention ratio in spite of little influence by heat treatment. The possible mechanism and reasons are analyzed using different techniques. Microstructure is superior to conductivity for enhancing the rechargeability and the cyclability, and heat treatment is effective for some carbon materials in improving the electrochemical performance of Li-O2 cells. © 2014 Elsevier Ltd.

A promising pollution control technology is cold plasma driven chemical processing. The plasma is a pulsed electric gas discharge inside a near atmospheric-pressure-temperature reactor. The system is energized by a continuous stream of very short high-voltage pulses. The exhaust gas to be treated flows through the reactor. The methods applied involve the development of robust cold plasma systems, industrial applications and measuring technologies. Tests of the systems were performed at many industrial sites and involved control of airborne VOC (volatile organic compound) and odor. Electrical, chemical and odor measuring data were collected with state-of-the-art methods. To explain the test data an approximate solution of global reaction kinetics of pulsed plasma chemistry was developed. It involves the Lambert function and, for convenience, a simple approximation of it. The latter shows that the amount of removal, in good approximation, is a function of a single variable. This variable is electric plasma power divided by gas flow divided by input concentration. In the results sections we show that in some cases up to 99% of volatile pollution can be removed at an acceptable energy requirement. In the final sections we look into future efficiency enhancements by implementation of (sub)nanosecond pulsed plasma and solid state high-voltage technology and by integration with catalyst technology. [ABSTRACT FROM AUTHOR]

Background: Cells constantly sense many internal and environmental signals and respond through their complex signaling network, leading to particular biological outcomes. However, a systematic characterization and optimization of multi-signal responses remains a pressing challenge to traditional experimental approaches due to the arising complexity associated with the increasing number of signals and their intensities.Results: We established and validated a data-driven mathematical approach to systematically characterize signal-response relationships. Our results demonstrate how mathematical learning algorithms can enable systematic characterization of multi-signal induced biological activities. The proposed approach enables identification of input combinations that can result in desired biological responses. In retrospect, the results show that, unlike a single drug, a properly chosen combination of drugs can lead to a significant difference in the responses of different cell types, increasing the differential targeting of certain combinations. The successful validation of identified combinations demonstrates the power of this approach. Moreover, the approach enables examining the efficacy of all lower order mixtures of the tested signals. The approach also enables identification of system-level signaling interactions between the applied signals. Many of the signaling interactions identified were consistent with the literature, and other unknown interactions emerged.Conclusions: This approach can facilitate development of systems biology and optimal drug combination therapies for cancer and other diseases and for understanding key interactions within the cellular network upon treatment with multiple signals. © 2011 Al-Shyoukh et al; licensee BioMed Central Ltd.

Sisi Ning,1,* Mengwei Yao,1,* Yuan Wu,1 Xunzhao Zhou,1 Changtao Zhong,1 Kui Yan,1 Zhengbo Wei,2 Ying Xie3,4 1Graduate School of Guangxi Medical University, Nanning, China; 2Department of Head and Neck Tumor Surgery, Affiliated Tumor Hospital of Guangxi Medical University, Nanning, China; 3Life Sciences Institute of Guangxi Medical University, Nanning, China; 4Key Laboratory for High-Incidence Tumor Prevention and Treatment, Guangxi Medical University, Ministry of Education, Nanning, China *These authors contributed equally to this work Objective: To evaluate the potential association of variations in the number of tandem repeats in the dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin (DC-SIGN) and dendritic cell-specific intercellular adhesion molecule-3 grabbing nonintegrin-related (DC-SIGNR) neck region with susceptibility to nasopharyngeal carcinoma (NPC).Methods: Variations in the number of repeats in the genotypes and alleles in the neck region of DC-SIGN/DC-SIGNR were analyzed in 477 unrelated NPC patients and 561 cancer-free controls.Results: Genotypes and alleles in the DC-SIGN neck region did not differ significantly between NPC patients and controls, but the 9-repeat genotype in the DC-SIGNR neck region was significantly more frequent among patients (OR 1.339, 95% CI 1.018–1.760, P=0.037). The association between this genotype and NPC remained significant after adjusting for sex, age, smoking history, and presence of immunoglobulin against Epstein–Barr virus viral capsid antigen (OR 1.625, 95% CI 1.134–2.329, P=0.0082).Conclusion: These results suggest that genotypes/alleles in the DC-SIGN neck region are not associated with NPC susceptibility, whereas the 9-repeat variant in the neck region of DC-SIGNR may increase the risk of NPC. Keywords: nasopharyngeal carcinoma, DC-SIGN, DC-SIGNR, genetic polymorphism, neck region repeat variation

Abstract Background Optimal anticoagulation strategy for cardiopulmonary bypass (CPB) in end-stage heart failure patients with heparin-induced thrombocytopenia (HIT) requiring left ventricular assist device (LVAD) implantation remains uncertain. Presently, there are no large-scale randomized studies comparing outcomes of alternative anticoagulation strategies for CPB in this patient population. A novel antiplatelet agent – cangrelor, which is a potent P2Y12 inhibitor with robust antiplatelet efficacy, rapid reversibility, and measurable drug effect, has become available since 2015. Intraoperative anticoagulation for CPB using cangrelor with heparin has not been reported before. Case presentation We report the case of a 47-year-old male with ischemic cardiomyopathy and acute HIT, who underwent an urgent LVAD implantation using cangrelor with heparin for anticoagulation on CPB. This novel strategy resulted in satisfactory anticoagulation for CPB without perioperative thromboembolic events or major bleeding requiring reoperation. Conclusions Cangrelor with heparin was an effective anticoagulation strategy for CPB in this critically ill patient with acute HIT requiring an urgent LVAD implantation. Further studies are warranted to evaluate its efficacy and replicability in other patients with acute or subacute HIT who require urgent cardiac surgery.

Breast cancer is one of the most common malignancies in females. It is an etiologically complex disease driven by a multitude of cellular pathways. The proliferation and spread of breast cancer is intimately linked to cellular glucose metabolism, given that glucose is an essential cellular metabolic substrate and that insulin signalling has mitogenic effects. Growing interest has focused on anti-diabetic agents in the management of breast cancer. Epidemiologic studies show that metformin reduces cancer incidence and mortality among type 2 diabetic patients. Preclinical in vitro and in vivo research provides intriguing insight into the cellular mechanisms behind the oncostatic effects of metformin. This article aims to provide an overview of the mechanisms in which metformin may elicit its anti-cancerous effects and discuss its potential role as an adjuvant in the management of breast cancer.