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Liping Chen,1 Tongwei Xiang,2 Jing Xing,2 Xinan Lu,2 Shan Wei,2 Huaying Wang,2 Jipeng Li,1 Wanjun Yu2 1Department of Central Laboratory, The Affiliated People’s Hospital of Ningbo University, Ningbo, People’s Republic of China; 2Department of Respiratory and Critical Care Medicine, The Affiliated People’s Hospital of Ningbo University, Ningbo, People’s Republic of ChinaCorrespondence: Liping Chen; Wanjun Yu, Email Chenliliy@outlook.com; nbyuwanjun@163.comBackground: It has been increasingly recognized that circular RNAs (circRNAs) act as a pivotal factor in the onset and progression of human malignancies. Yet, the specific activities and mechanistic roles of these RNAs in the context of lung adenocarcinoma (LUAD) are not fully understood.Methods: Microarray analysis identified a novel LUAD-associated circular RNA, termed hsa_circ_0006357 (also referred to as circEZH2). Reverse transcription–quantitative polymerase chain reaction (RT-qPCR) was utilized for the analysis of circEZH2 expression in tissues and cell lines. The characteristics of circEZH2 were verified by RNase R treatment and fluorescence in situ hybridization (FISH) assays. The functions of circEZH2 were detected by Cell Counting Kit-8 (CCK-8), colony formation, wound healing, and Transwell assays. The molecular mechanism of circEZH2 was clarified through bioinformatics analysis as well as RNA pulldown, dual-luciferase reporter, RT-qPCR, and immunoblotting assays. The role of circEZH2 in vivo was investigated using a xenograft model.Results: This investigation revealed that circEZH2 expression was elevated in LUAD cell lines and tumor samples. This elevation was associated with enhanced cell proliferation, migratory capacity, epithelial–mesenchymal transition (EMT), and invasion in vitro. Conversely, silencing of circEZH2 in vivo resulted in a notable decrease in LUAD tumorigenesis, whereas its overexpression led to the opposite effects. Mechanistically, circEZH2 appeared to act as a sponge for miR-495-3p, facilitating the upregulation of tumor protein D52 (TPD52) and triggering the nuclear factor kappa B (NF-κB) signaling pathway, thus contributing to the progression of LUAD.Conclusion: These findings indicate that circEZH2 may function as a competitive endogenous RNA (ceRNA), driving the progression of LUAD by manipulating the miR-495-3p/TPD52 axis and activating the NF-κB pathway.Keywords: lung adenocarcinoma, circular RNA, nuclear factor kappa B, tumor protein D52, miR-495-3p

Jun Lu,1,&ast; Huiqing Pan,1,&ast; Jingjing Xing,1 Bing Wang,1 Li Xu,2 Sheng Ye1,3 1Emergency Department, The Second Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, People’s Republic of China; 2Neurology Department, The Second Affiliated Hospital of Wannan Medical College, Wuhu, Anhui, People’s Republic of China; 3School of Clinical Medicine, Wannan Medical College, Wuhu, Anhui, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Sheng Ye, Emergency Department, The Second Affiliated Hospital of Wannan Medical College, 10 Kangfu Road, Jinghu District, Wuhu, Anhui, People’s Republic of China, Email yesheng0553@163.comBackground: A considerable proportion of hypertensive patients may experience lacunar infarction. Therefore, early identification of the risk for lacunar infarction in hypertensive patients is particularly important. This study aimed to develop and validate a concise nomogram for predicting lacunar infarction in hypertensive patients.Methods: Retrospectively analyzed the clinical data of 314 patients with accurate history of hypertension in the Second Affiliated Hospital of Wannan Medical College from January 2021 to December 2022. All the patients were randomly assigned to the training set (n=220) and the validation set (n=94) with 7:3. The diagnosis of lacunar infarction in patients was confirmed using cranial CT or MRI. The independent risk factors of lacunar infarction were determined by Least absolute shrinkage and selection operator (LASSO) regression and multivariable logistic regression analysis. The nomogram was built based on the independent risk factors. The nomogram’s discrimination, calibration, and clinical usefulness were evaluated by receiver operating characteristics (ROC) curve, calibration curve, and decision curve analysis (DCA) analysis, respectively.Results: The incidence of lacunar infarction was 34.50% and 33.00% in the training and validation sets, respectively. Five independent predictors were made up of the nomogram, including age (OR=1.142, 95% CI: 1.089– 1.198, P< 0.001), diabetes mellitus (OR=3.058, 95% CI: 1.396– 6.697, P=0.005), atrial fibrillation (OR=3.103, 95% CI: 1.328– 7.250, P=0.009), duration of hypertension (OR=1.130, 95% CI: 1.045– 1.222, P=0.002), and low-density lipoprotein (OR=2.147, 95% CI: 1.250– 3.688, P=0.006). The discrimination with area under the curve (AUC) was 0.847 (95% CI: 0.789– 0.905) in the training set and was a slight increase to 0.907 (95% CI: 0.838– 0.976) in the validation set. The calibration curve showed high coherence between the predicted and actual probability of lacunar infarction. Moreover, the DCA analysis indicated that the nomogram had a higher overall net benefit of the threshold probability range in both two sets.Conclusion: Age, diabetes mellitus, atrial fibrillation, duration of hypertension, and low-density lipoprotein were significant predictors of lacunar infarction in hypertensive patients. The nomogram based on the clinical data was constructed, which was a useful visualized tool for clinicians to assess the risk of the lacunar infarction in hypertensive patients.Keywords: lacunar infarction, nomogram, hypertension, lasso regression, predictive model

Abstract Background Non-beneficial treatment affects a considerable proportion of older people in hospital, and some will choose to decline invasive treatments when they are approaching the end of their life. The Intervention for Appropriate Care and Treatment (InterACT) intervention was a 12-month stepped wedge randomised controlled trial with an embedded process evaluation in three hospitals in Brisbane, Australia. The aim was to increase appropriate care and treatment decisions for older people at the end-of-life, through implementing a nudge intervention in the form of a prospective feedback loop. However, the trial results indicated that the expected practice change did not occur. The process evaluation aimed to assess implementation using the Consolidated Framework for Implementation Research, identify barriers and enablers to implementation and provide insights into the lack of effect of the InterACT intervention. Methods Qualitative data collection involved 38 semi-structured interviews with participating clinicians, members of the executive advisory groups overseeing the intervention at a site level, clinical auditors, and project leads. Online interviews were conducted at two times: implementation onset and completion. Data were coded to the Consolidated Framework for Implementation Research and deductively analysed. Results Overall, clinicians felt the premise and clinical reasoning behind InterACT were strong and could improve patient management. However, several prominent barriers affected implementation. These related to the potency of the nudge intervention and its integration into routine clinical practice, clinician beliefs and perceived self-efficacy, and wider contextual factors at the health system level. Conclusions An intervention designed to change clinical practice for patients at or near to end-of-life did not have the intended effect. Future interventions targeting this area of care should consider using multi-component strategies that address the identified barriers to implementation and clinician change of practice. Trial registration Australia New Zealand Clinical Trial Registry (ANZCTR), ACTRN12619000675123p (approved 06/05/2019).

Abstract Background Early Detection of Deterioration in Elderly Residents (EDDIE +) is a multi-modal intervention focused on empowering nursing and personal care workers to identify and proactively manage deterioration of residents living in residential aged care (RAC) homes. Building on successful pilot trials conducted between 2014 and 2017, the intervention was refined for implementation in a stepped-wedge cluster randomised trial in 12 RAC homes from March 2021 to May 2022. We report the process used to transition from a small-scale pilot intervention to a multi-site intervention, detailing the intervention to enable future replication. Methods The EDDIE + intervention used the integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) framework to guide the intervention development and refinement process. We conducted an environmental scan; multi-level context assessments; convened an intervention working group (IWG) to develop the program logic, conducted a sustainability assessment and deconstructed the intervention components into fixed and adaptable elements; and subsequently refined the intervention for trial. Results The original EDDIE pilot intervention included four components: nurse and personal care worker education; decision support tools; diagnostic equipment; and facilitation and clinical support. Deconstructing the intervention into core components and what could be flexibly tailored to context was essential for refining the intervention and informing future implementation across multiple sites. Intervention elements considered unsustainable were updated and refined to enable their scalability. Refinements included: an enhanced educational component with a greater focus on personal care workers and interactive learning; decision support tools that were based on updated evidence; equipment that aligned with recipient needs and available organisational support; and updated facilitation model with local and external facilitation. Conclusion By using the i-PARIHS framework in the scale-up process, the EDDIE + intervention was tailored to fit the needs of intended recipients and contexts, enabling flexibility for local adaptation. The process of transitioning from a pilot to larger scale implementation in practice is vastly underreported yet vital for better development and implementation of multi-component interventions across multiple sites. We provide an example using an implementation framework and show it can be advantageous to researchers and health practitioners from pilot stage to refinement, through to larger scale implementation. Trial registration The trial was prospectively registered with the Australia New Zealand Clinical Trial Registry (ACTRN12620000507987, registered 23/04/2020).

Danyang Wang,1,2 Jianfeng Xing,2 Ying Zhang,2 Ziyang Guo,2 Shujing Deng,2 Zelin Guan,2 Binyang He,2 Ruirui Ma,2 Xue Leng,2 Kai Dong,2 Yalin Dong1 1Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China; 2School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of ChinaCorrespondence: Kai Dong, School of Pharmacy, Xi’an Jiaotong University, 76 Yanta West Road, Xi’an, Shaanxi, 710061, People’s Republic of China, Tel/Fax +86-29-82655139, Email dongkai120@xjtu.edu.cn Yalin Dong, Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, People’s Republic of China, Te1 +86-29-85323241, Fax +86-29-85323240, Email dongyalin@mail.xjtu.edu.cn; donglyalin@medmail.com.cnAbstract: Chronic wounds are recalcitrant complications of a variety of diseases, with pathologic features including bacterial infection, persistent inflammation, and proliferation of reactive oxygen species (ROS) levels in the wound microenvironment. Currently, the use of antimicrobial drugs, debridement, hyperbaric oxygen therapy, and other methods in clinical for chronic wound treatment is prone to problems such as bacterial resistance, wound expansion, and even exacerbation. In recent years, researchers have proposed many novel materials for the treatment of chronic wounds targeting the disease characteristics, among which metal–phenolic networks (MPNs) are supramolecular network structures that utilize multivalent metal ions and natural polyphenols complexed through ligand bonds. They have a flexible and versatile combination of structural forms and a variety of formations (nanoparticles, coatings, hydrogels, etc.) that can be constructed. Functionally, MPNs combine the chemocatalytic and bactericidal properties of metal ions as well as the anti-inflammatory and antioxidant properties of polyphenol compounds. Together with the excellent properties of rapid synthesis and negligible cytotoxicity, MPNs have attracted researchers’ great attention in biomedical fields such as anti-tumor, anti-bacterial, and anti-inflammatory. This paper will focus on the composition of MPNs, the mechanisms of MPNs for the treatment of chronic wounds, and the application of MPNs in novel chronic wound therapies.Keywords: metal–phenolic networks, chronic wounds, antimicrobial, antioxidant, reactive oxygen species scavenging, revascularization

IntroductionHumans are similar but behave differently, and one main reason is the culture in which they are born and raised. The purpose of this research is to examine how the perception and reaction to those who transgress social norms may vary based on the individualism/collectivism of their culture.MethodsA study (N = 398) conducted in the United Kingdom, Spain, and China showed differences in the perception and reaction to incivilities based on individualism/collectivism.ResultsPeople from highly collective countries (China) perceive uncivil transgressors as immoral and enact more social control over them than people from highly individualistic countries (U.K.). They also experience more discomfort when facing uncivil transgressors, and this discomfort mediates the increasing immorality perceived on the agents of incivilities in contrast with people from less collective countries.DiscussionOur findings provide insights into how cultural factors shape individuals’ perceptions of social norm violations and emphasize the importance of considering cultural differences when addressing incivility.

Abstract Background Hospitalisation rates for older people are increasing, with end-of-life care becoming a more medicalised experience. Innovative approaches are warranted to support early identification of the end-of-life phase, communicate prognosis, provide care consistent with people’s preferences, and improve the use of healthcare resources. The Intervention for Appropriate Care and Treatment (InterACT) trial aimed to increase appropriate care and treatment decisions for older people at the end of life, through implementation of a prospective feedback loop. This paper reports on the care review outcomes. Methods A stepped-wedge randomised controlled trial was conducted in three large acute hospitals in Queensland, Australia between May 2020 and June 2021. The trial identified older people nearing the end of life using two validated tools for detecting deterioration and short-term death. Admitting clinical teams were provided with details of patients identified as at-risk with the goal of increasing awareness that end of life was approaching to facilitate appropriate patient centred care and avoid non-beneficial treatment. We examined the time between when the patient was identified as ‘at-risk’ and three outcomes: clinician-led care review discussions, review of care directive measures and palliative care referrals. These were considered useful indicators of appropriate care at the end of life. Results In two hospitals there was a reduction in the review of care directive measures during the intervention compared with usual care at 21 days (reduced probability of − 0.08; 95% CI: − 0.12 to − 0.04 and − 0.14; 95% CI: − 0.21 to − 0.06). In one hospital there was a large reduction in clinician-led care review discussions at 21 days during the intervention (reduced probability of − 0.20; 95% CI: − 0.28 to − 0.13). There was little change in palliative care referrals in any hospital, with average probability differences at 21 days of − 0.01, 0.02 and 0.04. Discussion The results are disappointing as an intervention designed to improve care of hospitalised older people appeared to have the opposite effect on care review outcomes. The reasons for this may be a combination of the intervention design and health system challenges due to the pandemic that highlight the complexity of providing more appropriate care at the end of life. Trial registration Australia New Zealand Clinical Trial Registry, ACTRN12619000675123 (registered 6 May 2019).

Zhengting Jiang,1,&ast; Wenjie Zhang,1,&ast; Jie Zhang,1 Tian Liu,1 Juan Xing,1 Huan Zhang,1 Dong Tang2 1Clinical Medical College, Yangzhou University, Yangzhou, 225000, People’s Republic of China; 2Department of General Surgery, Institute of General Surgery, Northern Jiangsu Province Hospital, Clinical Medical College, Yangzhou University, Yangzhou, 225000, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Dong Tang, Department of General Surgery, Institute of General Surgery, Northern Jiangsu Province Hospital, Clinical Medical College, Yangzhou University, Yangzhou, 225000, People’s Republic of China, Email 83392785@qq.comAbstract: Cancer immunotherapy, a major breakthrough in cancer treatment, has been successfully applied to treat a number of tumors. However, given the presence of factors in the tumor microenvironment (TME) that impede immunotherapy, only a small proportion of patients achieve a good clinical response. With the ability to increase permeability and cross biological barriers, nanomaterials have been successfully applied to deliver immunotherapeutic agents, thus realizing the anti-cancer therapeutic potential of therapeutic agents. This has driven a wave of research into systems for the delivery of immunotherapeutic agents, which has resulted in widespread interest in nanomaterial-based drug delivery systems. Nanomaterial-based drug delivery systems are able to overcome the challenges from TME and thus achieve good results in cancer immunotherapy. If it can make a breakthrough in improving biocompatibility and reducing cytotoxicity, it will be more widely used in clinical practice. Different types of nanomaterials may also have some subtle differences in enhancing cancer immunotherapy. Moreover, delivery systems made of nanomaterials loaded with drugs, such as cytotoxic drugs, cytokines, and adjuvants, could be used for cancer immunotherapy because they avoid the toxicity and side effects associated with these drugs, thereby enabling their reuse. Therefore, further insights into nanomaterial-based drug delivery systems will provide more effective treatment options for cancer patients.Keywords: drug repurposing, delivery system, immunotherapy, tumor microenvironment, nanomaterial

Xinhua Li,1 Jianxiao Xing,1 Fangdi Wang,1 Juan Li,1 Junqin Li,1 Ruixia Hou,1 Kaiming Zhang2 1Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, Shanxi Province, 030009, People’s Republic of China; 2Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Taiyuan Central Hospital, Taiyuan, Shanxi Province, 030009, People’s Republic of ChinaCorrespondence: Kaiming Zhang, Taiyuan Central Hospital, No, 5 Dong San Dao Xiang, Jiefang Road, Taiyuan, Shanxi Province, People’s Republic of China, Tel +86-351-5656080, Email zhangkaiming@sina.comPurpose: Psoriasis is a chronic recurring autoimmune skin disease with a complex etiology and chronic progression; however, its molecular mechanisms remain unclear.Patients and Methods: We performed transcriptomic analysis to profile the mRNA expression of psoriatic lesions (PL) and non-lesion (NL) tissues from psoriasis patients along with normal skin from healthy donors. RT-qPCR was used to validate the mRNA expression profiles.Results: A total of 237 differentially expressed genes were screened and identified by RNA sequencing. GO and KEGG analysis indicated that these DEGs were enriched in the PPAR signaling pathway and intermediate filament cytoskeleton. For PPAR signaling pathway, the expression of five genes, including ADIPOQ, AQP7, PLIN1, FABP4 and LPL, were all significantly decreased in psoriatic lesions compared to normal skin by RT-qPCR. There is a clear difference between psoriatic lesions and non-lesion in the expression of ADIPOQ, AQP7 and LPL. For intermediate filament cytoskeleton, including KRT27, KRT25, KRT71, KRT86 and KRT85 were significantly decreased in the psoriasis lesions, showing agreement with the RNA-seq data.Conclusion: This study revealed a significant difference between the mRNA expression profiles of PL, NL tissue and normal skin.Keywords: psoriasis, RNA-sequencing, PPAR signaling pathway, keratin

Aihong Peng,1 Funa Lu,1 Jianxiao Xing,1 Yu Dou,1 Yuanjun Yao,1 Juan Li,1 Junqin Li,1 Ruixia Hou,1 Kaiming Zhang,2 Guohua Yin1 1Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, People’s Republic of China; 2Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital, Taiyuan, People’s Republic of ChinaCorrespondence: Guohua Yin, Shanxi Key Laboratory of Stem Cells for Immunological Dermatosis, Institute of Dermatology, Taiyuan Central Hospital of Shanxi Medical University, No. 5, Dong San Dao Xiang, Jiefang Road, Taiyuan, People’s Republic of China, Tel +86-0351-5656080, Email yinguohua1999@sina.comPurpose: Our recent studies found a splice region mutation in C3 accompanied by a significantly increased C3 in psoriatic peripheral blood. Mesenchymal stem cells (MSCs) are a key immunological suppression cell. We further investigate the regulation of MSCs on C3 in psoriasis.Patients and Methods: We analyzed the C3 and its upstream S100A9, S100A8 and downstream MCP1 in psoriatic and control skin, and in normal human epidermal keratinocytes (NHEKs) co-cultured with psoriatic versus control dermal-derived mesenchymal stem cells (DMSCs) by mRNA, iTRAQ (isobaric tags for relative and absolute quantitative) and simple Western analysis.Results: The mRNA and Simple Western analysis showed that the expression of C3, S100A8 and S100A9 are upregulated in psoriatic lesion (C3: mRNA, 9.23-fold, p = 0.0092; protein, 3.56-fold, p = 0.0244. S100A8: mRNA, 28.35-fold, p = 0.0015; protein, 4.68-fold, p = 0.0215. S100A9: mRNA, 79.45-fold, p = 0.0066; protein, 12.42-fold, p > 0.05). Moreover, the iTRAQ showed that C3 and S100A9 were significantly increased in NHEKs after co-cultured with psoriatic DMSCs compared to that of control DMSCs (C3: 3.40-fold, p = 0, FDR = 0; S100A9: 2.30-fold, p = 9.86E-241, FDR = 6.50E-239), verified by Simple Western. However, the expression of S100A8 and MCP1 was slightly different between the two groups.Conclusion: Our results suggest that psoriatic DMSCs contribute to the increased C3 expression in psoriatic lesion via upregulating S100A9, providing the theoretical basis for the role of C3 and DMSCs in the pathogenesis of psoriasis.Keywords: psoriasis, dermal mesenchymal stem cells, keratinocytes, C3, S100A9

Lu Zhang,1 Yue Fang,1 Jianghao Xing,1 Hao Cheng,2 Xiaonan Sun,1 Zhichao Yuan,1 Yidan Xu,1 Jiqing Hao1 1Department of Oncology, The First Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of China; 2Department of Oncology, The Second Affiliated Hospital of Anhui Medical University, Hefei, People’s Republic of ChinaCorrespondence: Jiqing Hao, Department of Oncology, The First Affiliated Hospital of Anhui Medical University, 81 Meishan Road, Hefei, 230022, People’s Republic of China, Tel +86 13965029739, Email haojiqing@ahmu.edu.cnPurpose: This study aimed to analyze the association between venous thromboembolism (VTE) and inflammatory markers like systemic immune-inflammation index (SII) and prognosis nutritional index (PNI), and to evaluate their efficacy for the diagnosis of VTE in patients with gastrointestinal malignancies.Patients and Methods: A total of 1326 patients with the initial diagnosis of gastrointestinal cancer in the First Affiliated Hospital of Anhui Medical University (AHMU) were enrolled in the training cohort. Univariate and multivariate analysis was used to pinpoint independent predictors of VTE, which were eventually visualized as the nomogram models. The Akaike Information Criterion (AIC) was used to screen the best model. The receiver operating characteristic curve (ROC) and the clinical decision curve analysis (DCA) were utilized to evaluate the models’ predictive performance in the training queue and another external sample of 250 patients at the Second Affiliated Hospital of AHMU.Results: A total of 476 patients were complicated with VTE in the training cohort. Multifactorial analysis of clinical characteristics and inflammatory markers showed that PNI, SII, age, tumor location, and therapy were independent risk factors of VTE, visualized as model A. Another model B was constructed by adding coagulation markers to the previous analysis. Model B was the best prediction model with the minimum AIC value, followed by model A with an AUC of 0.806 (95% CI 0.782∼ 0.830) which was similar to model B’s 0.832 (95% CI 0.810∼ 0.855) but significantly higher than the currently widely used Khorana score’s 0.592 (95% CI 0.562∼ 0.621) and the CATS score’s 0.682 (95% CI 0.653∼ 0.712). The external verification yielded similar findings, with the AUC being 0.792 (95% CI 0.734∼ 0.851), 0.834 (95% CI 0.778∼ 0.890), 0.655 (95% CI 0.582∼ 0.729), and 0.774 (95% CI 0.699∼ 0.849) respectively. The DCA curves demonstrated that new models had excellent usefulness in screening patients with a high VTE risk.Conclusion: The SII and PNI were simple and viable inflammatory markers associated with VTE, and the nomogram based on them and clinical features had a meaningful clinical utility for VTE in patients with gastrointestinal malignancies.Keywords: venous thromboembolism, gastrointestinal cancers, inflammation, systemic immune-inflammation index, nomogram

Jianxiao Xing,1 Ying Wang,1 Xincheng Zhao,1 Junqin Li,1 Ruixia Hou,1 Xuping Niu,1 Guohua Yin,1 Xinhua Li,1 Kaiming Zhang2 1Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Taiyuan Central Hospital of Shanxi Medical University, Taiyuan, 030009, Shanxi Province, People’s Republic of China; 2Shanxi Key Laboratory of Stem Cell for Immunological Dermatosis, Taiyuan Central Hospital, Taiyuan, 030009, Shanxi Province, People’s Republic of ChinaCorrespondence: Kaiming Zhang, Taiyuan Central Hospital, No, 5 Dong San Dao Xiang, Jiefang Road, Taiyuan, Shanxi Province, People’s Republic of China, Tel +86-0351-5656080, Email zhangkaiming@sina.comPurpose: Psoriasis is a multifactorial disease with a complex genetic predisposition. The pathophysiology of psoriasis is associated with genetic variants. To better characterize gene variants in psoriasis and identify the relationship between clinical characteristics and variant genes in its pathogenesis.Patients and Methods: DNA was extracted and purified from eight pairs of monozygotic twins with psoriasis discordance and 282 type I psoriasis patients. Thirteen variable genes were amplified and sequenced using the Sanger method after whole genome sequencing.Results: Thirteen genes were found to be variable in eight pairs of monozygotic twins with psoriasis discordance. Among the 13 genes, the variant frequencies of protein kinase C epsilon (PRKCE) (c.240T>C, 35.9% vs 47.7%, P < 0.05) and kinesin light chain 1 (KLC1) (c.216A>G, 2.9% vs 98.1%, P< 0.01) were significantly lower in psoriasis than in normal Asian individuals. Additionally, we found considerable differences in the relationship between variants in genes CADM2, JPH2, SPTLC3 and clinical characteristics stratified by medical history and family history. Moreover, the variants in MEGF6 (39.52% vs 22.50%, χ2=3.83, p < 0.05) showed a stronger association with the mild group (PASI ≤ 10) than the heavy group.Conclusion: Our results provide a comprehensive correlation analysis of regulatory genes that are regulated in psoriasis. This integrated analysis offers novel insight into the pathogenic mechanisms involved in psoriasis.Graphical Abstract: Keywords: psoriasis, gene variants, PRKCE, KLC1

Civility is formed by social norms that guide our behavior and allow us to interact appropriately with others. These norms affect everyone and are learned through the socialization process. However, in the same process, people also learn gender norms that dictate how men and women should behave, leading to gender stereotypes and differentiated behavioral characteristics. The purpose of this research is to examine the relationship between gender and civility, and how we react to those who behave uncivilly given their gender. The results of Study 1 (N = 153) showed that even in a fictional and gender-neutral society, uncivil behaviors were associated with stereotypically masculine characteristics, and those who behaved uncivilly were dehumanized. In Study 2 (N = 144), gender differences were observed in incivility. Women were harsher when facing uncivil transgressors than men, especially if the transgressor was another woman. Our findings support the notion that gender norms are applied to civility, leading those supposedly equal social norms to unequal perceptions and evaluations.

Minwei Zhang,1,2,&ast; Shuxuan Shao,1,2,&ast; Haitao Yue,1,2 Xin Wang,3 Wenrui Zhang,1,2 Fei Chen,1,2 Li Zheng,1,2 Jun Xing,1,2 Yanan Qin1,2 1College of Life Science & Technology, Xinjiang University, Urumqi, 830046, People’s Republic of China; 2Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, Urumqi, 830046, People’s Republic of China; 3The First Hospital of Jilin University, Changchun, 130061, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yanan Qin Email qingyalan12345@sina.comAbstract: In recent years, Au-based nanomaterials are widely used in nanomedicine and biosensors due to their excellent physical and chemical properties. However, these applications require Au NPs to have excellent stability in different environments, such as extreme pH, high temperature, high concentration ions, and various biomatrix. To meet the requirement of multiple applications, many synthetic substances and natural products are used to prepare highly stable Au NPs. Because of this, we aim at offering an update comprehensive summary of preparation high stability Au NPs. In addition, we discuss its application in nanomedicine. The contents of this review are based on a balanced combination of our studies and selected research studies done by worldwide academic groups. First, we address some critical methods for preparing highly stable Au NPs using polymers, including heterocyclic substances, polyethylene glycols, amines, and thiol, then pay attention to natural product progress Au NPs. Then, we sum up the stability of various Au NPs in different stored times, ions solution, pH, temperature, and biomatrix. Finally, the application of Au NPs in nanomedicine, such as drug delivery, bioimaging, photothermal therapy (PTT), clinical diagnosis, nanozyme, and radiotherapy (RT), was addressed concentratedly.Keywords: high stability Au NPs, polymer, natural product, resistance, nanomedicine

Abstract Background Older people living in residential aged care homes experience frequent emergency transfers to hospital. These events are associated with risks of hospital acquired complications and invasive treatments or interventions. Evidence suggests that some hospital transfers may be unnecessary or avoidable. The Early Detection of Deterioration in Elderly residents (EDDIE) program is a multi-component intervention aimed at reducing unnecessary hospital admissions from residential aged care homes by empowering nursing and care staff to detect and manage early signs of resident deterioration. This study aims to implement and evaluate the program in a multi-site randomised study in Queensland, Australia. Methods A stepped-wedge randomised controlled trial will be conducted at 12 residential aged care homes over 58 weeks. The program has four components: education and training, decision support tools, diagnostic equipment, and implementation facilitation with clinical systems support. The integrated Promoting Action on Research Implementation in Health Services (i-PARIHS) framework will be used to guide the program implementation and process evaluation. The primary outcome measure will be the number of hospital bed days used by residents, with secondary outcomes assessing emergency department transfer rates, admission rates, length of stay, family awareness and experience, staff self-efficacy and costs of both implementation and health service use. A process evaluation will assess the extent and fidelity of program implementation, mechanisms of impact and the contextual barriers and enablers. Discussion The intervention is expected to improve outcomes by reducing unnecessary hospital transfers. Fewer hospital transfers and admissions will release resources for other patients with potentially greater needs. Residential aged care home staff might benefit from feelings of empowerment in their ability to proactively manage early signs of resident deterioration. The process evaluation will be useful for supporting wider implementation of this intervention and other similar initiatives. Trial registration The trial is prospectively registered with the Australia New Zealand Clinical Trial Registry ( ACTRN12620000507987 , registered 23/04/2020).

Yang J, Zhang J, Xing J, Shi Z, Han H, Li Q. Int J Nanomedicine. 2019;14:6371– 6385. The authors have advised that during the assembly of subfigures in the preparation stage of the manuscript, two images in each of the Figure S8 and Figure S9 were duplicated. On page 6380, supplementary Figure S8, image Calcein-AM, Dz13 and Calcein-AM, PP/Dz13 were duplicated. On page 6380, supplementary Figure S9, images a and b were duplicated. Read the original article

Pengchong Wang,1,2 Yan Yan,1,2 Ying Zhang,2 Tingting Gao,2 Hongrui Ji,2 Shiyan Guo,2 Ke Wang,2 Jianfeng Xing,2 Yalin Dong1 1Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of China; 2School of Pharmacy, Xi’an Jiaotong University, Xi’an, 710061, People’s Republic of ChinaCorrespondence: Yalin Dong; Jianfeng Xing Email dongyalin@mail.xjtu.edu.cn; xajdxjf@mail.xjtu.edu.cnBackground: Carbon dots (CDs) emitting near-infrared fluorescence were recently synthesized from green leaves. However, the Hg2+ detection of CDs was limited because of the insufficient water solubility, low fluorescence and poor stability.Methods: Dual fluorescence emission water-soluble CD (Dual-CD) was prepared through a solvothermal method from holly leaves and low toxic PEI1.8k. PEG was further grafted onto the surface to improve the water solubility and stability.Results: The Dual-CD solution can emit 487 nm and 676 nm fluorescence under single excitation and exhibit high quantum yield of 16.8%. The fluorescence at 678 nm decreased remarkably while the emission at 470 nm was slightly affected by the addition of Hg2+. The ratiometric Hg2+ detection had a wide linear range of 0– 100 μM and low detection limit of 14.0 nM. In A549 cells, there was a good linear relation between F487/F676 and the concentration of Hg2+ in the range of 0– 60 μM; the detection limit was 477 nM. Furthermore, Dual-CD showed visual fluorescence change under Hg2+.Conclusion: Dual-CD has ratiometric responsiveness to Hg2+ and can be applied for quantitative Hg2+ detection in living cells.Keywords: chlorophyll, polyethyleneimine, polyethylene glycol, ratiometric Hg2+ detection, A549 cells

Abstract Background Residential aged care facility residents experience high rates of hospital admissions which are stressful, costly and often preventable. The EDDIE program is a hospital avoidance initiative designed to enable nursing and care staff to detect, refer and quickly respond to early signals of a deteriorating resident. The program was implemented in a 96-bed residential aged care facility in regional Australia. Methods A prospective pre-post cohort study design was used to collect data on costs of program delivery, hospital admission rates and length of stay for the 12 months prior to, and following, the intervention. A Markov decision model was developed to synthesize study data with published literature in order to estimate the cost-effectiveness of the program. Quality adjusted life years (QALYs) were adopted as the measure of effectiveness. Results The EDDIE program was associated with a 19% reduction in annual hospital admissions and a 31% reduction in the average length of stay. The cost-effectiveness analysis found the program to be both more effective and less costly than usual care, with 0.06 QALYs gained and $249,000 health system costs saved in a modelled cohort of 96 residents. A probabilistic sensitivity analysis estimated that there was an 86% probability that the program was cost-effective after taking the uncertainty of the model inputs into account. Conclusions This study provides promising evidence for the effectiveness and cost-effectiveness of a nurse led, early intervention program in preventing unnecessary hospital admissions within a residential aged care facility. Further research in multi-site randomised studies is needed to confirm the generalisability of these results.

Jiadi Xing,* Maoxing Liu,* Kai Xu,* Pin Gao, Fei Tan, Zhendan Yao, Nan Zhang, Hong Yang, Chenghai Zhang, Ming Cui, Xiangqian Su Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital and Institute, Beijing 100142, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xiangqian Su KeyLaboratory of Carcinogenesis and Translational Research (Ministry of Education), Department of Gastrointestinal Surgery IV, Peking University Cancer Hospital and Institute, NO. 52 Fucheng Road, Haidian District, Beijing 100142, People’s Republic of ChinaTel +86-13801262916Email suxiangqian@bjmu.edu.cnBackground: Few studies have evaluated the outcomes of transhiatal and right thoracoabdominal resection of Siewert type II adenocarcinoma of the esophagogastric junction. This study investigated the relative effect of these two methods in the surgical treatment of Siewert type II adenocarcinoma of the esophagogastric junction.Methods: Clinical data for 211 Siewert type II cancer patients were collected and classified into transhiatal group (n = 181) and right thoracoabdominal group (n = 30) according to surgical approach. Short-term outcomes were compared between these two groups. A 1:1 propensity score matching was performed using a logistic regression model. Recurrence-free survival and overall survival were compared between the matched groups.Results: The right thoracoabdominal group had significantly greater intraoperative blood loss and longer operative time compared with transhiatal group. Complications corresponding to Clavien–Dindo grade III or higher were 4.4% in transhiatal group and 30% in right thoracoabdominal group (P < 0.05). The right thoracoabdominal group exhibited greater blood loss, longer operative time, longer hospitalization, and a smaller number of lymph nodes retrieved than the transhiatal group as evidenced by PSM analysis, and patients in transhiatal group also experienced significantly better survival than patients in right thoracoabdominal group.Conclusion: In this study, the transhiatal approach was associated with more favorable short-term and oncological outcomes than the right thoracoabdominal group approach for Siewert type II adenocarcinoma of the esophagogastric junction. The transhiatal approach with total gastrectomy appears to be an optional choice for this type of tumor, especially for esophagus invasion ≤ 2 cm. Well-designed randomized control trials are necessary to validate our findings.Keywords: adenocarcinoma of the esophagogastric junction, Siewert type II, transhiatal resection, right thoracoabdominal resection

Abstract Background Hospitalisation rates for the older population have been increasing with end-of-life care becoming a more medicalised and costly experience. There is evidence that some of these patients received non-beneficial treatment during their final hospitalisation with a third of the non-beneficial treatment duration spent in intensive care units. This study aims to increase appropriate care and treatment decisions and pathways for older patients at the end of life in Australia. This study will implement and evaluate a prospective feedback loop and tailored clinical response intervention at three hospitals in Queensland, Australia. Methods A stepped-wedge cluster randomised trial will be conducted with up to 21 clinical teams in three acute hospitals over 70 weeks. The study involves clinical teams providing care to patients aged 75 years or older, who are prospectively identified to be at risk of non-beneficial treatment using two validated tools for detecting death and deterioration risks. The intervention’s feedback loop will provide the teams with a summary of these patients’ risk profiles as a stimulus for a tailored clinical response in the intervention phase. The Consolidated Framework for Implementation Research will be used to inform the intervention’s implementation and process evaluation. The study will determine the impact of the intervention on patient outcomes related to appropriate care and treatment at the end of life in hospitals, as well as the associated healthcare resource use and costs. The primary outcome is the proportion of patients who are admitted to intensive care units. A process evaluation will be carried out to assess the implementation, mechanisms of impact, and contextual barriers and enablers of the intervention. Discussion This intervention is expected to have a positive impact on the care of older patients near the end of life, specifically to improve clinical decision-making about treatment pathways and what constitutes appropriate care for these patients. These will reduce the incidence of non-beneficial treatment, and improve the efficiency of hospital resources and quality of care. The process evaluation results will be useful to inform subsequent intervention implementation at other hospitals. Trial registration Australia New Zealand Clinical Trial Registry (ANZCTR), ACTRN12619000675123p (approved 6 May 2019),

Ya Li, Meng Gao, Kuo Zeng, Jia-xin Xing, Feng-ling Xu, Jin-feng Xuan, Xi Xia, Yong-ping Liu, Jun Yao, Bao-jie Wang School of Forensic Medicine, China Medical University, Shenyang 110122, People’s Republic of ChinaCorrespondence: Bao-jie Wang; Jun Yao Email wangbj77@163.com; yaojun198717@163.comBackground: Epidemiological studies have shown that genetic factors are among the causes of schizophrenia. Galanin receptor 1 is an inhibitory receptor of galanin that is widely distributed in the central nervous system. This study mainly explored the relationship between polymorphisms of the 5′ region of the GALR1 gene and schizophrenia in the northern Chinese Han population.Methods: A 1545 bp fragment of the 5′ regulatory region of the GALR1 gene was amplified and sequenced in 289 schizophrenia patients and 347 healthy controls.Results: Among the haplotypes composed of the 16 detected SNPs, the haplotype H3 was identified as conferring a risk of schizophrenia (p=0.011, OR=1.430, 95% CI=1.084– 1.886). In addition, the haplotypes H4 and H7 were both protective against schizophrenia (p=0.024, OR=0.526, 95% CI=0.298– 0.927; p=0.037, OR=0.197, 95% CI=0.044– 0.885, respectively). In the subgroup analysis by sex, it was found that seven SNP alleles (rs72978691, rs11662010, rs11151014, rs11151015, rs13306374, rs5373, rs13306375) conferred a risk of schizophrenia in females (p< 0.05), while allele G of rs7242919 (p=0.007) was protective against schizophrenia in females. Moreover, the rs72978691 AA+AC genotype (p=0.006, OR=1.874, 95% CI=1.196– 2.937, power=0.780), rs7242919 CC+CG genotype (p=0.002, OR=2.027, 95% CI=1.292– 3.180, power=0.861), rs11151014 GG+GT genotype (p=0.008, OR=1.834, 95% CI=1.168– 2.879, power=0.735), rs11151015 GG+AG genotype (p=0.002, OR=2.013, 95% CI =1.291– 3.137, power=0.843), rs13306374 CC+AC genotype (p=0.006, OR=1.881, 95% CI=1.198– 2.953, power=0.788), and rs13306375 GG+AG genotype (p=0.006, OR=1.868, 95% CI=1.194– 2.921, power=0.770) increased the risk of schizophrenia in females. The haplotype FH2 consisting of rs72978691, rs11662010, rs7242919, rs11151014, rs11151015, rs13306374, rs5373, and rs13306375 may also be associated with the risk of schizophrenia in females (p=0.024).Conclusion: This study identified an association between polymorphisms in the 5′ region of the GALR1 gene and schizophrenia, especially in females.Keywords: galanin receptor 1, schizophrenia, single-nucleotide variant, genetic polymorphism, northern Chinese Han population

Abstract Background Despite the rapid uptake of genomic technologies within cancer care, few studies provide detailed information on the costs of sequencing across different applications. The objective of the study was to examine and categorise the complete costs involved in genomic sequencing for a range of applications within cancer settings. Methods We performed a cost-analysis using gross and micro-costing approaches for genomic sequencing performed during 2017/2018 across different settings in Brisbane, Australia. Sequencing was undertaken for patients with lung, breast, oesophageal cancers, melanoma or mesothelioma. Aggregated resource data were captured for a total of 1433 patients and point estimates of per patient costs were generated. Deterministic sensitivity analyses addressed the uncertainty in the estimates. Estimated costs to the public health system for resources were categorised into seven distinct activities in the sequencing process: sampling, extraction, library preparation, sequencing, analysis, data storage and clinical reporting. Costs were also aggregated according to labour, consumables, testing, equipment and ‘other’ categories. Results The per person costs were AU$347–429 (2018 US$240–297) for targeted panels, AU$871–$2788 (2018 US$604–1932) for exome sequencing, and AU$2895–4830 (2018 US$2006-3347) for whole genome sequencing. Cost proportions were highest for library preparation/sequencing materials (average 76.8% of total costs), sample extraction (8.1%), data analysis (9.2%) and data storage (2.6%). Capital costs for the sequencers were an additional AU$34–197 (2018 US$24–67) per person. Conclusions Total costs were most sensitive to consumables and sequencing activities driven by commercial prices. Per person sequencing costs for cancer are high when tumour/blood pairs require testing. Using the natural steps involved in sequencing and categorising resources accordingly, future evaluations of costs or cost-effectiveness of clinical genomics across cancer projects could be more standardised and facilitate easier comparison of cost drivers.

Feng-ling Xu, Jun Yao, Xue Wu, Xi Xia, Jia-xin Xing, Jin-feng Xuan, Yong-ping Liu, Bao-jie Wang School of Forensic Medicine, China Medical University, Shenyang 110122, People’s Republic of ChinaCorrespondence: Bao-jie WangSchool of Forensic Medicine, China Medical University, No. 77 Puhe Road, Shenbei New District, Shenyang 110122, People’s Republic of ChinaEmail wangbj77@163.comBackground: Abnormal RGS4 gene expression may cause neurotransmitter disorders, resulting in schizophrenia. The association between RGS4 and the risk of schizophrenia is controversial, and there has been little research on the SNPs in the promoter region of RGS4.Purpose: The present study was performed to detect the association between SNPs in the promoter region of the RGS4 gene and the risk of schizophrenia.Materials and Methods: In this study, the 1757-bp fragment (− 1119–+600, TSS+1) of RGS4 was amplified and sequenced in 198 schizophrenia patients and 264 healthy controls of the northern Chinese Han population. Allele, genotype and haplotype frequencies were analyzed by chi‐square test.Results: Four SNPs were detected in the region. LD analysis determined that rs7515900 was linked to rs10917671 (D’ = 1, r2 = 1). Therefore, the data for rs10917671 were eliminated from further analysis. Genotype TT of rs12041948 (P = 0.009, OR = 1.829, and 95% CI = 0.038– 0.766) was significantly different between the two groups in the northern Chinese Han population. In males, genotype GG of rs6678136 (P = 0.009, OR = 2.292, and 95% CI = 1.256– 4.18) and CC of rs7515900 (P = 0.003, OR = 2.523, and 95% CI = 1.332– 4.778) were significantly different.Conclusion: The results of this study suggested that genotype TT of rs12041948 in the pooled male and female samples and GG of rs6678136 and CC of rs7515900 in the male samples could be risk factors for schizophrenia. The present study is the first to detect an association between SNPs in the promoter region of the RGS4 gene and the risk of schizophrenia in the northern Chinese Han population. Functional studies are required to confirm these findings.Keywords: RGS4, schizophrenia, promoter region, SNPs

Peide Bai,1 Wei Li,1 Zhenghua Wan,2 Yujuan Xiao,3 Wen Xiao,1 Xuegang Wang,1 Zhun Wu,1 Kaiyan Zhang,1 Yongfeng Wang,1 Bin Chen,1 Jinchun Xing,1 Tao Wang1 1The Key Laboratory of Urinary Tract Tumors and Calculi, Department of Urology Surgery, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen 361003, People’s Republic of China; 2Xiang’an Branch, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen 361101, People’s Republic of China; 3Department of Pediatrics, The First Affiliated Hospital, School of Medicine, Xiamen University, Xiamen 361003, People’s Republic of ChinaCorrespondence: Jinchun Xing; Tao WangThe First Affiliated Hospital of Xiamen University, Xiamen, Fujian 361003, People’s Republic of ChinaTel/Fax +86-592-2139814; +86-592-2137125Email xmcua2007@sina.com; taowang@xmu.edu.cnPurpose: Prostate cancer (PCa) is the third most common cancer in men and the second leading cause of cancer-related death in men. DLX1 belongs to the DLX homeobox family and exhibits antitumor activity in many kinds of tumors. MicroRNAs (miRNAs) play important roles in the progression of cancer. However, whether miRNAs affect the development of PCa by targeting DLX1 has not been determined. In this study, we aimed to investigate the role of miR-489-3p in the regulation of DLX1 expression and PCa progression and to provide a potential therapeutic target for PCa treatment.Methods and Materials: The Cancer Genome Atlas database was used to analyze the divergent expression of DLX1 in carcinomas and adjacent normal tissues. The expression level of DLX1 in malignant and normal prostate cells was also measured using RT-qPCR and Western blotting. A dual-luciferase reporter assay was performed to determine whether miR-489-3p directly targets DLX1. We transfected 22Rv1 and DU145 cells with miR-489-3p mimics to overexpress miR-489-3p and then evaluated its effect on cellular function. MTT, EdU, colony formation and cell cycle assays were used to evaluate cell growth. JC-1 and ROS assays with flow cytometry were performed to indirectly analyze apoptosis. Transwell assays were conducted to investigate metastasis.Results: The expression level of DLX1 was upregulated in both PCa tissues and cell lines. MiR-489-3p directly targeted DLX1 and downregulated its expression. Overexpression of miR-489-3p significantly suppressed cell growth. MiR-489-3p induced apoptosis through mitochondrial function impairment. Overexpression of miR-489-3p also inhibited cell migration and invasion. DLX1 overexpression reversed the above effects induced by miR-489-3p.Conclusion: We identified the involvement of the miR-489-3p/DLX1 pathway in PCa for the first time. In this pathway, miR-489-3p acts as a tumor suppressor by negatively regulating the expression of DLX1. MiR-489-3p may be a potential therapeutic target for PCa treatment.Keywords: prostate cancer, DLX1, miR-489-3p, growth, apoptosis, migration, invasion

Abstract Background Hospital infection control requires timely detection and identification of organisms, and their antimicrobial susceptibility. We describe a hybrid modeling approach to evaluate whole genome sequencing of pathogens for improving clinical decisions during a 2017 hospital outbreak of OXA-181 carbapenemase-producing Escherichia coli and the associated economic effects. Methods Combining agent-based and discrete-event paradigms, we built a hybrid simulation model to assess hospital ward dynamics, pathogen transmission and colonizations. The model was calibrated to exactly replicate the real-life outcomes of the outbreak at the ward-level. Seven scenarios were assessed including genome sequencing (early or late) and no sequencing (usual care). Model inputs included extent of microbiology and sequencing tests, patient-level data on length of stay, hospital ward movement, cost data and local clinical knowledge. The main outcomes were outbreak size and hospital costs. Model validation and sensitivity analyses were performed to address uncertainty around data inputs and calibration. Results An estimated 197 patients were colonized during the outbreak with 75 patients detected. The total outbreak cost was US$318,654 with 6.1% of total costs spent on sequencing. Without sequencing, the outbreak was estimated to result in 352 colonized patients costing US$531,109. Microbiology tests were the largest cost component across all scenarios. Conclusion A hybrid simulation approach using the advantages of both agent-based and discrete-event modeling successfully replicated a real-life bacterial hospital outbreak as a foundation for evaluating clinical outcomes and efficiency of outbreak management. Whole genome sequencing of a potentially serious pathogen appears effective in containing an outbreak and minimizing hospital costs.

Fei Liu,1,2 Yuedong Chen,2 Bin Chen,2 Chunxiao Liu,1 Jinchun Xing2 1Department of Urology, Zhujiang Hospital of Southern Medical University, Guangzhou 510280, People’s Republic of China; 2Department of Urology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, People’s Republic of ChinaCorrespondence: Chunxiao LiuDepartment of Urology, Zhujiang Hospital of Southern Medical University, Guangzhou 510280, People’s Republic of ChinaEmail zjhsmlc@163.comJinchun XingDepartment of Urology, The First Affiliated Hospital of Xiamen University, No. 55 Zhenhai Road, Xiamen 361003, People’s Republic of ChinaTel +86-138 0608 9889Email xmfhxjc@163.comPurpose: Clear cell renal cell carcinoma (ccRCC) has the highest rate of metastasis and invasion in RCC and is the third most common adult urinary malignancy. miRNA may serve a critical role in human cancer development and progression, has been confirmed to play a pivotal role in RCC cell invasion and migration. Since miR‑935 had been verified to be an oncogene or tumor suppressor in various cancers, the role of miR‑935 in RCC was unclear.Methods: Real-time quantitative polymerase chain reaction (qRT-PCR) was used to verify miR-935 expression. CCK-8 assay, wound healing assay and transwell assay were used to investigate the cell proliferation, migration and invasion of miR-935. Receiver operating characteristic (ROC) curve analysis was applied to discriminate different clinical classifications. Gain or loss of function approaches were used to investigate the cell proliferation, migration and invasion of miR-935 in vitro. Bioinformatics analysis and dual-luciferase reporter assay were used to identify the target of miR-935.Results: MiR-935 had a higher expression level in RCC cells and cancer tissues. MiR-935 mimics promoted cell proliferation, migration and invasion, and miR-935 inhibitor inhibited cell inhibit malignancy of cancer cells. Bioinformatics analysis and dual-luciferase reporter assay identified iron-responsive element-binding protein 2 (IREB2) as a direct target of miR-935. qRT-PCR showed IREB2 expression was downregulated in ccRCC cancer tissues and high IREB2 expression had a longer overall survival (OS) and disease-free survival (DFS). Silencing IREB2 could reverse the function of miR-935 inhibitor on cell proliferation and metastasis in renal cancer cells.Conclusion: The study indicated that miR-935 may act as an oncomiRNA and influenced migration and invasion progress of ccRCC by targeting IREB2. Oncogene miR-935 may be a molecular marker and uncover new strategies for ccRCC.Keywords: miR-935, clear cell renal cell carcinoma, IREB2, migration, invasion

Jiebing Yang,* Jiayuan Zhang,* Jiakai Xing, Zhiyuan Shi, Haobo Han, Quanshun LiKey Laboratory for Molecular Enzymology and Engineering of Ministry of Education, School of Life Sciences, Jilin University, Changchun 130012, People’s Republic of China*These authors contributed equally to this workBackground: The phenylboronic acid-functionalized polyamidoamine (PP) was employed as a gene carrier for Dz13 delivery, inducing an obvious anticancer response.Materials and methods: The Dz13 condensation ability of PP was evaluated through gel retardation assay. The cellular uptake mechanism of PP/Dz13 nanoparticles was studied using confocal laser scanning microscope and flow cytometer. The inhibition ability of cell proliferation, migration and invasion was investigated through MTT assay, flow cytometry, wound healing and Transwell migration assays, using hepatocarcinoma cell line HepG2 as a model. Finally, Western blotting analysis was used to detect the signaling pathway associated with the inhibition of cell apoptosis and migration induced by Dz13 delivery.Results: The carrier PP could efficiently condense Dz13 into stable nanoparticles at mass ratios of >1.5. The hydrodynamic diameter and zeta potential of PP/Dz13 nanoparticles were measured to be 204.77 nm and +22.00 mV at a mass ratio of 10.0, respectively. The nanoparticles could realize an efficient cellular uptake in sialic acid-dependent endocytosis manner. Moreover, the nanoparticles exhibited an obvious antiproliferation effect through the induction of cell apoptosis and cell cycle arrest due to the cleavage of c-Jun mRNA. Besides, the suppression of cell migration and invasion could be achieved after the PP/Dz13 transfection, attributing to the decreased expression level of MMP-2 and MMP-9.Conclusion: The PP provided a potential delivery system to achieve the tumor-targeting gene therapy.Keywords: phenylboronic acid, polyamidoamine, DNAzyme, gene therapy, antiproliferation effect, antimigration effect

Jing Xing,*,1,2 Xiquan Zhang,*,3 Zhe Wang,4 Huanqing Zhang,3 Peng Chen,1,2 Gaoxin Zhou,5 Chunlong Sun,6 Ning Gu,1,2 Min Ji1,21School of Biological Science and Medical Engineering, Southeast University, Nanjing 210096, People’s Republic of China; 2School of Biological Science and Medical Engineering and Collaborative Innovation Center of Suzhou Nano Science and Technology, Southeast University, Suzhou 215123, People’s Republic of China; 3Nanjing Institute of Pharmaceutical Research and Development, Chia-Tai Tianqing Pharmaceutical Group Co. Ltd, Nanjing 210023, People’s Republic of China; 4Emergency Department, The Second Affiliated Hospital of Nanjing Medical University, Nanjing 210029, People’s Republic of China; 5School of Biomedical Engineering, Shenzhen University, Shenzhen 518071, People’s Republic of China; 6College of Biological and Environmental Engineering, Binzhou University, Binzhou 256603, People’s Republic of China*These authors contributed equally to this workBackground: SN38 (7-ethyl-10-hydroxy camptothecin), as a potent metabolite of irinotecan, is highly efficacious in cancer treatment. However, the clinical utility of SN38 has been greatly limited due to its undesirable properties, such as poor solubility and low stability.Materials and methods: In order to overcome these weaknesses, moeixitecan, a lipophilic SN38 prodrug containing a SN-38, a trolox, a succinic acid linker, and a hexadecanol chain, was loaded into liposomal nanoparticles by ethanol injection method.Results: Experiments showed that the moeixitecan-loaded liposomal nanoparticles (MLP) with a diameter of 105.10±1.49 nm have a satisfactory drug loading rate (90.54±0.41%), high solubility and stability, and showed sustained release of SN38. Notably, MLP exhibited better antitumor activity against human colon adenocarcinoma cells than irinotecan, a FDA-approved drug for the treatment of advanced colorectal cancer. Furthermore, xenograft model results showed that MLP outperformed irinotecan in terms of pharmacokinetics, in vivo therapeutic efficacy and safety. Finally, we used molecular dynamic simulations to explore the association between the structure of MLP and the physical and functional properties of MLP, moeixitecan molecules in MLP folded themselves inside the hydrocarbon chain of the lipid bilayer, which led an increased acyl chain order of the lipid bilayer, and therefore enhanced the lactone ring stability protecting it from hydrolysis.Conclusion: Our MLP constructing strategy by liposome engineering technology may serve a promising universal approach for the effective and safe delivery of lipophilic prodrug.Keywords: SN38, lipophilic prodrug, liposomes, molecular dynamic simulations, cancer therapy

Jinyan Xing,1 Zhiyong Yuan,1 Yaqi Jie,2 Ying Liu,1 Mingxue Wang,1 Yunbo Sun11Department of Critical Care Medicine, the Affiliated Hospital of Qingdao University, Qingdao 266003, People’s Republic of China; 2School of Life Sciences, Qingdao University, Qingdao, 266071, People’s Republic of ChinaBackground: Delirium is associated with increased morbidity and mortality in critically ill patients. Research on risk factors for delirium allows clinicians to identify high-risk patients, which is the basis for early prevention and diagnosis. Besides the risk factors for delirium that are commonly studied, here we more focused on the less-studied therapeutic interventions for critically ill patients which are potentially modifiable.Materials and methods: A total of 320 non-comatose patients admitted to the ICU for more than 24 hrs during 9 months were eligible for the study. Delirium was screened once daily using the CAM-ICU. Demographics, admission clinical data, and daily interventions were collected.Results: Ninety-two patients (28.75%) experienced delirium at least once. Delirious patients were more likely to have longer duration of mechanical ventilation, ICU stay, and hospital stay. Most of the less-studied therapeutic interventions were linked to delirium in the univariate analysis, including gastric tube, artificial airway, deep intravenous catheter, arterial line, urinary catheter, use of vasoactive drugs, and sedative medication. After adjusting with age and ICU length of stay, mechanical ventilation (OR: 5.123; 95% CI: 2.501–10.494), Acute Physiology and Chronic Health Evaluation (APACHE) II score≥20 at admission (OR: 1.897; 95% CI: 1.045–3.441), and gastric tube (OR: 1.935, 95% CI: 1.012–3.698) were associated with increased risk of delirium in multivariate analysis.Conclusion: Delirium was associated with prolonged mechanical ventilation, ICU stay, and hospital stay. Multivariate risk factors were gastric tube, mechanical ventilation, and APACHE II score. Although being a preliminary study, this study suggests the necessity of earliest removal of tubes and catheters when no longer needed.Keywords: delirium, critical care, intensive care unit, risk factors, prevention

Abstract Background Valuation of the economic cost of antimicrobial resistance (AMR) is important for decision making and should be estimated accurately. Highly variable or erroneous estimates may alarm policy makers and hospital administrators to act, but they also create confusion as to what the most reliable estimates are and how these should be assessed. This study aimed to assess the quality of methods used in studies that quantify the costs of AMR and to determine the best available evidence of the incremental cost of these infections. Methods In this systematic review, we searched PubMed, Embase, Cinahl, Cochrane databases and grey literature sources published between January 2012 and October 2016. Articles reporting the additional burden of Enterococcus spp., Escherichia coli (E. coli), Klebsiella pneumoniae (K. pneumoniae), Pseudomonas aeruginosa (P. aeruginosa) and Staphylococcus aureus (S. aureus) resistant versus susceptible infections were sourced. The included studies were broadly classified as reporting oncosts from the healthcare/hospital/hospital charges perspective or societal perspective. Risk of bias was assessed based on three methodological components: (1) adjustment for length of stay prior to infection onset and consideration of time-dependent bias, (2) adjustment for comorbidities or severity of disease, and (3) adjustment for inappropriate antibiotic therapy. Results Of 1094 identified studies, we identified 12 peer-reviewed articles and two reports that quantified the economic burden of clinically important resistant infections. Two studies used multi-state modelling to account for the timing of infection minimising the risk of time dependent bias and these were considered to generate the best available cost estimates. Studies report an additional CHF 9473 per extended-spectrum beta-lactamases -resistant Enterobacteriaceae bloodstream infections (BSI); additional €3200 per third-generation cephalosporin resistant Enterobacteriaceae BSI; and additional €1600 per methicillin-resistant S. aureus (MRSA) BSI. The remaining studies either partially adjusted or did not consider the timing of infection in their analysis. Conclusions Implementation of AMR policy and decision-making should be guided only by reliable, unbiased estimates of effect size. Generating these estimates requires a thorough understanding of important biases and their impact on measured outcomes. This will ensure that researchers, clinicians, and other key decision makers concerned with increasing public health threat of AMR are accurately guided by the best available evidence.

Yan Yan,1,2 Pengchong Wang,2 Ruiying Li,3 Ying Sun,2 Rui Zhang,2 Chuanchuan Huo,2 Jianfeng Xing,2 Yalin Dong1 1Department of Pharmacy, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, Shaanxi, China; 2Department of Pharmaceutics, School of Pharmacy, Xi’an Jiaotong University, Xi’an, Shaanxi, China; 3Department of Clinical Medicine, College of Medicine, Xi’an Jiaotong University, Xi’an, Shaanxi, China Purpose: Budesonide (Bud) is a nonhalogenated glucocorticoid with high anti-inflammatory potency and low systemic side effects. However, the poor water solubility of Bud affects its dissolution and release behavior, thus influencing its anti-inflammatory effect. This study was aimed at synthesizing and evaluating novel conjugates of Bud, hoping to increase the anti-inflammatory activity of Bud by improving its water solubility.Materials and methods: Seven novel Bud conjugates (3a–3g) were designed and synthesized in this study. Besides, the equilibrium solubility, cell viability, in vitro and in vivo anti-inflammatory activity, and the hydrolysis behavior of the conjugates in different pH solutions, rat and human plasma, and rat lung homogenate were studied in detail.Results: As compared to Bud, the equilibrium solubility of 3a, 3c, and 3e was significantly increased; 3a, 3b, and 3c significantly inhibited the interleukin-6 production in lipopolysaccharide-induced A549 cells; 3a and 3e could significantly decrease the xylene-induced ear edema; and 3a and 3c were gradually and slowly hydrolyzed into Bud in the alveolar fluid and lung homogenate and broken down quickly in plasma.Conclusion: The amino acid ester compounds budesonide-21-glycine ester (3a) and budesonide-21-alanine ester (3c) were selected as potential conjugates of Bud. This study would provide a theoretical and an experimental basis for the in vivo process of glucocorticoids and the treatment of inflammatory diseases. Keywords: budesonide, glucocorticoid, anti-inflammatory effect, equilibrium solubility, hydrolysis behavior

Jie Xing,1 Li Min,1 Hao Zhang,2 Peng Li,1 Wei Li,1 Fujin Lv,1 Yongjun Wang,1 Zheng Zhang,1 Hengcun Li,1 Qingdong Guo,1 Siyi Wang,1 Yu Zhao,1 Junmin Wang,3 Xiaoyan Shi,4 Anxin Wang,5 Shengtao Zhu,1 Ming Ji,1 Yongdong Wu,1 Shutian Zhang1 On behalf of the NCECS Study Group 1Department of Gastroenterology, Beijing Friendship Hospital, Capital Medical University, National Clinical Research Center for Digestive Disease, Beijing Digestive Disease Center, Beijing Key Laboratory for Precancerous Lesion of Digestive Disease, Beijing 100050, People’s Republic of China; 2Department of Gastroenterology, Jizhong Energy Fengfeng Group Hospital, Handan, Hebei 056200, People’s Republic of China; 3Department of Gastroenterology, Handan Central Hospital, Handan, Hebei 056001, People’s Republic of China; 4Department of Pathology, Beijing Friendship Hospital, Capital Medical University, Beijing 100050, People’s Republic of China; 5Department of Epidemiology, Beijing Tiantan Hospital, Capital Medical University, Beijing 100029, People’s Republic of China Background: Endoscopy is the main approach used for esophageal squamous cell carcinoma (ESCC) screening, especially in high-risk areas. However, little consensus has been achieved in recent ESCC screening programs, and endoscopists have selected patients only by age and family history. Patients and methods: To generate a proper strategy for selecting an eligible population for endoscopic screening based on demographic factors, lifestyle, and eating habits, a total of 7,830 residents in an area with a high risk of ESCC were recruited for this study. All participants underwent endoscopic examinations that were conducted by experienced endoscopists. Risk factors for ESCC and other lesions were selected by univariate and multivariate logistic regressions. A nomogram for the prediction of ESCC and premalignant lesions was constructed, which included information on age, sex, occupation, labor intensity, income, and mining exposure. Receiver operating characteristic (ROC) curve analysis was performed to present the predictive accuracy of the nomograms. Results: The area under the curve (95% CI) was 0.749 (0.711–0.788) for this nomogram. By applying this nomogram, we could exclude 60% (4704/7830) of patients before endoscopy screening and detect all ESCC cases as well as most esophageal lesions in the remaining population. Conclusion: In conclusion, we provided a ready-to-use preclinical tool with the potential to select eligible people with high risk of ESCC for endoscopy screening. Keywords: nomogram, endoscopy screening, ESCC, population-based study

Pengfei Cao,1,2,* Jun Xing,1,* Yin Cao,3 Qi Cheng,1 Xiaojing Sun,1 Qi Kang,1 Libin Dai,1 Xianju Zhou,3 Zixiang Song1 1Psychological Centre for Adolescents and Children, The Affiliated 102nd Hospital of The Second Military Medical University of People’s Liberation Army of China, Shanghai, China; 2Department of Political Affairs, College of Politics, National Defense University of People’s Liberation Army of China, Beijing, China; 3Laboratory of Neurological Diseases, Department of Neurology, The Affiliated Changzhou No 2 People’s Hospital of Nanjing Medical University, Changzhou, China *These authors contributed equally to this work Objective: To explore the effect of repetitive transcranial magnetic stimulation (rTMS) combined with atomoxetine (ATX) in the treatment of attention-deficit hyperactivity disorder (ADHD). Methods: Sixty-four patients with newly diagnosed ADHD were enrolled from January 2016 to October 2017 from Psychological Centre for Adolescents and Children at 102th Hospital of People’s Liberation Army of China. These patients were randomly assigned to three groups according to treatment method: the rTMS group, the ATX group, and the rTMS+ ATX group. Before treatment and 6 weeks after treatment, clinical symptoms and executive functions of ADHD patients were evaluated with the Swanson, Nolan, and Pelham, Version IV (SNAP-IV) Questionnaire, continuous performance test, three subtests (arithmetic, digit span, and coding) of Wechsler Intelligence Scale for Children, as well as Iowa Gambling Tasks (IGT). The effects of treatment were compared among three groups. Results: After 6 weeks of treatment, the scores of all factors in the SNAP-IV questionnaire were lower than those before treatment in the three groups; the scores of three subtests of Wechsler Intelligence Scale for Children, continuous performance test, and IGT were also significantly higher than those before treatment. The rTMS+ ATX group had a better improvement in attention deficits and hyperactivity impulse on the SNAP-IV questionnaire compared with the other groups, and also had a higher efficacy on cold and hot executive functions such as arithmetic, forward numbers, coding, and IGT. In addition, the ATX group performed better than the rTMS group in coding and IGT. Conclusion: rTMS, ATX, and the combination therapy are effective in improving core symptoms and executive function in patients with ADHD. The combined treatment has significant therapeutic advantages over the single treatment groups. Compared with rTMS, the drug therapy has a better improvement in coding and IGT. Keywords: attention-deficit hyperactivity disorder, repetitive transcranial magnetic stimulation, atomoxetine, executive function

Ruijian Li,1–3,* Sumei Cui,1–3,* Youshun Xu,4 Junhui Xing,5 Li Xue,1–3 Yuguo Chen1–3 1Department of Emergency, Qilu Hospital, Shandong University, Jinan, China; 2Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Qilu Hospital, Shandong University, Jinan, China; 3Key Laboratory of Cardiovascular Remodeling & Function Research, Chinese Ministry of Education & Chinese Ministry of Public Health, Qilu Hospital, Shandong University, Jinan, China; 4Qilu Medical College of Shandong University, Jinan, China; 5Department of Cardiology, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China *These authors contributed equally to this work Background: The incidence of recurrent cardiovascular events from the progression of nontarget lesions (NTLs) is high for percutaneous coronary intervention-treated patients. However, the underlying mechanisms have not been thoroughly elucidated. Methods: In this study, ten atherosclerotic rabbits with multiple plaques in the upper and lower segments of abdominal aorta (group A) were randomly divided into two subgroups: group A1 underwent intravascular ultrasound examination and stent implantation in the lower segments of the abdominal aorta (n=5), whereas group A2 was without stenting (n=5). Group B was a control group without balloon injury. The serum levels of high-sensitivity CRP, interleukin-6 (IL-6), oxidized low-density lipoprotein, and CD36 were assessed via ELISA at five time points between the 10th and 18th weeks. The upper abdominal aorta was examined via the immunohistochemical stain and Western blotting of matrix metallopeptidase 9 (MMP-9), CD36, IL-6, and tumor necrosis factor α. Results: As a result, we found that stent implantation aggravated serum levels of CD36, oxidative stress, and inflammatory cytokines. Meanwhile, the upper abdominal arterial plaque burden significantly increased after stenting by intravascular ultrasound. Immunohistochemistry and Western blotting showed that the local NTLs’ matrix metallopeptidase 9, CD36, IL-6, and tumor necrosis factor α expressions in group A1 were significantly higher than those in groups A2 and B (P

Wen Xiao, Xuegang Wang, Tao Wang, Jinchun Xing Department of Urology, The First Affiliated Hospital of Xiamen University, Xiamen 361003, China Background and aim: Tripartite motif containing (TRIM) family protein has been involved in multiple pathogenesis of cancers. TRIM2 is a member of the family, and its role in clear cell renal cell carcinoma (ccRCC) remains to be unclarifid. Here, we showed the clinical value and biological role of TRIM2 in ccRCC. Methods: ROC curves analyzed the clinicopathological parameters, Kaplan-Meier survival analysis determined the correlation of OS and DFS time, multivariate analysis demonstrated the prognostic indicator in overall survival and disease-free survival of ccRCC with TRIM2 expression in The Cancer Genome Atlas Kidney Clear Cell Carcinoma (TCGA-KIRC) database. Western blotting and immunohistochemistry were used to check the level of TRIM2 expression. Gain-of-function assay by exogenous overexpression of TRIM2 studied the biological role of TRIM2 in renal cell carcinoma cells. Results: TRIM2 expression was associated with various clinicopathologicalfactors and lower TRIM2 expression was interrelated to a poor prognosis. The levels of TRIM2 expression were also scanty in ccRCC tissues and renal cancer cell lines than in normal control. The biological role of TRIM2 in ccRCC was identifid by bioinformatics analysis and functional analysis. Exogenous overexpression of TRIM2 with the gain-of-function assay in renal cell carcinoma cells showed that the cell proliferation, migration, and invasion were signifiantly suppressed. Conclusion: These results showed that TRIM2 acted as an antitumor gene and a specifi prognostic indicator for patients with ccRCC, which indicated that positive modulation of TRIM2 might be a novel treatment strategy for ccRCC. Keywords: TRIM2, ccRCC, tumor suppressor, prognostic indicator

Yue Liu,1,2 Yanlan Wang,1,2 Jieyu Xing,1,2 Yumei Li,1,2 Jiayu Liu,1,2 Zhong Wang1,2 1School of Pharmaceutical Sciences, 2Center for Cellular and Structural Biology, Sun Yat-Sen University, Guangzhou, People’s Republic of China Introduction: Interleukin-15 (IL-15) is an immunomodulatory cytokine. It can activate and expand cytotoxic CD8 T lymphocytes and natural killer cells, leading to potent antitumor effects. Various forms of IL-15 are now in different stages of development for cancer immunotherapy. One of the major issues with IL-15 or IL15–IL15Rα fusion is high toxicity due to systemic activation of immune cells. Materials and methods: In this study, we engineered a nanobody–cytokine fusion molecule, anti-CEA-IL15, in which an anti-CEA nanobody was linked to an IL15Rα–IL15 fusion. The nanobody–cytokine fusion exhibited multiple mechanisms to kill tumor cells, including promoting immune cell proliferation and directing antibody-dependent cytotoxicity against CEA-positive tumor cells. Results: In xenograft models, anti-CEA-IL15 was localized in the tumor microenvironment and exhibited more potent antitumor activities than non-targeting IL-15, supporting potential application of this multifunctional fusion molecule in tumor immunotherapy. Conclusion: We generated and validated a tumortargeting fusion protein, anti-CEA-IL15, which has potent cytokine activity to activate and mobilize the immune system to fight cancer cells. Such strategies may also be applied to other cytokines and tumor-targeting molecules to increase antitumor efficacy. Keywords: immunotherapy, IL-15, nanobody, CEA, antibody–cytokine fusion

Haitao Pan,1,2 Jiayu Liu,1,2 Wentong Deng,1,2 Jieyu Xing,1,2 Qing Li,1,2 Zhong Wang1,2 1School of Pharmaceutical Sciences, 2Centre for Cellular & Structural Biology, Sun Yat-Sen University, Guangzhou, People’s Republic of China Introduction: Bispecific antibodies that engage immune cells to kill cancer cells are actively pursued in cancer immunotherapy. Different types of bispecific antibodies, including single-chain fragments, Fab fragments, nanobodies, and immunoglobulin Gs (IgGs), have been studied. However, the low molecular weight of bispecific antibodies with single-chain or Fab fragments generally leads to their rapid clearance in vivo, which limits the therapeutic potential of these bispecific antibodies. Materials and methods: In this study, we used a site-specific PEGylation strategy to modify the bispecific single-domain antibody-linked Fab (S-Fab), which was designed by linking an anticarcinoembryonic antigen (anti-CEA) nanobody with an anti-CD3 Fab. Results: The half-life (t1/2) of PEGylated S-Fab (polyethylene glycol-S-Fab) was increased 12-fold in vivo with a slightly decreased tumor cell cytotoxicity in vitro as well as more potent tumor growth inhibition in vivo compared to S-Fab. Conclusion: This study demonstrated that PEGylation is an effective approach to enhance the antitumor efficacy of bispecific antibodies. Keywords: Fab, nanobody, PEGylation, bispecific antibody, half-life, CEA

Seuli Bose-Brill,1 Jinming Xing,2 Debra J Barnette,1,2 Christopher Hanks1 1Internal Medicine and Pediatrics at Grandview, Wexner Medical Center, 2Department of Practice and Science, College of Pharmacy, The Ohio State University, Columbus, OH, USA Abstract: Adolescents with autism have higher rates of anxiety than the general adolescent population. They often struggle to express psychological symptoms verbally where their symptoms may manifest as withdrawal and agitation. Adolescent patients with autism have higher rates of polypharmacy and high-risk psychiatric medication use (eg, atypical antipsychotics) than other patients with psychiatric illness. Primary care pediatricians are at the front lines of psychiatric management for patients with autism. Yet, they have inadequate access to pediatric psychiatry for complex medication management. Pharmacogenomic testing can provide personalized drug metabolism profiles for a majority of psychotropic medications. Primary care based pharmacogenomic testing for adolescents with autism on one or more psychiatric medications may help individualize and optimize complex medication regimens, while promoting drug safety. Keywords: autism, pharmacogenomic, pharmacogenetic, pharmacotherapy, anxiety, depression, psychiatry, pediatrics

Liu F, Chen Y, Chen B, Liu C, Xing J. Cancer Manag Res. 2019;11:10891–10900. At the authors request, the Editor-in-Chief and Publisher of Cancer Management and Research wish to retract the published article. Following a review of their article the authors found some errors had been made in Figure 4E, specifically images in panels Migration miR-935 inhibitor +/si-IREB2 + and Invasion miR-935 inhibitor +/si-IREB2 +. After carefully going through the raw data for their study the authors were unable to locate the original images for Figure 4E. The authors were also unable to locate the original images for the western blots shown in the article. Both the editor and authors determined the findings of this study could no longer be supported and agreed for the article to be retracted. The authors wish to apologise for this error. Our decision-making was informed by our policy on publishing ethics and integrity and the COPE guidelines on retraction. The retracted article will remain online to maintain the scholarly record, but it will be digitally watermarked on each page as “Retracted”. This retraction relates to this paper

Sisi Zheng, Li Luo, Ruonan Bo, Zhenguang Liu, Jie Xing, Yale Niu, Yuanliang Hu, Jiaguo Liu, Deyun Wang Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, People’s Republic of China Abstract: This study aimed to optimize the preparation conditions of pachyman (PHY)-loaded poly(D,L-lactic acid) (PLA) (PHYP) nanospheres by response surface methodology, explore their characteristics, and assess their effects on splenic lymphocytes. Double emulsion solvent evaporation was used to synthesize PHYP nanospheres, and the optimal preparation conditions were identified as a concentration of poloxamer 188 (F68) (w/v) of 0.33%, a concentration of PLA of 30 mg/mL, and a ratio of PLA to drug (w/w) of 10.25:1 required to reach the highest encapsulation efficiency, which was calculated to be 59.10%. PHYP had a spherical shape with a smooth surface and uniform size and an evident effect of sustained release and relative stability. Splenic lymphocytes are crucial and multifunctional cells in the immune system, and their immunological properties could be enhanced significantly by PHYP treatment. This study confirmed that PHY encapsulated in PLA nanospheres had comparatively steady properties and exerted obvious immune enhancement. Keywords: PHYP, optimal preparation condition, RSM, in vitro study

Zhenguang Liu, Li Luo, Sisi Zheng, Yale Niu, Ruonan Bo, Yee Huang, Jie Xing, Zhihua Li, Deyun Wang Institute of Traditional Chinese Veterinary Medicine, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, People’s Republic of China Abstract: Cubosomes have been explored as drug and antigen carriers in the past few years. A few reports have described that cubosomes can enhance the ability of immunostimulants to generate strong immune responses. Polysaccharide (PS), an immunostimulant, has been reported to be a promising adjuvant for vaccines. Herein, we incorporated PS into cubosomes to generate PS–cubosome (Cub-PS) nanoparticles, and Cub-PS was characterized by small-angle X-ray scattering scattering and cryo-field emission scanning electron microscopy. The immunological activity of Cub-PS was compared with that of Cub and PS. The results demonstrated that Cub-PS elicited more potent immune responses than Cub or PS alone. The enhanced immune responses might be attributed to the promotion of antigen transport into draining lymph nodes and efficient dendritic cell activation and memory T-helper cell differentiation in draining lymph nodes. Overall, these findings indicate that cubosomes have the potential to enhance the ability of immunostimulants to generate an immune response. Keywords: cubosomes, polysaccharides, cryo-FESEM, lymph nodes, dendritic cells, memory T-helper cells

Previous studies have linked GJB2 gene and mitochondrial DNA (mtDNA) mutations to nonsyndromic hearing impairment (NSHI), but no study in China has yet investigated these mutations across all age groups. To fill the gap, this study ascertained 263 patients with NSHI between ages 2 months and 60 years and analyzed the presence of GJB2 gene and mtDNA A1555G/C1494T mutations by polymerase chain reaction (PCR) and DNA sequencing. A total of 20 types of mutations were detected for the GJB2 gene. The GJB2 gene and mtDNA A1555G/C1494T mutations were detected in 18.63 and 11.41% cases, respectively. At the first hospital visit, GJB2 gene mutations were detected in 5.97% of adult patients (>18 years) and 22.96% pediatric patients (

Rui Li,1 Jing Xing,1 Xaojing Mu,2 Hui Wang,1 Lei Zhang,3 Yu Zhao,1 Yu Zhang1 1Emergency Department, First Affiliated Hospital of Dalian Medical University, 2Dalian Hospital of Traditional Chinese Medicine, Dalian, People’s Republic of China; 3Intensive Care Unit, Tianjin First Central Hospital, People’s Republic of China Abstract: Sulodexide is a heterogeneous group of sulfated glycosaminoglycans (GAGs) that is mainly composed of low-molecular-weight heparin. Clinical studies have demonstrated that sulodexide is capable of reducing urinary albumin excretion rates in patients with type 1 and type 2 diabetes, suggesting that sulodexide has renal protection. However, this efficacy remains inconclusive. In this article, we used meta-analysis to summarize the clinical results of all prospective clinical studies in order to determine the clinical efficacy and safety of sulodexide in diabetic patients with nephropathy. Overall, sulodexide therapy was associated with a significant reduction in urinary protein excretion. In the sulodexide group, 220 (17.7%) achieved at least a 50% decrease in albumin excretion rate compared with only 141 (11.5%) in the placebo. The odds ratio comparing proportions of patients with therapeutic success between the sulodexide and placebo groups was 3.28 (95% confidence interval, 1.34–8.06; P=0.01). These data suggest a renoprotective benefit of sulodexide in patients with diabetes and micro- and macroalbuminuria, which will provide important information for clinical use of this drug as a potential modality for diabetic nephropathy, specifically, the prevention of end-stage renal disease that is often caused by diabetes. Keywords: sulodexide, diabetic nephropathy, meta-analysis, odds ratio

Yanwei Teng,1,2,* Min Bai,3,* Ying Sun,2 Qi Wang,1,2 Fan Li,3 Jinfang Xing,3 Lianfang Du,3 Tao Gong,1 Yourong Duan2 1Key Laboratory of Drug Targeting and Novel Drug Delivery Systems, Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, People’s Republic of China; 3Department of Ultrasound, Shanghai First People’s Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, People’s Republic of China *These authors contributed equally to this work Abstract: The gene knockdown activity of small interfering RNA (siRNA) has led to their use as potential therapeutics for a variety of diseases. However, successful gene therapy requires safe and efficient delivery systems. In this study, we choose mPEG-PLGA-PLL nanoparticles (PEAL NPs) with ultrasound targeted microbubble destruction (UTMD) to efficiently deliver siRNA into cells. An emulsification-solvent evaporation method was used to prepare siRNA-loaded PEAL NPs. The NPs possessed an average size of 132.6±10.3 nm (n=5), with a uniform spherical shape, and had an encapsulation efficiency (EE) of more than 98%. As demonstrated by MTT assay, neither PEAL NPs nor siRNA-loaded PEAL NPs showed cytotoxicity even at high concentrations. The results of cellular uptake showed, with the assistance of UTMD, the siRNA-loaded PEAL NPs can be effectively internalized and can subsequently release siRNA in cells. Taken together, PEAL NPs with UTMD may be highly promising for siRNA delivery, making it possible to fully exploit the potential of siRNA-based therapeutics. Keywords: gene delivery, mPEG-PLGA-PLL, UTMD, emulsification-solvent evaporation method, orthogonal design