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Hongqiang Wu,1–3,* Jian Ding,1–3,* Lei Wang,3 Jinti Lin,1–3 Shihen Li,1–3 Guangheng Xiang,1–3 Liangfu Jiang,1–3 Huazi Xu,1–3 Weiyang Gao,1–3 Kailiang Zhou1–3 1Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325027, China; 2Zhejiang Provincial Key Laboratory of Orthopaedics, Wenzhou 325027, China; 3The Second Clinical Medical College of Wenzhou Medical University, Wenzhou 325027, China *These authors contributed equally to this work Background: Random skin flaps are commonly applied during plastic surgery, but distal flap necrosis limits their clinical applications. Valproic acid (VPA), a histone deacetylase inhibitor and a traditional antiepileptic agent, may promote flap survival.Materials and methods: Sprague–Dawley rats were randomly divided into VPA-treated and control groups. All rats received VPA or saline by intraperitoneal injections once daily for 7 days after the modified McFarlane flap model was established. On postoperative day 7, flap survival, laser Doppler blood flow, and water content were examined for flap viability, hematoxylin and eosin staining (H&E), immunohistochemistry (IHC), and Western blot analysis, and the status of angiogenesis, apoptosis, and oxidative stress were detected in the ischemic flaps.Results: VPA increased the survival area, blood flow, and number of microvessels in skin flaps on postoperative day 7 and reduced edema. VPA promoted angiogenesis by enhancing vascular endothelial growth factor (VEGF) mRNA transcription and upregulating VEGF and cadherin 5 expression, inhibited apoptosis via reduction of caspase 3 cleavage, and relieved oxidative stress by increasing superoxide dismutase (SOD) and glutathione (GSH) levels and reducing the malondialdehyde (MDA) level.Conclusion: VPA promoted random skin flap survival by enhancing angiogenesis and inhibiting oxidative stress and apoptosis. Keywords: valproic acid, random skin flap, angiogenesis, oxidative stress, apoptosis

Hui Wu,1 Kexin Zhou,1 Peiyao Xu,1 Jiayu Xue,1 Xin Xu,2 Li Liu1 1Department of Social Medicine, School of Public Health, China Medical University, Shenyang, Liaoning, China; 2Department of Clinical Epidemiology, Shengjing Hospital of China Medical University, Shenyang, Liaoning, China Purpose: Cortisol in fingernails could retrospectively reflect cumulative stress over a long period. However, the association between fingernail cortisol and perceived stress needs to be validated. This exploratory study aimed to investigate the associations of perceived stress with the present and subsequent cortisol levels in fingernails of the subjective stress measurement among medical students. Methods: Students were recruited from a medical university in Shenyang, China. The final sample consisted of 51 students (16 men, 35 women). On the Day 30 of our data and fingernail collection procedure, the 10-item Perceived Stress Scale was used to measure perceived stress. Fingernail samples were collected twice, on Days 15 (denoted as FD15) and 45 (denoted as FD45) of the procedure, and participants were asked to grow fingernails for 15 days in each collection. Cortisol was determined by an enzyme immunoassay method using the ELISA kit. Multiple linear regression was performed to examine the association between perceived stress and cortisol level. The Bonferroni correction was made for multiple comparisons. Results: The level of cortisol was 5.65 pg/mg (SD =1.88) for FD15 and 5.41 pg/mg (SD =1.63) for FD45. Perceived stress was not associated with the cortisol level of FD15 (β=−0.014, P=0.924), but it was significantly and positively associated with the cortisol level of FD45 (β=0.436, P=0.003), which remained significant after Bonferroni correction. The associations between fingernail cortisol and demographic variables (gender, age, BMI, and physical activity) were not significant. Conclusion: This study was the first to investigate fingernail cortisol in China. Perceived stress was positively associated with the subsequent cortisol levels in fingernails, but not the present. The findings suggested that fingernail cortisol could indicate stress exposure in the past. Furthermore, a simple and easy self-reported measure could reflect cumulative stress as measured by fingernail cortisol. Keywords: cortisol, fingernail, perceived stress, chronic stress, China

Jiaxing Huang,1,2,* Weiting Liao,1,2,* Jing Zhou,1,2 Pengfei Zhang,1,2 Feng Wen,1,2 Xinyuan Wang,1,2 Mengxi Zhang,1,2 Kexun Zhou,1,2 Qiuji Wu,1,2 Qiu Li1,2 1Department of Medical Oncology, Cancer Center, West China Hospital, Sichuan University, Chengdu 610041, China; 2West China Biomedical Big Data Center, Sichuan University, Chengdu 610041, China *These authors contributed equally to this work Background: The effectiveness of gemcitabine plus capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer has been evaluated in the ESPAC-4 trial. We aimed to assess the cost-effectiveness of these adjuvant regimens on resected pancreatic cancer. Methods: A Markov model was established to simulate the disease process of resected pancreatic cancer (relapse-free survival, progressive disease, and death). The efficacy and toxicity profiles were collected from the ESPAC-4 trial. Transition probabilities were calculated based on survival in each group. Cost data were calculated from the perspective of the Chinese healthcare payer. The primary endpoint in the analysis was the incremental cost-effectiveness ratio (ICER), and model uncertainties were explored by one-way sensitivity analysis and probabilistic sensitivity analysis. Results: Our results demonstrated that gemcitabine monotherapy cost $36,028.45 and yielded a survival of 1.02 quality-adjusted life year (QALY), while gemcitabine plus capecitabine cost $46,095.05 and yielded a survival of 1.23 QALY. Therefore, the incremental cost-effectiveness ratio of gemcitabine plus capecitabine vs gemcitabine monotherapy was $45,191.23 which surpassed the willingness-to-pay threshold of $29,291.42 per QALY in China. Conclusion: The gemcitabine monotherapy regimen is more cost-effective compared with gemcitabine plus capecitabine regimen for the patients with postoperative pancreatic cancer from the Chinese societal perspective. Keywords: cost-effectiveness, Markov model, gemcitabine, capecitabine, resected pancreatic cancer

Renjin Lin,1,2,* Jinti Lin,1,2,* Shihen Li,1,2 Jian Ding,1,2 Hongqiang Wu,1,2 Guangheng Xiang,1,2 Shi Li,1,2 Yijia Huang,2 Dingsheng Lin,1,2 Weiyang Gao,1,2 Jianzhong Kong,1,2 Huazi Xu,1,2 Kailiang Zhou1,2 1Department of Orthopaedics, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou 325027, China; 2The Second Clinical Medical College of Wenzhou Medical University, Wenzhou 325027, China *These authors contributed equally to this work Background: Random skin flaps are routinely placed during plastic and reconstructive surgery, but the distal areas often develop ischemia and necrosis. Baicalein, a major flavonoid extracted from the traditional Chinese herbal medicine huangqin, Scutellaria baicalensis Georgi, may improve flap viability. Materials and methods: Rats were randomly divided into baicalein and control groups and they underwent placement of modified McFarlane flaps after intraperitoneal administration of baicalein or vehicle. Flap survival and water content were measured 7 days later, as were angiogenesis, apoptosis, and oxidative stress in ischemic flaps. Results: Baicalein promoted flap survival, reduced edema, increased mean vessel density, and enhanced vascular endothelial growth factor production at both the translational and transcriptional levels. Baicalein reduced caspase 3 cleavage, increased superoxidase dismutase and glutathione levels, and decreased the malondialdehyde level. Conclusion: Baicalein promoted flap viability by stimulating angiogenesis and inhibiting apoptosis and oxidation. Keywords: baicalein, random skin flap, angiogenesis, apoptosis, oxidation

Zhenhua Chen,* Mengen Zhao,* Jie Zhang, Kang Zhou, Xiuli Ren, Xifan Mei Jinzhou Medical University, Jinzhou, 121001, People’s Republic of China *These authors contributed equally to this work Introduction: Treatment of infection within bone is difficult, and conventional surgical treatment brings intense pain to the patients physically and mentally. There is an urgent need to develop injectable nano- and/or micro-medicine for minimally invasive treatment of osteomyelitis. Methods: In this paper, amino acid (L-lysine [Lys]) was mineralized into yolk-shell structured CaCO3 microspheres (MSs). The morphologies of the obtained MSs were investigated by scanning electron microscopy and transmission electron microscopy. The composition of CaCO3 MSs was identified by using Fourier transform infrared spectroscopy. The as-prepared CaCO3 MSs were examined with power X-ray diffraction analysis to obtain the crystallographic structure of the MSs. Results: The as prepared Lys encapsulated CaCO3 MSs (Lys@CaCO3 MSs) were used as micro-drug to improve acidic environment of osteomyelitis caused by bacterial infection and promote osteoblast proliferation under oxidative stress. These pH responsive Lys@CaCO3 MSs have a drug loading efficiency of 89.8 wt % and drug loading content (DLC) of 22.3 wt %. Conclusion: Our results demonstrated that Lys@CaCO3 MSs can effectively kill Staphylococcus aureus and promote proliferation and differentiation of osteoblasts under stimulation of H2O2 at pH = 5.5. Keywords: osteomyelitis, oxidative stress, L-Lysine, micro-medicine, delivery vehicle

Wei Yu,1,2,* Qixia Luo,1,* Qingyi Shi,1 Chen Huang,1 Xiao Yu,1 Tianshui Niu,1 Kai Zhou,1 Jiajie Zhang,2 Yonghong Xiao1 1State Key Laboratory for Diagnosis and Treatment of Infectious Disease, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, People’s Republic of China; 2Department of Infectious Diseases, Zhejiang Provincial People’s Hospital, People’s Hospital of Hangzhou Medical College, Hangzhou, People’s Republic of China *These authors contributed equally to this work Objectives: Colistin is still a “last-resort” antibiotic used to manage human infections due to multidrug-resistant (MDR) Klebsiella pneumoniae. However, colistin-resistant K. pneumoniae (CR-Kp) isolates emerged a decade ago and had a worldwide distribution. The purpose of this study was to evaluate the genetic data of CR-Kp and identify the antibacterial activity of fosfomycin (FM) alone and in combination with amikacin (AMK) or colistin (COL) against CR-Kp in vitro. Methods: Three clinical CR-Kp isolates from three patients were collected. Whole-genome sequencing and bioinformatics analysis were performed. The Pharmacokinetics Auto Simulation System 400, by simulating human pharmacokinetics in vitro, was employed to simulate FM, AMK, and COL alone and in combination. Different pharmacodynamic parameters were calculated for determining the antimicrobial effect. Results: Whole-genome sequencing revealed that none of the three isolates contain mcr gene and that no insertion was found in pmrAB, phoPQ, or mgrB genes. We found the antibacterial activity of AMK alone was more efficient than FM or COL against CR-Kp. The area between the control growth and antibacterial killing curves of FM (8 g every 8 hours) combined with AMK (15 mg/kg once daily) was higher than 170 LogCFU/mL·h–1. In addition, the area between the control growth and antibacterial killing curves of FM (8 g every 8 hours) combined with COL (75,000 IU/kg every12 hours) was higher than that of monotherapies (>100 LogCFU/mL·h–1 vs

Shuangjiang Li,1,* Zhiqiang Wang,2,* Kun Zhou,1,* Yan Wang,1 Yanming Wu,1 Pengfei Li,1 Guowei Che1 1Department of Thoracic Surgery, West China Hospital, Sichuan University, Chengdu, 2Department of Thoracic Surgery, Chongqing University Cancer Hospital, Chongqing Cancer Institute, Chongqing Cancer Hospital, Chongqing University, Chongqing China *These authors contributed equally to this work Background: To evaluate the clinical significance of degree of pulmonary fissure completeness (PFC) on major in-hospital outcomes following video-assisted thoracoscopic (VATS) lobectomy for non-small-cell lung cancer (NSCLC). Materials and methods: We carried out a single-center retrospective analysis on the prospectively maintained database at our unit between August 2014 and October 2015. Patients were divided into two groups based on their fissure sum average (FSA). Patients with FSA >1 (1< FSA ≤3) were considered to have incomplete pulmonary fissures (group A), while patients with FSA of 0–1 were considered to have complete pulmonary fissures (group B). Demographic differences in perioperative characteristics and surgical outcomes between these two groups were initially assessed. Then, a multivariate logistic-regression analysis was further conducted to identify the independent predictors for major in-hospital outcomes. Results: A total of 563 patients undergoing VATS lobectomy for NSCLC were enrolled. There were 190 patients in group A and 373 patients in group B. The overall morbidity and mortality rates of our cohort were 30.6% and 0.5%, respectively. Group A patients had a significantly higher overall morbidity rate than group B patients (42.1% vs 24.7%, P

Xingxing Shi,* Kai Zhou,* Fei Huang,* Juan Zhang, Chen Wang Department of Prosthodontics, Jiangsu Key Laboratory of Oral Diseases, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, China *These authors contributed equally to this work Background: As a potentially bioactive material, the widespread application of nanosized hydroxyapatite (nano-HAP) in the field of bone regeneration has increased the risk of human exposure. However, our understanding of the interaction between nano-HAP and stem cells implicated in bone repair remains incomplete. Methods: Here, we characterized the adhesion and cellular internalization of HAP nanoparticles (HANPs) with different sizes (20 nm np20 and 80 nm np80) and highlighted the involved pathway in their uptake using human umbilical cord Wharton’s jelly-derived mesenchymal stem cells (hWJ-MSCs). In addition, the effects of HANPs on cell viability, apoptosis response, osteogenic differentiation, and underlying related mechanisms were explored. Results: It was shown that both types of HANPs readily adhered to the cellular membrane and were transported into the cells compared to micro-sized HAP particles (m-HAP; 12 µm). Interestingly, the endocytic routes of np20 and np80 differed, although they exhibited similar kinetics of adhesion and uptake. Our study revealed involvement of clathrin- and caveolin-mediated endocytosis as well as macropinocytosis in the np20 uptake. However, for np80, clathrin-mediated endocytosis and some as-yet-unidentified important uptake routes play central roles in their internalization. HANPs displayed a higher preference to accumulate in the cytoplasm compared to m-HAP, and HANPs were not detected in the nucleolus. Exposure to np20 for 24 h caused a decrease in cell viability, while cells completely recovered with an exposure time of 72 h. Furthermore, HANPs did not influence apoptosis and necrosis of hWJ-MSCs. Strikingly, HANPs enhanced mRNA levels of osteoblast-related genes and stimulated calcium mineral deposition, and this directly correlated with the activation in c-Jun N-terminal kinases and p38 pathways. Conclusion: Our data provide additional insight about the interactions of HANPs with MSCs and suggest their application potential in hard tissue regeneration. Keywords: HANPs, hWJ-MSCs, internalization, osteogenic differentiation, JNK, p38

Here we are trying to answer the question why one of the smallest genome Sporobolomyces roseus has one of the most introns of all fungal genomes in the context of fungal intron evolution. In this study we used a statistical comparative genomics approach toward intron number evolution among 16 fungal genomes.

Aolin Ren,1,* Na Zhang,1,* He Zhu,1 Kang Zhou,1 Yuan Cao,1 Jindong Liu1,2 1Department of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China; 2Jiangsu Province Key Laboratory of Anesthesiology, Xuzhou Medical University, Xuzhou, Jiangsu, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jindong LiuDepartment of Anesthesiology, Affiliated Hospital of Xuzhou Medical University, Huaihai West Road #99, Xuzhou, Jiangsu, 221000, People’s Republic of ChinaEmail liujindong1818@163.com View the original paper by Dr Ren and colleagues This is in response to the Letter to the Editor

OBJECTIVE: Osteoporosis (OP) is closely associated with gut microbiota (GM), yet the nature of their causal relationship remains elusive. Therefore, this study aims to reverse causality between GM and OP by using population cohorts and two-sample MR (TSMR) analysis. MATERIALS AND METHODS: In this study, we conducted an extensive genome-wide association study (GWAS) using publicly accessible summary statistics data for GM and OP. Employing rigorous criteria (p < 1*e-5), we identified independent genetic loci that exhibited significant associations with GM relative abundances as instrumental variables (IVs). A causal evaluation was primarily carried out using the inverse variance- weighted (IVW) method, supplemented by additional analyses such as MR-Egger, weighted median, simple mode, and weighted mode. RESULTS: We unveiled that increased abundances of the family Pasteurellaceae, order Pasteurellales, and genus Ruminococcaceae UCG004 were linked to an increased risk of OP. Conversely, the family Oxalobacteraceae, unknown family id.1000006161, genus Lachnospiraceae NK4A136 group, unknown genus id.1000006162, and order NB1n were associated with a reduced risk of OP. To ensure the reliability of our findings, we conducted quality assessments through Cochrane's Q test and a leave-one-out analysis. Furthermore, the stability and consistency of the results were con- firmed by the MR-Egger intercept test, Mendelian randomization pleiotropy residual sum and outlier (MR-PRESSO) global test, and sensitivity analysis (p > 0.05). Our study reveals the causal relationships between 211 GM taxa and OP, pinpointing specific GM taxa associated with the risk of OP. This research sheds light on the genetic mechanisms that underlie GM-mediated OP and opens up promising avenues for identifying valuable biomarkers and potential therapeutic targets in future OP research. CONCLUSIONS: This study establishes a substantial GM-OP link with specific taxa being identified, offering biomarkers for early detection, tailored interventions, and improved patient education. These findings enhance OP diagnosis, prevention, and treatment, promising more effective, individualized care and inspiring future research. [ABSTRACT FROM AUTHOR]

Shuangjiang Li,1 Kun Zhou,1 Guowei Che,1 Mei Yang,1 Jianhua Su,2 Cheng Shen,1 Pengming Yu2 1Department of Thoracic Surgery, 2Department of Rehabilitation, Rehabilitation Medicine Center, West China Hospital, Sichuan University, Chengdu, China Background: Enhanced recovery after surgery (ERAS) program is an effective evidence-based multidisciplinary protocol of perioperative care, but its roles in thoracic surgery remain unclear. This systematic review of randomized controlled trials (RCTs) aims to investigate the efficacy and safety of the ERAS programs for lung cancer surgery. Materials and methods: We searched the PubMed and EMBASE databases to identify the RCTs that implemented an ERAS program encompassing more than four care elements within at least two phases of perioperative care in lung cancer surgery. The heterogeneity levels between studies were estimated by the Cochrane Collaborations. A qualitative review was performed if considerable heterogeneity was revealed. Relative risk (RR) and weighted mean difference served as the summarized statistics for the meta-analyses. Additional analyses were also performed to perceive potential bias risks. Results: A total of seven RCTs enrolling 486 patients were included. The meta-analysis indicated that the ERAS group patients had significantly lower morbidity rates (RR=0.64; p

Xingxing Shi,* Kai Zhou,* Fei Huang, Chen Wang Department of Prosthodontics, Jiangsu Key Laboratory of Oral Diseases, Affiliated Hospital of Stomatology, Nanjing Medical University, Nanjing, People’s Republic of China *These authors contributed equally to this work Abstract: Nano-hydroxyapatite (nano-HAP) has been proposed as a better candidate for bone tissue engineering; however, the interactions of nano-HAP with endothelial cells are currently unclear. In this study, HAP nanoparticles (HANPs; 20 nm np20 and 80 nm np80) and micro-sized HAP particles (m-HAP; 12 µm) were employed to explore and characterize cellular internalization, subcellular distribution, effects of HANPs on endothelial cell function and underlying mechanisms using human umbilical vein endothelial cells (HUVECs) as an in vitro model. It was found that HANPs were able to accumulate in the cytoplasm, and both adhesion and uptake of the HANPs followed a function of time; compared to np80, more np20 had been uptaken at the end of the observation period. HANPs were mainly uptaken via clathrin- and caveolin-mediated endocytosis, while macropinocytosis was the main pathway for m-HAP uptake. Unexpectedly, exposure to HANPs suppressed the angiogenic ability of HUVECs in terms of cell viability, cell cycle, apoptosis response, migration and capillary-like tube formation. Strikingly, HANPs reduced the synthesis of nitric oxide (NO) in HUVECs, which was associated with the inhibition of phosphatidylinositol 3-kinase (PI3K) and phosphorylation of eNOS. These findings provide additional insights into specific biological responses as HANPs interface with endothelial cells. Keywords: HANPs, HUVECs, internalization, angiogenesis, PI3K/Akt

Ji-Hui Zhao,1,* Qi-Bo Zhang,1,* Bao Liu,2 Xiang-Hua Piao,1 Yu-Lu Yan,1 Xiao-Ge Hu,1 Kuan Zhou,1 Yong-Tai Zhang,1 Nian-Ping Feng1 1School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, People’s Republic of China; 2Anethesiology Department, Augusta University, Augusta, GA, USA *These authors contributed equally to this work Purpose: To enhance the immunogenicity of the model subunit vaccine, ovalbumin (OVA) was combined with platycodin (PD), a saponin adjuvant. To reduce the toxicity of PD, OVA, and adjuvant were loaded together into liposomes before being incorporated into a dissolving microneedle array.Methods: OVA- and PD-loaded liposomes (OVA-PD-Lipos) were prepared using the film dispersion method. Their uptake behavior, toxicity to mouse bone marrow dendritic cells (BMDCs), and hemolytic activity to rabbit red blood cells (RBCs) were evaluated. The OVA-PD-Lipos were incorporated into a dissolving microneedle array. The chemical stability of OVA and the physical stability of OVA-PD-Lipos in microneedle arrays were investigated. The immune response of Institute of Cancer Research mice and potential skin irritation reaction of rabbits to OVA-PD-Lipos-MNs were evaluated.Results: The uptake of OVA by mouse BMDCs was greatly enhanced when OVA was prepared as OVA-PD-Lipos, and in this form, the toxicity of PD was dramatically reduced. OVA was chemically stable as OVA-PD-Lipos, when OVA-PD-Lipos was incorporated into a dissolving microneedle array. Institute of Cancer Research mice treated with OVA-PD-Lipos-MNs showed a significantly enhanced immune response. PD combined with OVA elicited a balanced Th1 and Th2 humoral immune response in mice, with minimal irritation in rabbit skin.Conclusion: The dissolving microneedle array-based system is a promising delivery vehicle for subunit vaccine and its adjuvant. Keywords: subunit vaccine, saponin adjuvant, liposomes, dissolving microneedle array, intradermal vaccination

Many viruses and certain cellular mRNAs initiate protein synthesis from a highly structured RNA sequence in the 5' untranslated region, called the internal ribosome entry site (IRES). In hepatitis C virus (HCV), the IRES RNA functionally replaces several large initiation factor proteins by directly recruiting the 43S particle. Using quantitative binding assays, modification interference of binding, and chemical and enzymatic footprinting experiments, we show that three independently folded tertiary structural domains in the IRES RNA make intimate contacts to two purified components of the 43S particle: the 40S ribosomal subunit and eukaryotic initiation factor 3 (eIF3). We measure the affinity and demonstrate the specificity of these interactions for the first time and show that the high affinity interaction of IRES RNA with the 40S subunit drives formation of the IRES RNA-40S-eIF3 ternary complex. Thus, the HCV IRES RNA recruits 43S particles in a mode distinct from both eukaryotic cap-dependent and prokaryotic ribosome recruitment strategies, and is architecturally and functionally unique from other large folded RNAs that have been characterized to date.