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Dan Liu,1 Jing-Jie Bai,2 Jun-Jie Yao,1 Yong-Bo Wang,1 Tong Chen,1 Qian Xing,1 Ran Bai1 1Department of Endocrinology, First Affiliated Hospital of Dalian Medical University, Dalian, Liaoning, People’s Republic of China; 2Department of Endocrinology, Dalian Children’s Hospital, Dalian, Liaoning, People’s Republic of ChinaCorrespondence: Dan Liu; Ran BaiDepartment of Endocrinology, First Affiliated Hospital of Dalian Medical University, Zhongshan Str.222, Dalian, 116011, People’s Republic of ChinaEmail liudandan303114@163.com; bairan5556@163.comPurpose: To assess the association of type 2 diabetes mellitus (T2DM) and insulin glargine treatment with bone mineral density (BMD) in Chinese people.Methods: This retrospective study included 50 subjects with T2DM: 25 received oral glucose-lowering medication (ORL group), and 25 received oral glucose-lowering medication in combination with insulin glargine injection (CGI group). Thirty non-diabetic control subjects were also included. BMD was measured at lumbar vertebrae 1– 4 (L1–L4), spine bone mineral density (sBMD) results summary (L2–L4), femoral neck and trochanter by dual-energy x-ray absorptiometry.Results: Compared with non-diabetic controls, people with T2DM had significantly lower mean BMD at L2 (1.073± 0.120 vs 0.984± 0.158), L3 (1.094± 0.129 vs 0.991± 0.163) and L4 (1.089± 0.130 vs 0.982± 0.165) (all P< 0.05), significantly lower levels of serum calcium (2.02± 0.22 vs 2.27± 0.17 mmol/L, P< 0.05), PTH (24.19± 9.71 vs 31.52± 8.96 pg/mL, P< 0.05), and higher serum phosphate levels (1.43± 0.37 vs 1.20± 0.15 mmol/L, P< 0.05). The CGI group had higher L2, L3 and L4 BMD and sBMD (L2–L4) (P< 0.05), higher serum calcium levels (2.19± 0.11 vs 1.98± 0.20 mmol/L, P< 0.05) and lower serum phosphate levels (1.28± 0.20 vs 1.58± 0.43 mmol/L, P< 0.05) versus the ORL group. BMD and serum calcium levels were associated with the application of insulin glargine.Conclusion: These results suggest that insulin glargine may affect bone metabolism in patients diagnosed with T2DM. The study has implications for the selection of hypoglycemic agents for diabetic patients at risk of osteoporosis.Keywords: type 2 diabetes mellitus, insulin glargine, osteoporosis, bone mineral density

Wei-Ling Yu,1,2,* Jin-Jian Yao,2,3,* Zong-Zhou Xie,1 Yan-Jing Huang,4 Sha Xiao5 1Oncology Department of Haikou City People’s Hospital, Haikou 570208, Hainan, People’s Republic of China; 2Key Laboratory of Emergency and Trauma, Ministry of Education of Hainan Medical University, Haikou 571199, Hainan, People’s Republic of China; 3Emergency Center of Hainan General Hospital Affiliated to Hainan Medical University, Haikou 570311, Hainan, People’s Republic of China; 4Oncology Department of Hainan General Hospital Affiliated to Hainan Medical University, Haikou 570311, Hainan, People’s Republic of China; 5School of Public Health of Hainan Medical University, Haikou 571199, Hainan, People’s Republic of China*These authors contributed equally to this workCorrespondence: Sha XiaoSchool of Public Health of Hainan Medical University, Haikou 571199, Hainan, People’s Republic of ChinaTel +86-18808977719Email xiaosha4226@126.comBackground: Long noncoding RNA single nucleotide polymorphisms (lncRNA-SNPs) PCAT1 rs710886, PRNCR1 rs1456315 and CCAT2 rs6983267 on 8q24 region present generalizability in the susceptibility to multiple cancers, however, the influence of rs710886, rs1456315 and rs6983267 on lung cancer has not been assessed. The aim of this study was to investigate associations between three lncRNA-SNPs and lung cancer.Methods: A case–control study was performed on 438 patients with lung cancer and 456 healthy controls in the Han population from southern China. The collected samples were genotyped by the TaqMan genotyping, and the association with clinical characteristics, including age, gender, drinking status, smoking status, pathological types and clinical stages were analyzed. And the SNP function prediction was based on lncRNASNP2, RNAfold and GTEx.Results: The rs1456315 T allele increased the risk of lung cancer [OR=1.95, 95% CI (1.58– 2.43), P=0.003] compared to the rs1456315 C allele, and rs1456315 significantly increased the risk of lung cancer in the dominant model [OR=1.86, 95% CI (1.16– 3.00), P=0.002]. The rs6983267 G allele, compared with the T allele, increased the risk of lung cancer [OR=1.29, 95% CI (1.07– 1.57), P=0.007], and rs6983267 was identified as a risk factor for lung cancer [OR=1.28, 95% CI (1.06– 1.55), P=0.003] in the additive model. Both rs1456315 and rs6983267 demonstrated significance after adjusting for the smoking status, drinking status and age. The structure prediction found rs6983267 and rs1456315 influence the secondary structure of its lncRNA. The results from lncRNASNP2 indicated that rs6983267 and rs1456315 change gain/loss target of miRNAs.Conclusion: PRNCR1 rs1456315 and CCAT2 rs6983267 on 8q24 region are significantly associated with lung cancer in the Han population of southern China and alter the potential biological function in bioinformatic analysis, and the results further extended generalism of the susceptibility of cancer-associated lncRNA-SNPs to lung cancer and underlying mechanism involved in lung cancer.Keywords: prostate cancer-associated transcript 1, prostate cancer noncoding RNA 1, colon cancer-associated transcript 2, long noncoding RNAs, single nucleotide polymorphism

Ji-Jin Yao,1,2,* Fan Zhang,2,* Guang-Shun Zhang,1 Xiao-Wu Deng,1 Wang-Jian Zhang,3 Wayne R Lawrence,3 Lu Zou,1 Xiao-Shi Zhang,4 Li-Xia Lu1 1Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, Guangdong Province, People’s Republic of China; 2Department of Radiation Oncology, The Fifth Affiliated Hospital of Sun Yat-Sen University, Zhuhai 519001, Guangdong Province, People’s Republic of China; 3Department of Environmental Health Sciences, School of Public Health, University at Albany, State University of New York, Rensselaer, NY 12144, USA; 4Department of Melanoma, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou 510060, Guangdong Province, People’s Republic of China *These authors contributed equally to this work Background: There still remains no well-established treatment strategy for head and neck mucosal melanoma (HNMM). We aim to evaluate the effectiveness and safety of primary surgery with postoperative radiotherapy for this disease.Patients and methods: A single-arm, Phase II clinical trial was conducted at Sun Yat-Sen University Cancer Center. Patients with nonmetastatic, histologically proven HNMM were prospectively enrolled. Patients received primary surgery followed by intensity-modulated radiotherapy with an equivalent dose at 2 Gy per fraction of 65–70 Gy to CTV1 (high-risk regions including tumor bed) and 50–55 Gy to CTV2 (low-risk regions). Additional use of adjuvant chemotherapy (AC) depended on consultation from a multidisciplinary team. This trial is registered with ClinicalTrials.gov, number NCT03138642.Results: A total of 33 patients were enrolled and analyzed between July 2010 and November 2016. There were 18 (54.5%) patients with T3 disease and 15 (45.5%) patients with T4a disease. The median age at diagnosis was 58 years (range 27–83 years), and 61% of the cohort were males. The overall median follow-up duration was 25.3 months (range 5.3–67.1 months). The 3-year overall survival (OS), local relapse-free survival (LRFS), regional relapse-free survival (RRFS), and distant metastasis-free survival (DMFS) rates were 44.4, 91.7, 78.1, and 41.7%, respectively. Patients with T4a disease showed significantly inferior OS (P=0.049) and DMFS (P=0.040) than those with T3 disease. Prophylactic neck radiation (PNR) was nearly associated with superior RRFS (P=0.078). However, there was no significant difference in OS, LRFS, RRFS, and DMFS for patients treated with or without AC (P>0.05 for all). Toxicities were generally mild to moderate.Conclusion: Primary surgery with postoperative radiotherapy yielded excellent local control and acceptable toxicity profile for HNMM. Nevertheless, high rates of distant metastases resulted in limited survival. Keywords: head and neck mucosal melanoma, efficacy, safety, primary surgery, postoperative radiotherapy

Yipeng Ding,* Heping Xu,* Jinjian Yao, Dongchuan Xu, Ping He, Shengyang Yi, Quanni Li, Yuanshui Liu, Cibing Wu, Zhongjie Tian Department of Emergency, People’s Hospital of Hainan Province, Haikou, Hainan, People’s Republic of China *These authors contributed equally to this work Objective: We investigated the association between single-nucleotide polymorphisms in regulation of telomere elongation helicase 1 (RTEL1), which has been associated with telom­ere length in several brain cancers and age-related diseases, and the risk of chronic obstructive pulmonary disease (COPD) in a Chinese Han population.Methods: In a case–control study that included 279 COPD cases and 290 healthy controls, five single-nucleotide polymorphisms in RTEL1 were selected and genotyped using the Sequenom MassARRAY platform. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated using unconditional logistic regression after adjusting for age and gender.Results: In the genotype model analysis, we determined that rs4809324 polymorphism had a decreased effect on the risk of COPD (CC versus TT: OR =0.28; 95% CI =0.10–0.82; P=0.02). In the genetic model analysis, we found that the “C/C” genotype of rs4809324 was associated with a decreased risk of COPD based on the codominant model (OR =0.33; 95% CI =0.13–0.86; P=0.022) and recessive model (OR =0.32; 95% CI =0.12–0.80; P=0.009).Conclusion: Our data shed new light on the association between genetic polymorphisms of RTEL1 and COPD susceptibility in the Chinese Han population. Keywords: RTEL1, chronic obstructive pulmonary disease, COPD, gene polymorphisms, association study, case-control study

Yipeng Ding,1,* Junxu Xu,2,* Jinjian Yao,1 Yu Chen,2 Ping He,1 Yanhong Ouyang,1 Huan Niu,1 Zhongjie Tian,1 Pei Sun1 1Department of Emergency, People’s Hospital of Hainan Province, 2Department of Respiratory, The Third People’s Hospital of Haikou, Haikou, Hainan, People’s Republic of China *These authors contributed equally to this work Objective: To study the risk factors for chronic obstructive pulmonary disease (COPD) in Li population in Hainan province, People’s Republic of China.Methods: Li people above 40 years of age from Hainan were chosen by stratified random cluster sampling between 2012 and 2014. All participants were interviewed with a home-visiting questionnaire, and spirometry was performed on all eligible participants. Patients with airflow limitation (forced expiratory volume in 1 second [FEV1]/forced vital capacity [FVC] 20 cigarettes/day, smoking for 40 years or more, second-hand smoking, recurrent respiratory infections, and induced cough were risk factors for COPD, whereas high BMI, high education level, and presence of ventilated kitchen were protective factors. Subsequent multivariate logistic regression model further demonstrated that aging, low BMI, biomass smoke, >20 cigarettes/day, and recurrent respiratory tract infections were high-risk factors for COPD in the Li population.Conclusion: The incidence of COPD has a strong correlation with age, BMI, biomass smoke, >20 cigarettes/day, and recurrent respiratory infections, suggesting they were high-risk factors for COPD in Li population. Keywords: chronic obstructive pulmonary disease, epidemiology, survey, Li population

Jing-Jing Yao, Yong-Zhong Du, Hong Yuan, Jian You, Fu-Qiang HuCollege of Pharmaceutical Sciences, Zhejiang University, Hangzhou, People’s Republic of ChinaAbstract: Cis-aconitate-modified chitosan-g-stearic acid (CA-CSO-SA) micelles were ­synthesized in this study to improve the gene transfection efficiency of chitosan-g-stearic acid (CSO-SA). The CA-CSO-SA micelles had a similar size, critical micelle concentration, and ­morphology, but their zeta potential and cytotoxicity were reduced compared with CSO-SA micelles. After modification with cis-aconitate, the CA-CSO-SA micelles could also compact plasmid DNA (pDNA) to form nanocomplexes. However, the DNA binding ability of CA-CSO-SA was slightly reduced compared with that of CSO-SA. The transfection efficiency mediated by CA-CSO-SA/pDNA against HEK-293 cells reached up to 37%, and was much higher than that of CSO-SA/pDNA (16%). Although the cis-aconitate modification reduced cellular uptake kinetics in the initial stages, the total amount of cellular uptake tended to be the same after 24 hours of incubation. An endocytosis inhibition experiment showed that the internalization mechanism of CA-CSO-SA/pDNA in HEK-293 cells was mainly via clathrin-mediated endocytosis, as well as caveolae-mediated endocytosis and macropinocytosis. Observation of intracellular trafficking indicated that the CSO-SA/pDNA complexes were trapped in endolysosomes, but CA-CSO-SA/pDNA was more widely distributed in the cytosol. This study suggests that modification with cis-aconitate improves the transfection efficiency of CSO-SA/pDNA.Keywords: chitosan-g-stearic acid, cis-aconitate, micelles, transfection efficiency, intracellular trafficking

Objective: To investigate the correlation between bone marrow microvascular density, angiogenesis factors and bortezomib resistance in multiple myeloma (MM)., Methods: The data of 200 patients with MM treated in our hospital from January 2020 to August 2023 were retrospectively analyzed, and the patients with MM were divided into drug-resistant group( n =68) and non-drug-resistant group( n =132) according to their drug resistance during bortezomib treatment. The univariate and multivariate logistic analysis were used to screen the independent influencing factors of bortezomib resistance in MM patients during treatment. The receiver operating characteristic (ROC) curve and clinical decision curve (DCA) were used to evaluate the predictive performance and clinical application value of the risk prediction model, the consistency between the actual incidence rate and the predicted incidence rate was judged by validating the calibration chart, and the goodness-of-fit of the model was judged by H-L test., Results: 68 of the 200 MM patients developed resistance and poor clinical efficacy during bortezomib treatment, and the clinical resistance rate of bortezomib was 34.0%. The results of multivariate analysis showed that high bone marrow microvessel density (MVD) and high bone marrow supernatant VEGF, HGF, and bFGF expression levels were independent risk factors for bortezomib resistance in MM patients ( P < 0.05). The area under the ROC curve (AUC) of the model jointly constructed by bone marrow MVD, serum VEGF, HGF, bFGF and TNF-α levels was 0.924, and its sensitivity and specificity were 92.6% and 78.8%, which were higher than those of the bone marrow MVD model (AUC=0.743) and the vasogenesis factor model (AUC=0.878). The calibration curve of the joint prediction model was close to the standard curve, indicating that the model is more consistent. The results of H-L goodness -of - fit test showed χ 2 =14.748， P =0.164, the joint prediction model had a good fit. The DCA curve showed that the clinical net benefit of intervention in the range of 0.0~1.0 was greater than that of full intervention and no intervention., Conclusion: The prediction model based on bone marrow MVD and vasogenesis factors (VEGF, HGF, bFGF) in MM patients has higher clinical evaluation performance and predictive value.

Objective: This study aimed to evaluate the efficacy of a double-lumen biliary-enteric tube (DBET) for enteral nutrition (EN) in individuals with malignant obstructive jaundice (MOJ)., Methods: A retrospective cohort study was conducted using data from a prospectively maintained single-center database, including patients with MOJ. In the intervention group, DBET placement was performed concurrently with percutaneous transhepatic cholangiodrainage and biliary stenting, followed by postoperative EN (DBET-EN). In the control group, deep vein catheterization was undertaken after endoscopic biliary stenting, and parenteral nutrition (PN) was provided. A multivariable generalized linear model was used to assess the association between DBET-EN and 6-month mortality., Results: A total of 74 patients were included in this study, comprising 28 patients in the intervention group (DBET-EN group) and 46 patients in the control group (PN group). Within the 6-month follow-up, 5 patients (17.9%) in the DBET-EN group and 20 (43.5%) in the PN group died. The multivariable generalized linear model demonstrated a significantly reduced 6-month mortality in the DBET-EN group compared to the PN group (adjusted odds ratio [OR]: 0.25, 95% CI: 0.08-0.81, P  = 0.020). Secondary outcomes indicated that patients in the DBET-EN group had lower 9-month mortality rates and longer tube retention durations compared to the PN group (all adjusted P  < 0.05). Postoperative liver function improved similarly in both groups. At 3, 6, and 9 months postoperatively, patient-generated subjective global assessment (PG-SGA) scores and the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) scores were significantly higher in the DBET-EN group than in the PN group ( P  < 0.05)., Conclusion: The implementation of DBET for EN in patients in the advanced stage of MOJ proved to be a minimally invasive and safe intervention. It significantly improved patients' nutritional status and quality of life while reducing mortality.

Gemcitabine (GEM) based induction chemotherapy is a standard treatment for locoregionally advanced nasopharyngeal carcinoma (NPC). However, approximately 15 % of patients are still resistant to GEM-containing chemotherapy, which leads to treatment failure. Nevertheless, the underlying mechanisms of GEM resistance remain poorly understood. Herein, based on a microarray analysis, we identified 221 dysregulated lncRNAs, of which, DYNLRB2-AS1 was one of the most upregulated lncRNAs in GEM-resistance NPC cell lines. DYNLRB2-AS1 was shown to function as contain an oncogenic lncRNA that promoted NPC GEM resistance, cell proliferation, but inhibited cell apoptosis. Mechanistically, DYNLRB2-AS1 could directly bind to the DHX9 protein and prevent its interaction with the E3 ubiquitin ligase PRPF19, and thus blocking PRPF19-mediated DHX9 degradation, which ultimately facilitated the repair of DNA damage in the presence of GEM. Clinically, higher DYNLRB2-AS1 expression indicated an unfavourable overall survival of NPC patients who received induction chemotherapy. Overall, this study identified the oncogenic lncRNA DYNLRB2-AS1 as an independent prognostic biomarker for patients with locally advanced NPC and as a potential therapeutic target for overcoming GEM chemoresistance in NPC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

Acute-on-chronic liver failure (ACLF) and decompensated cirrhosis (DC) are life-threatening syndromes that can develop at the end-stage of chronic hepatitis B virus (HBV) infection. Both ACLF and DC are complicated by hepatic and extrahepatic pathogeneses. To better understand the compartment-specific metabolic modulations related to their pathogenesis, HBV-DC, HBV-ACLF patients, and controls (30 each) were analyzed by metabolomics using portal (Port), hepatic vein (Hep), and peripheral (Peri) serum. Compartment ratios of metabolites (Ratio Hep/Port , Ratio Peri/Hep , and Ratio Port/Peri ) were calculated. The liver tissues (10 per group) were analyzed using transcriptomics and metabolomics. An additional 75 patients with ACLF, 20 with DC, and 20 with liver cirrhosis (LC) were used to confirm oxlipid dysregulation. Both multi-omics datasets suggest suppressed energy, amino acid, and pyrimidine metabolism in the ACLF/DC liver. The serum metabolomic variations were contributed primarily by disease rather than sampling compartments, as both HBV-ACLF and HBV-DC patients demonstrated abnormal profiles of amino acids and peptides, indoles, purines, steroids, and benzimidazoles. In ACLF/DC patients, impaired hepatic metabolism resulted in a highly correlated hepatic and portal vein serum metabolome and release of inflammatory lipids and heme metabolites from the liver. HBV-ACLF showed higher Ratio Peri/Hep of extrahepatic inflammatory oxlipids, while HBV-DC patients showed higher Ratio Port/Peri of gut microbial metabolites. An inflammatory oxlipid outburst was confirmed in the early stages of HBV-ACLF. The inflammatory effects of the selected oxlipids were confirmed in monocytes. These findings support a synergy between liver-specific mechanisms and systemic inflammation in ACLF/DC development, and that pro-inflammatory oxlipids are metabolic signatures of early HBV-ACLF.

Chronic obstructive pulmonary disease (COPD) is a common chronic disease characterized by airflow obstruction, which seriously threatens people's health. The COPD mouse model was established with cigarette smoke induction. Hematoxylin-eosin staining and Masson staining were carried out to observe the pathological changes of lung tissues in COPD mice. RTEL1 was silenced in COPD mice, and immunohistochemistry was used to detect RTEL1, ki67 and Caspase-3 expression. The role of RTEL1 in inflammation were evaluated by ELISA, and the impacts of RTEL1 on M1 and M2 macrophage markers (iNOS and CD206) were evaluated by qPCR and western blotting. In COPD model, there was an increase in the number of inflammatory cells, with slightly disorganized cell arrangement, unclear hierarchy, condensed and solidified nuclei, while knockdown of RTEL1 improved the inflammatory infiltration. Moreover, knockdown of RTEL1 reduced ki67-positive cells and increased Caspase-3 positive cells in COPD group. The increased inflammatory factors (IL-1β, MMP-9, TNF-α, IL-4, IL-6, and IL-23) in COPD were suppressed by knockdown of RTEL1, while iNOS was raised and CD206 was inhibited. In conclusion, knockdown of RTEL1 promoted M1 and inhibited M2 macrophage polarization and inflammation to alleviate COPD.

Purpose: To evaluate the outcomes and toxicities of adding neoadjuvant chemotherapy (NAC) to concurrent chemoradiotherapy (CCRT) in elderly (≥65 years) patients with locoregionally advanced nasopharyngeal carcinoma (LANPC, stage III-IVa)., Methods and Materials: Using an NPC-specific database, 245 elderly patients with stage III-IVa NPC, receiving CCRT +/- NAC, and an Adult Co-morbidity Evaluation 27 (ACE-27) score <2 were included. Recursive partitioning analysis (RPA) based on TNM stage and Epstein-Barr virus (EBV) DNA were applied for risk stratification. The primary end point was disease-free survival (DFS)., Results: Two risk groups were generated by the RPA model. In the high-risk group (EBV DNA < 4000 copy/ml with stage IVa & EBV DNA ≥4000 copy/ml with stage III-IVa), patients treated with NAC plus CCRT achieved improved 5-year DFS rates compared to those who received CCRT alone (56.9% vs. 29.4%; p = 0.003). But we failed to observe the survival benefit of additional NAC in the low-risk group (EBV DNA <4000 copy/ml with stage III). The most common severe acute toxic effects were leucopenia (46.8% vs. 24.4%) and neutropenia (43.7% vs. 20.2%) in the NAC plus CCRT group versus CCRT group with statistically significant differences., Conclusions: The addition of NAC to CCRT was associated with better DFS for the high-risk group of elderly LANPC patients with ACE-27 score <2. However, the survival benefit of additional NAC was not observed in low-risk patients., (© 2024 Wiley Periodicals LLC.)

➤ Large language models are a subset of artificial intelligence. Large language models are powerful tools that excel in natural language text processing and generation.➤ There are many potential clinical, research, and educational applications of large language models in orthopaedics, but the development of these applications needs to be focused on patient safety and the maintenance of high standards.➤ There are numerous methodological, ethical, and regulatory concerns with regard to the use of large language models. Orthopaedic surgeons need to be aware of the controversies and advocate for an alignment of these models with patient and caregiver priorities., Competing Interests: Disclosure: One of the authors (M.A.) is an employee of Google, which developed Med-PaLM, one of the discussed medical large language models in this study. The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/I72)., (Copyright © 2024 by The Journal of Bone and Joint Surgery, Incorporated.)

The root of Aconitum carmichaelii Debx. (Fuzi) is an herbal medicine used in China that exerts significant efficacy in rescuing patients from severe diseases. A key toxic compound in Fuzi, aconitine (AC), could trigger unpredictable cardiotoxicities with high-individualization, thus hinders safe application of Fuzi. In this study we investigated the individual differences of AC-induced cardiotoxicities, the biomarkers and underlying mechanisms. Diversity Outbred (DO) mice were used as a genetically heterogeneous model for mimicking individualization clinically. The mice were orally administered AC (0.3, 0.6, 0.9 mg· kg -1  ·d -1 ) for 7 d. We found that AC-triggered cardiotoxicities in DO mice shared similar characteristics to those observed in clinic patients. Most importantly, significant individual differences were found in DO mice (variation coefficients: 34.08%-53.17%). RNA-sequencing in AC-tolerant and AC-sensitive mice revealed that hemoglobin subunit beta (HBB), a toxic-responsive protein in blood with 89% homology to human, was specifically enriched in AC-sensitive mice. Moreover, we found that HBB overexpression could significantly exacerbate AC-induced cardiotoxicity while HBB knockdown markedly attenuated cell death of cardiomyocytes. We revealed that AC could trigger hemolysis, and specifically bind to HBB in cell-free hemoglobin (cf-Hb), which could excessively promote NO scavenge and decrease cardioprotective S-nitrosylation. Meanwhile, AC bound to HBB enhanced the binding of HBB to ABHD5 and AMPK, which correspondingly decreased HDAC-NT generation and led to cardiomyocytes death. This study not only demonstrates HBB achievement a novel target of AC in blood, but provides the first clue for HBB as a novel biomarker in determining the individual differences of Fuzi-triggered cardiotoxicity., (© 2024. The Author(s).)

Background: Despite the success of PD-1 blockade in recurrent/metastatic nasopharyngeal carcinoma (NPC), its effect for locoregionally advanced NPC (LANPC) remains unclear. This study aimed to evaluate the benefit of adding PD-1 blockade to the current standard treatment (gemcitabine and cisplatin IC  plus cisplatin CCRT ) for LANPC patients., Methods: From January 2020 to November 2022, 347 patients with non-metastatic high-risk LANPC (stage III-IVA, excluding T3-4N0) were included. Of the 347 patients, 268 patients were treated with standard treatment (IC-CCRT), and 79 received PD-1 blockade plus IC-CCRT (PD-1 group). For the PD-1 group, PD-1 blockade was given intravenously once every 3 weeks for up to 9 cycles (3 induction and 6 adjuvant). The primary endpoint was disease-free survival (DFS) (i.e. freedom from local/regional/distant failure or death). The propensity score matching (PSM) with the ratio of 1:2 was performed to control confounding factors., Results: After PSM analysis, 150 patients receiving standard treatment and 75 patients receiving additional PD-1 blockade remained in the current analysis. After three cycles of IC, the PD-1 group had significantly higher rates of complete response (defined as disappearance of all target lesions; 24% vs. 9%; P = 0.006) and complete biological response (defined as undetectable cell-free Epstein-Barr virus DNA, cfEBV DNA; 79% vs. 65%; P = 0.046) than that in the standard group. And the incidence of grade 3-4 toxicity during IC was 47% in the PD-1 group and 41% in the standard group, with no significant difference (P = 0.396). During follow-up period, additional PD-1 blockade to standard treatment improved 3-year DFS from 84 to 95%, with marginal statistical significance (HR, 0.28; 95%CI, 0.06-1.19; P = 0.064)., Conclusion: Additiaonl PD-1 blockade to gemcitabine and cisplatin IC and adjuvant treatment results in significant improvement in tumor regression, cfEBV DNA clearance, superior DFS, and comparable toxicity profiles in high-risk LANPC patients., (© 2024. The Author(s).)

Objective: The purpose of this study was to explore the clinical benefits of establishing an enteral nutrition (EN) pathway via percutaneous transhepatic cholangiography drainage (PTCD) catheterization in patients with late-stage malignant obstructive jaundice (MOJ). Methods: We selected 30 patients diagnosed as having late-stage MOJ with malnutrition. A dual-lumen biliary-enteral nutrition tube was placed via PTCD along with a biliary stent implantation. Postoperative EN was provided, and we observed the time taken for tube placement, its success rate, complications, and therapeutic efficacy. Results: Tube placement was successful in all 30 patients with an average procedural time of 5.7 ± 1.4 min with no tube placement complications. Compared to preoperative measures, there was a significant improvement in postoperative jaundice reduction and nutritional indicators one month after the procedure ( p  < 0.05). Post-placement complications included tube perileakage in 5 cases, entero-biliary reflux in 4 cases, tube blockage in 6 cases, tube displacement in 4 cases, accidental tube removal in 3 cases, and tube replacement due to degradation in 8 cases, with tube retention time ranging from 42 to 314 days, averaging 124.7 ± 37.5 days. All patients achieved the parameters for effective home-based enteral nutrition with a noticeable improvement in their quality of life. Conclusion: In this study, we found that the technique of establishing an EN pathway via PTCD catheterization was minimally invasive, safe, and effective; the tube was easy to maintain; and patient compliance was high. It is, thus, suitable for long-term tube retention in patients with late-stage MOJ.

Background : Paraquat (PQ) plays an important role in agricultural production due to its highly effective herbicidal effect. However, it has led to multiple organ failure in those who have been poisoned, with damage most notable in the lungs and ultimately leading to death. Because of little research has been performed at the genetic level, and therefore, the specific genetic changes caused by PQ exposure are unclear. Methods : Paraquat poisoning model was constructed in Sprague Dawley (SD) rats, and SD rats were randomly divided into Control group, paraquat (PQ) poisoning group and Anthrahydroquinone-2,6-disulfonate (AH 2 QDS) treatment group. Then, the data was screened and quality controlled, compared with reference genes, optimized gene structure, enriched at the gene expression level, and finally, signal pathways with significantly different gene enrichment were screened. Results : This review reports on lung tissues from paraquat-intoxicated Sprague Dawley (SD) rats that were subjected to RNA-seq, the differentially expressed genes were mainly enriched in PI3K-AKT, cGMP-PKG, MAPK, Focal adhesion and other signaling pathways. Conclusion : The signaling pathways enriched with these differentially expressed genes are summarized, and the important mechanisms mediated through these pathways in acute lung injury during paraquat poisoning are outlined to identify important targets for AH 2 QDS treatment of acute lung injury due to paraquat exposure, information that will be used to support a subsequent in-depth study on the mechanism of PQ action.

This study aimed to observe the differential expression of Annexin-A1 in esophageal squamous cell carcinoma (ESCC) and explored the effect of small interfering ribonucleic acid (RNAi)-Annexin-A1 on the biological behavior of CE81T-0 cells. An immunohistochemical approach was used to detect the expression of Annexin-A1 in 86 pairs of ESCC samples. Quantitative reverse transcription polymerase chain reaction was used to detect the expression of Annexin-A1 in CE81T-0 and CE81T-4 cells, and the expression of Annexin-A1 in CE81T-0 cells was knocked out by RNAi. A methyl-thiazolyl-tetrazolium assay was used to observe the effect of Annexin-A1 on cell proliferation, and flow cytometry was conducted to analyze its effect on cell cycles and apoptosis. A scratch assay and a Transwell chamber were used to detect changes in cell migration and invasion. From the results, compared with the Annexin-A1 expression rate of 59.3% in para-carcinoma tissues, the expression of Annexin-A1 in cancer was reduced to only 32.6% in ESCC cells. Annexin-A1 was strongly expressed in highly differentiated ESCC cells without lymphatic metastasis and highly expressed in the CE81T-0 cell group with low metastasis. Annexin-A1 gene silencing promoted cell proliferation and inhibited apoptosis, blocked cells in the S-phase, and increased cell migration, leading to an increase in the number of invaded cells. Above all, Annexin-A1 could reflect the differentiation degree and lymph node metastasis of ESCC cells to some extent and was involved in the invasion, metastasis, proliferation, and other biological behaviors of ESCC cells, indicating an experimental basis for Annexin-A1 as a molecular marker in the early diagnosis of ESCC and the prediction of cell metastasis, invasion, and differentiation degree.

Objectives: To compare neoadjuvant chemotherapy (NAC) plus concurrent chemoradiotherapy (CCRT) to CCRT alone in children and adolescents (age ≤ 18 years) with locoregionally advanced nasopharyngeal carcinoma (CA-LANPC, stage III-IVA)., Materials and Methods: 195 CA-LANPC patients who were treated through CCRT with or without NAC between 2008 and 2018 were enrolled in this study. A matched cohort composed of CCRT patients and NAC-CCRT patients was generated by propensity score matching (PSM) at a 1:2 ratio. Survival outcomes and toxicities were compared between the CCRT group and NAC-CCRT group., Results: Of the 195 patients, 158 (81%) received NAC plus CCRT, and 37 (19%) received CCRT alone. The NAC-CCRT group had higher EBV DNA levels (≥ 4000 copy/mL), more advanced TNM stage (stage IV disease), and lower incidence of a high radiation dose (> 6600 cGy) than the CCRT group. To avoid bias in treatment selection within retrospectively analysis, 34 patients from the CCRT group were matched with 68 patients from the NAC-CCRT group. In the matched cohort, the 5-year DMFS rate was 94.0% in the NAC-CCRT group versus 82.4% in the CCRT group, with marginal statistical significance (HR = 0.31; 95%CI 0.09-1.10; P = 0.055). During treatment, the accumulate incidence of severe acute toxicities (65.8% vs 45.9%; P = 0.037) in the NAC-CCRT group was higher than the CCRT group. However, the CCRT group had significantly higher accumulate incidence of severe late toxicities (30.3% vs 16.8%; P = 0.041) than the NAC-CCRT group., Conclusions: Addition of NAC to CCRT tended to improve long-term DMFS in CA-LANPC patients with acceptable toxicity. However, relative randomized clinical trial is still needed in the future., (© 2023. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Herein, we successfully fabricated an Al-doped α-Ga 2 O 3 nanorod array on FTO using the hydrothermal and post-annealing processes. To the best of our knowledge, it is the first time that an Al-doped α-Ga 2 O 3 nanorod array on FTO has been realized via a much simpler and cheaper way than that based on metal-organic chemical vapor deposition, magnetron sputtering, molecular beam epitaxy, and pulsed laser deposition. And, a self-powered Al-doped α-Ga 2 O 3 nanorod array/FTO photodetector was also realized as a photoanode at 0 V (vs. Ag/AgCl) in a photoelectrochemical (PEC) cell, showing a peak responsivity of 1.46 mA/W at 260 nm. The response speed of the Al-doped device was 0.421 s for rise time, and 0.139 s for decay time under solar-blind UV (260 nm) illumination. Compared with the undoped device, the responsivity of the Al-doped device was ~5.84 times larger, and the response speed was relatively faster. When increasing the biases from 0 V to 1 V, the responsivity, quantum efficiency, and detectivity of the Al-doped device were enhanced from 1.46 mA/W to 2.02 mA/W, from ~0.7% to ~0.96%, and from ~6 × 10 9 Jones to ~1 × 10 10 Jones, respectively, due to the enlarged depletion region. Therefore, Al doping may provide a route to enhance the self-powered photodetection performance of α-Ga 2 O 3 nanorod arrays.

Background: Ream-and-run arthroplasty offers improvements in shoulder pain and function for patients with primary glenohumeral arthritis who wish to avoid limitations associated with a polyethylene glenoid component. Longer-term clinical outcome assessments of the ream-and-run procedure are sparse in the literature. This study aimed to present minimum 5-year functional outcomes in a large cohort following ream-and-run arthroplasty to determine factors associated with clinical success and reoperation., Methods: Patients who underwent ream-and-run surgery with a minimum of 5 years of follow-up were identified through a retrospective review of a prospectively maintained database from a single academic institution. To assess clinical outcomes, the Simple Shoulder Test (SST) was administered and assessed to determine achievement of the minimal clinically important difference, as well as the necessity for open revision surgery. Factors associated with P < .1 on univariate analysis were included in multivariate analysis., Results: Of 228 patients who consented to undergo long-term follow-up, 201 (88%) were included in our analysis (mean follow-up period, 7.6 ± 2.1 years). The average age was 59.4 ± 8.8 years, and 93% of patients were men. The majority of patients had a diagnosis of osteoarthritis (79%) or capsulorrhaphy arthropathy (10%). SST scores improved from a mean of 4.9 ± 2.5 preoperatively to a mean of 10.2 ± 2.6 at latest follow-up. The minimal clinically important difference in the SST score of 2.6 was reached by 165 patients (82%). Male sex (P = .020), nondiabetic status (P = .080), and lower preoperative SST score (P < .001) were included in a multivariate analysis. Male sex (P = .010) and lower preoperative SST score (P < .001) were associated with clinically important improvements in SST scores on multivariate analysis. Open revision surgery was required in 22 patients (11%). Younger age (P < .001), female sex (P = .055), and higher preoperative pain score (P = .023) were included in a multivariate analysis. Only younger age was predictive of open revision surgery (P = .003)., Conclusions: Ream-and-run arthroplasty can provide significant and clinically important improvements in clinical outcomes at minimum 5-year follow-up. Successful clinical outcomes were significantly associated with male sex and lower preoperative SST scores. Reoperation was more common in younger patients., (Copyright © 2023 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Vitamin C, as an antioxidant, may play a role in the treatment of NAFLD. This research aimed to investigate the association of serum vitamin C levels with the risk of NAFLD and to further examine the causal relationship by Mendelian randomization (MR) method., Methods: The cross-sectional study selected 5,578 participants of the National Health and Nutrition Examination Survey (NHANES), 2005-2006 and 2017-2018. The association of serum vitamin C levels with NAFLD risk was evaluated under a multivariable logistic regression model. A two-sample MR study, using genetic data from large-scale genome-wide association studies (GWAS) of serum vitamin C levels (52,014 individuals) and NAFLD (primary analysis: 1,483 cases /17,781 controls; secondary analysis: 1,908 cases/340,591 controls), was conducted to infer causality between them. The inverse-variance-weighted (IVW) was applied as the main method of MR analysis. A series of sensitivity analyzes were used to evaluate the pleiotropy., Results: In the cross-sectional study, results showed that Tertile 3 group (Tertile 3: ≥1.06 mg/dl) had a significantly lower risk (OR = 0.59, 95% CI: 0.48 ~ 0.74, p  < 0.001) of NAFLD than Tertile 1 group (Tertile 1: ≤0.69 mg/dl) after full adjustments. In regard to gender, serum vitamin C was protective against NAFLD in both women (OR = 0.63, 95% CI: 0.49 ~ 0.80, p  < 0.001) and men (OR = 0.73, 95% CI: 0.55 ~ 0.97, p  = 0.029) but was stronger among women. However, in the IVW of MR analyzes, no causal relationship between serum vitamin C levels and NAFLD risk was observed in the primary analysis (OR = 0.82, 95% CI: 0.47 ~ 1.45, p  = 0.502) and secondary analysis (OR = 0.80, 95% CI: 0.53 ~ 1.22, p  = 0.308). MR sensitivity analyzes yielded consistent results., Conclusion: Our MR study did not support a causal association between serum vitamin C levels and NAFLD risk. Further studies with greater cases are warranted to confirm our findings., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Wu, Guo, Yao, Yu, Xia, Huang, Tang and He.)

Ream-and-run arthroplasty can improve pain and function in patients with glenohumeral arthritis while avoiding the complications and activity restrictions associated with a prosthetic glenoid component. However, stiffness is a known complication after ream-and-run arthroplasty and can lead to repeat procedures such as a manipulation under anesthesia (MUA) or open surgical revision. The objective of this study was to determine risk factors associated with repeat procedures indicated for postoperative stiffness after ream-and-run arthroplasty., Methods: We conducted a retrospective review of our shoulder arthroplasty database to identify patients who underwent ream-and-run arthroplasty and determined which patients underwent subsequent repeat procedures (MUA and/or open revision) indicated for postoperative stiffness. The minimum follow-up was 2 years. We collected baseline demographic information and preoperative and 2-year patient-reported outcome scores and analyzed preoperative radiographs. Univariate and multivariate analyses determined the factors significantly associated with repeat procedures to treat postoperative stiffness., Results: There were 340 patients who underwent ream-and-run arthroplasty. The mean Simple Shoulder Test (SST) scores for all patients improved from 5.0 ± 2.4 preoperatively to 10.2 ± 2.6 postoperatively (p < 0.001). Twenty-six patients (7.6%) underwent open revision for stiffness. An additional 35 patients (10.3%) underwent MUA. Univariate analysis found younger age (p = 0.001), female sex (p = 0.034), lower American Society of Anesthesiologists (ASA) class (p = 0.045), posterior decentering on preoperative radiographs (p = 0.010), and less passive forward elevation at the time of discharge after ream-and-run arthroplasty (p < 0.001) to be significant risk factors for repeat procedures. Multivariate analysis found younger age (p = 0.040), ASA class 1 compared with class 3 (p = 0.020), and less passive forward elevation at discharge (p < 0.001) to be independent risk factors for repeat procedures. Of the patients who underwent open revision for stiffness, 69.2% had multiple positive cultures for Cutibacterium., Conclusions: Younger age, ASA class 1 compared with class 3, and less passive forward elevation in the immediate postoperative period were independent risk factors for repeat procedures to treat postoperative stiffness after ream-and-run arthroplasty., Level of Evidence: Prognostic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSOA/A510)., (Copyright © 2023 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

Purpose: The objective was to determine factors associated with a successful outcome at a minimum of two years after revision of a failed shoulder arthroplasty., Methods: We conducted a retrospective study of revision shoulder arthroplasties performed over a ten year period and collected patient-reported outcome data and re-revision data. A successful outcome was defined by improvement greater than the minimal clinically important difference (MCID) for the Simple Shoulder Test (SST)., Results: One hundred twelve patients with average follow-up of five years were included. Improvement of VAS pain scores (6.6 ± 2.3 to 2.9 ± 2.6) and SST scores (2.7 ± 2.6 to 6.6 ± 3.3) were significant (p < 0.001). Males were more likely to have a successful outcome than females (p = 0.01)., Conclusion: Two-thirds of patients experienced clinically significant improvement at a minimum of two years after revision shoulder arthroplasty. Male sex was the strongest independent predictor of a successful outcome., (© 2022. The Author(s) under exclusive licence to SICOT aisbl.)

Background: Total shoulder arthroplasty (TSA) provides excellent long-term clinical outcomes in the treatment of glenohumeral arthritis. However, symptomatic glenoid polyethylene loosening can be seen at intermediate follow-up and can lead to shoulder pain and dysfunction. The purpose of this study was to perform a systematic review of the available literature to determine the optimal management of symptomatic glenoid loosening with regard to reoperation and patient satisfaction following various approaches to symptomatic glenoid loosening., Methods: This study was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement. Studies investigating revision arthroplasty for the treatment of glenoid loosening with clinical outcomes were identified. Clinical failure was defined as a repeat procedure after revision arthroplasty., Results: Overall, 14 studies met inclusion criteria that included 483 patients with a mean age of 66.5 ± 3.0 years who underwent revision arthroplasty for symptomatic glenoid loosening. There were 8 studies that discussed conversion to a hemiarthroplasty (HA, 148 patients), 7 studies that discussed glenoid reimplantation in a single setting (1-stage TSA, 157 patients), 2 studies that discussed glenoid reimplantation in a staged setting (2-stage TSA, 18 patients), and 2 studies that discussed conversion to a reverse shoulder arthroplasty (RSA, 164 patients). All patients underwent glenoid component removal. The length of follow-up was significantly shorter in the RSA group (41 months for RSA vs. 56 months for HA vs. 55 months for 1-stage TSA vs. 62 months for 2-stage TSA, P < .001). The reoperation rate at the final follow-up was 19% for the HA cohort, 20% for the 1-stage TSA cohort, 22% for the 2-stage TSA cohort, and 21% for the RSA cohort (P = .971). Patient satisfaction rate at the final follow-up was 62% for the HA cohort, 66% for the 1-stage TSA cohort, 71% for the 2-stage TSA cohort, and 86% for the RSA cohort (P = .045). Positive cultures were noted in 15% of patients with Cutibacterium acnes comprising 72% of positive cultures., Conclusions: Overall, the optimal management of symptomatic glenoid loosening remains unclear. All 4 types of revision arthroplasty (HA, 1-stage TSA, 2-stage TSA, and RSA) had a similar reoperation rate (20%) at the latest follow-up. Conversion to RSA provided a higher proportion of patients satisfied with the procedure. However, the length of follow-up was significantly shorter than other groups, and therefore longer-term follow-up of this group is needed to determine if results are durable., (Copyright © 2022 Journal of Shoulder and Elbow Surgery Board of Trustees. Published by Elsevier Inc. All rights reserved.)

Objective: To analyze the bronchoscopic manifestations and interventional treatment of pulmonary mucormycosis. Methods: Clinical data of patients with pulmonary mucormycosis undergoing bronchoscopy and interventional therapy in 4 tertiary general hospitals in China from May 2006 to May 2022 were retrospectively analyzed and the literature on the subject were reviewed. Results: The data of 10 patients with pathologically diagnosed pulmonary mucormycosis undergoing bronchoscopy and interventional therapy were collected, including 8 males and 2 females. The patients' age ranged from 21 to 72 (44±15) years. The underlying diseases included 6 cases of diabetes ketoacidosis, 3 cases of leukemia, 1 case after operation of lung cancer. Bronchoscopy showed that white viscous necrotic matters grew along the airway and blocked the airway in 9 cases, accompanied by airway bleeding in 3 cases, bloody secretion blocked the airway in 1 case, and bronchopulmonary cavity fistula in 2 cases. The biopsy histopathology of white necrotic matters showed that many mucor filaments were tangled together which were named mucormycelium. Among the 10 patients, 9 were treated with systemic drugs, including intravenous application of amphotericin B deoxycholate in 5 cases, intravenous application of amphotericin B liposome in 4 cases, oral posaconazole in 6 cases and intravenous injection in 1 case. Local drug therapy included aerosol inhalation of amphotericin B deoxycholate in 8 cases and local perfusion under bronchoscope in 5 cases. Bronchoscopic interventional therapy was used to remove mucormycelium in the bronchus, including cryotherapy in 8 cases, biopsy forceps in 7 cases, snare treatment in 2 cases and foreign body forceps in 2 cases. All 10 patients were clinical cured and with no death. Conclusions: Pulmonary mucormycosis is more common in immunocompromised hosts. Bronchoscopy often showed mucormycelium blocking the airway. Systemic and local drug therapy combined with bronchoscopic interventional therapy can achieve good clinical efficacy.

The human gut bacterial genotoxin colibactin is a possible key driver of colorectal cancer (CRC) development. Understanding colibactin's biological effects remains difficult owing to the instability of the proposed active species and the complexity of the gut microbiota. Here, we report small molecule boronic acid inhibitors of colibactin biosynthesis. Designed to mimic the biosynthetic precursor precolibactin, these compounds potently inhibit the colibactin-activating peptidase ClbP. Using biochemical assays and crystallography, we show that they engage the ClbP binding pocket, forming a covalent bond with the catalytic serine. These inhibitors reproduce the phenotypes observed in a clbP deletion mutant and block the genotoxic effects of colibactin on eukaryotic cells. The availability of ClbP inhibitors will allow precise, temporal control over colibactin production, enabling further study of its contributions to CRC. Finally, application of our inhibitors to related peptidase-encoding pathways highlights the power of chemical tools to probe natural product biosynthesis., (© 2022. The Author(s).)

Background: To assess the feasibility of adjusting radiation dose (RD) in childhood NPC with favorable tumor response after neoadjuvant chemotherapy (NAC)., Patients and Methods: Using an NPC-specific database, children and adolescents (≤18 years) with locoregionally advanced NPC (CA-LANPC) were retrospectively analyzed. Enrolled patients were those who received favorable tumor response after 2-4 cycles of NAC followed by concurrent chemoradiotherapy. Survival outcomes and treatment-related toxicities were compared for the standard RD on primary tumors (PT-RD standard , 66-72 Gy) and the reduced RD on primary tumors (PT-RD reduced , 60-65.9 Gy)., Results: A total of 132 patients were included, and the median follow-up time was 75.2 months (IQR, 53.2-98.7 months) for the entire cohort. The PT-RD reduced group had a significantly decreased incidence of severe mucositis (51.3 % vs 32.1 %; P = 0.034) when compared to the PT-RD standard group. The total incidence of severe sequela in the PT-RD standard group were significantly higher than those in the PT-RD reduced group (31.8 % vs 13.7 %; P = 0.029). In the propensity-matched analysis, the PT-RD reduced group resulted in parallel 5-year survival with the PT-RD standard group from the matched cohort (disease-free survival, 82.7 % vs 80.3 %, P = 0.841; overall survival, 91.7 % vs 91.3 %, P = 0.582; distant metastasis-free survival, 87.5 % vs 82.8 %, P = 0.573; and locoregional relapse-free survival, 95.6 % vs 97.3 %, P = 0.836). In multivariate analysis, the impact of PT-RD reduced on all survival end points remained insignificant., Conclusions: Chemoradiotherapy with RD at levels of 60-65.9 Gy may be a reasonable strategy for CA-LANPC with favorable tumor response after NAC., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2022 Elsevier B.V. All rights reserved.)

Based on the data of A-share listed companies in China from 2016 to 2020, this study empirically analyzes the relationship among corporate social responsibility, debt financing cost and enterprise innovation by constructing a regulated mediation effect model. The results show that enterprises perform social responsibility actively can enhance the level of enterprise innovation. Besides, debt financing cost plays a part of the intermediary role between corporate social responsibility and enterprise innovation. It is found that market competition degree positively regulates the relationship between corporate social responsibility and enterprise innovation, and market competition degree strengthens the part of the intermediary effect of debt financing cost. The conclusions not only help to reveal the impact mechanism of corporate social responsibility on enterprise innovation, but also provide empirical evidence for promoting enterprises to actively assume social responsibility, improve the level of innovation, and provide empirical evidence for the government to formulate corresponding policies according to the degree of competition in different markets., (© 2022. The Author(s).)

Background: Adding neoadjuvant chemotherapy (NAC) to concurrent chemoradiotherapy (CCRT) is the main strategy in treatment of children and adolescents with locoregionally advanced nasopharyngeal carcinoma (CA-LANPC). Yet, an optimal number of NAC cycles remains unknown. We aimed to optimize the NAC cycle and potentially contribute to clinical decision making for the individual treatment of CA-LANPC., Patients and Methods: Utilizing an NPC-specific database through an acknowledged big-data information system at our center, we identified 143 CA-LANPC treated with NAC followed by CCRT between September 2007 through April 2018. Recursive partitioning analysis (RPA) was performed to categorize the patients and predict disease-free survival (DFS). The clinical benefits of NAC cycles (two cycles vs three cycles) were assessed in each risk group., Results: Independent factors derived from multivariable analysis to predict DFS were T stage (T1-3 vs T4) and plasma Epstein-Barr virus (EBV) DNA (< 4000 vs ≥ 4000 copies/mL) for risk stratification. Consequently, 87 (61%) participants were classified as low-risk group (T1-3 with low or high EBV DNA, and T4 with low EBV DNA) and the other 56 patients (39%) were classified as a high-risk group (T4 with high EBV DNA) through RPA, and corresponding 5-year DFS rates of 91.9% and 71.2%, respectively (p = 0.001). Among the high-risk group, patients receiving three cycles of NAC had statistically significant improvement in 5-year DFS over those who received two cycles of NAC (86.7% vs 59.1%; p = 0.020), while the survival benefit of three cycles NAC for low-risk groups were not observed (94.7% vs 89.7%; p = 0.652)., Conclusions: We found three cycles of NAC with CCRT was a positive prognostic indicator for improved DFS for the high-risk group among CA-LANPC. However, whether low-risk patients could benefit from three cycles NAC needs further study., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: To investigate the clinicopathological, molecular genetic, immunohistochemical and prognostic features of spinal solitary fibrous tumor (SFT). Methods: The clinical data of 12 cases of spinal SFT in Beijing Tsinghua Changgung Hospital, Affiliated to Tsinghua University, diagnosed from January 2015 to December 2021 were collected and reclassified. The clinical data, histopathology, immunohistochemistry and molecular genetics were analyzed. Follow-up and related literature reviews were conducted. Results: Among the 12 patients, there were 5 males and 7 females; the age ranged from 31 to 73 years, with a median age of 50.5 years. All 12 cases were primary tumors, including 4 cases diagnosed at the first time and 8 recurrent cases. Among the 12 cases, 8 were WHO grade 1, 3 were WHO grade 2, and 1 was WHO grade 3. Microscopically, the spinal SFT appeared as a spindle cell tumor, the stroma was rich in many thin-walled blood vessels with various histological features such as cell morphology and necrosis according to the different tumor grade. All (12/12) of the cases expressed vimentin and STAT6 (diffuse and strong nuclear stain), 11 cases (11/12) expressed both CD34 and bcl-2, and 7 cases (7/12) expressed CD99. Next-generation sequencing showed that 12 (12/12) of the patients had NAB2-STAT6 gene fusion. The 12 patients were followed up for 6 to 80 months. There were no recurrences or metastases in the 4 first cases after operation. Among the 8 recurrent cases, 2 of the patients relapsed and 2 died. Conclusions: Spinal SFT is rare and has a high recurrence tendency. Many aspects need to be considered in the diagnosis process. STAT6 is a relatively specific marker for the diagnosis of this tumor. Complete surgical resection is the preferred treatment while postoperative radiotherapy is recommended to reduce tumor recurrence.

Inhibitor of apoptosis protein (IAP) is a class of E3 ubiquitin ligases functioning to support cancer survival and growth. Many small-molecule IAP antagonists have been developed, aiming to degrade IAP proteins to kill cancer. We have evaluated the effect of lipopolysaccharide (LPS), a component of the bacterial outer membrane, on IAP antagonists in treating breast cancer in a mouse model to guide future clinical trials. We show that LPS promotes IAP antagonist-induced regression of triple-negative breast cancer (TNBC) from MDA-MB-231 cells in immunodeficient mice. IAP antagonists such as SM-164, AT-406, and BV6, do not kill MDA-MB-231 cells alone, but allow LPS to induce cancer cell apoptosis rapidly. The apoptosis caused by LPS plus SM-164 is blocked by toll-like receptor 4 (TLR4) or MyD88 inhibitor, which inhibits LPS-induced TNFα production by the cancer cells. Consistent with this, MDA-MB-231 cell apoptosis induced by LPS plus SM-164 is also blocked by the TNF inhibitor. LPS alone does not kill MDA-MB-231 cells because it markedly increases the protein level of cIAP1/2, which is directly associated with and stabilized by MyD88, an adaptor protein of TLR4. ER + MCF7 breast cancer cells expressing low levels of cIAP1/2 undergo apoptosis in response to SM-164 combined with TNFα but not with LPS. Furthermore, TNFα but not LPS alone inhibits MCF7 cell growth in vitro . Consistent with these, LPS combined with SM-164, but not either of them alone, causes regression of ER + breast cancer from MCF7 cells in immunodeficient mice. In summary, LPS sensitizes the therapeutic response of both triple-negative and ER + breast cancer to IAP antagonist therapy by inducing rapid apoptosis of the cancer cells through TLR4- and MyD88-mediated production of TNFα. We conclude that antibiotics that can reduce microbiota-derived LPS should not be used together with an IAP antagonist for cancer therapy., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Liu, Yao, Chen, Lei, Duan and Yao.)

The first asymmetric total synthesis of (+)-alstonlarsine A has been realized. The prominent features of the current synthesis include the following: (i) a Pd/self-adaptable ligand complex-catalyzed asymmetric allylic alkylation of 2-methyl-2-cyclopentenyl carbonate with 2-indolylsubstituted dimethyl malonate to establish the key stereocenter of C15, (ii) an intramolecular nitrile oxide-alkene [3 + 2] cycloaddition (INOC [3 + 2]) to construct the cyclohepta[ b ]indole backbone with the installment of the requisite stereochemistry of the all-carbon quaternary center of C20, and (iii) a late-stage interrupted Pictet-Spengler reaction (IPSR) to rapidly assemble the core structure of (+)-alstonlarsine A.

The present study aimed to establish esophageal squamous carcinoma cell (ESCC) sublines with different invasive and metastatic potentials. Gene microarrays were used for differential gene screening with the establishment of ESCC invasive metastatic gene expression profiles. Some differential gene expressions were validated. Parent line Eca109-T0 was screened in a Transwell chamber to establish Eca109-T4 with high invasion and metastasis. The migrative and proliferative capacities of ESCCs were compared. The Eca109-T0 and Eca109-T4 cell lines were taken as the research objects and were hybridized with gene chips to obtain cell sublines for the screening of differential genes of ESCCs with varying invasive and metastatic potentials. Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) clustering analyses were conducted. Some differential genes (HSP90AA1, ANXA1, YWHAB, CXCR7, SDC2, and TNFRSF10D messenger ribonucleic acid) were validated by qualitative real-time polymerase chain reaction and Western blot analysis. As a result, some Eca109-T4 ESCC sublines with high invasive and metastatic potential were screened in a Transwell chamber. The gene chip analysis screened out 326 differential genes, of which 123 were upregulated and 203 were downregulated by Eca109-T4. The GO cluster analysis indicated that the genes were in the cytoplasm, nucleus, and cytosol. The molecular functions of these genes involved the binding of proteins and metal ions and participation in biological processes, including cell signal transduction, transcription, and apoptosis. The KEGG clustering showed that these genes were mainly involved in signaling pathways, such as actin cytoskeleton regulation, the mitogen-activated protein kinase pathway, and the cancer pathway. The validation results were basically consistent with the gene microarray screening results. In Eca109-T4 and CE81T-4, HSP90AA1, YWHAB, and CXCR7 were highly expressed, while the expression of ANXA1 was low. In conclusion esophageal squamous carcinoma cell models with different invasive and metastatic potentials were established. The establishment of differential gene expression profiles for invasion and metastasis together with a bioinformatics analysis provided rich information for studies related to ESCC invasion and metastasis. HSP90α, 14-3-3β, and CXCR7 were highly expressed in ESCCs with high invasion and metastasis, while Annexin A1 was highly expressed in ESCCs with low metastasis.

Ras has long been viewed as a promising target for cancer therapy. Farnesylthiosalicylic acid (FTS), as the only Ras inhibitor has ever entered phase II clinical trials, has yielded disappointing results due to its strong hydrophobicity, poor tumor-targeting capacity, and low therapeutic efficiency. Thus, enhancing hydrophilicity and tumor-targeting capacity of FTS for improving its therapeutic efficacy is of great significance. In this study we conjugated FTS with a cancer-targeting small molecule dye IR783 and characterized the anticancer properties of the conjugate FTS-IR783. We showed that IR783 conjugation greatly improved the hydrophilicity, tumor-targeting and therapeutic potential of FTS. After a single oral administration in Balb/c mice, the relative bioavailability of FTS-IR783 was increased by 90.7% compared with FTS. We demonstrated that organic anion transporting polypeptide (OATP) and endocytosis synergistically drove the uptake of the FTS-IR783 conjugate in breast cancer MDA-MB-231 cells, resulting in superior tumor-targeting ability of the conjugate both in vitro and in vivo. We further revealed that FTS-IR783 conjugate could bind with and directly activate AMPK rather than affecting Ras, and subsequently regulate the TSC2/mTOR signaling pathway, thus achieving 2-10-fold increased anti-cancer therapeutic efficacy against 6 human breast cancer cell lines compared to FTS both in vivo and in vitro. Overall, our data highlights a promising approach for the modification of the anti-tumor drug FTS using IR783 and makes it possible to return FTS back to the clinic with a better efficacy., (© 2021. The Author(s), under exclusive licence to CPS and SIMM.)

Background: To assess the prognostic value of the systemic inflammation response index (SIRI) combined with plasma load of Epstein-Barr virus (EBV) DNA in children and adolescents with locoregionally advanced nasopharyngeal carcinoma (CALANPC)., Methods: A total of 205 consecutive patients with CALANPC were enrolled. We used recursive partitioning analysis (RPA) to classify patients into various risk groups, with a primary endpoint of overall survival (OS)., Results: Elevated SIRI (≥1.53) and EBV DNA (≥4000 copy/ml) were significantly associated with inferior OS in CALANPC. RPA categorized patients into low- and high-risk groups based on prognostic factors. Survival curves showed excellent discrimination in OS (95.3% vs 77.6%; p < 0.001) between the low- and high-risk groups. A significant improvement was confirmed using the prognostic methods for conventional TNM staging systems (p < 0.05)., Conclusions: The combination of SIRI with EBV DNA provided a more detailed understanding of patient risks, and enhanced risk discrimination in CALANPC., (© 2022 Wiley Periodicals LLC.)

Background: We aim to investigate the prognostic value of weight loss during radiotherapy (RT) among patients with nasopharyngeal carcinoma (NPC)., Methods: A total of 1149 NPC patients who received radical RT were retrospectively analyzed. Patients' weight were measured at initiation of RT (W Pre-RT ) and every week during RT (W RT1,2,3,4,5,6,7 ). Percentage of weight loss (PWL) at 1st, 2nd, 3rd, 4th, 5th, 6th, and 7th week of RT (RT-PWL 1,2,3,4,5,6,7 ) were calculated using the following equation: (W Pre-RT -W RT1,2,3,4,5,6,7 )/W Pre-RT  × 100%. The optimal threshold of RT-PWL 7 was determined by recursive partitioning analyses (RPAs). Our endpoints included disease-free survival (DFS), overall survival (OS), distant metastasis-free survival (DMFS), and locoregional relapse-free survival (LRRFS)., Results: The median RT-PWLs were 0, 0, 1.5, 2.9, 4.1, 5.5, 6.6% at 1st, 2nd, 3rd, 4th, 5th, 6th, and 7th week of RT, respectively. RT-PWL 7 optimal threshold with respect to DFS was 5.3% based on RPAs. Therefore, a consistent threshold of 5% (<5% vs > ≥5%) was selected to classify NPC patients into low RT-PWL 7 and high RT-PWL 7 groups for survival analysis. Compared to high RT-PWL 7 (≥5%), patients with low RT-PWL 7 (< 5%) had significantly better ten-year DFS (61.2% vs 78.8%; P < 0.001), OS (70.1% vs 86.6%; P < 0.001), and DMFS (80.2% vs 88.5%; P = 0.007). However, no difference was observed between LRRFS groups (91.7% vs 94.3%; P = 0.173). In multivariate analysis, high RT-PWL 7 was an independent risk factor for DFS (HR, 1.56; 95%CI, 1.19-2.03; P = 0.001), OS (HR, 1.54; 95%CI, 1.11-2.15; P = 0.011), and DMFS (HR, 1.47; 95%CI, 1.03-2.10; P = 0.033) in patients with NPC. In addition, treatment strategy, plasma Epstein-Barr virus DNA, and N stage were associated with weight loss., Conclusions: High RT-PWL 7 was significantly associated with decreased DFS, OS, and DMFS for NPC patients. Clinicians should continuously inform patients on the health impact of minimizing RT-PWL 7 under 5% during radiotherapy., (© 2022. The Author(s).)

Introduction: The newly developed Composite Activity-related Risk of Falls Scale (CARFS) is designed to measure composite activity-related risk of falls (CARF) in relation to the activity-specific fear of falling and physical behavior. This study tested the reliability and validity of the CARFS in older people with various health statuses and persons with stroke or spinal cord injury., Methods: Participants included 70 older adults, 38 persons with stroke, and 18 with spinal cord injury. They were first surveyed using a combined questionnaire including the CARFS and activity-specific balance confidence (ABC) scale in addition to items asking for personal and disease-related information, fall history, walking independence levels for examining internal consistency, ceiling and floor effects, and convergent validity in each participant group. One week after the initial survey, 33 older participants were reexamined using the CARFS to analyze test-retest reliability, where a minimal detectable change was found. Significance was set at α = 0.05 for all analyses., Results: The CARFS showed excellent test-retest reliability in the dimensions of fear of falling, physical behavior, and CARF [ICC (3,1) = 0.972, 0.994, and 0.994, respectively for their overall score], with a minimal detectable change of 3.944 in the older population. The internal consistency of CARFS items was excellent in the older participants, good in participants with stroke or spinal cord injury (Cronbach's alpha = 0.945, 0.843, 0.831 in each participant group, respectively). No ceiling and floor effects were demonstrated in the wide range of people. For the convergent validity, overall CARF score was significantly correlated with the average ABC score in each participant group (rho = -0.824, -0.761, and -0.601, respectively; p < 0.01), and was significantly correlated with walking independence levels in each participant group (rho = -0.636, -0.423, and -0.522, respectively; p < 0.01). It showed weak correlation with the number of previous falls only in participants with stroke (rho = 0.291, p = 0.076)., Conclusion: The CARFS is a reliable and valid tool for measuring fall risk in older people and persons with stroke or spinal cord injury., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Jiang, Wang, Chen, Yao, Ni, Sheng and Shen.)

Silicosis is the most serious occupational pulmonary fibrosis caused by excessive inhalation of silica particles, whereas viable therapeutic choices are constrained. Epigallocatechin gallate (EGCG) presents massive health benefits, but unfortunately with stability absence. Here, encapsulation of EGCG in poly(n-butylcyanoacrylate) nanoparticles (EGCG/PBCA-NPs) were fabricated by self-polymerization for gastrointestinal delivery in silicosis fibrosis treatment. The obtained nano-enabled delivery of EGCG was produced using a medical adhesive approved by FDA as carrier, and presented spherical particles with approximate diameter of 160 nm, a narrow PDI value of 0.2, Zeta potential value of 30 mV as well as a high EGCG incorporation (90 %) and loading efficiency (20 %). In evaluating the protect effects of nano-formulations, EGCG/PBCA-NPs shown excellent stability in gastric fluid with pH-triggered release in intestine and strong EGCG gastrointestinal retention against degradation. After daily gastrointestinal administration, EGCG/PBCA-NPs exhibited the superior anti-fibrosis efficacy in silicosis model rats induced by silica, involving lung index decline, hydroxyproline content decrease, histological improvement, collagen accumulation reduction and α-SMA down-regulation in comparison with naked EGCG. These results strongly demonstrated that PBCA-based NPs may be a promising nano-enabled delivery carrier for enhancing the gastrointestinal stability and anti-fibrotic effects of EGCG., (Copyright © 2022. Published by Elsevier B.V.)

Background: The high prevalence of falling among older adults constitutes a major public and clinical health concern. Many elderly persons may develop activities-specific restriction due to the risk of falling. This highlights the need for relevant evaluative tools., Methods: This cross-sectional study used activities-specific performance frequency indicators to quantify activity restrictions in elderly participants, with all measures based on items from the Activities-Specific Balance Confidence (ABC) scale. Specifically, we tested for correlations between activities-specific performance frequency and balance confidence, functional balance/mobility, and fall history. There were 88 elderly participants, including 28 with stroke, 30 with Parkinson's disease, and 30 with no neurological diseases. In addition to their activities-specific performance frequency measures, we collected a series of demographic and health-related characteristics from each participant. We analyzed between-group differences in activities-specific performance frequency and other demographic and health-related characteristics via the one-way analysis of variance and Kruskal-Wallis test. Next, we used the Spearman's rank correlation test and binary logistic regression to investigate the correlations between activities-specific performance frequency and demographic/other health-related characteristics., Results: There were significant group differences in performance frequency for all ABC activity items except for walking around the house, average ABC scores, and functional balance/mobility among normal older adults, participants with strokes and those with Parkinson's disease. Activities-specific performance frequency showed stronger correlations with activities-relevant functional mobility (r=0.250-0.713 for 15 items with significant correlations, 13 activity items with r≧0.4) than with balance confidence (r=0.279-0.668 for 13 items with significant correlations, 10 activity items with r≧0.4). The performance frequency of walking in crowds/bumped was the most sensitive measure for predicting fallers (odd ratio=3.310, p<0.05)., Conclusions: This study proposed and validated the usage of activities-specific performance frequency as an alternative method for quantifying activity restrictions among older adults., (© 2022. The Author(s).)

Background: Following revision shoulder arthroplasty, postoperative antibiotics are selected before the results of intraoperative cultures become available. We determined infection-free survival, revision-free survival, complications, and patient-reported outcomes for patients selected to receive oral or intravenous (IV) antibiotics after revision arthroplasty., Methods: This study included 92 patients who had revision shoulder arthroplasty. IV antibiotics were administered if the surgeon had a high index of suspicion for infection, and oral antibiotics were given if there was a low suspicion. Antibiotic therapy was modified based on intraoperative culture results. Patient-reported outcomes and adverse events were documented at a mean of 4.1 years., Results: In selecting antibiotic therapy, surgeons correctly predicted the presence or absence of multiple positive cultures of specimens from the revision surgery in 72% of the 92 cases. Subsequent re-revision surgery was required in 17 (18%) of the patients; 8 of these 17 patients had ≥2 positive cultures at re-revision. Patients who initially received IV antibiotics and those who initially received oral antibiotics had similar revision-free (p = 0.202) and infection-free (p = 0.155) survivorship. Patients requiring a change from oral to IV antibiotics based on positive cultures had similar survivorship compared with those initially treated with IV antibiotics. The IV and oral antibiotic groups had similar postoperative Simple Shoulder Test (SST), American Shoulder and Elbow Surgeons (ASES), and satisfaction scores. Patients receiving IV antibiotics had a higher rate of antibiotic-related adverse events., Conclusions: Post-revision antibiotic therapy was associated with an infection-free survival rate of 91% at a mean of >4 years of follow-up. Infection-free survival, revision-free survival, and patient-reported outcomes were similar in high-risk patients placed on IV antibiotics and low-risk patients placed on oral antibiotics. Further study is needed to define the indications for IV or oral antibiotics after revision arthroplasty., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJS/G783)., (Copyright © 2021 by The Journal of Bone and Joint Surgery, Incorporated.)

Purpose: To quantify and predict the survival benefits of cumulative cisplatin dose during concurrent chemoradiotherapy (CC-CCD) in children and adolescents with locoregionally advanced nasopharyngeal carcinoma (CA-LANPC)., Materials and Methods: Patients with CA-LANPC who received first-line neoadjuvant chemotherapy (NAC) followed by concurrent chemoradiotherapy (CCRT) between September 2007 and April 2018 were evaluated. Recursive partitioning analyses (RPAs) helped identify the ideal thresholds of CC-CCD on disease-free survival (DFS). We then developed a web-based predictive model to quantify the survival benefit of CC-CCD for CA-LANPC., Results: In total, 139 patients were eligible for the analysis. The median CC-CCD was 162 mg/m 2 (IQR, 138-192 mg/m 2 ). The optimum cut-off point of CC-CCD was 160 mg/m 2 for DFS. Hence, we selected 160 mg/m 2 as the cut-off to classify CA-LANPC into either high or low CC-CCD groups for survival analysis. The 5-year DFS rates were 91.6% in the high (≥160 mg/m 2 ) CC-CCD group and 77.8% in the low (<160 mg/m 2 ) CC-CCD group (P = 0.011). Multivariate analysis indicated CC-CCD (HR, 0.34; 95%CI, 0.13-0.87; P = 0.024), T stage (HR, 3.72; 95%CI, 1.35-10.22; P = 0.011), and EBV DNA (HR, 3.00; 95%CI, 1.00-8.97; P = 0.049) were independent prognostic factors and were incorporated into the prognostic model. N stage was also included due to its clinical importance. The predictive model was demonstrably accurate (C-index, 0.741) when predicting 5-year DFS rates., Conclusions: We built a predictive model to quantify the survival benefit of CC-CCD for CA-LANPC treated with NAC plus CCRT. This tool may improve individual treatment consultations and facilitate evidence-based decision-making., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Cutibacterium periprosthetic joint infections are important complications of shoulder arthroplasty. Although it is known that these infections are more common among men and that they are more common in patients with high levels of Cutibacterium on the skin, the possible relationship between serum testosterone levels and skin Cutibacterium levels has not been investigated., Methods: In 51 patients undergoing shoulder arthroplasties, total serum testosterone, free testosterone, and sex hormone binding globulin levels obtained in the clinic before the surgical procedure were compared with the levels of Cutibacterium on the skin in clinic, on the skin in the operating room prior to the surgical procedure, and on the dermal wound edge of the incised skin during the surgical procedure., Results: Clinic skin Cutibacterium loads were strongly associated with both clinic free testosterone levels (tau, 0.569; p < 0.001) and total serum testosterone levels (tau, 0.591; p < 0.001). The prepreparation skin and wound Cutibacterium levels at the time of the surgical procedure were also significantly associated with both the clinic total serum testosterone levels (p < 0.001) and the clinic free testosterone levels (p < 0.03). A multivariate analysis demonstrated that serum testosterone was an independent predictor of high skin Cutibacterium loads, even when age and sex were taken into account. Patients taking supplemental testosterone had higher free testosterone levels and tended to have higher skin Cutibacterium loads. Patients who underwent the ream-and-run procedure had higher total and free testosterone levels and higher skin Cutibacterium loads., Conclusions: Testosterone levels are predictive of skin Cutibacterium levels in patients undergoing shoulder arthroplasty. This relationship deserves further investigation both as a risk stratification tool and as a potential area for intervention in reducing shoulder periprosthetic joint infection., Level of Evidence: Prognostic Level II. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: Disclosure: The Disclosure of Potential Conflicts of Interest forms are provided with the online version of the article (http://links.lww.com/JBJSOA/A341)., (Copyright © 2021 The Authors. Published by The Journal of Bone and Joint Surgery, Incorporated. All rights reserved.)

The Coronavirus disease 2019 (COVID-19) pandemic is still spread and has made a severe public health threat around the world. To improve disease progression, emerging Chinese herbal compounds were used in clinical practice and some agents have proven beneficial in treating COVID-19. Here, the relevant literature from basic researches to clinical application were identified and comprehensively assessed. A variety of Chinese herbal compounds have been reported to be effective in improving symptoms and outcomes in patients with COVID-19, particularly together with routine treatment strategy. The pharmacological activities were mainly attributed to the relief of clinical symptoms, inhibition of cytokine storm, and improvement of organ function. Besides, the development of novel antiviral drugs from medicinal herbs were further discussed. The updated laboratory and clinical studies provided the evidence of Chinese herbal compounds such as Lianhua Qingwen prescription, Shufeng Jiedu prescription, and Qingfei Paidu Tang for the relief of COVID-19. However, both of the randomized controlled trials and real world researches need to be done for supporting the evidence including the efficacy and safety in fighting COVID-19., (© 2021. The Author(s).)

Metal orthopedic implants are largely biocompatible and generally achieve long-term structural fixation. However, some orthopedic implants may loosen over time even in the absence of infection. In vivo fixation failure is multifactorial, but the fundamental biological defect is cellular dysfunction at the host-implant interface. Strategies to reduce the risk of short- and long-term loosening include surface modifications, implant metal alloy type, and adjuvant substances such as polymethylmethacrylate cement. Surface modifications (e.g., increased surface rugosity) can increase osseointegration and biological ingrowth of orthopedic implants. However, the localized responses of cells to implant surface modifications need to be better characterized. As an in vitro model for investigating cellular responses to metallic orthopedic implants, we cultured mesenchymal stromal/stem cells on clinical-grade titanium disks (Ti6Al4V) that differed in surface roughness as high (porous structured), medium (grit blasted), and low (bead blasted). Topological characterization of clinically relevant titanium (Ti) materials combined with differential mRNA expression analyses (RNA-seq and real-time quantitative polymerase chain reaction) revealed alterations to the biological phenotype of cells cultured on titanium structures that favor early extracellular matrix production and observable responses to oxidative stress and heavy metal stress. These results provide a descriptive model for the interpretation of cellular responses at the interface between native host tissues and three-dimensionally printed modular orthopedic implants, and will guide future studies aimed at increasing the long-term retention of such materials after total joint arthroplasty. Impact statement Using an in vitro model of implant-to-cell interactions by culturing mesenchymal stromal cells (MSCs) on clinically relevant titanium materials of varying topological roughness, we identified mRNA expression patterns consistent with early extracellular matrix (ECM) production and responses to oxidative/heavy metal stress. Implants with high surface roughness may delay the differentiation and ECM formation of MSCs and alter the expression of genes sensitive to reactive oxygen species and protein kinases. In combination with ongoing animal studies, these results will guide future studies aimed at increasing the long-term retention of widely used titanium materials after total joint arthroplasty.

Background: We aimed to comprehensively investigate the optimal cumulative cisplatin dose during concurrent chemoradiotherapy (CC-CCD) for locoregionally advanced nasopharyngeal carcinoma (CA-LANPC) with different tumor responses after neoadjuvant chemotherapy (NAC)., Methods: Patients with CA-LANPC who underwent NAC followed by cisplatin-based concurrent chemoradiotherapy were retrospectively analyzed. Evaluation of tumor response in patients was conducted by Response Evaluation Criteria for Solid Tumor (RECIST) 1.1 after two to four cycles NAC. Multivariate Cox proportional hazards models were used for prognosis. Recursive partitioning analysis (RPA) was conducted to classify participates and predict disease-free survival (DFS)., Results: One hundred and thirty-two patients with favorable response after NAC were included. The median CC-CCD was 163 mg/m 2 (IQR, 145-194 mg/m 2 ), and 160 mg/m 2 was selected as the cutoff point to group patients into low and high CC-CCD groups (< 160 vs. ≥ 160 mg/m 2 ). There was significant improvement in 5-year DFS (91.2% vs. 72.6%; P = 0.003) for patients receiving high CC-CCD compared to those receiving low CC-CCD. Multivariate analysis revealed that CC-CCD, T stage, and Epstein-Barr virus (EBV) DNA were independent prognostic factors for DFS (P < 0.05 for all). Patients were further categorized into two prognostic groups by RPA: the low-risk group (T1-3 disease with regardless of EBV DNA, and T4 disease with EBV DNA < 4000 copy/mL), and the high-risk group (T4 disease with EBV DNA ≥ 4000 copy/mL). Significant 5-year DFS improvement was observed for the high-risk group (P = 0.004) with high CC-CCD. However, DFS improvement was relatively insignificant in the low-risk group (P = 0.073)., Conclusions: CC-CCD was a positive prognostic factor for responders after NAC in CA-LANPC. Furthermore, CC-CCD ≥ 160 mg/m 2 could significantly improve DFS in the high-risk group with CA-LANPC, but the benefit of high CC-CCD in the low-risk group needs further study., (© 2021. The Author(s).)