Search

Fengting Wang,1,* Limin Rong,1,* Linlin Luo,2 Fuqin Mu,1 Liju Qian,3 Yandan Qian,4 Xinyao Zhang,1 Yuying Lang,1 Weijia Wang,1 Yan Liu,5,6 Ying Zhang,7 Jianli Wang1,8 1School of Mental Health, Jining Medical University, Jining, Shandong, People’s Republic of China; 2Department of Hematology, Tai’an Central Hospital, Tai’an, Shandong, People’s Republic of China; 3Shandong Daizhuang Hospital, Jining, Shandong, People’s Republic of China; 4The Third People’s Hospital of Jiashan County, Jiashan, Zhejiang, People’s Republic of China; 5School of Public Health, Jining Medical University, Jining, Shandong, People’s Republic of China; 6Center of Evidence-Based Medicine, Jining Medical University, Jining, Shandong, People’s Republic of China; 7School of Public Health, University of Sydney, Sydney, NSW, Australia; 8Department of Community Health and Epidemiology, Dalhousie University, Halifax, Nova Scotia, Canada*These authors contributed equally to this workCorrespondence: Fengting Wang, School of Mental Health, Jining Medical University, Jining, Shandong, 272013, People’s Republic of China, Email wft.0810@163.com Yan Liu, School of Public Health, Jining Medical University, Jining, Shandong, 272013, People’s Republic of China, Email hakunaly@163.comBackground: Youth and young adults have a high prevalence of major depressive disorder (MDD). Limited longitudinal research has explored the relationship between different dimensions of psychological stress and MDD. This study aimed to estimate the effect of psychological stress on the risk of first onset MDD in a sample of Chinese freshmen.Methods: Using a longitudinal design, 8079 Chinese first-year students were recruited at baseline, and 6985 were followed up one year later. The Psychological Stress Scale for College Students was utilized to evaluate the levels of psychological stress. MDD was evaluated using the Chinese version of the Composite International Diagnostic Interview (CIDI-3.0). Logistic regression modeling was utilized to estimate the associations between dimensions of psychological stress and the risk of MDD.Results: Two dimensions of psychological stress, namely learning stress (OR=1.05, 95% CI:1.01– 1.09, P=0.017) and economic stress (OR=1.11, 95% CI:1.04– 1.19, P=0.001), were significantly associated with the risk of MDD. Other dimensions of psychological stress (specify family stress, interpersonal stress, intimate relationship stress, employment stress and appearance stress) were not associated with MDD.Conclusion: Psychological stress, especially learning and economic stresses, could increase the risk of MDD in university students. These factors should be incorporated into mental health prevention and intervention programs at universities to reduce the risks of MDD.Keywords: major depressive disorder, psychological stress, longitudinal study, freshmen

Xiaoqing Ma,* Ruoying Zhang,* Xinjun Cai, Yuying Lang, Huaichong Wang, Jinmeng Li Department of Pharmacy, Hangzhou Red Cross Hospital, Hangzhou, People’s Republic of China*These authors contributed equally to this workCorrespondence: Jinmeng Li, Department of Pharmacy, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang Province, 310000, People’s Republic of China, Email jinmeng608@163.comAbstract: As a new generation of oxazolidinone antibacterial drugs, contezolid has been shown to have comparable or even stronger activity than linezolid and has a low risk of adverse reactions such as bone marrow suppression toxicity. However, there are currently very few clinical reports and pharmacokinetic data of contezolid on the anti-tuberculosis therapy. Therefore, we report a case study of the pharmacokinetic study of contezolid in elderly patients with renal insufficiency and tuberculosis. The patient’s condition improved after receiving an anti-tuberculosis regimen containing contezolid, with significant absorption of pleural effusion and lung plaques and nodules reduced. During the treatment, the patients’ platelet and white blood cell levels fluctuated within normal ranges, but hemoglobin levels significantly decreased and did not recover after discontinuation of contezolid. The trough concentration of contezolid and the concentration at 2, 4, 6, and 10 h after administration were 1.27μg/mL, 3.88μg/mL, 6.32μg/mL, 8.99μg/mL, and 3.14μg/mL, respectively. The plasma concentrations of bedaquiline and cycloserine during the treatment were also monitored. This study demonstrated the efficacy and safety of contezolid in the treatment of multidrug-resistant tuberculosis and analyzed its pharmacokinetic changes in elderly patients with renal insufficiency, providing a reference for the clinical use of contezolid.Keywords: contezolid, tuberculosis, plasma concentration, efficacy, safety

Huaichong Wang,1 Yuying Lang,1 Xinjun Cai,1 Liujie Gao,2 Shengya Yang,3 Jie Jin1 1Department of Pharmacy, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang Province, People’s Republic of China; 2Department of Oncology, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang Province, People’s Republic of China; 3Tuberculosis Diagnosis and Treatment Center, Hangzhou Red Cross Hospital, Hangzhou, Zhejiang Province, People’s Republic of ChinaCorrespondence: Jie Jin, Department of Pharmacy, Hangzhou Red Cross Hospital, East Huancheng Road No. 208, Hangzhou, Zhejiang Province, People’s Republic of China, Email jinjie0916@163.comBackground: Lymphoma is complicated by intricate infections, notably Pneumocystis jirovecii pneumonia (PJP), marked by rapid progression, respiratory failure, and high mortality. Rapid diagnosis of PJP and effective administration of the first-line treatment trimethoprim-sulfamethoxazole (TMP-SMX) are important. For patients intolerant to TMP-SMX, selecting appropriate alternatives is challenging, necessitating careful decisions to optimize diagnosis and treatment. We present a lymphoma case complicated by PJP, illustrating medication adjustment until a positive response was observed.Case Description: A 41-year-old male patient with lymphoma presented with a week-long history of fever, fatigue, cough, sputum, chest tightness, and exertional dyspnea, unresponsive to treatment. Routine laboratory examinations revealed no pathogenic bacteria. PJ and Mycobacterium tuberculosis (MTB) were detected in bronchoalveolar lavage fluid (BALF) using metagenomic next-generation sequencing (mNGS). On Day 1 of admission, meropenem, TMP-SMX, and rifampicin+isoniazid+levofloxacin were administered. However, the patient developed drug-induced hepatotoxicity and gastrointestinal adverse reactions after six days of treatment. After a multidisciplinary team discussion, anti-tuberculosis therapy was stopped because of insufficient evidence of tuberculosis infection. A reduced dose of TMP-SMX with micafungin was used for PJP; however, symptoms persisted and repeated computed tomography showed extensive deterioration of bilateral pulmonary plaques. The PJP regimen was modified to include a combination of TMP-SMX and caspofungin. Due to the high fever and elevated infection indices, the patient was treated with teicoplanin to enhance the anti-infection effects. By Day 13, the patient’s temperature had normalized, and infection control was achieved by Day 30. CT revealed that the infection in both lung lobes fully resolved. Subsequently, lymphoma treatment commenced.Conclusion: BALF-NGS facilitates early and rapid diagnosis of PJP. mNGS reads of MTB bacillus < 5 may indicate a bacterial carrier state, warranting other detection techniques to support it. There is insufficient evidence for using TMP-SMX with micafungin to treat PJP; however, TMP-SMX combined with caspofungin is suitable.Keywords: bronchoalveolar lavage fluid, metagenomic next-generation sequencing, Pneumocystis jirovecii pneumonia, Mycobacterium tuberculosis, trimethoprim-sulfamethoxazole

Kai Rong, Yi Lang, Yubo Zhou, Liangtao Ni, Lei Wang, Long Wang, Yaowu Zhang, Fengli Wen, Zhan Wang, Pingbo Chen Department of Traumatology, Traditional Chinese Medicine Hospital Affiliated to Xinjiang Medical University, Wulumuqi, Xinjiang, People’s Republic of ChinaCorrespondence: Pingbo Chen, Department of Traumatology, Traditional Chinese Medicine Hospital Affiliated to Xinjiang Medical University, No. 116, Huanghe Street, Wulumuqi, Xinjiang, People’s Republic of China, Tel/Fax +86-13899907800, Email xj.2016@foxmail.comBackground: Osteoporosis (OP) is a common metabolic bone disease characterized by loss of bone mass. IL-10 is considered to be a powerful immune and inflammatory suppressor. This study aimed to assess association between genetic loci in IL-10 and susceptibility to OP.Methods: Association analysis between IL-10 genetic loci and OP risk through SNPStats online software. FPRP analysis (false-positive report probability) verified whether the positive results were noteworthy findings. Linkage disequilibrium (LD) and haplotype analysis were completed by Haploview 4.2 and SNPStats. Multi-factor dimensionality reduction (MDR) was used to assess interaction of SNP–SNP in susceptibility to OP.Results: Allele “G” of IL-10-rs1554286 (OR = 1.21, p = 0.013), allele “C” of IL-10-rs1518111 (OR = 1.22, p = 0.011), allele “C” of IL-10-rs3024490 (OR = 1.20, p = 0.018), and allele “G” of IL-10-rs1800871 (OR = 1.21, p = 0.015) were risk factors for OP. In females, smoking, drinking, or aging ≤ 60 years old participants, the above genetic loci are also significantly associated with the increased risk of OP. FPRP analysis showed that all positive results are noteworthy findings. There are significant differences in serum levels of uric acid, mean hemoglobin concentration, or mean hemoglobin among different genotypes of IL-10 gene loci. MDR showed that four loci model composed rs1554286, rs1518111, rs3021094, and rs1800871 is the best model for predicting OP risk.Conclusion: IL-10-rs1554286, -rs1518111, -rs3021094, and -rs1800871 are risk factors for susceptibility to OP.Keywords: osteoporosis, IL-10, genetic loci, Han population from northwest China

Yitian Lang,1 Bin Wu,2 Xiaoyan Liu1 1Department of Pharmacy, Huangpu Branch, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, People’s Republic of China; 2Medical Decision and Economic Group, Department of Pharmacy, Ren Ji Hospital, South Campus, School of Medicine, Shanghai Jiaotong University, Shanghai, People’s Republic of ChinaCorrespondence: Xiaoyan Liu, Department of Pharmacy, Huangpu Branch, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, No. 58 Puyu East Roa, Huangpu Districtd, Shanghai, 200011, People’s Republic of China, Email liuxiaoyanrj@sjtu.edu.cnPurpose: Recently, the DESTINY-Breast04 trial revealed that significant benefits in both overall survival (OS) and progression-free survival (PFS) in patients with HER2-low advanced or metastatic breast cancer treated with trastuzumab deruxtecan (T-DXd) compared with chemotherapy. The current study assessed the cost-effectiveness of T-DXd from the perspective of the United States payer.Methods: We developed a partitioned survival model to project the disease course of breast cancer. The OS and PFS data were derived from the DESTINY-Breast04 trial. We extrapolate the survival data beyond the follow-up time to assess the long-term survival prognosis. Direct medical costs and utility data were collected. The incremental cost-utility ratio (ICUR) was the primary outcome that evaluated the cost-effectiveness of a therapy regimen. One-way sensitivity and probabilistic sensitivity analysis were implemented to explore the uncertainty of outputs.Results: In the base-case, the ICUR of T-DXd versus chemotherapy is &dollar;346,571.8/QALY and &dollar;337,789.4/QALY for all patients group and hormone-receptor-positive (HR+) subgroup, respectively. One-way sensitivity analyses revealed that the hazard ratio of OS, the unit cost of T-DXd, and body weight had a relatively large impact on the base-case result. Probabilistic sensitivity analyses showed that the likelihood that T-DXd was cost-effective is 14.5% and 12.6% for all patients group and HR+ subgroup, respectively.Conclusion: The cost-effectiveness analysis suggested that, at current price, trastuzumab deruxtecan is unlikely to be a preferred option for patients with HER2-low breast cancer at a threshold of &dollar;150,000/QALY from a US payer perspective.Keywords: cost-effectiveness, HER2-low breast cancer, trastuzumab deruxtecan, partitioned survival approach

Pan Li, Xinfeng Liu, Yanmei Lang, Xiaowei Cui, Yanxi Shi Respiratory Department, Children’s Hospital of Hebei Province, Shijiazhuang, 050031, People’s Republic of ChinaCorrespondence: Yanxi Shi, Respiratory Department, Children’s Hospital of Hebei Province, 133 Jianhua South Street, Shijiazhuang, 050031, People’s Republic of China, Email Daniel_2022@126.comIntroduction: Influenza B viruses are less common than influenza A viruses in most seasons and cause relatively milder forms of infection that are less studied. We witnessed a dominance of influenza B in Shijiazhuang, China, in the 2021– 2022 winter season. In this study, we comparatively investigated the severe and critical influenza B in pediatric patients.Methods: Children who were hospitalized from December 2021 to January 2022 and diagnosed with influenza B were included in this study. Those who tested positive for COVID-19 were excluded. Demographic data, clinical features, underlying medical conditions, laboratory testing results, and treatment outcomes were retrieved and analyzed retrospectively. Disease severity was classified as severe or critical according to Chinese expert consensus on diagnosis and treatment of influenza in children.Results: A significantly greater proportion of patients with critical influenza had extra-pulmonary complications and bacterial coinfections. Children with critical influenza B had substantially higher levels of procalcitonin and lactate dehydrogenase, a markedly higher neutrophil percentage and a significantly lower CD4+ lymphocyte percentage.Conclusion: Our findings suggest that, to effectively manage critical influenza B, therapeutic regimens should consist of organ-specific supportive care, antibiotic application if bacterial coinfection is present, and anti-inflammatory and immune-boosting treatments.Keywords: influenza B, critically ill children, extra-pulmonary complication, bacterial coinfection, treatment

Yitian Lang,1 Bin Wu,2 Zhilin Sun,3 Erjia Ye,4 Guanshen Dou,4 Xin Guan3 1Department of Pharmacy, Huangpu Branch, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, People’s Republic of China; 2Medical Decision and Economic Group, Department of Pharmacy, Renji Hospital, School of Medicine, Shanghai Jiaotong University, Shanghai, 201100, People’s Republic of China; 3Department of Dermatology, Peking University Third Hospital, Peking University, Haidian District, Beijing, People’s Republic of China; 4Lilly China Drug Development and Medical Affairs Center, Eli Lilly and Company, Shanghai, People’s Republic of ChinaCorrespondence: Xin Guan, Department of Dermatology, Peking University Third Hospital, Peking University, No. 49, Huayuan North Road, Haidian District, Beijing, People’s Republic of China, Email guanxin1@sina.comObjective: Assessments of patients’ preferences can support in clinical decision-making regarding biologic therapies for psoriasis. Our objective was to investigate patient preference for biologic treatments in patients with psoriasis in China.Methods: From October 2020 to January 2021, psoriasis patients were recruited for a survey that included demographic and disease-related questions, as well as a discrete choice experiment to measure their preferences for biologic therapy. A discrete-choice experiment was used in which respondents selected psoriasis treatments based on benefits (ie, early onset of efficacy, long-term efficacy, sustained efficacy) and treatment costs. We analyzed choice data using conditional logit model.Results: This study included 236 patients with moderate-to-severe psoriasis. The relative importance of the cost of biologic treatments, probability of keeping PASI100 at 5 years, probability of achieving PASI100 at 3 months and time to achieve PASI50 after initiation the biologic treatment were 0.593, 0.137, 0.185 and 0.085. Over 50% of patients regarded the cost of biologic treatments as the most important attribute. High-income and low-income subgroups had higher preference weight in probability of achieving PASI100 at 3-month and monthly cost.Conclusion: The cost of biologic treatments was found as the most important attribute for Chinese patients with psoriasis. Among efficacy attributes, the probability of achieving PASI100 at 3 months showed most sensitive. These results may be helpful to understand patient preference for biologic treatments used for psoriasis in China.Keywords: biologics, discrete choice experiment, Chinese setting, patient preference, psoriasis

Wenshu Cheng,1,&ast; Xinyue Xu,1,&ast; Yuanyuan Lang,2,&ast; Zugen Cheng,1 Mohammad Rizwan,1 Xiaomin Tang,1 Lixin Xie,1 Yanling Liu,1 Hengyi Xu,3 Yang Liu1 1Department of Pediatrics, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, People’s Republic of China; 2Medical Imaging Center, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi Province, 330006, People’s Republic of China; 3State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang, Jiangxi Province, 330047, People’s Republic of China&ast;These authors contributed equally to this workCorrespondence: Yang LiuDepartment of Pediatrics, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang, Jiangxi Province, People’s Republic of ChinaTel +0086-791-8631-1209Email ocean3166@yeah.netPurpose: To evaluate the effects of anatase and rutile TiO2 nanoparticles (NPs) on the growth and development of bones in young rats and explore their possible mechanisms.Methods: Three-week-old male rats were orally administered anatase TiO2 NPs and rutile TiO2 NPs for 28 days. The indicators of rat growth and development, liver function, bone metabolism, and insulin-like growth factor-1 (IGF-1) levels were evaluated. Micro-computed tomography (micro-CT) and immunohistochemistry were used to evaluate the tibia.Results: No significant differences were observed among growth and development indicators in young rats. Significant differences were found in IGF-1 levels, phosphorus levels, and liver function. Micro-CT revealed osteoporosis in the bones. The micro-CT data supported the same result. Bone immunohistochemistry results showed that the expression of osteoprotegerin (OPG) was decreased and the expression of receptor activator of nuclear factor-κB ligand (RANKL) and cathepsin K (CTSK) was increased.Conclusion: This study demonstrated that TiO2 NPs can damage bones via the IGF-1/OPG/RANKL/CTSK pathway in young rats. Furthermore, rutile TiO2 NPs damaged the bones more seriously than anatase TiO2 NPs.Keywords: TiO2 NPs, different crystal forms, IGF-1/OPG/RANKL/CTSK pathway, young rats, bone growth

Le Zhang,1,2,* Fangfang Chen,2,* Shikai Geng,2,* Xiaodong Wang,2 Liyang Gu,2 Yitian Lang,1 Ting Li,2 Shuang Ye2 1Department of Pharmacy, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China; 2Department of Rheumatology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of China*These authors contributed equally to this workCorrespondence: Shuang Ye; Ting LiDepartment of Rheumatology, Ren Ji Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, People’s Republic of ChinaTel +86-2134506393Fax +86-2163363475Email ye_shuang2000@163.com; leeting007@163.comPurpose: To compare the efficacy, safety, and cost-effectiveness of methotrexate (MTX) plus hydroxychloroquine (HCQ) vs MTX plus leflunomide (LEF) in established rheumatoid arthritis (RA) with inadequate response to MTX monotherapy in a real-world Chinese cohort.Patients and Methods: A prospective RA cohort (n=549) was screened with eligible patients who had inadequate response (disease activity score in 28 joints using erythrocyte sedimentation rate, DAS28-ESR> 3.2) to initial MTX monotherapy and subsequently received either MTX+HCQ or MTX+LEF. Propensity score matching (PSM) was applied to adjust the possible baseline confounders between two groups. The primary outcome was the proportion of patients achieving first remission (DAS28-ESR< 2.6) during follow-up by log rank test. Secondary outcomes were changes of DAS28, glucocorticoids (GCs) exposure, safety, cost-effectiveness, sustained remission, and low disease activity (LDA) rate after 24-month follow-up.Results: Overall, 222 eligible patients were subjected to the aforementioned two treatment protocols (MTX+HCQ, n=102; MTX+LEF, n=120). After PSM adjustment, 97 patients in each group were analyzed. A higher remission rate was observed in the MTX+HCQ group than in the MTX+LEF group (70.1% vs 56.7%, P=0.048). The median time to remission was 11 and 16 months in the two groups, respectively. At the endpoint, more patients achieved remission (46.8% vs 32.5%, P=0.063) and maintained sustained LDA in the HCQ group (53.2% vs 38.6%, P=0.062) and also more patients withdrew GCs in this group (32% vs 16.7%, P=0.053) than those in the LEF group. Safety profiles were non-alarming, with no significant difference between the two groups. The incremental cost-effectiveness ratio yielded by MTX+HCQ over MTX+LEF was $1,111.8 per quality-adjusted life-year (QALY), within the cost-effective threshold set as the per capita gross domestic product (GDP) of China.Conclusion: The MTX+HCQ combination was seemingly superior to MTX+LEF in a real-world cohort of Chinese RA patients with inadequate response to methotrexate monotherapy in respect of the efficacy and cost-effectiveness.Keywords: hydroxychloroquine, leflunomide, methotrexate-resistant, rheumatoid arthritis, efficacy, cost-effectiveness

Xinyue Xu,1,* Yizhou Tang,2,* Yuanyuan Lang,3,* Yanling Liu,1 Wenshu Cheng,1 Hengyi Xu,2 Yang Liu1 1Department of Pediatrics, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, People’s Republic of China; 2State Key Laboratory of Food Science and Technology, Nanchang University, Nanchang 330047, People’s Republic of China; 3Medical Imaging Center, The Second Affiliated Hospital of Nanchang University, Nanchang 330006, Jiangxi Province, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yang LiuDepartment of Pediatrics, The Second Affiliated Hospital of Nanchang University, No. 1 Minde Road, Donghu District, Nanchang 330006 Jiangxi Province, People’s Republic of ChinaTel +86-791-8631-1209Email ocean3166@yeah.netHengyi XuState Key Laboratory of Food Science and Technology, Nanchang University, 235 Nanjing East Road, Nanchang 330047, People’s Republic of ChinaTel +86-791-8830-4447-ext-9520Fax +86-791-8830-4400Email kidyxu@163.comPurpose: To evaluate the effects of ZnO NPs on bone growth in rats and explore the possible mechanisms of action.Materials and Methods: Three-week-old male rats received ultrapure water or 68, 203, and 610 mg/kg zinc oxide nanoparticles (ZnO NPs) for 28 days, orally.Results: The high-dosage groups caused significant differences in weight growth rate, body length, and tibia length (P< 0.05), all decreasing with increased ZnO NP dosage. There were no significant differences in body mass index (BMI) (P> 0.05). The zinc concentration in liver and bone tissue increased significantly with increased ZnO NP dosage (P< 0.05). Clearly increased aspartate aminotransferase (AST) and alanine aminotransferase (ALT) levels were observed in the 610 mg/kg ZnO NP group (P> 0.05), whereas alkaline phosphatase (ALP) increased in the 610 mg/kg ZnO NP group (P< 0.05). Significant differences in insulin-like growth factor type 1 (IGF-1) levels and a decrease in calcium (Ca) levels were observed in 203 and 610 mg/kg ZnO NP groups (P< 0.05). Phosphorus (P) levels increased and the Ca/P ratio decreased in the 610 mg/kg ZnO NP group (P< 0.05). Micro-computed tomography (micro-CT) of the tibia demonstrated signs of osteoporosis, such as decreased bone density, little trabecular bone structure and reduced cortical bone thickness. Micro-CT data further demonstrated significantly decreased bone mineral density (BMD), trabecular number (Tb.N), and relative bone volume (BV/TV) with increasing dosage of ZnO NPs. Osteoprotegerin (OPG) expression and the ratio of OPG to receptor activator of nuclear factor-κB ligand (RANKL) were statistically lower in the 610 mg/kg ZnO NP group (P< 0.05), whereas RANKL expression did not change significantly (P> 0.05).Conclusion: We infer that ZnO NPs affect bone growth in young rats directly or indirectly by altering IGF-1 levels. Overall, the results indicate that ZnO NPs promote osteoclast activity and increase bone loss through the OPG/RANK/RANKL/IGF-1 pathway.Keywords: ZnO NPs, young rats, bone growth, OPG/RANK/RANKL/IGF-1 pathway

Yitian Lang,1,2 Deshi Dong1,2 1Department of Pharmacy, The First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of China; 2College of Pharmacy, Dalian Medical University, Dalian, People’s Republic of ChinaCorrespondence: Deshi DongDepartment of Pharmacy, The First Affiliated Hospital of Dalian Medical University, Dalian, People’s Republic of ChinaTel +86-411-83635963Fax +86-411-83634643Email dongdeshi@dmu.edu.cnObjective: The EXTREME clinical trial revealed that cetuximab plus chemotherapy improved the overall survival time of patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) versus chemotherapy alone. The current study examined the cost-effectiveness of cetuximab plus chemotherapy compared with chemotherapy alone in HNSCC patients from the perspective of China.Materials and Methods: A partitioned survival model was implemented for R/M HNSCC patients. Survival information was derived from the CHANGE-2 trial. The model was designed as a ten-year time horizon, a 3-week cycle, and a 3% discount rate for costs and utilities. An incremental cost-effectiveness ratio (ICER) value is less than $30,201/quality-adjusted life-year (QALY) was considered cost-effective in China. We analyzed the uncertainty by performing one-way and probabilistic sensitivity analyses.Results: In the base-case analysis, we found that the ICER of cetuximab plus chemotherapy compared with chemotherapy alone is $172,702/QALY. The results of one-way sensitivity analysis and probabilistic analysis showed that the fluctuations of each variable in its ranges do not cause ICERs to reach acceptable thresholds.Conclusion: The current observations suggested that treatment with cetuximab plus chemotherapy is not a cost-effective strategy for R/M HNSCC patients in China at a $30,201 willingness to pay threshold.Keywords: recurrent or metastatic head and neck squamous cell carcinoma, HNSCC, cetuximab, CHANGE-2, cost-effectiveness

Wenjing Huang,1 Yan Lang,1 Abdul Hakeem,1 Yan Lei,2 Lu Gan,1 Xiangliang Yang1 1Department of Nanomedicine and Biopharmaceuticals, National Engineering Research Center for Nanomedicine, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan 430074, China; 2Pharmacy of School Hospital, Huazhong University of Science and Technology, Wuhan 430074, China Background: Multidrug resistance (MDR) is one of the major obstacles to successful cancer chemotherapy. Developing efficient strategies to reverse MDR remains a major challenge. Surfactin (SUR), a cyclic lipopeptide biosurfactant, has been found to display anticancer activity. Methods: In this paper, SUR was assembled by solvent-emulsion method to load the anticancer drug doxorubicin (DOX). The cytotoxicity of DOX-loaded SUR nanoparticles (DOX@SUR) against DOX-resistant human breast cancer MCF-7/ADR is measured by MTT assay. The cellular uptake and intracellular retention of DOX@SUR are determined by flow cytometry. The tumor accumulation and anticancer activity of DOX@SUR are evaluated in MCF-7/ADR-bearing nude mice. Results: DOX@SUR induce stronger cytotoxicity against DOX-resistant human breast cancer MCF-7/ADR cells compared to free DOX. DOX@SUR nanoparticles exhibit enhanced cellular uptake and decreased cellular efflux, which might be associated with reduced P-glycoprotein expression. After internalization into MCF-7/ADR cells by macropinocytosis- and caveolin-mediated endocytosis, DOX@SUR nanoparticles are colocalized with the lysosomes and translocated to the nucleus to exert cytotoxicity. Furthermore, in vivo animal experiment shows that the DOX@ SUR nanoparticles are accumulated more efficiently in tumors than free DOX. Meanwhile, DOX@SUR nanoparticles display stronger tumor inhibition activity and fewer side effects in MCF-7/ADR-bearing nude mice. Conclusion: This study indicates that SUR-based nanocarrier might present a promising platform to reverse MDR in cancer chemotherapy. Keywords: multidrug resistance, cellular uptake, cellular efflux, biodistribution

Yan Xiong,1 Zeping Yu,1 Yun Lang,1 Juanyu Hu,1 Hong Li,2 Yonggang Yan,2 Chongqi Tu,1 Tianfu Yang,1 Yueming Song,1 Hong Duan,1 Fuxing Pei11Department of Orthopedics, West China Hospital, Sichuan University, Chengdu, Sichuan, People’s Republic of China; 2Laboratory of Biomechanical Engineering, Sichuan University, Chengdu, Sichuan, People’s Republic of ChinaObjective: To study the degradation and basic fibroblast growth factor (bFGF) release activity of bFGF – poly(lactic-co-glycolic-acid) microsphere (bFGF-PLGA MS) under stress in vitro, including the static pressure and shearing force-simulating mechanical environment of the joint cavity.Method: First, bFGF-PLGA MSs were created. Meanwhile, two self-made experimental instruments (static pressure and shearing force loading instruments) were initially explored to provide stress-simulating mechanical environment of the joint cavity. Then, bFGF-PLGA MSs were loaded into the two instruments respectively, to study microsphere degradation and drug release experiments. In the static pressure loading experiment, normal atmospheric pressure loading (approximately 0.1 MPa), 0.35 MPa, and 4.0 MPa pressure loading and shaking flask oscillation groups were designed to study bFGF-PLGA MS degradation and bFGF release. In the shearing force loading experiment, a pulsating pump was used to give the experimental group an output of 1,000 mL/min and the control group an output of 10 mL/min to carry out bFGF-PLGA MS degradation and drug release experiments. Changes of bFGF-PLGA MSs, including microsphere morphology, quality, weight-average molecular weight of polymer, and microsphere degradation and bFGF release, were analyzed respectively.Results: In the static pressure loading experiment, bFGF-PLGA MSs at different pressure were stable initially. The trend of molecular weight change, quality loss, and bFGF release was consistent. Meanwhile, microsphere degradation and bFGF release rates in the 4.0 MPa pressure loading group were faster than those in the normal and 0.35 MPa pressure loading groups. It was the fastest in the shaking flask group, showing a statistically significant difference (P

Yan Xiong,1 Cheng Ren,1 Bin Zhang,1 Hongsheng Yang,1 Yun Lang,1 Li Min,1 Wenli Zhang,1 Fuxing Pei,1 Yonggang Yan,2 Hong Li,2 Anchun Mo,3 Chongqi Tu,1 Hong Duan11Department of Orthopedics, West China Hospital, 2School of Physical Science and Technology, 3Department of Oral Implant, West China College of Stomatology, Sichuan University, Chengdu, People's Republic of ChinaAbstract: The aim of this study was to analyze the behavior of the porous nano-hydroxyapatite/polyamide 66 (n-HA/PA66) composite grafted for bone defect repair through a series of biological safety experiments, animal experiments, and a more than 5-year long clinical follow-up. The biological safety experiments, carried out in accordance with the Chinese Guo Biao and Tolerancing (GB/T)16886 and GB/T16175, revealed that porous n-HA/PA66 composite had no cytotoxicity, no sensitization effect, no pyrogenic reaction, and that its hemolysis rate was 0.59% (less than 5%). Rabbit models of tibia defects with grafted porous n-HA/PA66 composite were established. After 2 weeks, the experiment showed that osteogenesis was detected in the porous n-HA/PA66 composite; the density of new bone formation was similar to the surrounding host bone at 12 weeks. After 26 weeks, the artificial bone rebuilt to lamellar bone completely. In the clinical study, a retrospective review was carried out for 21 patients who underwent serial radiographic assessment after treatment with porous n-HA/PA66 composite grafts following bone tumor resection. All wounds healed to grade A. No postoperative infections, delayed deep infection, nonspecific inflammation, rejection, or fractures were encountered. At a mean follow-up of 5.3 years, the mean Musculoskeletal Tumor Society's (MSTS) 93 score was 29.3 points (range: 28–30 points) and mean radiopaque density ratio was 0.77±0.10. The radiologic analysis showed that porous n-HA/PA66 composite had been completely incorporated with the host bone about 1.5 years later. In conclusion, this study indicated that the porous n-HA/PA66 composite had biological safety, and good biocompatibility, osteoinduction, and osseointegration. Thus, the porous n-HA/PA66 composite is an ideal artificial bone substitute and worthy of promotion in the field.Keywords: biomaterial, artificial bone materials, porous n-HA/PA66 composite (n-HA/PA66), bone defects healing, bone grafting

Chinese medicine plays a crucial role in maintaining the equilibrium of the intestinal microbiome, and this microbiome, in turn, plays a pivotal role in mediating the pharmacological effects of Chinese medicine on the host. Despite the significance of this interplay, there is a paucity of studies investigating the impact of orally administered Traditional Chinese Medicine (TCM) on the co-occurrence patterns of intestinal gut bacteria. In the present study, we incorporated Coix seed, Chinese yam, Semen euryales, and their combination into the diet of mice. Subsequently, we assessed the effects of these TCM on the diversity, community composition, and co-occurrence networks of gut bacteria by oral administration. Our findings underscored the substantial influence of the three TCM varieties and their mixture on the diversity and community composition of gut bacteria. Notably, all TCM utilized in our study exhibited the ability to enrich beneficial gut bacteria and inhibit pathogenic bacteria within the intestinal microbiome. Furthermore, oral administration of Coix seed, Chinese yam, Semen euryales, or their combinations resulted in increased thymus and spleen indices. Examination of network topological features revealed marked dissimilarities between the control group and the TCM oral administration groups. The co-occurrence pattern of bacteria in the TCM oral administration groups exhibited less complexity but greater stability compared to that in the control groups. These observations suggest that the bacterial community in TCM oral administration groups is more resilient to disturbances than in the control groups. [ABSTRACT FROM AUTHOR]

Background Observational studies have reported structural changes in the brains of patients with coronavirus disease 2019 (COVID-19); it remains unclear whether these associations are causal. Aim We evaluated the causal effects of COVID-19 susceptibility, hospitalization and severity on cortical structures. Design Mendelian randomization (MR) study. Methods Data on the different COVID-19 phenotypes were obtained from the latest large-scale genome-wide association study (R7) of the COVID-19 Host Genetics Initiative. Brain structure data, including cortical thickness (TH) and surface area (SA), were obtained from the ENIGMA Consortium. Additionally, we employed the round 5 dataset released in January 2021 as the validation cohort. The inverse-variance weighted (IVW) method was used as the primary analysis in MR. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy. We performed enrichment analysis on the MR analyses that passed the sensitivity analysis filtering. Results After IVW and sensitivity analyses, we observed causal associations between COVID-19 susceptibility and rostral middle frontal SAw (P  = 0.0308, β  = −39.1236), cuneus THw (P  = 0.0170, β  = −0.0121), medial orbitofrontal THw (P  = 0.0002, β  = 0.0225), postcentral THw (P  = 0.0217, β  = −0.0106), temporal pole THw (P  = 0.0077, β  = 0.0359), medial orbitofrontal SAnw (P  = 0.0106, β  = −24.0397), medial orbitofrontal THnw (P  = 0.0007, β  = 0.0232), paracentral SAnw (P  = 0.0483, β  = −20.1442), rostral middle frontal SAnw (P  = 0.0368, β  = −81.9719) and temporal pole THnw (P  = 0.0429, β  = 0.0353). COVID-19 hospitalization had causal effects on medial orbitofrontal THw (P  = 0.0053, β  = 0.0063), postcentral THw (P  = 0.0143, β  = −0.0042), entorhinal THnw (P  = 0.0142, β  = 0.0142), medial orbitofrontal THnw (P  = 0.0147, β  = 0.0065) and paracentral SAnw (P  = 0.0119, β  = −7.9970). COVID-19 severity had causal effects on rostral middle frontal SAw (P  = 0.0122, β  = −11.8296), medial orbitofrontal THw (P  = 0.0155, β  = 0.0038), superior parietal THw (P  = 0.0291, β  = −0.0021), lingual SAnw (P  = 0.0202, β  = −11.5270), medial orbitofrontal THnw (P  = 0.0290, β  = 0.0039), paracentral SAnw (P  = 0.0180, β  = −5.7744) and pars triangularis SAnw (P  = 0.0151, β  = −5.4520). Conclusion Our MR results demonstrate a causal relationship between different COVID-19 phenotypes and cortical structures. [ABSTRACT FROM AUTHOR]

Abstract Rotavirus group C is an important cause of sporadic cases and outbreaks of gastroenteritis worldwide. Whole-Genome sequences of human rotavirus C (RVC) in public databases are limited. We performed genome sequencing to analyze a RVC outbreak of acute gastroenteritis in China. Samples from 22 patients were screened for pathogens using RT-PCR, and six samples were positive for rotavirus. Whole-Genome sequencing analysis showed that the outbreak strain SJZ217 belongs to the G4-P[2]-I2-R2-C2-M3-A2-N2-T2-E2-H2 genotype and shares almost identical genomic sequences with Chungnam isolated in Korea. Phylogenetic analysis revealed strain SJZ217 also fell into a cluster with rotavirus C strains from Japan and Europe. Reassortment in the VP4 fragment was observed. These results helped to understand the genetic diversity and possible spread of RVC strains.

Abstract Background In edentulous jaws, factors such as the number of implants, cross-arch distribution, and the angle among implants may affect the accuracy of the implant impression. This study explored factors influencing the accuracy of implant abutment-level digital impressions using stereophotogrammetry in edentulous jaws. Methods Two standard all-on-4 and all-on-6 models of edentulous jaws were constructed in vitro. In the stereophotogrammetry group (PG), the implant digital impression was made using stereophotogrammetry and saved as an STL file. In the conventional group (CNV), the impression was made using the open-tray splint impression technique. An electronic and optical 3D measuring instrument was used to scan the standard model and the conventional plaster model to obtain STL files. Using 3D data processing software (GOM Inspect Pro, Zeiss), the distance and angle between the abutments in the CNV impression and the PG impression were measured and compared with the data from the standard model. Results The distance deviation in the PG and the CNV was 145 ± 196 μm and 96 ± 150 μm, respectively, with a significant difference (P

In Laser Powder Bed Fusion (L-PBF), surface roughness is pivotal for controlling the mechanical and functional performances, as well as the geometrical accuracy of the final product. This study extensively investigated the interactions of hatch and contour processing parameters, along with contour offset distance, on vertical surface roughness for 316L stainless steel in L-PBF. Melt pool morphology and surface arithmetic average roughness (Sa) were quantified using confocal microscopy, while scanning electron microscopy was employed to interpret the detailed microstructure of surface features. Under low volumetric energy density (VED) hatch conditions (e.g., 66.7 J/mm3), varying the contour offset distance has a negatable effect on the surface roughness when the contour VED is lower than 121.6 J/mm3, remaining relatively smooth surfaces dominated by bare melt tracks with sparely attached partially melted particles. Increasing the hatch or contour VED (e.g., 166.7 J/mm3), dross formation, identified by the microstructural differences and explained by the melt pool instability and migration, is inevitable, which dictates the surface roughness with higher Sa values. The larger contour offset distance further promotes the dross occurrence with irregularity and increases Sa. Employing a low contour VED with an appropriate offset distance and adopting the contour-first scan strategy was demonstrated as an effective solution to reduce the dross formation. Through the analysis of melt pool behavior, surface topography, and microstructure, this study elucidates the mechanisms governing dominant surface characteristics under the combined influence of hatch and contour parameters. It lays the foundation for precise control of surface roughness without altering hatching parameters, enabling the tailored manipulation of performance in additively manufactured structures.

Abstract Background and purpose Ir192 vaginal brachytherapy (IBT) is commonly used for patients with postoperative endometrial cancer (EC). We devised a novel multichannel vaginal applicator that could be equipped with an electronic brachytherapy (EBT) device. We aimed to explore the differences in physical parameters between the EBT and IBT. Materials and methods This retrospective study included 20 EC patients who received adjuvant IBT from March 1, 2023, to May 1, 2023. Multichannel vaginal cylinders were used, and three-dimensional plans were generated. We designed an electronic multichannel vaginal applicator model and simulated a three-dimensional EBT plan. In order to ensure comparability, D90 of the CTV for the EBT plan was normalized to be equivalent to that of the IBT plan for the same patient. Results Twenty EBT plans were compared with 20 IBT plans. Results showed, the mean D90 value of clinical target volume (CTV) was 536.1 cGy for both treatment plans. For the mean dose of CTV, the EBT was significantly greater (738.3 vs. 684.3 cGy, p = 0.000). There was no significant difference in CTV coverage between the EBT and IBT plans. For high-dose areas (V200% and V150%), the EBTs were significantly greater. There were no significant differences in the maximum doses to the vaginal mucosa between the EBT and IBT, whether at the apex or in the middle segment. For the bladder and rectum, both the low-dose area and high-dose area were significantly lower in the EBT plans. For the conformity index, there was no significant difference between the EBT and IBT plans. For the dose homogeneity index, the EBT value was lower. Conclusion In conclusion, under the premise of a three-dimensional brachytherapy plan, for patients receiving multichannel vaginal applicator brachytherapy, compared with IBT, EBT could reduce the dose to the surrounding organs at risk while maintaining the dose in the target area.

Abstract Background The number of spikelets per spike is a key trait that affects the yield of bread wheat (Triticum aestivum L.). Identification of the QTL for spikelets per spike and its genetic effects that could be used in molecular assistant breeding in the future. Results In this study, four recombinant inbred line (RIL) populations were generated and used, having YuPi branching wheat (YP), with Supernumerary Spikelets (SS) phenotype, as a common parent. QTL (QSS.sicau-2 A and QSS.sicau-2D) related to SS trait were mapped on chromosomes 2 A and 2D through bulked segregant exome sequencing (BSE-Seq). Fourteen molecular markers were further developed within the localization interval, and QSS.sicau-2 A was narrowed to 3.0 cM covering 7.6 Mb physical region of the reference genome, explaining 13.7 − 15.9% the phenotypic variance. Similarly, the QSS.sicau-2D was narrowed to 1.8 cM covering 2.4 Mb physical region of the reference genome, and it explained 27.4 − 32.9% the phenotypic variance. These two QTL were validated in three different genetic backgrounds using the linked markers. QSS.sicau-2 A was identified as WFZP-A, and QSS.sicau-2D was identified a novel locus, different to the previously identified WFZP-D. Based on the gene expression patterns, gene annotation and sequence analysis, TraesCS2D03G0260700 was predicted to be a potential candidate gene for QSS.sicau-2D. Conclusion Two significant QTL for SS, namely QSS.sicau-2 A and QSS.sicau-2D were identified in multiple environments were identified and their effect in diverse genetic populations was assessed. QSS.sicau-2D is a novel QTL associated with the SS trait, with TraesCS2D03G0260700 predicted as its candidate gene.

BackgroundWHIM syndrome is a rare, autosomal dominant inborn error of immunity characterized by warts, hypogammaglobulinemia, infection, and myelokathexis. It is caused mainly by heterozygous mutations at the C-terminus of the C-X-C chemokine receptor type 4 (CXCR4) gene.MethodsWe described the detailed clinical, genetic, immunological and treatment characteristic of four WHIM patients from a single Chinese family.ResultsHere, we report four patients from a family carrying a variant of CXCR4 (c.1016_1017dupCT), which introduces a frameshift at codon V340, resulting in an extension of 14 amino acids (p.V340L fs*27). We provide and in-depth analysis of their clinical, genetic, immunological and treatment characteristic, noting that these patients exhibited an atypical clinical phenotype when compared to reported CXCR4R334X patients. Additionally, the frameshift variant CXCR4V340fs led to impaired receptor downregulation in patients’ PBMCs, and in HEK293T cells transfected with the variant plasmids.ConclusionsOur study provided detailed clinical features of four CXCR4V340fs WHIM patients from one Chinese family who presented atypical phenotype and enrich the spectrum of WHIM syndrome.

The solute diffusion zone plays a critical role in determining nucleation efficiency during heterogeneous nucleation. In this study, in-situ synchrotron X-radiography and numerical modeling were employed to investigate the Solute Suppressed Nucleation Zone (SSNZ) surrounding growing equiaxed grains in Al-13Cu alloys. Quantitative analysis of SSNZ and constitutional undercooling was conducted using image processing techniques. Solute concentration and SSNZ length in the direction exceed those in the direction, suggesting higher solute enrichment in dendrite centers. This causes greater undercooling in the dendrite growth direction () with faster dendrite growth rates. As equiaxed dendrites grow, SSNZ length in the direction decreases while increasing significantly in the direction. Utilizing data obtained from numerical simulations, we refined the analytical equation governing solute distribution preceding the solid–liquid interface under three-dimensional conditions, and the computational equation determining the SSNZ length. The SSNZ lengths derived from the optimized equation along the and directions demonstrate more agreement with both experimental observations and numerical simulation outcomes. Higher growth rates rapidly increase undercooling, limiting the development of nucleation-free zone. Additionally, SSNZ area growth slows at higher cooling rate, correlating with increased solute concentration and reduced area in SSNZ.

Purpose: This study represents a prospective phase I clinical research to verify the effectiveness and reliability of hydrogel application in Chinese cervical cancer patients. Materials and Methods: Eight patients were enrolled in the study. After completing intensity-modulated radiotherapy at 50.4 Gy/28 fractions, a 10 mL injection of hydrogel was administered to each patient through the posterior vaginal fornix under CT-guidance. Image-guided brachytherapy under CT or MRI guidance was given with a target dose of 6 Gy in 5 fractions to the high-risk clinical target volume. Rectal, sigmoid colon, and bladder D2cm3 were recorded for each brachytherapy. MRI scans were performed to measure the distance between the rectum and the cervix or tumor, as well as the spacer gel volume. Patients’ QLQ-C30 and QLQ-CX24 scores were recorded to assess treatment outcomes, and all adverse events were documented. Results: Among the eight patients, the average D2cc was 60.9 ± 3.4 Gy for the rectum, 64.7 ± 6.8 Gy for sigmoid colon and 77.1 ± 7.4 Gy for bladder, respectively. The distance between the cervix and rectum significantly increased after gel injection. None of the eight patients experienced grade 3 or higher acute toxic reactions during brachytherapy. None patient experienced late rectal toxicity. No adverse events definitively associated with the hydrogel were observed. Patients’ subjective quality of life scores did not significantly change before and after gel injection. The reduction ro the volume of the hydrogel were observed during the 24 to 36 weeks after injection. Conclusion: The application of the hydrogel effectively increased the distance between the cervix and rectum in brachytherapy for cervical cancer, limiting the rectal dose without increasing doses to other critical organs. In the short term, no severe adverse events were observed, indicating the safety and reliability of this approach. Further research is warranted to confirm its long-term safety and effectiveness.

Background and purposeThe systemic immune-inflammation index (SII) is a novel immune inflammatory marker which has been proven to have excellent predictive value for many diseases. The aim of this study was to investigate the predictive value of SII at different time points after admission for functional outcome at discharge in patients with intracerebral hemorrhage (ICH).MethodsThe clinical data of patients with ICH who were treated at a medical center for neurological diseases in China between October 2012 and April 2022 were analyzed in this retrospective study. The SII was calculated based on neutrophil×platelet/lymphocyte counts and collected within the first 14 days after admission to analyze the dynamic changes. Adverse outcome was defined as a modified Rankin Scale (mRS) score of 4–6 at discharge. The correlation between the SII and the outcome was assessed using univariate and multivariate logistic regression analyses. The ability of SII to predict outcome was evaluated by the area under the receiver operating characteristic (ROC) curve (AUC).ResultsA total of 1,569 patients with ICH were included, of whom 790 had adverse outcome (50.35%). The Univariate logistic regression analysis showed that SII at any time point within 14 days after admission was significantly associated with adverse outcome. In the multivariate logistic regression analysis, the SII within 7 days after admission was found to be an independent predictor of adverse functional outcome in ICH patients at discharge. The ROC curve demonstrated that compared to other time points, the SII on day 2 after admission exhibited stronger predictive power for the functional outcome of patients with ICH at discharge (AUC:0.733, 95%CI = 0.679–0.787) (sensitivity 47.09%, specificity 87.02%) (OR 1.074, 95%CI = 1.033–1.126, p = 0.001).ConclusionSII within 7 days after admission, especially on day 2, is independently associated with adverse functional outcome in ICH patients at discharge. This association could be utilized in clinical practice and warrants further investigation.

Abstract This study aimed to evaluate the safety and efficiency of hybrid endoscopic submucosal dissection (H-ESD) using a newly developed ALL IN ONE (AIO) snare. This was a matched control study in a porcine model. Five paired simulated stomach lesions 2–2.5 cm in size were removed by H-ESD using an AIO snare or conventional ESD (C-ESD) using an endoscopic knife. The outcomes of the two procedures were compared, including en-bloc resection rates, procedure times, intraprocedural bleeding volumes, muscular injuries, perforations, thicknesses of the submucosal layer in resected specimens, and stomach defects. All simulated lesions were resected en-bloc. Specimens resected by H-ESD and C-ESD were similar in size (7.68 ± 2.92 vs. 8.42 ± 2.42 cm2; P = 0.676). H-ESD required a significantly shorter procedure time (13.39 ± 3.78 vs. 25.99 ± 4.52 min; P = 0.031) and submucosal dissection time (3.99 ± 1.73 vs. 13.1 ± 4.58 min; P = 0.003) versus C-ESD; H-ESD also yielded a faster dissection speed (241.37 ± 156.84 vs. 68.56 ± 28.53 mm2/min; P = 0.042) and caused fewer intraprocedural bleeding events (0.40 ± 0.55 vs. 3.40 ± 1.95 times/per lesion; P = 0.016) than C-ESD. The thicknesses of the submucosal layer of the resected specimen (1190.98 ± 134.07 vs. 1055.90 ± 151.76 μm; P = 0.174) and the residual submucosal layer of the stomach defect (1607.94 ± 1026.74 vs. 985.98 ± 445.58 μm; P = 0.249) were similar with both procedures. The AIO snare is a safe and effective device for H-ESD and improves the treatment outcomes of gastric lesions by shortening the procedure time.

Background: Revealing out the hot zone and feature of early gastric cancers (EGCs) and dysplasia frequently developed is important for endoscopic screening and surveillance. This study aimed to investigate the distribution and location characteristics of EGCs and dysplasia. Methods: A total of 503 pathological diagnosed EGCs and dysplasia from 445 patients were reviewed retrospectively. The distribution of EGCs and dysplasia in stomach was mapped, and its associated clinicopathological findings were analyzed. Results: EGCs and dysplasia were predominately in the lesser curvature transversely, and vertical distributed frequently in lower third (51.7%) of stomach. In addition, lesions in upper third is associated with older age (p ​= ​0.014), male sex (p ​= ​0.002), smaller size (p < 0.001) and more differentiated EGCs, but fewer low-grade dysplasia and undifferentiated EGCs (p < 0.001). Moreover, most (461/503, 91.7%) lesions were found in endoscopy diagnosed atrophic mucosa, and are predominately differentiated EGCs and dysplasia (384/461, 83.3%). For the lesions in endoscopy diagnosed non-atrophic mucosa, more than half (23/42, 54.8%) are undifferentiated EGCs, which predominantly in middle (52.2%) and lower third (39.1%) of stomach. Whereas, differentiated EGCs accounts for 23.8% (10/42), and mainly (90%) located in the upper third of the stomach. Conclusions: The distribution of dysplasia, differentiated and undifferentiated EGCs was associated to location and atrophic mucosa. Those location characteristics are useful for endoscopic screening and surveillance.

Abstract PANoptosis plays a crucial role in cancer initiation and progression. However, the roles of PANoptosis-related genes (PARGs) in the prognosis and immune landscape of head and neck squamous cell carcinoma (HNSCC) remain unclear. Integrated bioinformatics analyses based on the data of HNSCC patients in the TCGA database were conducted. We extracted 48 PARGs expression profile and then conducted differentially expressed analysis, following building a Cox model to predict the survival of HNSCC patients. Subsequently, the relationships between the risk score, immune landscape, chemo-, and immune-therapy responses were analyzed, respectively. Moreover, we investigated the prognostic value, and further predicted the pathways influenced by PARGs. Finally, we identified the biological function of crucial PARGs. A total of 18 differentially expressed PARGs were identified in HNSCC, and a Cox model including CASP8, FADD, NLRP1, TNF, and ZBP1 was constructed, which showed that the risk score was associated with the prognosis as well as immune infiltration of HNSCC patients, and the risk score could be regarded as an independent biomarker. Additionally, patients with high-risk score might be an indicator of lymph node metastasis and advanced clinical stage. High-risk scores also contributed to the chemotherapy resistance and immune escape of HNSCC patients. In addition, FADD and ZBP1 played a crucial role in various cancer-related pathways, such as the MAPK, WNT, and MTOR signaling pathways. On the other hand, we suggested that FADD facilitated the progression and 5-fluorouracil (5-FU) resistance of HNSCC cells. A signature based on PANoptosis showed great predictive power for lymph node metastasis and advanced stage, suggesting that the risk score might be an independent prognostic biomarker for HNSCC. Meanwhile, FADD, identified as a prognostic biomarker, may represent an effective therapeutic target for HNSCC.

Abstract DNA double-strand breaks (DSBs) are repaired by a hierarchically regulated network of pathways. Factors influencing the choice of particular repair pathways, however remain poorly characterized. Here we develop an Integrated Classification Pipeline (ICP) to decompose and categorize CRISPR/Cas9 generated mutations on genomic target sites in complex multicellular insects. The ICP outputs graphic rank ordered classifications of mutant alleles to visualize discriminating DSB repair fingerprints generated from different target sites and alternative inheritance patterns of CRISPR components. We uncover highly reproducible lineage-specific mutation fingerprints in individual organisms and a developmental progression wherein Microhomology-Mediated End-Joining (MMEJ) or Insertion events predominate during early rapid mitotic cell cycles, switching to distinct subsets of Non-Homologous End-Joining (NHEJ) alleles, and then to Homology-Directed Repair (HDR)-based gene conversion. These repair signatures enable marker-free tracking of specific mutations in dynamic populations, including NHEJ and HDR events within the same samples, for in-depth analysis of diverse gene editing events.

ABSTRACT Over-application of chemical fertilizers and continuous cropping obstacles seriously restrict the sustainable development of tobacco production. Localized fertilization of beneficial microbes has potential advantages in achieving higher productivity, but the underlying biological mechanisms of interactions between rhizospheric microorganisms and the related metabolic cycle remain poorly characterized. Here, an integrative analysis of microbiomes with non-targeted metabolomics was performed on 30 soil samples of rhizosphere, root surrounding, and bulk soils from flue‐cured tobacco under continuous and non-continuous monocropping systems. The analysis was conducted using UPLC-MS/MS platforms and high-throughput amplicon sequencing targeting the bacterial 16S rRNA gene and fungal ITS gene. The microbial inoculant consisted of Bacillus subtilis, B. velezensis, and B. licheniformis at the ratio of 1:1:1 in effective microbial counts, improved the cured leaf yield and disease resistance of tobacco, and enhanced nicotine and nitrogen contents of tobacco leaves. The bacterial taxa Rhizobium, Pseudomonas, Sphingomonadaceae, and Burkholderiaceae of the phylum Proteobacteria accumulated in high relative abundance and were identified as biomarkers following the application of the microbial inoculant. Under continuous monocropping, metabolomics demonstrated that the application of the microbial inoculant significantly affected the soil metabolite spectrum, and the differential metabolites were significantly enriched to the synthesis and degradation of nicotine (nicotinate and nicotinamide metabolism and biosynthesis of alkaloids derived from nicotinic acid). In addition, microbes were closely related to the accumulation of metabolites through correlation analysis. The interactions between plant roots and rhizospheric microorganisms provide valuable information for understanding how these beneficial microbes affect complex biological processes and the adaption capacity of plants to environments.IMPORTANCEThis study elaborated on how the microbial fertilizer significantly changed overall community structures and metabolite spectrum of rhizospheric microbes, which provide insights into the process of rhizosphere microbial remolding in response to continuous monocropping. we verified the hypothesis that the application of the microbial inoculant in continuous cropping would lead to the selection of distinct microbiota communities by establishing models to correlate biomarkers. Through correlation analysis of the microbiome and metabolome, we proved that rhizospheric microbes were closely related to the accumulation of metabolites, including the synthesis and degradation of nicotine. The interactions between plant roots and rhizospheric microorganisms provide valuable information for understanding how these beneficial microbes affect complex biological processes and the adaption capacity of plants to environments.

Pemphigus foliaceus (PF) is a superficial form of pemphigus. Treatment options for PF resemble pemphigus vulgaris, including glucocorticosteroids, immunosuppressive agents and rituximab et al. These treatment approaches can effectively improve the condition but may also be accompanied by high risks of side effects. Therefore, it is crucial to find a safe and effective treatment options for patients with PF. It will not only benefit/be necessary for patients who refuse glucocorticosteroids or immunosuppressive agents treatments, but also for patients who cannot be treated with glucocorticosteroids or immunosuppressive agents. Herein, we reported a case of PF that was treated with apremilast without systemic glucocorticosteroids or immunosuppressive agents. A 54-year-old woman presented with itchy erythema and erosions on the trunk for more than 1 month. The patient applied mometasonefuroate cream without improvement for a duration of two weeks. The past history of diabetes mellitus and atrophic gastritis was reported. Physical examination revealed scattered erythematous macules and erosions on the trunk. No mucosal involvement was observed. The condition was assessed by the pemphigus disease area index and numerical rating scale, with baseline scores of 7 and 8, respectively. Histopathological examination showed acantholysis and intraepithelial blister. Direct immunofluorescence revealed the presence of IgG and Complement 3 deposition between the acanthocytes with the reticular distribution. Based on enzyme-linked immunosorbent assay results, the levels of Dsg1 and Dsg3 antibodies were 28.18 and 0.26 kU/L respectively. The diagnosis of PF was made. This patient was successfully treated with apremilast without systemic glucocorticosteroids or immunosuppressive agents. The patient has continued with apremilast 30mg once daily for maintenance and no adverse events related to apremilast such as gastrointestinal side effects were observed during the 9-month follow-up period. In conclusion, apremilast therapy without systemic glucocorticosteroids nor immunosuppressive agents might provide an effective alternative to management of mild PF without obvious side effect.

Linking outbreaks of Shigella spp. to specific foods is challenging due to poor selectivity of current enrichment media. We have previously shown that enrichment media, tailored to the genomically-predicted antimicrobial resistance (AMR) of Shiga toxigenic E. coli strains, enhances their isolation from foods. This study investigates the application of this approach for Shigella isolation. The AMR gene profiles of 21,908 published S. sonnei genomes indicated a high prevalence of genes conferring resistance to streptomycin (aadA, aph(3″)-Ib, aph(6)-Id, 92.8%), sulfonamides (sul1, sul2, 74.8%), and/or trimethoprim (dfrA, 96.2%). Genomic analysis and antibiotic susceptibility testing conducted with a panel of 17 outbreak-associated S. sonnei strains confirmed the correlation of AMR gene detection with resistance phenotypes. Supplementation of Shigella Broth (SB) with up to 400 µg/mL of trimethoprim or sulfadiazine did not suppress the growth of sensitive strains, whereas 100 µg/mL of streptomycin increased the selectivity of this broth. All three antibiotics increased the selectivity of modified Tryptone Soya Broth (mTSB). Based on these results, supplemented media formulations were developed and assessed by measuring the relative growth of S. sonnei in cultures coinoculated with a strain of bacteriocin-producing E. coli that is inhibitory to Shigella growth. S. sonnei was not recovered from cocultures grown in SB or mTSB without antibiotics. In contrast, media supplemented with streptomycin at 50 and 100 µg/mL, trimethoprim at 25 and 50 µg/mL, and sulfadiazine at 100 µg/mL increased the relative proportion of S. sonnei in postenrichment cultures. The enhanced recovery of resistant S. sonnei strains achieved in this study indicates that, in cases where genomic data are available for clinical S. sonnei isolates, customization of selective enrichment media based on AMR gene detection could be a valuable tool for supporting the investigation of foodborne shigellosis outbreaks.