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Yu Lu,1 Jing-Jing Zhao,2 Ping He1 1Department of Ultrasonography, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, People’s Republic of China; 2Department of Pathology, Shanghai Key Laboratory of Maternal Fetal Medicine, Shanghai Institute of Maternal-Fetal Medicine and Gynecologic Oncology, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, Shanghai, 200092, People’s Republic of ChinaCorrespondence: Ping He, Department of Ultrasonography, Shanghai First Maternity and Infant Hospital, School of Medicine, Tongji University, No. 2699 Gaoke West Road, Pudong District, Shanghai, 201204, People’s Republic of China, Tel +86-2120261000, Email hepinghmp0@126.comBackground: Microphthalmia is a rare autosomal recessive condition commonly known as Waardenburg anophthalmia syndrome (WAS) or oculo-acromal formation syndrome (MIM#206920).Case Description: Here, we report the case of a woman whose fetal ultrasonography at 12 weeks of pregnancy revealed multiple fetal abnormalities. These included the absence of the left upper limb, an unclear display of the right orbit, a visible maxillary space, and a round, echoless appearance measuring 4 mm in diameter in the middle of the forehead. There was also a significant echo in the sac wall. The possibility of a frontal meningocele or a proboscis-like nose was considered. The fetus was delivered with absence of the left upper limb, absence of the right eye, a cleft lip on the right side, and a milky white sac with a diameter of 5 mm on the forehead after the pregnancy was terminated at the hospital. Pathological investigation revealed a mature cystic teratoma. The conclusion was microphthalmia with limb anomalies (MLA) after missing limbs, absence of eyes, and cleft lip were input into the Online Mendelian Inheritance in Man database. The case was diagnosed with fetal microphthalmia with limb anomalies and an interfrontal teratoma.Conclusion: In this case, the entire exon analysis was not conducted, and as a result, the final diagnosis remains unclear. Based exclusively on the phenotype of the induced fetus, MLA was diagnosed. It is proposed that cases satisfying the requirements for a pathological diagnosis should undergo a pathological examination to establish a definitive diagnosis.Keywords: cleft lip, limb anomalies, microphthalmia, teratoma

Yuan Liu,1,2,* Jing-Jing Zhao,1,2,* Zi-Qi Zhou,1,2 Qiu-Zhong Pan,1,2 Qian Zhu,1,2 Yan Tang,1,2 Jian-Chuan Xia,1,2 De-Sheng Weng1,21State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 2Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China*These authors contributed equally to this workIntroduction: IL-37 is a cytokine of IL-1 family that plays an important role in innate immunity and inflammation, and has been studied as a tumor suppressor in many cancers. However, it remains unclear whether IL-37 plays a regulatory role in tumor-infiltrating dendritic cells (DCs) in hepatocellular carcinoma (HCC).Materials and methods: We evaluated the relationship between IL-37 expression and tumor infiltration by DCs in 155 HCC samples through immunohistochemical analysis and Kaplan–Meier survival analysis. The effects of IL-37 on the anti-tumor activity of DCs were investigated by ELISA, flow cytometry, real-time quantitative PCR, cytotoxicity assays and tumorigenicity assays.Results: The expression level of IL-37 in HCC samples was positively correlated with the degree of CD1a+ DCs infiltration. The survival rates of patients with both a high expression of IL-37 and a high infiltration by CD1a+ DCs were significantly higher than those of patients with a low expression of IL-37 and a low infiltration by CD1a+ DCs. In vitro chemotaxis analysis indicated that HCC cells overexpressing IL-37 recruited more DCs by secreting higher levels of specific chemokines (eg, CCL3 and CCL20). In addition, IL-37 indirectly up-regulated the expression of major histocompatibility class II molecules, CD86 and CD40 on DCs by acting on tumor cells; IL-37 also indirectly enhanced the anti-tumor effect of T lymphocytes by stimulating DCs to secrete cytokines such as IL-2, IL-12, IL-12p70, interferon-α (IFN-α) and IFN-γ. Finally, overexpression IL-37 in HCC cells significantly delayed tumor growth and increased recruitment of CD11c+ DCs to tumor tissues was also revealed in vivo mouse model.Conclusion: DCs play an important role in IL-37 mediated anti-tumor immune responses in HCC, which may contribute to the development of novel cancer immunotherapeutic strategies.Keywords: IL-37, dendritic cells, antitumor immunity, hepatocellular carcinoma

Jing-Jing Zhao,1,2,* Zi-Qi Zhou,1,2,* Peng Wang,3,4,* Chang-Long Chen,1,2 Yuan Liu,1,2 Qiu-Zhong Pan,1,2 Qian Zhu,1,2 Yan Tang,1,2 De-Sheng Weng,1,2 Jian-Chuan Xia1,2 1Department of Experimental Research, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China; 2Department of Biotherapy, Sun Yat-Sen University Cancer Center, Guangzhou, China; 3Department of Emergency Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China; 4Department of Medical Research, Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, China *These authors contributed equally to this work Introduction: Esophageal squamous cell carcinoma (ESCC) develops in a background of chronic inflammation; therefore, it is a promising candidate for treatment by immunotherapy. Although tumor immunity is critically involved in tumor growth and metastasis in ESCC, important gaps exist in our understanding of its immune microenvironment. This study aimed to investigate the expression and prognostic significance of immune checkpoint proteins in ESCC and the associated T-cell densities.Materials and methods: We investigated the infiltration of CD8+ T cells and the expressions of immune checkpoint proteins (PD-1, TIGIT, PD-L1, and PD-L2) in 154 primary ESCC patients by immunohistochemistry. The correlation of immune checkpoint proteins’ expression and clinical outcomes was determined by Kaplan–Meier test and multivariate Cox regression analysis.Results: PD-L1 and PD-L2 expression were detected in 45.5 and 59.7% of the ESCC samples, respectively. The high densities of PD-1+ and TIGIT+ tumor-infiltrating lymphocytes (TILs) were expressed in 47.4 and 49.4% of the ESCC patients, respectively. The number of PD-1+ TILs was significantly positively correlated with CD8+ TILs (P

Yi Que,1,* Yao Liang,2,* Jingjing Zhao,1 Ya Ding,1 Ruiqing Peng,1 Yuanxiang Guan,2 Xing Zhang1 1Department of Medical Melanoma and Sarcoma, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China; 2Department of Gastric and Pancreatic Surgery, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Sun Yat-Sen University Cancer Center, Guangzhou, People’s Republic of China *These authors contributed equally to this work Objective: Research efforts have investigated therapies targeting tyrosine kinase signaling pathways. We performed a pooled analysis to determine the frequency of severe adverse effects in patients with soft tissue sarcoma treated with pazopanib, sorafenib and sunitinib. Materials and methods: We performed a comprehensive search of PubMed, Web of Science, Ovid, the Cochrane Library and Embase databases from the drugs’ inception to May 2017 to identify clinical trials. All-grade and severe adverse events (AEs; grade≥3) were analyzed. Results: A total of 10 trials published between 2009 and 2016, including 843 patients, were eligible for analysis. We included 424 patients (three studies) who received pazopanib 800 mg daily, 353 patients (five studies) who received sorafenib 400 mg twice daily and 66 patients (two studies) who received sunitinib 37.5 mg daily. The incidence of AEs is different among the three VEGFR-tyrosine kinase inhibitors (TKIs). Pazopanib showed higher incidence of all-grade nausea, diarrhea and hypertension compared with sorafenib and sunitinib. However, patients in the sorafenib group experienced a significantly higher frequency of all-grade rash (26.1%), hand–foot syndrome (33.4%) and mucositis (38.5%). The difference was highly significant for sorafenib vs. pazopanib in the incidence of all-grade rash (odds ratio [OR] 1.649, 95% CI 1.086–2.505, P=0.023), hand–foot syndrome (OR 3.096, 95% CI 1.271–7.544, P=0.009) and mucositis (OR 4.562, 95% CI 2.132–9.609, P

Xiao-long Wu,1,* Zhi-yu Li,1,* Xin-yu Bi,1 Hong Zhao,1 Jian-jun Zhao,1 Jian-guo Zhou,1 Yue Han,2 Zhen Huang,1 Ye-fan Zhang,1 Jian-qiang Cai1 1Department of Hepatobiliary Surgery, 2Department of Interventional Therapies, National Cancer Center/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China *These authors contributed equally to this work Background: Systemic inflammation (SI) is associated with tumor progression and overall survival (OS) in patients with hepatocellular carcinoma (HCC). The presence of some single nucleotide polymorphisms (SNPs) in the human leukocyte antigen (HLA) region can influence the prognosis of patients with hepatitis B virus (HBV)-related HCC, although the mechanism remains unknown. This study aimed to analyze the correlations between HLA gene polymorphisms and SI. Patients and methods: This study included 330 patients with HCC. The clinical parameters were reviewed, and five SNPs, namely rs2647073, rs3997872, rs3077, rs7453920, and rs7768538, were genotyped using the MassARRAY system. Results: The rs3997872, rs7453920, and rs7768538 genotypes were found to be significantly associated with OS (P

Wenxin Yao,1 Peicheng Xu,1 Zhiqing Pang,2,3 Jingjing Zhao,2,3 Zhilan Chai,2,3 Xiaoxia Li,4 Huan Li,2,3 Menglin Jiang,2,3 Hongbo Cheng,2,3 Bo Zhang,2,3 Nengneng Cheng4 1Shanghai Xuhui District Dental Center, 2Key Laboratory of Smart Drug Delivery, Ministry of Education, 3Department of Pharmaceutics, School of Pharmacy, Fudan University, 4Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, People’s Republic of China Background: Rapid local drug clearance of antimicrobials is a major drawback for the treatment of chronic periodontitis. In the study reported here, minocycline-loaded poly(ethylene glycol)-poly(lactic acid) nanoparticles were prepared and administered locally for long drug retention and enhanced treatment of periodontitis in dogs.Methods: Biodegradable poly(ethylene glycol)-poly(lactic acid) was synthesized to prepare nanoparticles using an emulsion/solvent evaporation technique. The particle size and zeta potential of the minocycline-loaded nanoparticles (MIN-NPs) were determined by dynamic light scattering and the morphology of the nanoparticles was observed by transmission electron microscopy. The in vitro release of minocycline from MIN-NPs and in vivo pharmacokinetics of minocycline in gingival crevice fluid, after local administration of MIN-NPs in the periodontal pockets of beagle dogs with periodontitis, were investigated. The anti-periodontitis effects of MIN-NPs on periodontitis-bearing dogs were finally evaluated.Results: Transmission electron microscopy examination and dynamic light scattering results revealed that the MIN-NPs had a round shape, with a mean diameter around 100 nm. The in vitro release of minocycline from MIN-NPs showed a remarkably sustained releasing characteristic. After local administration of the MIN-NPs, minocycline concentration in gingival crevice fluid decreased slowly and retained an effective drug concentration for a longer time (12 days) than Periocline®. Anti-periodontitis effects demonstrated that MIN-NPs could significantly decrease symptoms of periodontitis compared with Periocline and minocycline solution. These findings suggest that MIN-NPs might have great potential in the treatment of periodontitis. Keywords: minocycline, nanoparticles, periodontitis, local delivery

Simvastatin and fenofibrate are both commonly used lipid-regulating agents with distinct mechanisms of action, and their coadministration may be an attractive treatment for some patients with dyslipidemia. A 2-period, randomized, open-label, crossover study was conducted in 12 subjects to determine if fenofibrate and simvastatin are subject to a clinically relevant pharmacokinetic interaction at steady state. In treatment A, subjects received an 80-mg simvastatin tablet in the morning for 7 days. In treatment B, subjects received a 160-mg micronized fenofibrate capsule in the morning for 7 days, followed by a 160-mg micronized fenofibrate capsule dosed together with an 80-mg simvastatin tablet on days 8 to 14. Because food increases the bioavailability of fenofibrate, each dose was administered with food to maximize the exposure of fenofibric acid. The steady-state pharmacokinetics (AUC(0-24h), C(max), and t(max)) of active and total HMG-CoA reductase inhibitors, simvastatin acid, and simvastatin were determined following simvastatin administration with and without fenofibrate. Also, fenofibric acid steady-state pharmacokinetics were evaluated with and without simvastatin. The geometric mean ratios (GMRs) for AUC(0-24h) (80 mg simvastatin [SV] + 160 mg fenofibrate)/(80 mg simvastatin alone) and 90% confidence intervals (CIs) were 0.88 (0.80, 0.95) and 0.92 (0.82, 1.03) for active and total HMG-CoA reductase inhibitors. The GMRs and 90% CIs for fenofibric acid (80 mg SV + 160 mg fenofibrate/160 mg fenofibrate alone) AUC(0-24h) and C(max) were 0.95 (0.88, 1.04) and 0.89 (0.77, 1.02), respectively. Because both the active inhibitor and fenofibric acid AUC GMR 90% confidence intervals fell within the prespecified bounds of (0.70, 1.43), no clinically significant pharmacokinetic drug interaction between fenofibrate and simvastatin was concluded in humans. The coadministration of simvastatin and fenofibrate in this study was well tolerated. [ABSTRACT FROM AUTHOR]

Objective: Epilepsy is one of the most prevalent brain diseases. Approximately one third of patients consistently experience drug-resistant epilepsy (DRE), a condition where seizures persist despite the use of antiseizure medications. Exploration of new therapies for DRE is urgently needed. In this single-center, randomized, sham-controlled, crossover clinical trial (NCT05042726), we aimed to investigate the effectiveness and safety of transcranial magnetic continuous theta burst stimulation (cTBS) targeting the cerebellum to treat DRE., Methods: Patients with DRE for ≥2 years and a seizure frequency of ≥2 seizures per month were enrolled and randomized 1:1 to receive active stimulation followed by sham stimulation or vice versa. The bilateral cerebellum was targeted by navigated cTBS focusing on the cerebellar dentate nucleus, once daily on workdays for 2 weeks. The primary outcomes were the percentage of seizure reduction and 50% responder rate in the per-protocol population within 2 months after treatment., Results: Forty-four patients were enrolled and randomized; 18 patients in the active stimulation-first group and 20 in the sham stimulation-first group were included in the final analysis. Active cTBS significantly reduced seizures compared to sham stimulation (difference in percentage of seizure reduction between treatments = 25%, 95% confidence interval [CI] = 5%-46%, p = .018). The 50% responder rate after active stimulation was significantly higher than that after sham stimulation (difference in 50% responder rate between treatments = 24%, 95% CI = 11%-40%, p = .029). Adverse events occasionally occurred during active stimulation (moderate headache in 5% of patients, tinnitus in 3% of patients, dizziness in 3% of patients) but resolved spontaneously within days after treatment completion., Significance: This trial suggested that cTBS targeting the cerebellum was effective and well tolerated in the treatment of DRE. Further studies are warranted to confirm its effectiveness and mechanism., (© 2024 International League Against Epilepsy.)

Background: Ascites is common in advanced gastrointestinal cancers with peritoneal metastases (PM) and negatively impacts patient survival. No study to date has specifically evaluated the relationship between ascites, PM and survival outcomes in metastatic colorectal cancer (mCRC) and metastatic gastric cancer (mGC)., Objectives: This study aims to investigate and elucidate the relationship between malignant ascites, PM and survival outcomes in both mCRC and mGC patients., Design: This is a retrospective analysis of prospectively collected clinical trial data of mCRC and mGC patients with PM., Methods: We performed two pooled analyses, firstly of two Italian randomized trials enrolling patients with mCRC eligible for systemic therapy (TRIBE2; VALENTINO), and secondly of gastric cancer and peritoneal metastasis (GCPM) patients who underwent bi-directional therapeutic treatment comprising systemic and peritoneal-directed therapies., Results: Of 900 mCRC patients, 39 (4.3%) had PM with malignant ascites. Compared to the group without PM, median progression-free and overall survival were significantly inferior in the ascites group (hazard ratio (HR) for progression-free survival (PFS) 1.68, 95% confidence interval (CI): 1.21-2.35, p  = 0.007; HR for overall survival (OS) 2.14, 95% CI: 1.57-3.01, p  < 0.001), but not in the group of PM without ascites (HR for PFS 1.10, 95% CI: 0.91 - 1.34; HR for OS 1.04, 95% CI: 0.84 - 1.30). Of 170 patients with GCPM, those with ascites had higher median Peritoneal Cancer Index scores (23 vs 9, p  < 0.001). Median OS was significantly inferior among those with ascites compared to those without (13.0 vs 21.0 months, HR 1.71, 95% CI: 1.16-2.52, p  = 0.007)., Conclusion: Ascites identifies a subgroup of patients with PM and poor outcomes, for whom tailored research are needed., Competing Interests: F.P. reported receiving institutional research grants from BMS, Incyte, Agenus, Amgen, Lilly and AstraZeneca, and personal fees from BMS, MSD, Amgen, Merck-Serono, Pierre-Fabre, Servier, Bayer, Takeda, Astellas, Johnson&Johnson, Rottapharm, Ipsen, AstraZeneca, GSK, Daiichi-Sankyo, Seagen outside the submitted work. C.C. received honoraria from Amgen, Bayer, Merck, Roche and Servier; has consulting or advisory role at Amgen, Bayer, MSD and Roche; was a speakers bureau member at Servier; received research funding from Bayer, Merck and Servier; and received travel and accommodation expenses from Roche and Servier outside the submitted work. S.L. reports research funding from Amgen,Merck Serono, Bayer, Roche, Eli Lilly, AstraZeneca, Bristol Myers Squibb; honoraria from Roche, Eli Lilly, Bristol Myers Squibb, Servier, Merck Serono, Pierre Fabre, GlaxoSmithKline, Amgen; participation in advisory board for Amgen, Merck Serono, Eli Lilly, AstraZeneca, Incyte, Daiichi-Sankyo, Bristol Myers Squibb, Servier, Merck Sharp & Dohme. M.G. reports honoraria from Roche, Amgen. W.P.Y. has consulting or advisory role at AbbVie/Genentech, Amgen, Bristol Myers Squibb, Ipsen, Novartis, AstraZeneca; is a speakers’ bureau member at Lilly, Sanofi/Aventis, Taiho Pharmaceutical, Eisai, Bayer, MSD Oncology; received travel and accommodations expenses from Pfizer. P.T. has stocks in Tempus Healthcare, Auristone Pte Ltd. R.S. reports grants from National Medical Research Council (NMRC/CIRG23Jul-0035 and NMRC/MOH-000627) during the conduct of the study, as well as other support from Bristol Myers Squibb, Merck, Eisai, Bayer, Taiho, Novartis, Eli Lilly, Roche, AstraZeneca, DKSH, MSD, Paxman Coolers, Natera, Astellas, GSK, Ipsen, Pierre-Fabre, Tavotek, Sanofi, Daichii Sankyo, Beigene, CytoMed and Auristone outside the submitted work., (© The Author(s), 2024.)

Background: While the benefit of immune checkpoint inhibitors (ICI) is well established in programmed death-ligand 1 high (PD-L1 high ) advanced gastroesophageal adenocarcinoma (GEAC), there remains significant controversy about their benefit in PD-L1 low GEAC. To elucidate the benefit of ICI in PD-L1 low and PD-L1 negative GEAC, we conducted an analysis leveraging individual patient data (IPD) extracted from Kaplan-Meier (KM) plots of pivotal trials., Methods: KM curves from randomized clinical trials investigating the efficacy of ICI for advanced GEAC were extracted from published articles. IPD were extracted from the reported curves, and, in the case of unreported KM plots, KMSubtraction was used to retrieve survival data. A patient-level meta-analysis was conducted for PD-L1 low tumors., Results: In the human epidermal growth factor receptor 2 (HER2)-negative setting, pooled PD-L1 combined positive score (CPS) 1-4 subgroup KM plots from KEYNOTE-859, CHECKMATE-649, and RATIONALE-305 showed a modest overall survival (OS) benefit with the addition of an anti-programmed cell death protein 1 (anti-PD-1) agent [hazard ratio (HR) 0.868, P = 0.018]. Similarly, a modest OS benefit was shown by our IPD meta-analysis of PD-L1 CPS 1-9 subgroups from KEYNOTE-859, KEYNOTE-062, and RATIONALE-305 (HR 0.840, P = 0.002.) Conversely, when CPS 5-9 subgroup KM plots from KEYNOTE-859 and RATIONALE-305 were pooled together, no significant OS benefit was found in the ICI-chemotherapy arm (HR 0.867, P = 0.181), although this subgroup was relatively small., Conclusions: In PD-L1 low HER-2 negative GEAC, the benefit of first-line ICI is modest, yet significant. Further translational work is warranted to better select patients who could benefit from immunotherapy in this setting. Meanwhile, alternative therapeutic options such as zolbetuximab in Claudin18.2-positive disease must be taken into account., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Ovarian cancer is the fifth most prevalent cancer in women. Chemotherapy is a major treatment option for patients with advanced ovarian cancer (OC). Quinoline-2-thione and its derivatives are potential candidates for tumor therapy. In this study, we investigated the anticancer activity of the quinoline-2-thione derivative KA3D against ovarian cancer. The effect of KA3D on the viability of ovarian cancer cells was evaluated using MTT assay, and its effects on apoptosis and the cell cycle were detected using flow cytometry. Western blotting was performed to identify apoptosis-and cell cycle-related proteins altered by KA3D treatment. A xenograft model was used to verify the inhibitory effect of KA3D in vivo. H&E staining, biochemical indicator detection, and blood cell counts were used to observe the toxicity and side effects of KA3D. KA3D treatment impeded cell viability, induced apoptosis, and impeded the G2 phase of the cell cycle in ovarian cancer cells. Mechanistically, we found that KA3D enhanced the expression of proapoptotic molecules such as BAX and Caspase 3, while antiapoptotic proteins such as BCL2 were inhibited. The G0/G1 phase-related protein cyclin D1 was reduced and the G2 phase-related protein cyclin B1 was upregulated. In vivo, KA3D displayed potent anticancer activity, with no apparent toxicity in BABLC/c nude mice bearing SKOV3 cells. KA3D demonstrated remarkable chemotherapeutic drug efficacy in terms of significant cancer suppression in vitro and in vivo with low toxicity., (© 2024. The Author(s).)

Using big data and artificial intelligence to establish a multi-point monitoring, early warning, and disposal system to achieve early warning and intervention of infectious disease outbreaks is an important means of controlling the spread of the epidemic. Taking Xiaoshan district as an example, this study analyzes the monitoring contents, warning methods, and application effectiveness of the infectious disease monitoring, early warning and disposal system. Based on Xiaoshan's health big data resources, the system starts with syndrome, disease diagnosis and etiology. Through advanced technologies such as artificial intelligence and block chain, it realizes early identification of infectious disease outbreaks, data fusion, multi-cross collaboration, and closed-loop management. It has improved the sensitivity of clustered outbreaks monitoring and the effectiveness of epidemic disposal and provided a reference for grassroots disease prevention and control departments to establish an infectious disease monitoring and early warning system.

Background and Objective: Tucatinib is a highly selective, oral, reversible, human epidermal growth factor receptor 2 (HER2)-specific tyrosine kinase inhibitor. Tucatinib is approved at a 300-mg twice-daily dose in adults in combination with trastuzumab and capecitabine for advanced HER2-postitive (HER2+) unresectable or metastatic breast cancer and in combination with trastuzumab for RAS wild-type HER2+ unresectable or metastatic colorectal cancer. This study sought to characterize the pharmacokinetics (PK) and assess sources of PK variability of tucatinib in healthy volunteers and in patients with HER2+ metastatic breast or colorectal cancers., Methods: A population pharmacokinetic model was developed based on data from four healthy participant studies and three studies in patients with either HER2+ metastatic breast cancer or metastatic colorectal cancer using a nonlinear mixed-effects modeling approach. Clinically relevant covariates were evaluated to assess their impact on exposure, and overall model performance was evaluated by prediction-corrected visual predictive checks., Results: A two-compartment pharmacokinetic model with linear elimination and first-order absorption preceded by a lag time adequately described tucatinib pharmacokinetic profiles in 151 healthy participants and 132 patients. Tumor type was identified as a significant covariate affecting tucatinib bioavailability and clearance, resulting in a 1.2-fold and 2.1-fold increase in tucatinib steady-state exposure (area under the concentration-time curve) in HER2+ metastatic colorectal cancer and HER2+ metastatic breast cancer, respectively, compared with healthy participants. No other covariates, including mild renal or hepatic impairment, had an impact on tucatinib pharmacokinetics., Conclusions: The impact of statistically significant covariates identified was not considered clinically meaningful. No tucatinib dose adjustments are required based on the covariates tested in the final population pharmacokinetic model., Clinical Trial Registration: NCT03723395, NCT03914755, NCT03826602, NCT03043313, NCT01983501, NCT02025192., (© 2024. The Author(s).)

Background: This study aimed to investigate the risk factors for complication of intra-abdominal infection (IAI) after endoscopic full-thickness resection of gastric submucosal tumors (GSMT) and to establish a nomogram prediction model for the occurrence of IAI., Methods: Clinical data of patients with GSMT who underwent endoscopic full-thick resection (EFR) from January 2018 to July 2023 were retrospectively analyzed. The patients were divided into IAI and non-IAI groups according to whether IAI occurred during postoperative hospitalization. Univariate and multivariate logistic regression analyses were performed on the relevant clinical data of patients in the two groups to screen the independent influencing factors for the occurrence of IAI. The nomogram model was constructed based on the independent influencing factors. Model discrimination was assessed by the area under the curve (AUC) of the receiver operating characteristic (ROC) curve. The consistency of model-predicted risk with actual risk was evaluated using the Hosmer-Lemeshow goodness-of-fit test. The clinical performance of the nomogram model was evaluated using decision curve analysis., Results: A total of 240 GSMT patients who underwent EFR procedures were finally included in this study, including 14 patients (5.83 %) in the IAI group and 226 patients in the non-IAI group. Univariate and multivariate logistic regression analyses showed that age (OR = 1.283, 95 % CI = 1.029-1.600), preoperative albumin (OR = 0.575, 95 % CI = 0.395-0.837), duration of operation (OR = 1.222, 95 % CI = 1.060-1.409), and hospitalization time (OR = 4.089, 95 % CI = 1.190-14.043) were independent influencing factors for the incidence of IAI in GSMT patients undergoing EFR surgery (P < 0.05). A Nomogram model was established based on the above factors. The Hosmer ⁃ Lemeshow test value of this model was 4.230 (P = 0.836). The AUC value of the predictive model was 0.992 (95 % CI: 0.983 to 1.000), with a C-index of 0.992 (95 % CI: 0.983-1.000), indicating that the nomogram model had good accuracy and discrimination. Decision curve analysis showed that the nomogram model had a good predictive performance., Conclusions: Age, preoperative albumin, duration of operation, and hospitalization time were independent influences on the occurrence of IAI in GSMT patients undergoing EFR surgery. A nomogram model based on these factors had a high predictive efficacy and may provide a guiding intervention for the prevention of postoperative IAI in GSMT patients., Competing Interests: 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., (© 2024 Published by Elsevier Ltd.)

Abscisic acid signaling has been implicated in plant responses to water deficit-induced osmotic stress. However, the underlying molecular mechanism remains unelucidated. This study identified the RING-type E3 ubiquitin ligase RING ZINC FINGER PROTEIN1 (PtrRZFP1) in poplar (Populus trichocarpa), a woody model plant. PtrRZFP1 encodes a ubiquitin E3 ligase that participates in protein ubiquitination. PtrRZFP1 mainly functions in the nucleus and endoplasmic reticulum and is activated by drought and abscisic acid. PtrRZFP1-overexpressing transgenic poplars (35S:PtrRZFP1) showed greater tolerance to drought, whereas PtrRZFP1-knockdown lines (KD-PtrRZFP1) showed greater sensitivity to drought. Under treatment with polyethylene glycol and abscisic acid, PtrRZFP1 promoted the production of NO and H2O2 in stomatal guard cells, ultimately enhancing stomatal closure and improving drought tolerance. Additionally, PtrRZFP1 physically interacted with the clade A Protein Phosphatase 2C protein PtrPP2C-9, a core regulator of abscisic acid signaling, and mediated its ubiquitination and eventual degradation through the ubiquitination-26S proteasome system, indicating that PtrRZFP1 positively regulates the abscisic acid signaling pathway. Furthermore, the PtrPP2C-9-overexpression line was insensitive to abscisic acid and more sensitive to drought than the wild-type plants, whereas the opposite phenotype was observed in 35S:PtrRZFP1 plants. In general, PtrRZFP1 negatively regulates the stability of PtrPP2C-9 to mediate poplar drought tolerance. The results of this study provide a theoretical framework for the targeted breeding of drought-tolerant traits in perennial woody plants., (© The Author(s) 2024. Published by Oxford University Press on behalf of American Society of Plant Biologists. All rights reserved. For commercial re-use, please contact reprints@oup.com for reprints and translation rights for reprints. All other permissions can be obtained through our RightsLink service via the Permissions link on the article page on our site—for further information please contact journals.permissions@oup.com.)

Introduction: Pressurized intraperitoneal aerosol chemotherapy-oxaliplatin (PIPAC-OX) induces direct DNA damage and immunogenic cell death in patients with gastric cancer peritoneal metastases (GCPM). Combining PIPAC-OX with immune checkpoint inhibition remains untested. We conducted a phase I first-in-human trial evaluating the safety and efficacy of PIPAC-OX combined with systemic nivolumab (NCT03172416)., Methods: Patients with GCPM who experienced disease progression on at least first-line systemic therapy were recruited across three centers in Singapore and Belgium. Patients received PIPAC-OX at 90 mg/m 2 every 6 weeks and i.v. nivolumab 240 mg every 2 weeks. Translational studies were carried out on GCPM samples acquired during PIPAC-OX procedures., Results: In total, 18 patients with GCPM were prospectively recruited. The PIPAC-OX and nivolumab combination was well tolerated with manageable treatment-related adverse events, although one patient suffered from grade 4 vomiting. At second and third PIPAC-OX, respectively, the median decrease in peritoneal cancer index (PCI) was -5 (interquartile range: -12 to +1) and -7 (interquartile range: -6 to -20) and peritoneal regression grade 1 or 2 was observed in 66.7% (6/9) and 100% (3/3). Translational analyses of 43 GCPM samples revealed enrichment of immune/stromal infiltration and inflammatory signatures in peritoneal tumors after PIPAC-OX and nivolumab. M2 macrophages were reduced in treated peritoneal tumor samples while memory CD4+, CD8+ central memory and naive CD8+ T-cells were increased., Conclusions: The first-in-human trial combining PIPAC-OX and nivolumab demonstrated safety and tolerability, coupled with enhanced T-cell infiltration within peritoneal tumors. This trial sets the stage for future combinations of systemic immunotherapy with locoregional intraperitoneal treatments., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Natriuretic peptide receptor-C (NPR-C) is highly expressed in adipose tissues and regulates obesity-related diseases; however, the detailed mechanism remains unknown. In this research, we aimed to explore the potential role of NPR-C in cold exposure and high-fat/high-sugar (HF/HS) diet-induced metabolic changes, especially in regulating white adipose tissue (WAT) mitochondrial function. Our findings showed that NPR-C expression, especially in epididymal WAT (eWAT), was reduced after cold exposure. Global Npr3 (gene encoding NPR-C protein) deficiency led to reduced body weight, increased WAT browning, thermogenesis, and enhanced expression of genes related to mitochondrial biogenesis. RNA-sequencing of eWAT showed that Npr3 deficiency enhanced the expression of mitochondrial respiratory chain complex genes and promoted mitochondrial oxidative phosphorylation in response to cold exposure. In addition, Npr3 KO mice were able to resist obesity induced by HF/HS diet. Npr3 knockdown in stromal vascular fraction (SVF)-induced white adipocytes promoted the expression of proliferator-activated receptor gamma coactivator 1α (PGC1α), uncoupling protein one (UCP1), and mitochondrial respiratory chain complexes. Mechanistically, NPR-C inhibited cGMP and calcium signaling in an NPR-B-dependent manner but suppressed cAMP signaling in an NPR-B-independent manner. Moreover, Npr3 knockdown induced browning via AKT and p38 pathway activation, which were attenuated by Npr2 knockdown. Importantly, treatment with the NPR-C-specific antagonist, AP-811, decreased WAT mass and increased PGC-1α, UCP1, and mitochondrial complex expression. Our findings reveal that NPR-C deficiency enhances mitochondrial function and energy expenditure in white adipose tissue, contributing to improved metabolic health and resistance to obesity., Competing Interests: Conflict of interest The authors declare that they have no conflict of interest with the contents of this article., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background & Aims: Peritoneal metastasis (PM) in gastric cancer (GC) is associated with poor prognosis and significant morbidity. We sought to understand the genomic, transcriptomic, and tumor microenvironment (TME) features that contribute to peritoneal organotropism in GC., Methods: We conducted a comprehensive multi-omic analysis of 548 samples from 326 patients, including primary tumors, matched normal tissues; peritoneal metastases, and adjacent-normal peritoneal tissues. We used whole exome sequencing, whole transcriptome sequencing, and digital spatial profiling to investigate molecular alterations, gene expression patterns, and TME characteristics associated with PM., Results: Our analysis identified specific genomic alterations in primary tumors, including mutations in ELF3, CDH1, and PIGR, and TME signatures, such as stromal infiltration and M2 macrophage enrichment, associated with increased risk of PM. We observed distinct transcriptional programs and immune compositions in GCPM compared with liver metastases, highlighting the importance of the TME in transcoelomic metastasis. We found differential expression of therapeutic targets between primary tumors and PM, with lower CLDN18.2 and FGFR2b expression in PM. We unravel the roles of the TME in niche reprogramming within the peritoneum, and provide evidence of pre-metastatic niche conditioning even in early GC without clinical PM. These findings were further validated using a humanized mouse model, which demonstrated niche remodeling in the peritoneum during transcoelomic metastasis., Conclusion: Our study provides a comprehensive molecular characterization of GCPM and unveils key biological principles underlying transcoelomic metastasis. The identified predictive markers, therapeutic targets, and TME alterations offer potential avenues for targeted interventions and improved patient outcomes., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Aim: This study aims to utilize machine learning (ML) and logistic regression (LR) models to predict surgical outcomes among patients with traumatic brain injury (TBI) based on admission examination, assisting in making optimal surgical treatment decision for these patients., Method: We conducted a retrospective review of patients hospitalized in our department for moderate-to-severe TBI. Patients admitted between October 2011 and October 2022 were assigned to the training set, while patients admitted between November 2022 and May 2023 were designated as the external validation set. Five ML algorithms and LR model were employed to predict the postoperative Glasgow Outcome Scale (GOS) status at discharge using clinical and routine blood data collected upon admission. The Shapley (SHAP) plot was utilized for interpreting the models., Results: A total of 416 patients were included in this study, and they were divided into the training set (n = 396) and the external validation set (n = 47). The ML models, using both clinical and routine blood data, were able to predict postoperative GOS outcomes with area under the curve (AUC) values ranging from 0.860 to 0.900 during the internal cross-validation and from 0.801 to 0.890 during the external validation. In contrast, the LR model had the lowest AUC values during the internal and external validation (0.844 and 0.567, respectively). When blood data was not available, the ML models achieved AUCs of 0.849 to 0.870 during the internal cross-validation and 0.714 to 0.861 during the external validation. Similarly, the LR model had the lowest AUC values (0.821 and 0.638, respectively). Through repeated cross-validation analysis, we found that routine blood data had a significant association with higher mean AUC values in all ML and LR models. The SHAP plot was used to visualize the contributions of all predictors and highlighted the significance of blood data in the lightGBM model., Conclusion: The study concluded that ML models could provide rapid and accurate predictions for postoperative GOS outcomes at discharge following moderate-to-severe TBI. The study also highlighted the crucial role of routine blood tests in improving such predictions, and may contribute to the optimization of surgical treatment decision-making for patients with TBI., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

The objective of this study was to investigate the potential mechanisms by which (+)-catechin alleviates neuropathic pain. Thirty-two male Sprague-Dawley rats were divided into four groups: the sham group, the chronic constriction injury (CCI)group, the CCI+ ibuprofen group, and the CCI+ (+)-catechin group. CCI surgery induces thermal hyperalgesia in rats and (+)-catechin ameliorated CCI-induced thermal hyperalgesia and repaired damaged sciatic nerve in rats. CCI decreased SOD levels in male rat spinal cord dorsal horn and promoted MDA production, induced oxidative stress by increasing NOX4 levels and decreasing antioxidant enzyme HO-1 levels, and also increased protein levels of TLR4, p-NF-κB, NLRP3 inflammasome components, and IL-1β. In contrast, (+)-catechin reversed the above results. In i vitro experiments, (+)-catechin reduced the generation of reactive oxygen species (ROS) in GMI-R1 cells after LPS stimulation and attenuated the co-expression of IBA-1 and NLRP3. It also showed significant inhibition of the NF-κB and NLRP3 inflammatory pathways and activation of the Nrf2-mediated antioxidant system. Overall, these findings suggest that (+)-catechin inhibits the activation of the NLRP3 inflammasome through the triggering of the Nrf2-induced antioxidant system, the inhibition of the TLR4/NF-κB pathway, and the production of ROS to alleviate CCI-induced neuropathic pain in male rats., (© 2024 Wiley Periodicals LLC.)

The aim of this study was to investigate the potential therapeutic applications of (+)-catechin in the treatment of neuropathic pain. In vivo study, 32 SD rats were randomly divided into four groups: sham group, chronic constriction injury (CCI) group, CCI + ibuprofen group and CCI+ (+)-catechin group. They were subjected to behavioural tests, ELISA, immunohistochemistry and Western blotting. The mechanisms involved were investigated using specific inhibitors in cell experiments. Results of in vivo experiments showed that (+)-catechin could reduce the cold sensitivity pain in a rat model of CCI; ELISA and immunohistochemistry results showed that (+)-catechin could decrease the levels of IL-8, IL-6, TNF-α, CCL2 and CCL5 in serum and the expression levels of nNOS, COX2, IL6, TNF-α, IBA-1 and CSF1R in DRG of CCI rats. Finally, western blot confirmed that (+)-catechin could diminish the levels of IL-34/CSF1R/JAK2/STAT3 signalling pathway in DRG of CCI rats. In vitro studies showed that (+)-catechin reduced IL-34 secretion in LPS-induced RSC96 cells. Meanwhile, (+)-catechin administration in LPS-induced Schwann cell-conditioned medium (L-CM) significantly inhibited the proliferation and migration of RAW264.7 cells; in addition, L-CM+(+)-catechin reduced the activation of the CSF1R/JAK2/STAT3 signalling pathway. (+)-Catechin attenuated the Schwann cell-macrophage cascade response in the DRG by modulating the IL34/CSFIR axis and inhibiting activation of the JAK2/STAT3 pathway, thereby attenuating CCI-induced neuropathic pain in rats., (© 2023. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

Protein citrullination is an irreversible post-translational modification process regulated by peptidylarginine deiminases (PADs) in the presence of Ca 2+ . This process is closely related to the occurrence and development of autoimmune diseases, cancers, neurological disorders, cardiovascular and cerebrovascular diseases, and other major diseases. The analysis of protein citrullination by biomass spectrometry confronts great challenges owing to its low abundance, lack of affinity tags, small mass-to-charge ratio change, and susceptibility to isotopic and deamidation interferences. The methods commonly used to study the protein citrullination mainly involve the chemical derivatization of the urea group of the guanine side chain of the peptide to increase the mass-to-charge ratio difference of the citrullinated peptide. Affinity-enriched labels are then introduced to effectively improve the sensitivity and accuracy of protein citrullination by mass spectrometry. 2,3-Butanedione or phenylglyoxal compounds are often used as derivatization reagents to increase the mass-to-charge ratio difference of the citrullinated peptide, and the resulting derivatives have been observed to contain α -dicarbonyl structures. To date, however, no relevant studies on the reactivity of dicarbonyl compounds with citrullinated peptides have been reported. In this study, we determined whether six α -dicarbonyl and two β -dicarbonyl compounds undergo derivatization reactions with standard citrullinated peptides using matrix-assisted laser desorption ionization-time-of-flight mass spectrometry (MALDI-TOF MS). Among the α -dicarbonyl compounds, 2,3-butanedione and glyoxal reacted efficiently with several standard citrullinated peptides, but yielded a series of by-products. Phenylglyoxal, methylglyoxal, 1,2-cyclohexanedione, and 1,10-phenanthroline-5,6-dione also derivated efficiently with standard citrullinated peptides, generating a single derivative. Thus, a new derivatization method that could yield a single derivative was identified. Among the β -dicarbonyl compounds, 1,3-cyclohexanedione and 2,4-pentanedione successfully reacted with the standard citrullinated peptides, and generated a single derivative. However, their reaction efficiency was very low, indicating that the β -dicarbonyl compounds are unsuitable for the chemical derivatization of citrullinated peptides. The above results indicate that the α -dicarbonyl structure is necessary for realizing the efficient and specific chemical derivatization of citrullinated peptides. Moreover, the side chains of the α -dicarbonyl structure determine the structure of the derivatives, derivatization efficiency, and generation (or otherwise) of by-products. Therefore, the specific enrichment and precise identification of citrullinated peptides can be achieved by synthesizing α -dicarbonyl structured compounds containing affinity tags. The proposed method enables the identification of citrullinated proteins and their modified sites by MS, thereby providing a better understanding of the distribution of citrullinated proteins in different tissues. The findings will be beneficial for studies on the mechanism of action of citrullinated proteins in a variety of diseases.

As an important force in promoting the transformation and upgrading of the national economy, the occupational health of the Internet industry's employees has received widespread attention. This paper examines the current situation of occupational health risks and management in the Internet industry at home and abroad, and on this basis reveals the physical and mental health problems of Internet industry employees. Combining the existing regulations, policies and standard documents at home and abroad, countermeasures are proposed to improve the relevant laws and regulations and their guidelines, implement relevant job design requirements, build a healthy working environment, optimise the work management system and carry out workplace health promotion, in order to provide ideas to accelerate the improvement of occupational health issues in the Internet industry.

Although bile acids play a notable role in depression, the pathological significance of the bile acid TGR5 membrane-type receptor in this disorder remains elusive. Using depression models of chronic social defeat stress and chronic restraint stress in male mice, we found that TGR5 in the lateral hypothalamic area (LHA) predominantly decreased in GABAergic neurons, the excitability of which increased in depressive-like mice. Upregulation of TGR5 or inhibition of GABAergic excitability in LHA markedly alleviated depressive-like behavior, whereas down-regulation of TGR5 or enhancement of GABAergic excitability facilitated stress-induced depressive-like behavior. TGR5 also bidirectionally regulated excitability of LHA GABAergic neurons via extracellular regulated protein kinases-dependent Kv4.2 channels. Notably, LHA GABAergic neurons specifically innervated dorsal CA3 (dCA3) CaMKIIα neurons for mediation of depressive-like behavior. LHA GABAergic TGR5 exerted antidepressant-like effects by disinhibiting dCA3 CaMKIIα neurons projecting to the dorsolateral septum (DLS). These findings advance our understanding of TGR5 and the LHA GABA →dCA3 CaMKIIα →DLS GABA circuit for the development of potential therapeutic strategies in depression., Competing Interests: Declaration of interests The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Gastroesophageal cancers (GECs) represent a significant clinical challenge. For early resectable GEC, the integration of immune checkpoint inhibitors into the perioperative chemotherapy and chemoradiation treatment paradigms are being explored and showing promising results. Frontline management of metastatic GEC is exploring the role of targeted therapies beyond PD-1 inhibitors, including anti-human epidermal growth factor receptor 2 agents, Claudin 18.2 inhibitors, and FGFR2 inhibitors, which have shown considerable efficacy in recent trials. Looking ahead, ongoing trials and emerging technologies such as bispecific antibodies, antibody-drug conjugates, and adoptive cell therapies like chimeric antigen receptor T cells are expected to define the future of GEC management. These advancements signify a paradigm shift toward personalized and immunotherapy-based approaches, offering the potential for improved outcomes and reduced toxicity for patients with GEC.

Objective: Sleep-related hypermotor epilepsy (SHE) is a focal epilepsy syndrome characterized by seizures that predominantly occur during sleep. The pathogenesis of these seizures remains unclear. We previously detected rare variants in GABRG2, which encodes the γ 2 subunit of γ-aminobutyric acid type A receptor (GABA A R), in patients with SHE and demonstrated that these variants impaired GABA A R function in vitro. However, the mechanisms by which GABRG2 variants contribute to seizure attacks during sleep remain unclear., Methods: In this study, we designed a knock-in (KI) mouse expressing the mouse Gabrg2 T316N variant, corresponding to human GABRG2 T317N variant, using CRISPR/Cas9. Continuous video-electroencephalogram monitoring and in vivo multichannel electrophysiological recordings were performed to explore seizure susceptibility to pentylenetetrazol (PTZ), alterations in the sleep-wake cycle, spontaneous seizure patterns, and synchronized activity in the motor thalamic nuclei (MoTN) and secondary motor cortex (M2). Circadian variations in the expression of total, membrane-bound, and synaptic GABA A R subunits were also investigated., Results: No obvious changes in gross morphology were detected in Gabrg2 T316N/+ mice compared to their wild-type (Gabrg2 +/+ ) littermates. Gabrg2 T316N/+ mice share key phenotypes with patients, including sleep fragmentation and spontaneous seizures during sleep. Gabrg2 T316N/+ mice showed increased susceptibility to PTZ-induced seizures and higher mortality after seizures. Synchronization of the local field potentials between the MoTN and M2 was abnormally enhanced in Gabrg2 T316N/+ mice during light phase, when sleep dominates, accompanied by increased local activities in the MoTN and M2. Interestingly, in Gabrg2 +/+ mice, GABA A R γ2 subunits showed a circadian increase on the neuronal membrane and synaptosomes in the transition from dark phase to light phase, which was absent in Gabrg2 T316N/+ mice., Conclusion: We generated a new SHE mouse model and provided in vivo evidence that rare variants of GABRG2 contribute to seizure attacks during sleep in SHE., Competing Interests: Declaration of competing interest None., (Copyright © 2023. Published by Elsevier Inc.)

Background: Carbapenem-resistant (Car-R) Pseudomonas aeruginosa is an urgent threat. These isolates may remain susceptible to traditional noncarbapenem antipseudomonal β-lactams, but it is unclear if carbapenem resistance impacts the effectiveness of these agents., Objective: The purpose of this study was to compare clinical outcomes in Car-R and cephalosporin-susceptible (Ceph-S) P. aeruginosa pneumonia treated with cefepime versus other susceptible agents., Methods: This retrospective cohort study evaluated patients diagnosed with hospital-acquired or ventilator-associated pneumonia who had a respiratory isolate of Car-R Ceph-S P. aeruginosa . Patients were excluded if they had polymicrobial respiratory cultures, other concomitant infections, empyema, death within 3 days of index culture, or received less than 3 days of susceptible therapy. Patients treated with cefepime were compared to other susceptible therapies. The primary endpoint was 30-day in-hospital mortality., Results: Eighty-seven patients were included: cefepime, n = 61; other susceptible therapies, n = 26. There were no differences in 30-day in-hospital mortality between cefepime and other susceptible therapies (19.6% vs. 19.2%, p value = 0.719). In addition, there were no differences between clinical cure rates (cefepime 65.6% vs. other therapies 72 %, p value = 0.47). In multivariate logistic regression, treatment with cefepime (odds ratio [OR], 0.57; 95% confidence interval [CI], 0.11-2.52) was not independently associated with 30-day in-hospital mortality., Conclusion and Relevance: For the treatment of Car-R Ceph-S P. aeruginosa pneumonia, cefepime showed similar rates of 30-day in-hospital mortality and clinical outcomes when compared to other susceptible therapies. Cefepime may be utilized to conserve novel β-lactam and β-lactamase inhibitors., Competing Interests: Declaration of Conflicting InterestsThe authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Objective: To clarify the clinicopathological features, prognosis, and recurrence pattern of early-onset gastric cancer (EOGC). Methods: Using data from the gastric cancer database of Zhongshan Hospital, Fudan University, we performed a retrospective, large-scale, real-world study of 5046 patients with gastric cancer who had undergone redical or palliative gastrectomy from January 2013 to December 2018, including 425 patients with EOGC (age ≤45 years) and 4621 controls. All those patients were pathologically confirmed adenocarcinoma with complete follow-up of five years. Residue gastric cancer and patients without complete clinical or follow-up data were excluded. We used a combination of outpatient and telephone follow-up, ending in October 2022 (median duration of follow-up 60 months), and compared the clinicopathological features and prognosis of the two groups. Results: The clinicopathological features of EOGC included female predominance (61.1% [262/425 vs. 26.3% [1217/4621], χ 2 =234.215, P <0.001), fewer comorbidities (31.3% [133/425] vs. 58.5% [2703/4621], χ 2 =34.378, P <0.001), poorer differentiation (90.6% [385/425] vs. 78.2% [3614/4621], χ 2 =30.642, P <0.001), higher proportion of diffuse type (53.9% [229/425] vs. 18.3% [846/4621], χ 2 =274.474, P <0.001), higher proportion of T4 stage (44.7% [190/425] vs. 37.5% [1733/4621], χ 2 =17.535, P =0.001), more lymph node metastases (60.5% [257/425] vs. 53.9% [2491/4621], χ 2 =6.764, P =0.009), and higher proportion of pathological stage III/IV (47.5% [202/425] vs. 42.4% [1959/4621], χ 2 =4.093, P =0.043). The 5-year overall survival rates of the EOGC and control groups were 55.1% and 49.1%, respectively. Overall survival was significantly better in the EOGC than in the control group ( P <0.001). According to subgroup analysis, the prognosis of pathological stage I/II/III EOGC was better than that of the control group. Recurrence rates were similar in the two groups, whereas patients with EOGC had a higher proportion of peritoneal recurrence (7.8% [33/425] vs. 3.2% [146/4621], χ 2 =23.741, P <0.001) and a lower proportion of distant metastasis (4.9% [21/425] vs. 8.3% [385/4621], χ 2 =6.247, P =0.012). Conclusion: EOGC has unique clinicopathological features and recurrence patterns and resectable EOGC has a better prognosis, suggesting that patients with EOGC should be actively treated with the focus on preventing peritoneal recurrence.

Background: In critically ill patients receiving invasive mechanical ventilation (IMV), it is unable to determine early which patients require tracheotomy and whether early tracheotomy is beneficial., Methods: Clinical data of patients who were first admitted to the ICU and underwent invasive ventilation for more than 24 h in the Medical Information Marketplace in Intensive Care (MIMIC)-IV database were retrospectively collected. Patients were categorized into successful extubation and tracheotomy groups according to whether they were subsequently successfully extubated or underwent tracheotomy. The patients were randomly divided into model training set and validation set in a ratio of 7:3. Constructing predictive models and evaluating and validating the models. The tracheotomized patients were divided into the early tracheotomy group (< = 7 days) and the late tracheotomy group (> 7 days), and the prognosis of the two groups was analyzed., Results: A total of 7 key variables were screened: Glasgow coma scale (GCS) score, pneumonia, traumatic intracerebral hemorrhage, hemorrhagic stroke, left and right pupil responses to light, and parenteral nutrition. The area under the receiver operator characteristic (ROC) curve of the prediction model constructed through these seven variables was 0.897 (95% CI: 0.876-0.919), and 0.896 (95% CI: 0.866-0.926) for the training and validation sets, respectively. Patients in the early tracheotomy group had a shorter length of hospital stay, IMV duration, and sedation duration compared to the late tracheotomy group (p < 0.05), but there was no statistically significant difference in survival outcomes between the two groups., Conclusion: The prediction model constructed and validated based on the MIMIC-IV database can accurately predict the outcome of tracheotomy in critically ill patients. Meanwhile, early tracheotomy in critically ill patients does not improve survival outcomes but has potential advantages in shortening the duration of hospitalization, IMV, and sedation., (© 2024. The Author(s).)