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Abstract This multicentre, two-arm, phase 2 study aimed to explore the efficacy and safety of neoadjuvant camrelizumab plus chemotherapy or apatinib in patients with initially unresectable stage II–III non-small-cell lung cancer (NSCLC). Eligible patients regardless of PD-L1 expression received neoadjuvant camrelizumab 200 mg and platinum-doublet chemotherapy every 3 weeks (arm A) or those with PD-L1-positive tumors received neoadjuvant camrelizumab and apatinib 250 mg once daily (arm B), for 2–4 cycles, followed by surgery. The primary endpoint was major pathological response (MPR) rate. Thirty patients in arm A and 21 in arm B were enrolled. Surgery rates were 50.0% (15/30) in arm A and 42.9% (9/21) in arm B, with all patients achieving R0 resections. Of these patients, the MPR and pathological complete response rates were both 20.0% (95% CI 4.3–48.1) in arm A and were 55.6% (95% CI 21.2–86.3) and 11.1% (95% CI 0.3–48.2) in arm B, respectively. The corresponding objective response rates were 33.3% (95% CI 11.8–61.6) and 55.6% (95% CI 21.2–86.3). With a median follow-up of 22.4 months (95% CI 19.0–26.0), the median event-free survival was not reached (NR; 95% CI 13.6-NR) in arm A and 16.8 months (95% CI 8.6-NR) in arm B. Grade 3 or above treatment-related adverse events occurred in eight (26.7%) patients in arm A and three (14.3%) in arm B. Biomarker analysis showed baseline TYROBP expression was predictive of treatment response in arm B. Neoadjuvant camrelizumab plus chemotherapy or apatinib exhibits preliminary efficacy and manageable toxicity in patients with initially unresectable stage II–III NSCLC.

ObjectiveSevere cutaneous adverse reactions (SCARs) are rare but life-threatening, with antibiotics being the main cause. This retrospective study from a single center was designed to analyze the culprit drugs, clinical features and treatment outcomes of antibiotic-induced SCARs.MethodsWe analyzed cases of antibiotic-induced SCARs in a tertiary hospital in China between January 2013 and January 2024, including Steven-Johnson syndrome (SJS) or Stevens-Johnson syndrome-toxic epidermal necrolysis (SJS-TEN) overlap, toxic epidermal necrolysis (TEN), drug reaction with eosinophilia and systemic symptoms (DRESS) and acute generalized exanthematous pustulosis (AGEP). Descriptive analysis of the demographic characteristics, clinical manifestations, treatment and prognosis were carried out.ResultsAmong 354 cases of SCARs, 63 validated antibiotic-related cases were included. Cephalosporins (31.7%), penicillins (25.4%), and quinolones (19.0%) were the most common triggers for SCARs. Overall, liver (50.8%), lungs (31.7%), and kidneys (23.8%) were the most frequently affected organ in SCARs cases. Eight patients (28.6%) in the SJS/SJS-TEN overlap group and 8 patients (80.0%) in the TEN group received combination therapy of corticosteroids and IVIG. Patients with SCARs caused by penicillins or cephalosporins could receive alternative treatments such as lincomamides, quinolones, and tetracyclines. The mortality rate in the TEN group was the highest at 20.0%, followed by the SJS/SJS-TEN overlap group (7.1%), and no deaths were observed in the DRESS and AGEP groups.ConclusionThe identification of the culprit antibiotics and the application of alternative antibiotic therapies are crucial for the management of antibiotic-induced SCARs. If complicated underlying conditions and complications like advanced age, cancer and pneumonia coexist with SCARs, patients might be more at risk for mortality.

Abstract Kinematic calibration is a reliable way to improve the accuracy of parallel manipulators, while the error model dramatically affects the accuracy, reliability, and stability of identification results. In this paper, a comparison study on kinematic calibration for a 3-DOF parallel manipulator with three error models is presented to investigate the relative merits of different error modeling methods. The study takes into consideration the inverse-kinematic error model, which ignores all passive joint errors, the geometric-constraint error model, which is derived by special geometric constraints of the studied RPR-equivalent parallel manipulator, and the complete-minimal error model, which meets the complete, minimal, and continuous criteria. This comparison focuses on aspects such as modeling complexity, identification accuracy, the impact of noise uncertainty, and parameter identifiability. To facilitate a more intuitive comparison, simulations are conducted to draw conclusions in certain aspects, including accuracy, the influence of the S joint, identification with noises, and sensitivity indices. The simulations indicate that the complete-minimal error model exhibits the lowest residual values, and all error models demonstrate stability considering noises. Hereafter, an experiment is conducted on a prototype using a laser tracker, providing further insights into the differences among the three error models. The results show that the residual errors of this machine tool are significantly improved according to the identified parameters, and the complete-minimal error model can approach the measurements by nearly 90% compared to the inverse-kinematic error model. The findings pertaining to the model process, complexity, and limitations are also instructive for other parallel manipulators.

Coordinated manipulators can construct a series system, such that all the position error of the end-effector is required to remain within the permissible limit. This article proposed a new method to handle the problem of reliability analysis involving in multiple failure modes. The extreme value of the position error is introduced to construct a surrogate model to replace the original failure event, the moment with fraction order instead of the traditional integer is applied to derive the best-fit distribution of the extreme value based on the maximum entropy principle. The innovations mainly include: (1) the high efficient dimension reduction via the surrogate model constructed with the extreme value and (2) a better probability density function is derived through the fractional moment. A series system consists of three manipulators is used as an example to demonstrate the efficiency and accuracy of the proposed method.

Abstract Background Lung squamous cell carcinoma (LUSC) is prone to metastasis and likely to develop resistance to chemotherapeutic drugs. DNA repair has been reported to be involved in the progression and chemoresistance of LUSC. However, the relationship between LUSC patient prognosis and DNA damage repair genes is still unclear. Methods The clinical information of LUSC patients and tumour gene expression level data were downloaded from the TCGA database. Unsupervised clustering and Cox regression were performed to obtain molecular subtypes and prognosis-related significant genes based on a list including 150 DNA damage repair genes downloaded from the GSEA database. The coefficients determined by the multivariate Cox regression analysis and the expression level of prognosis-related DNA damage repair genes were employed to calculate the risk score, which divided LUSC patients into two groups: the high-risk group and the low-risk group. Immune viability, overall survival, and anticarcinogen sensitivity analyses of the two groups of LUSC patients were performed by Kaplan–Meier analysis with the log rank test, ssGSEA and the pRRophetic package in R software. A time-dependent ROC curve was applied to compare the survival prediction ability of the risk score, which was used to construct a survival prediction model by multivariate Cox regression. The prediction model was used to build a nomogram, the discriminative ability of which was confirmed by C-index assessment, and its calibration was validated by calibration curve analysis. Differentially expressed DNA damage repair genes in LUSC patient tissues were retrieved by the Wilcoxon test and validated by qRT–PCR and IHC. Result LUSC patients were separated into two clusters based on molecular subtypes, of which Cluster 2 was associated with worse overall survival. A prognostic prediction model for LUSC patients was constructed and validated, and a risk score calculated based on the expression levels of ten DNA damage repair genes was employed. The clinical utility was evaluated by drug sensitivity and immune filtration analyses. Thirteen-one genes were upregulated in LUSC patient samples, and we selected the top four genes that were validated by RT–PCR and IHC. Conclusion We established a novel prognostic model based on DNA damage repair gene expression that can be used to predict therapeutic efficacy in LUSC patients.

BackgroundSince 2009, a series of ambitious health system reforms have been launched in China, including the zero mark-up drug policy (ZMDP); the policy was intended to reduce substantial medicine expenses for patients by abolishing the 15% mark-up on drugs. This study aims to evaluate the impacts of ZMDP on medical expenditures from the perspective of disease burden disparities in western China.MethodTwo typical diseases including Type 2 diabetes mellitus (T2DM) in internal medicine and cholecystolithiasis (CS) in surgery were selected from medical records in a large tertiary level-A hospital in SC Province. The monthly average medical expenses of patients from May 2015 to August 2018 were extracted to construct an interrupted time series (ITS) model to evaluate the impact of policy implementation on the economic burden.ResultsA total of 5,764 cases were enrolled in our study. The medicine expenses for T2DM patients maintained a negative trend both before and after the intervention of ZMDP. It had declined by 74.3 CNY (P < 0.001) per month on average in the pre-policy period and subsequently dropped to 704.4 CNY (P = 0.028) immediately after the policy. The level change of hospitalization expenses was insignificant (P = 0.197), with a reduction of 677.7 CNY after the policy, while the post-policy long-term trend was significantly increased by 97.7 CNY (P = 0.035) per month contrasted with the pre-policy period. In addition, the anesthesia expenses of T2DM patients had a significant increase in the level under the impact of the policy. In comparison, the medicine expenses of CS patients significantly decreased by 1,014.2 CNY (P < 0.001) after the policy, while the total hospitalization expenses had no significant change in level and slope under the influence of ZMDP. Furthermore, the expenses of surgery and anesthesia for CS patients significantly increased by 320.9 CNY and 331.4 CNY immediately after the policy intervention.ConclusionOur study indicated that the ZMDP has been an effective intervention to reduce the excessive medicine expenses for both researched medical and surgical diseases, but failed to show any long-term advantage. Moreover, the policy has no significant impact on relieving the overall hospitalization burden for either condition.

Abstract Objective The aim of this study was to assess the efficacy and safety of intrapleural perfusion with hyperthermic chemotherapy (IPHC) in treating malignant pleural effusion (MPE) compared to normothermic chemoperfusion of the pleural cavity (NCPC), and to investigate the better treatment to control MPE. Methods Malignant pleural effusion patients were enrolled in the study and treated with NCPC or IPHC under video‐assisted thoracoscopic surgery (VATS). The chest drainage duration, clinical characteristics, and recurrence time of pleural effusion of patients were collected for statistical analysis. The chi‐squared test and the Fisher's exact test were applied to compare the distribution differences in categorical variables. Progression‐free survival (PFS) was estimated by the Kaplan–Meier method and was compared by the log‐rank test. The survival analysis was performed using the Cox proportional hazards method. Results A total of 37 MPE patients were enrolled in this study. Twenty‐seven patients received NCPC and 10 patients received IPHC under VATS. Significant differences were found in pathological types (p = 0.011), chest drainage duration (p = 0.005), and remission rate (p = 0.009) between two different treatment groups. The chest drainage duration of IPHC under VATS was shorter than the NCPC group (t = 2.969, p = 0.005). The remission rate of MPE in IPHC group was better than the NCPC one (OR = 0.031, 95% CI: 0.002–0.507, p = 0.015). The result of the Kaplan–Meier method showed that IPHC group could significantly prolong the PFS of patients with MPE compared to NCPC group (log‐rank p = 0.002). Univariate cox regression analysis showed that patients with MPE in the IPHC group presented significant longer PFS than the NCPC group (HR = 0.264, 95% CI: 0.098–0.713, p = 0.009). Multivariate cox regression analysis further verified this conclusion (HR = 0.268, 95% CI: 0.096–0.753, p = 0.012). Conclusion Compared to the NCPC, the IPHC under VATS presents a better control effect on MPE, shorter tube placement time, and longer complete remission time. For this reason, we recommend IPHC under VATS as the first‐line treatment for patients with MPE those who can tolerate minimally invasive surgery.

Abstract Background It has been demonstrated by studies globally that RNA binding proteins (RBPs) took part in the development of cervical cancer (CC). Few studies concentrated on the correlation between RBPs and overall survival of CC patients. We retrieved significant DEGs (differently expressed genes, RNA binding proteins) correlated to the process of cervical cancer development. Methods Expressions level of genes in cervical cancer and normal tissue samples were obtained from GTEx and TCGA database. Differently expressed RNA binding proteins (DEGs) were retrieved by Wilcoxon sum-rank test. ClusterProfiler package worked in R software was used to perform GO and KEGG enrichment analyses. Univariate proportional hazard cox regression and multivariate proportional hazard cox regressions were applied to identify DEGs equipped with prognostic value and other clinical independent risk factors. ROC curve was drawn for comparing the survival predict feasibility of risk score with other risk factors in CC patients. Nomogram was drawn to exhibit the prediction model and validated by C-index and calibration curve. Correlations between differentially expressed RNA binding proteins (DEGs) and other clinical features were investigated by t test or Cruskal Wallis analysis. Correlation between Immune and DEGs in cervical cancer was investigated by ssGSEA. Results 347 differentially expressed RBPs (DEGs) were retrieved from cervical cancer tissue and normal tissue samples. GO enrichment analysis showed that these DEGs involved in RNA splicing, catabolic process and metabolism. Cox regression model showed that there were ten DEGs significantly associated with overall survival of cervical cancer patients. WDR43 (HR = 0.423, P = 0.008), RBM38 (HR = 0.533, P

Background: Many biological clocks related to aging have been linked to the development of cancer. A recent study has identified that the inflammatory aging clock was an excellent indicator to track multiple diseases. However, the role of the inflammatory aging clock in glioblastoma (GBM) remains to be explored. This study aimed to investigate the expression patterns and the prognostic values of inflammatory aging (iAge) in GBM, and its relations with stem cells.Methods: Inflammation-related genes (IRG) and their relations with chronological age in normal samples from the Cancer Genome Atlas (TCGA) were identified by the Spearman correlation analysis. Then, we calculated the iAge and computed their correlations with chronological age in 168 patients with GBM. Next, iAge was applied to classify the patients into high- and low-iAge subtypes. Next, the survival analysis was performed. In addition, the correlations between iAge and stem cell indexes were evaluated. Finally, the results were validated in an external cohort.Results: Thirty-eight IRG were significantly associated with chronological age (|coefficient| > 0.5), and were used to calculate the iAge. Correlation analysis showed that iAge was positively correlated with chronological age. Enrichment analysis demonstrated that iAge was highly associated with immune cells and inflammatory activities. Survival analysis showed the patients in the low-iAge subtype had significantly better overall survival (OS) than those in the high-iAge subtype (p < 0.001). In addition, iAge outperformed the chronological age in revealing the correlations with stem cell stemness. External validation demonstrated that iAge was an excellent method to classify cancer subtypes and predict survival in patients with GBM.Conclusions: Inflammatory aging clock may be involved in the GBM via potential influences on immune-related activities. iAge could be used as biomarkers for predicting the OS and monitoring the stem cell.

In this article, an impedance control-based framework for human-robot composite layup skill transfer was developed, and the human-in-the-loop mechanism was investigated to achieve human-robot skill transfer. Although there are some works on human-robot skill transfer, it is still difficult to transfer the manipulation skill to robots through teleoperation efficiently and intuitively. In this article, we developed an impedance-based control architecture of telemanipulation in task space for the human-robot skill transfer through teleoperation. This framework not only achieves human-robot skill transfer but also provides a solution to human-robot collaboration through teleoperation. The variable impedance control system enables the compliant interaction between the robot and the environment, smooth transition between different stages. Dynamic movement primitives based learning from demonstration (LfD) is employed to model the human manipulation skills, and the learned skill can be generalized to different tasks and environments, such as the different shapes of components and different orientations of components. The performance of the proposed approach is evaluated on a 7 DoF Franka Panda through the robot-assisted composite layup on different shapes and orientations of the components.

Background: The role of ferroptosis in breast cancer brain metastasis (BCBM) is unclear. This study aimed to explore the ferroptosis-related genes (FRG) relations with the tumor microenvironment, as well as evaluate their values in predicting survival and drug sensitivity in patients with BCBM.Materials and Methods: Genes expression and clinical data were downloaded from Gene Expression Omnibus (GEO). Univariate and multivariate Cox regression analyses were performed to explore the independent prognostic factors. Consensus cluster principal component analysis (PCA) was used to establish the ferroptosis score. Immunological signatures were analyzed by the single-sample gene set enrichment analysis (ssGSEA). Drug sensitivity was evaluated through the estimated half-maximal inhibitory concentration (IC50). Finally, results were validated in external cohorts.Results: Fourteen significantly different FRG were identified between breast cancer (BC) and BCBM tissues. Survival analysis demonstrated HMOX1, PEBP1, KEAP1, and LPCAT3 were significantly associated with overall survival (OS) and relapse-free survival (RFS) (all p < 0.05). High ferroptosis score was correlated with iron ion homeostasis, iron metabolism, higher stromal cells and immune cells scores. Patients with high- and low-ferroptosis scores were characterized by different drug sensitivities. Following external validations, the ferroptosis had distinct expression profiles between the BC and BCBM, and could serve as biomarkers for OS and drug response.Conclusion: Our findings suggested that ferroptosis may be involved in the process of BCBM, and ferroptosis could serve as prognostic biomarkers. Evaluation of ferroptosis may deepen our understanding about the tumor microenvironment, and could help clinicians to make individualized therapy.

Background: Esophageal cancer is one of the most leading and lethal malignancies. Glycolysis and the tumor microenvironment (TME) are responsible for cancer progressions. We aimed to study the relationships between glycolysis, TME, and therapeutic response in esophageal adenocarcinoma (EAC).Materials and Methods: We used the ESTIMATE algorithm to divide EAC patients into ESTIMATE high and ESTIMATE low groups based on the gene expression data downloaded from TCGA. Weighted gene co-expression network analysis (WGCNA) and Gene Set Enrichment Analysis (GSEA) were performed to identify different glycolytic genes in the TME between the two groups. The prognostic gene signature for overall survival (OS) was established through Cox regression analysis. Impacts of glycolytic genes on immune cells were assessed and validated. Next, we conducted the glycolytic gene mutation analysis and drug therapeutic response analysis between the two groups. Finally, the GEO database was employed to validate the impact of glycolysis on TME in patients with EAC.Results: A total of 78 EAC patients with gene expression profiles and clinical information were included for analysis. Functional enrichment results showed that the genes between ESTIMATE high and ESTIMATE low groups (N = 39, respectively) were strongly related with glycolytic and ATP/ADP metabolic pathways. Patients in the low-risk group had probabilities to survive longer than those in the high-risk group (p < 0.001). Glycolytic genes had significant impacts on the components of immune cells in TME, especially on the T-cells and dendritic cells. In the high-risk group, the most common mutant genes were TP53 and TTN, and the most frequent mutation type was missense mutation. Glycolysis significantly influenced drug sensitivity, and high tumor mutation burden (TMB) was associated with better immunotherapeutic response. GEO results confirmed that glycolysis had significant impacts on immune cell contents in TME.Conclusion: We performed a comprehensive study of glycolysis and TME and demonstrated that glycolysis could influence the microenvironment and drug therapeutic response in EAC. Evaluation of the glycolysis pattern could help identify the individualized therapeutic regime.

Redundantly actuated parallel manipulators (PMs) have attracted a great deal of attention since they generally have better stiffness than non-redundantly actuated ones. This paper presents an analytical elastostatic stiffness modeling and performance study of a 2UPR–2PRU PM with actuation redundancy, which has two rotational and one translational degrees of freedom (U: universal joint; P: prismatic joint; R: revolute joint). First, the inverse displacement is reviewed and verified briefly. Second, the stiffness matrices of UPR and PRU limbs are deduced by using the principle of strain energy, followed by the overall stiffness matrix of the 2UPR–2PRU PM. Combined with the ANSYS software, the finite element analysis method is then used to verify the correctness and universality of the stiffness models by calculating the deformations of four selected configurations. Finally, the stiffness index based on the virtual work is used to evaluate the performance of the 2UPR–2PRU PM, and the influence of different external loads and operational heights on the stiffness performance is discussed. The relationship between singular configurations and the stiffness index is also presented. The stiffness models and performance distributions of the 2UPR–2PRU PM with actuation redundancy can provide references for the actual applications.

This paper presents the type synthesis of 4-DOF non-overconstrained parallel mechanisms (PMs) with symmetrical structures. A special topological structure that includes two intermediate platforms and one moving platform is employed. Constraint conditions for 3R1T, 2R2T, and 1R3T (R: rotation; T: translation) symmetrical PMs are analyzed. Several classes of hybrid limbs that exert a constraint force or a constraint couple are synthesized using screw theory. These limbs are then used to construct 4-DOF PMs, resulting in many novel non-overconstrained 3R1T, 2R2T, and 1R3T PMs with symmetrical structures. The non-overconstrained feature is verified based on the Grübler/Kutzbach criterion.