Patient Clinical Information Research Articles

Exploring the effect of NK-cell related molecules on the prognosis and tumor microenvironment of gastric cancer patients: Evidence from large sample populations

BackgroundNatural killer (NK) cells play a significant role in anti-tumor immunity, and their involvement has been documented in various cancers. However, a deeper understanding of the mechanisms by which NK cells influence gastric cancer progression remains necessary. MethodsWe utilized the Cancer Genome Atlas (TCGA) database to acquire transcriptional profiles, clinical information, and mutation data for gastric cancer patients. R software and associated packages were employed for all analyses of this publicly available data. ResultsWe used multiple algorithms to evaluate the tumor microenvironment in gastric cancer samples. We performed differential expression analysis to pinpoint genes related to NK cells. Utilizing this data, we developed a prognostic model featuring three crucial NK cell-related genes: MAB21L2, ARPP21, and MUCL1. This model showed strong predictive performance in the training and validation groups. Consistently, patients identified as high-risk according to our model had worse overall survival rates. To further elucidate the biological differences between high-risk and low-risk patients, we performed enrichment analyses focusing on biological pathways and immune-related factors. Additionally, we observed a correlation between higher risk scores and non-responsiveness to treatment. Interestingly, high-risk patients were found to be potentially more sensitive to axitinib. We selected MUCL1 for further investigation due to its potential role in the model. While MUCL1 mRNA levels were elevated in both gastric cancer and paired normal tissues, protein expression analysis using the Human Protein Atlas database revealed a decrease in MUCL1 protein levels within tumor tissues. ConclusionsOur findings contribute to a more comprehensive understanding of the role of NK cells in gastric cancer and highlight MUCL1 as a promising therapeutic target.

Low serum complements in idiopathic inflammatory myositis: clinical features and impact on the prognosis

This study investigated the clinical features and prognostic relevance of decreased serum complement levels in patients with idiopathic inflammatory myositis (IIM). The clinical information of IIM patients with less than normal serum complement levels (L-Com) and that of those with normal serum complement levels (N-Com) was compared. In patients with interstitial lung disease (ILD), regression analyses were used to investigate the implication of L-Com in their PaO2/FiO2 (P/F) ratio. Prognostic outcomes of ILD were evaluated using the log-rank test. Of 94 IIM patients, 26 with L-Com (median age, 56.0 years) and 68 with N-Com (56.5 years) were included. The prevalence of women was significantly higher in patients with L-Com (92.3%) than in those with N-Com (67.6%). ILD was observed in 17 (65.4%) patients with L-Com and in 46 (67.6%) with N-Com. Among patients with ILD, the P/F ratio was significantly lower in those with L-Com than in those with N-Com. Serum C3 levels were correlated with decreased P/F ratio. Inferior prognosis of ILD was significantly demonstrated in patients with L-Com, especially in those positive for anti-melanoma differentiation-associated protein 5 antibody. L-Com may be implicated in reduced arterial oxygen levels and a poorer prognosis in patients with IIM-related ILD.

Identification of novel disulfidptosis-related lncRNA signatures to predict the prognosis and immune microenvironment of skin cutaneous melanoma patients.

Skin cutaneous melanoma (SKCM) is an aggressive form of malignant melanoma with poor prognosis and high mortality rates. Disulfidptosis is a newly discovered cell death regulatory mechanism caused by the abnormal accumulation of disulfides. This unique pathway is guiding significant new research to understand cancer progression for targeted treatment. However, the correlation between disulfidptosis with long non-coding RNAs (lncRNAs) in SKCM remains unknown at present. The Cancer Genome Atlas database furnished lncRNA expression data and clinical information for SKCM patients. Pearson correlation and Cox regression analyses identified disulfidptosis-related lncRNAs associated with SKCM prognosis. ROC curves and a nomogram validated the model. TME, immune infiltration, GSEA analysis, immune checkpoint gene expression profiling, and drug sensitivity were assessed in high and low-risk groups. Consistent clustering categorized SKCM patients for personalized clinical treatment guidance. A total of twelve disulfidptosis-related lncRNAs were identified for the development of prognosis prediction models. The area under the curve (AUC) values of the ROC curve and the nomogram provided reliable discrimination to evaluate the prognostic potential for SKCM patients. The TME played a crucial role in tumorigenesis, progression and prognosis, and the risk scores were closely related to immune cell infiltration. Meanwhile, the combination of chemotherapy, targeted therapy, and immunotherapy was recommended for low-risk patients based on drug sensitivity and immune efficacy analyses. We identified a risk model of twelve disulfidptosis-related lncRNAs that could be used to predict the prognosis of SKCM patients and help guide immunotherapy and chemotherapy for personalized treatment plans.

Single-Stage Bronchoscopy-Guided Protocol for Tracheostomy Decannulation in Adult Patients

IntroductionTracheostomy decannulation is a routine procedure in airway management. There is no standard decannulation method; however, the two commonly practiced approaches are tracheostomy downsizing and intermittent capping, which are both accompanied by multiple visits to the clinic and increase patient discomfort. Herein, we explore fiberoptic bronchoscopy application in a novel single-stage decannulation protocol. MethodsWe conducted a retrospective study on tracheostomy patients eligible for decannulation. Fiberoptic bronchoscopy was performed on patients with spontaneous ventilation for ≥48 h, age ≥18, hemodynamic stability, normal chest X-ray, adequate swallowing, effective cough, adequate consciousness, patent speaking valve, and absent history of recurrent aspiration. Tracheostomy removal occurred after evaluating the airway and ruling out tracheomalacia, tracheitis with stenosis, obstructive granulation tissue, and moderate-to-severe stenosis. We documented patients' demographic and clinical information, along with details of their post-decannulation course. ResultsOut of 58 patients admitted for tracheostomy removal, we excluded six patients (10.3%) from the study because, despite clinical indications for successful weaning, they exhibited abnormalities that interrupted the decannulation process. Of the remaining 52 patients, 50 (96.1%) were successfully weaned off, while two needed reinsertion during their hospital course. Bronchoscopy findings were unremarkable in 33 (63.5%) patients, and the most frequently observed abnormalities were paucity of vocal cord movement in 5 (9.6%) patients and granulation tissue formation in 5 (9.6%) patients. No further airway management was necessary after discharge. ConclusionsOur study introduces the innovative approach of single-stage bronchoscopic decannulation as a potentially beneficial tool for immediate decannulation. Based on our experience, we achieved a relatively satisfactory outcome following single-stage tracheostomy decannulation with bronchoscopy. The approach shows promise in providing valuable airway insights and predicting possible decannulation failures. Further research is needed to evaluate its impact on stress reduction for patients and surgeons, its superiority compared to traditional techniques, its long-term effects on healthcare, and its potential cost-effectiveness.

Evaluation of centralised and decentralised models of care during the 2020 Ebola Virus Disease outbreak in Equateur Province, Democratic Republic of the Congo: A brief report

Background Traditionally in the Democratic Republic of the Congo (DRC), centralised Ebola treatment centres (ETCs) have been set exclusively for Ebola virus disease (EVD) case management during outbreaks. During the 2020 EVD outbreak in DRC’s Equateur Province, existing health centres were equipped as decentralised treatment centres (DTC) to improve access for patients with suspected EVD. Between ETCs and DTCs, we compared the time from symptom onset to admission and diagnosis among patients with suspected EVD. Methods This was a cohort study based on analysis of a line-list containing demographic and clinical information of patients with suspected EVD admitted to any EVD health facility during the outbreak. Results Of 2359 patients with suspected EVD, 363 (15%) were first admitted to a DTC. Of 1996 EVD-suspected patients initially admitted to an ETC, 72 (4%) were confirmed as EVD-positive. Of 363 EVD-suspected patients initially admitted to a DTC, 6 (2%) were confirmed and managed as EVD-positive in the DTC. Among all EVD-suspected patients, the median (interquartile range) duration between symptom onset and admission was 2 (1-4) days in a DTC compared to 4 (2-7) days in an ETC (p<0.001). Similarly, time from symptom onset to admission was significantly shorter among EVD-suspected patients ultimately diagnosed as EVD-negative. Conclusions Since <5% of the EVD-suspected patients admitted were eventually diagnosed with EVD, there is a need for better screening to optimise resource utilization and outbreak control. Only one in seven EVD-suspected patients were admitted to a DTC first, as the DTCs were piloted in a limited and phased manner. However, there is a case to be made for considering decentralized care especially in remote and hard-to-reach areas in places like the DRC to facilitate early access to care, contain viral shedding by patients with EVD and ensure no disrupted provision of non-EVD services.

Investigating the Prevalence of Protein S, Protein C, Factor V Leiden, and Homocysteine Disorders in Patients with Antiphospholipid Syndrome: A Retrospective Study

Background: Antiphospholipid syndrome (APS) is a non-inflammatory autoimmune disease primarily characterized by thrombosis. Previous studies have indicated that disorders in proteins S and C, Factor V Leiden, and homocysteine levels can contribute to the occurrence of miscarriage in patients with APS. Objectives: This study aims to determine the prevalence of protein S, protein C, Factor V Leiden, and homocysteine disorders in patients with APS. Methods: This research was conducted as a retrospective study, utilizing the clinical information of patients who were referred to Golestan Ahvaz Hospital and whose records were available. A pre-prepared checklist was used to extract and record patients' clinical information, including demographic data, prevalence of miscarriage, vascular disorders (arterial and venous), pulmonary and venous thrombosis, preterm labor, intrauterine fetal demise (IUFD), intrauterine growth restriction (IUGR), and disorders or deficiencies of proteins C and S, as well as homocysteine levels. Results: In the present study, the results showed that a reduction in proteins C and S was observed in 18 (15.1%) and 20 (16.8%) patients, respectively. Thrombosis was present in 103 (86.6%) patients, and 27 (22.7%) patients had Aps Ab. The results indicated a statistically significant relationship between protein C deficiency, thrombosis, vascular events, and the presence of Abs in patients (P < 0.05) Additionally, a significant relationship was found between protein C deficiency and IUFD (P < 0.05). However, no significant relationship was observed between Aps Ab and IUFD or IUGR (P > 0.05). Conclusions: The results indicated that protein C can be used as a diagnostic factor in AP patients. Additionally, protein C was associated with IUFD in these patients.

Identification of potential novel N6-methyladenosine effector-related lncRNA biomarkers for serous ovarian carcinoma: a machine learning-based exploration in the framework of 3P medicine.

Serous ovarian carcinoma (SOC) is considered the most lethal gynecological malignancy. The current lack of reliable prognostic biomarkers for SOC reduces the efficacy of predictive, preventive, and personalized medicine (PPPM/3PM) in patients with SOC, leading to unsatisfactory therapeutic outcomes. N6-methyladenosine (m6A) modification-associated long noncoding RNAs (lncRNAs) are effective predictors of SOC. In this study, an effective risk prediction model for SOC was constructed based on m6A modification-associated lncRNAs. Transcriptomic data and clinical information of patients with SOC were downloaded from The Cancer Genome Atlas. Candidate lncRNAs were identified using univariate and multivariate and least absolute shrinkage and selection operator-penalized Cox regression analyses. The molecular mechanisms of m6A effector-related lncRNAs were explored via Gene Ontology, pathway analysis, gene set enrichment analysis, and gene set variation analysis (GSVA). The extent of immune cell infiltration was assessed using various algorithms, including CIBERSORT, Microenvironment Cell Populations counter, xCell, European Prospective Investigation into Cancer and Nutrition, and GSVA. The calcPhenotype algorithm was used to predict responses to the drugs commonly used in ovarian carcinoma therapy. In vitro experiments, such as migration and invasion Transwell assays, wound healing assays, and dot blot assays, were conducted to elucidate the functional roles of candidate lncRNAs. Six m6A effector-related lncRNAs that were markedly associated with prognosis were used to establish an m6A effector-related lncRNA risk model (m6A-LRM) for SOC. Immune microenvironment analysis suggested that the high-risk group exhibited a proinflammatory state and displayed increased sensitivity to immunotherapy. A nomogram was constructed with the m6A effector-related lncRNAs to assess the prognostic value of the model. Sixteen drugs potentially targeting m6A effector-related lncRNAs were identified. Furthermore, we developed an online web application for clinicians and researchers (https://leley.shinyapps.io/OC_m6A_lnc/). Overexpression of the lncRNA RP11-508M8.1 promoted SOC cell migration and invasion. METTL3 is an upstream regulator of RP11-508M8.1. The preliminary regulatory axis METTL3/m6A/RP11-508M8.1/hsa-miR-1270/ARSD underlying SOC was identified via a combination of in vitro and bioinformatic analyses. In this study, we propose an innovative prognostic risk model and provide novel insights into the mechanism underlying the role of m6A-related lncRNAs in SOC. Incorporating the m6A-LRM into PPPM may help identify high-risk patients and personalize treatment as early as possible.

Impact of Exigent Research Network’s partnership with the Tempus AI TIME Program on the screening and matching of patients for clinical trials.

e13599 Background: Exigent Research is comprised of independent community oncology practices with a central patient data repository to support clinical research. The Tempus AI TIME program provides clinical trials solutions including a diverse trial portfolio, TApp an AI powered patient matching platform, patient tracking LINK portal, and a rapid trial activation process. This partnership facilitated Tempus AI to continuously search the data repository and enabled Exigent to increase trial enrollment. Methods: TApp is a clinical trial matching platform that utilizes patient data, trial eligibility criteria, and NLP models to execute AI powered matching of subjects to trials. TApp searches the entire patient population for TIME trial matches. New patient clinical information or changes to trial eligibility criteria triggers a new TApp search and matches are reviewed by Tempus AI nurses. Trials were opened in an accelerated “just in time” manner if a subject was ready immediately or prospectively prior to a first patient being identified. Data collected included trial activations, number of patients, available studies, patient and trial updates, TApp searches, nursing effort, matches, and consents. Interventional Phase I to III trials and observational studies were included. Results: From 2022 - 2023, there were 16 Exigent sites in the TIME network. The patient population screened was 244,986 matched to 189 clinical trials. There were 3,179,079 changes to individual patient records and 2,152 trial updates. This triggered 216,712,093 unique TApp searches and 33,083 matches reviewed by nurses. In total, 1,312 patients matched to observational studies and 6,040 patients for interventional trials. Cumulatively, nurses spent 6,617 hours on patient screening resulting in a $330,830 cost. There were 71 trial activations resulting in 312 patient consents (169 observational, 143 interventional). The average duration for study activation was 12.3 days for a just in time activation and 33.8 days for a prospective activation. Conclusions: Exigent Research leveraged a central data repository with the Tempus AI TIME program to continuously screen a large patient population for 185+ trials. During a two-year period, 215M+ unique TApp searches occurred which resulted in over 310 patient consents with rapid activation times. Future clinical trial strategies should partner AI screening technologies with robust trial infrastructure solutions to maximize enrollment success. [Table: see text]

Cost-effectiveness study of atezolizumab (ATZ) vs. durvalumab (DUR): Real-world data (RWD) on first-line chemotherapy combined with immune-checkpoint inhibitors (Chemo-ICIs) for extensive disease small-cell lung cancer (ED-SCLC).

8097 Background: Chemo-ICI is the standard of care in first-line therapy for ED-SCLC. Although there is no comparative data on ATZ vs. DUR, their efficacies appear to be equivalent based on results from IMpower133 and CASPIAN trials. On the other hand, the drug price of DUR is higher than that of ATZ, suggesting a different cost-effectiveness. Methods: This is a multicenter retrospective study of RWD. Clinical outcomes and safety information of ED-SCLC patients (pts) who had received Chemo-ICIs were collected from electronic medical records, and the total cost incurred during ICIs was obtained from the receipts of each hospital. Propensity score matching (PSM) was performed to adjust difference of pts' backgrounds of two groups (ATZ-G vs. DUR-G). The total monthly medical costs incurred during ICI administration for both groups were compared by cost minimization analysis to evaluate cost-effectiveness. Results: From August 2018 to December 2022, 274 pts (ATZ/DUR: 176/98) were extracted from 8 hospitals in Japan. After PSM and exclusion of cisplatin-treated pts, total 128 pts: 64 pts in each group were evaluated. The mean total medical costs per month during ICIs were 1,003,922 (±310,192) JPY (6,783 USD) in the ATZ-G and 1,596,511 (±371,405) JPY (10,787 USD) in the DUR-G (Wilcoxon rank sum test: p < 0.001). Mean ICI drug costs per month during ICIs were 799,079 (±89,555) JPY (5,399 USD) in the ATZ-G and 1,570,744 (±371,405) JPY (10,163 USD) in the DUR-G (p < 0.001). Response rate was 73.4% for ATZ-G and 75.0% for DUR-G. Median overall survivals (OSs) of ATZ-G vs. DUR-G were 13.9 (95% confidence interval [CI]: 11.7-17.5) vs. 13.6 (95% CI: 11.0-20.0) months, respectively (p = 0.919). Median progression-free survivals of ATZ-G vs. DUR-G were 4.9 (95% CI: 4.4-5.6) vs. 5.6 (95% CI: 5.0-6.7) months, respectively (p = 0.060). Cox-proportional hazard model identified poor performance status (hazard ratio [HR]: 5.5, p < 0.001) and bone metastases (HR: 1.8, p = 0.029) as significant factors for shorter OS, while ATZ vs. DUR was not significant. ATZ-G revealed lower incidences of immune-related adverse events (irAEs) ≥grade 2 (10.9 vs. 31.3%, p = 0.009) and any grade interstitial lung disease (ILD) (3.1 vs. 20.3%, p = 0.004) than DUR-G. Number of hospitalizations in ATZ-G (median 1, range 0-6) was lower than that in DUR-G (median 2, range 0-7) (p = 0.005). Conclusions: Our RWD demonstrated a superior cost-effectiveness of ATZ to that of DUR. Total efficacies were similar, whereas the safety profiles, including irAE and ILD were more favorable in ATZ-G. Further discussion is required regarding not only cost-effectiveness but also clinical practicality such as: dose schedule of 3 weeks vs. 4 weeks; regimen flexibility of carboplatin vs. cisplatin; and etoposide dose adjustment of 100 mg/m2 vs. 80 mg/m2. Clinical trial information: 000053483.

Association of a clinical model based on skeletal muscle radiation attenuation with efficacy for patients with gastric cancer treated with chemotherapy plus PD-1 antibodies: A single-center retrospective study.

e16029 Background: Biomarkers to select gastric cancer (GC) patients who can benefit from PD-1 antibody-based treatment are under investigation. We aimed to assess the association between body composition parameters and efficacy of chemotherapy plus PD-1 antibodies in GC patients. Methods: Clinical information of GC patients receiving perioperative chemotherapy with or without PD-1 antibodies was reviewed. Tumor regression grade (TRG) of gastric cancer was recorded after resection. Radiation attenuation and index of skeletal muscle, visceral adipose tissue and subcutaneous adipose tissue were calculated based on computed tomography (CT) images at the third lumbar (L3) level using SliceOmatic software. Associations between clinical parameters and patients’ outcomes including TRG, progression-free survival (PFS), and overall survival (OS) were analyzed. Results: A total of 120 patients treated with chemotherapy plus PD-1 antibodies (IO cohort) and 82 patients treated with chemotherapy alone (CTx cohort) were enrolled. TRG0/1 rates in the IO cohort and CTx cohort were 45.8% and 32.9%. High skeletal muscle radiation attenuation (SMRA), neutrophil to lymphocyte ratio (NLR) < 2.65, and weight loss < 5% were associated with TRG0/1 in the IO cohort but not in the CTx cohort. High SMRA was an independent prognostic factor of PFS in the IO cohort (HR = 0.333, 95%CI 0.115-0.970, P= 0.044). A clinical model based on SMRA, NLR and weight loss was established to stratify patients into 3 groups, including group 1: High SMRA with NLR < 2.65 and weight loss < 5%, group 2: High SMRA with NLR≥2.65 and/or weight loss≥5%, and group 3: Low SMRA. In the IO cohort, patients in group 1 showed higher TRG0/1 rate (n = 27/40, 67.5%, P< 0.001) than group 2 (n = 26/63, 41.3%) and group 3 (n = 2/17, 11.8%). The clinical model was also associated with patients’ survival. Conclusions: A clinical model combining baseline SMRA, NLR and weight loss could identify well-responding GC patients treated with chemotherapy plus PD-1 antibodies.

A novel signature of seven aging-related genes for risk stratification, prognosis prediction and benefit evaluation of chemotherapy, and immunotherapy in elderly patients with lung adenocarcinoma

BackgroundAging, a multifaceted biological process, is thought to be associated with lung adenocarcinoma (LUAD) development and progression. However, it is unclear whether aging-related genes (ARGs) can predict tumor risk, chemotherapy and immunotherapy benefits, and prognosis in LUAD patients at different ages. MethodsGene expression datasets and clinical information of LUAD patients were downloaded from TCGA and GEO database. Univariate and multivariate Cox regression, and lasso algorithm were employed to identify the ARG signatures. Patients were stratified into high-risk and low-risk groups to evaluate the predictive accuracy using Kaplan-Meier curves, ROC curves, and time-dependent AUC. A nomogram was established to predict the survival probability. GSEA revealed potential pathways, and CIBERSORT indicated different immunologic status. TIDE score was used to predict the potential tumor response to immune checkpoint inhibitors, and GDSC was employed to evaluate the sensitivity of chemotherapeutic drugs. The correlation of TIDE score and patient age, as well as that of ARGs and patient age was investigated. And cell Culture and RT-qPCR for external validation for key gene. ResultsA novel gene signature based on seven ARGs was established, including BMP15, CD79A, CDKN3, CDX2, COL1A1, DKK1, and GRIK2. Our model demonstrated exceptional prediction accuracy for elderly LUAD patients of 71–90 years old. A nomogram model was constructed to predict the survival probability, and the C-index value was 0.737, indicating our prognostic nomogram model has high accuracy. Through external RT-qPCR validation, we found that CD79A expression in H1299 was higher than that of BEAS-2B. And novel immunotherapy and chemotherapy regimens were accordingly proposed for the elderly LUAD patients. ConclusionWe identified a novel gene signature based on seven ARGs for risk stratification, prognosis prediction and benefit evaluation of immunotherapy and chemotherapy in elderly LUAD patients.

Extemporaneous combination therapy with nebivolol/valsartan for the treatment of hypertension: a study of real-world evidence in Europe

Objective To explore real-life use of the extemporaneous combination of nebivolol and valsartan (NV-EXC) in adult hypertensive patients in Europe. Methods Retrospective analysis of patients starting NV-EXC treatment conducted using prescription databases in Italy, Germany, Hungary, and Poland. The selection period during which study patients were identified covered a time span ranging from 3 to 9 years (until 30 June 2020) according to availability of the different data sources. Patient demographics, clinical information, and treatment adherence, measured by proportion of days covered, were evaluated. Additionally, the potential eligibility of Italian patients for the single pill combination (SPC) of nebivolol and valsartan over a one-year period was estimated. Results The study included 170,682 patients initiating NV-EXC across the databases. Most patients were females (from 51 to 60%) and primarily aged over 60 years. Few patients received prescriptions of both available dosages of valsartan (80 and 160 mg) during follow-up (from 3.2 to 8.5%). Common comorbidities included dyslipidemia (19.2%) and diabetes (19.1%). Around 59.5% of patients did not require cardiologic visits during the study period. Adherence to NV-EXC, as indicated by the Italian database, was low in 53.3% of patients, with only 16.1% showing high adherence. The Italian database revealed 680 prevalent NV-EXC users in 2019, estimating a potential 30,222 adult patients eligible for the nebivolol/valsartan SPC. Conclusions The combination of nebivolol and valsartan is frequently prescribed for hypertension, but adherence remains a challenge. A potential nebivolol/valsartan SPC holds promise in enhancing adherence and optimizing therapeutic outcomes for hypertension management.

Risk factor evaluation of cuff pressure of >30 cmH2O to stop air leakage during mechanical ventilation: A prospective observational study.

The commonly recommended endotracheal tube cuff pressure is 20-30 cmH2O. However, some patients require a cuff pressure of >30 cmH2O to prevent air leakage. The study aims to determine the risk factors that contribute to the endotracheal tube cuff pressure of >30 cmH2O to prevent air leakage. A multi-centre prospective observational study. Eligible patients undergoing mechanical ventilation in the intensive care unit of three hospitals between March 2020 and July 2022 were included. The endotracheal tube cuff pressure to prevent air leakage was determined using the minimal occlusive volume technique. The patient demographics and clinical information were collected. A total of 284 patients were included. Among these patients, 55 (19.37%) patients required a cuff pressure of >30 cmH2O to prevent air leakage. The multivariate logistic regression results revealed that the surgical operation (odds ratio [OR]: 8.485, 95% confidence interval [CI]: 1.066-67.525, p = 0.043) was inversely associated with the endotracheal tube cuff pressure of >30 cmH2O, while the oral intubation route (OR: 0.127, 95% CI: 0.022-0.750, p = 0.023) and cuff inner diameter minus tracheal area (OR: 0.949, 95% CI: 0.933-0.966, p < 0.001) were negatively associated with the endotracheal tube cuff pressure of >30 cmH2O. Therefore, a significant number of patients require an endotracheal tube cuff pressure of ＞30 cmH2O to prevent air leakage. Several factors, including the surgical operation, intubation route, and difference between the cuff inner diameter and tracheal area at the T3 vertebra, should be considered when determining the appropriate cuff pressure during mechanical ventilation.

Prognositic value of anoikis and tumor immune microenvironment-related gene in the treatment of osteosarcoma.

Osteosarcoma is a highly aggressive primary malignant bone tumor commonly seen in children and adolescents, with a poor prognosis. Anchorage-dependent cell death (anoikis) has been proven to be indispensable in tumor metastasis, regulating the migration and adhesion of tumor cells at the primary site. However, as a type of programmed cell death, anoikis is rarely studied in osteosarcoma, especially in the tumor immune microenvironment. This study aims to clarify prognostic value of anoikis and tumor immune microenvironment-related gene in the treatment of osteosarcoma. Anoikis-related genes (ANRGs) were obtained from GeneCards. Clinical information and ANRGs expression profiles of osteosarcoma patients were sourced from the therapeutically applicable research to generate effective therapies and Gene Expression Omnibus (GEO) databases. ANRGs highly associated with tumor immune microenvironment were identified by the estimate package and the weighted gene coexpression network analysis (WGCNA) algorithm. Machine learning algorithms were performed to construct long-term survival predictive strategy, each sample was divided into high-risk and low-risk subgroups, which was further verified in the GEO cohort. Finally, based on single-cell RNA-seq from the GEO database, analysis was done on the function of signature genes in the osteosarcoma tumor microenvironment. A total of 51 hub ANRGs closely associated with the tumor microenvironment were identified, from which 3 genes (MERTK, BNIP3, S100A8) were selected to construct the prognostic model. Significant differences in immune cell activation and immune-related signaling pathways were observed between the high-risk and low-risk groups based on tumor microenvironment analysis (all P<0.05). Additionally, characteristic genes within the osteosarcoma microenvironment were identified in regulation of intercellular crosstalk through the GAS6-MERTK signaling pathway. The prognostic model based on ANRGs and tumor microenvironment demonstrate good predictive power and provide more personalized treatment options for patients with osteosarcoma.

Multiple institutions’ research findings using the National Mesothelioma Virtual Bank

Mesothelioma remains an under-researched cancerous disease due to the lack of high-quality patient samples and clinical information especially outcomes and asbestos exposure data. The National Mesothelioma Virtual Bank (NMVB) is a biobank in which mesothelioma annotated biospecimens can be made widely available to the research community. Here, we summarized the significant research findings from 20 publications that utilized the NMVB samples for novel biomarker and therapeutic discoveries. The results showed that the use of the NMVB resource was dispersed among a variety of basic science topics including, but not limited to, biomarkers, abnormal gene expression, and potential therapeutic targets. Positive biomarkers included several miRNAs and antibodies, HMGB1, ATG5, PIAS3, pancytokeratin and GATA3. Genes that had mutations or high/low levels of expression were BAP1, a human control gene of importance in this disease, as well as various cytokines, and checkpoint inhibitors TM4SF1, PKM2, ARHGDIA, COBLL1, WT1, FOXM1, and CD30. Treatments investigated include thiostrepton, interferon-β gene, and Brentuximab. Publications reviewed indicated a significant impact of the NMVB resource utilized in significant studies focusing on biomarker and therapeutic discoveries, which can act as a model for rare diseases, especially in oncology.

Bioinformatics Identification and Experimental Validation of a Prognostic Model for the Survival of Lung Squamous Cell Carcinoma Patients.

Lung squamous cell carcinoma (LUSC) kills more than four million people yearly. Creating more trustworthy tumor molecular markers for LUSC early detection, diagnosis, prognosis, and customized treatment is essential. Cuproptosis, a novel form of cell death, opened up a new field of study for searching for trustworthy tumor indicators. Our goal was to build a risk model to assess drug sensitivity, monitor immune function, and predict prognosis in LUSC patients. The 19 cuproptosis-related genes were found in the literature, and patient genomic and clinical information was collected using the Cancer Genomic Atlas (TCGA) database. The LUSC patients were grouped using unsupervised clustering techniques, and 7626 differentially expressed genes were identified. Using univariate COX analysis, LASSO regression analysis, and multivariate COX analysis, a prognostic model for LUSC patients was developed. The tumor immune escape was evaluated using the Tumor Immune Dysfunction and Exclusion (TIDE) method. The R packages 'pRRophetic,' 'ggpubr,' and 'ggplot2' were utilized to examine drug sensitivity. For modeling, a 6-cuproptosis-based gene signature was found. Patients with high-risk LUSC had significantly worse survival rates than those with low-risk conditions. The possibility of tumor immunological escape was increased in patients with higher risk scores due to more immune cell inactivation. For patients with high-risk LUSC, we discovered seven potent potential drugs (AZD6482, CHIR.99021, CMK, Embelin, FTI.277, Imatinib, and Pazopanib). In conclusion, the cuproptosis-based genes predictive risk model can be utilized to predict outcomes, track immune function, and evaluate medication sensitivity in LUSC patients.

Cardiac implantable electronic devices following orthotopic heart transplantation: insights on indications and outcomes from a single centre experience

Abstract Background Need for cardiac implantable electronic devices (CIED) after orthotopic heart transplantation (OHT) ranges from 7 to 24% of cases depending on several patient and procedural related factors. Purpose The aims of this study were to investigate the frequency, indications and the predictors of CIED implantation (especially permanent pacemaker [PPM]) following biatrial anastomosis OHT. Methods A retrospective, single centre, observational study was conducted, including all the patients who underwent OHT between May 1990 and October 2023 at our Institution. For each patient clinical and procedural information were collected and a long-term active follow-up was performed. The primary endpoint of the study was PPM or implantable cardioverter defibrillator (ICD) implantation while all-cause mortality or de novo OHT was a secondary endpoint. Uni- and multivariable logistic regression analyses were performed to identify factors associated with PPM implantation. Results Overall, 546 patients were included and followed-up for a median of 8 years [IQR 1.2-14.3]. During this time frame, 89 (16.3%) patients required PPM implantation (only one patient [0.2%] underwent ICD implantation) at median time of 110 days [IQR 25-2230] after OHT. The main indication for PPM implantation was the development of sinus node dysfunction in 60 patients (67.4%) whereas 29 (32.6%) patients with atrioventricular block required PPM implantation. During follow-up, 265 deaths (48.5%) occurred but no significant differences in long-term prognosis were observed between patients requiring CIED implantation and those who did not (45.5% vs. 49.1%, p-value=0.53, figure). At multivariable analysis, impaired renal function (i.e. low eGFR), cardiac allograft vasculopathy, the occurrence of severe heart transplant rejection and a higher BMI were factors associated with PPM implantation (table). Conclusions Among patients undergoing OHT with biatrial anastomosis technique, PPM implantation is not uncommon but it does not negatively impact on prognosis. Several factors, especially severe heart transplant rejection, cardiac allograft vasculopathy and impaired renal function can help identifying patients at higher risk of PPM.TableFigure

#2113 Membranoproliferative glomerulonephritis experience over 20 years in a tertiary centre in the United Kingdom

Abstract Background and Aims Membranoproliferative Glomerulonephritis (MPGN) is a histological pattern of injury which typically accounts for light microscopy findings on 1-3% of kidney biopsies. It is classified based on immunofluorescence into complement-mediated, immune complex-mediated (IC) and immunofluorescence negative. The underlying aetiologies such as C3 Glomerulopathy are rare diseases, and thus longitudinal real-world experience in terms of underlying causes, treatment and outcomes is valuable. Method This study presents a retrospective review of biopsy data from January 2000 through to December 2020 in a tertiary renal referral centre in the United Kingdom (UK). This review was conducted using the organisation's biopsy database, with patient demographics and clinical information obtained from the Electronic Patient Record. All patients with an MPGN pattern on biopsy were reviewed. Those with new MPGN post-transplant, with an MPGN pattern on biopsy but subsequently diagnosed as IgA Nephropathy, and with an MPGN pattern but a known lupus diagnosis, were excluded. Results A histological finding of MPGN on kidney biopsy was found in 67 patients. Of these, 41 remained in the study following application of the exclusion criteria, with an additional 3 excluded as there was insufficient information available for classification in their biopsy reports. Of the 38 remaining, 28 had IC MPGN and 10 had C3 Glomerulopathy (C3G) - 8 with C3 Glomerulonephritis (C3GN) and 2 with C3 Dense Deposit Disease (DDD). Median follow up was 72 (range 45-126) months. Median age was 64 years in the IC MPGN and 55 years in the C3G groups (p 0.125). The majority in both groups were female, 60.7% (17) and 60% (6) respectively. There was no significant difference in renal function, blood pressure, or proteinuria at presentation between the groups. MPGN was associated with infections in 8 patients (21.1%), connective tissue disease in 3 patients (7.9%), monoclonal gammopathies or haematological malignancies in 8 patients (21.1%), and 2 had identified complement deficiencies (5.3%). Over the study period 47.4% (18) of patients progressed to end stage kidney disease and 50% (19) died. There was no significant difference in these outcomes between the IC MPGN and the C3G groups. Progression to renal replacement therapy (RRT) was seen in 42.9% (12) of the IC MPGN group, and 60% (6) of the C3G group (p=0.287). This included two patients who received a kidney transplant (both in the C3G group), one of whom developed recurrence during the available follow up. Conclusion This study adds a UK perspective with long term data and outcomes in a rare condition. Almost half of patients progressed to RRT and half of patients died during the follow-up period. These outcomes were seen at similar rates in those with IC MPGN and those with C3G. A variety of associated conditions were observed, and the low number of complement deficiencies identified is likely due to the historical nature of the review with reduced screening for complement abnormalities and genetics in the earlier period. Outcomes on follow-up:

Programmed Cell Death-Related Gene Signature Associated with Prognosis and Immune Infiltration and the Roles of HMOX1 in the Proliferation and Apoptosis were Investigated in Uveal Melanoma

BackgroundUveal melanoma (UVM) is the most common primary ocular malignancy, with a wide range of symptoms and outcomes. The programmed cell death (PCD) plays an important role in tumor development, diagnosis, and prognosis. There is still no research on the relationship between PCD-related genes and UVM. A novel PCD-associated prognostic model is urgently needed to improve treatment strategies.ObjectiveWe aim to screen PCD-related prognostic signature and investigate its proliferation ability and apoptosis in UVM cells.MethodsThe clinical information and RNA-seq data of the UVM patients were collected from the TCGA cohort. All the patients were classified using consensus clustering by the selected PCD-related genes. After univariate Cox regression and PPI network analysis, the prognostic PCD-related genes were then submitted to the LASSO regression analysis to build a prognostic model. The level of immune infiltration of 8-PCD signature in high- and low-risk patients was analyzed using xCell. The prediction on chemotherapy and immunotherapy response in UVM patients was assessed by GDSC and TIDE algorithm. CCK-8, western blot and Annexin V-FITC/PI staining were used to explore the roles of HMOX1 in UVM cells.ResultsA total of 8-PCD signature was constructed and the risk score of the PCD signature was negatively correlated with the overall survival, indicating strong predictive ability and independent prognostic value. The risk score was positively correlated with CD8 Tcm, CD8 Tem and Th2 cells. Immune cells in high-risk group had poorer overall survival. The drug sensitivity demonstrated that cisplatin might impact the progression of UVM and better immunotherapy responsiveness in the high-risk group. Finally, Overespression HMOX1 (OE-HMOX1) decreased the cell viability and induced apoptosis in UVM cells. Recuse experiment results showed that ferrostatin-1 (fer-1) protected MP65 cells from apoptosis and necrosis caused by OE-HMOX1.ConclusionThe PCD signature may have a significant role in the tumor microenvironment, clinicopathological characteristics, prognosis and drug sensitivity. More importantly, HMOX1 depletion greatly induced tumor cell growth and inhibited cell apoptosis and fer-1 protected UVM cells from apoptosis and necrosis induced by OE-HMOX1. This work provides a foundation for effective therapeutic strategy in tumour treatment.

Unraveling tuberculosis patient cluster transmission chains: integrating WGS-based network with clinical and epidemiological insights.

Tuberculosis remains a global health threat, and the World Health Organization reports a limited reduction in disease incidence rates, including both new and relapse cases. Therefore, studies targeting tuberculosis transmission chains and recurrent episodes are crucial for developing the most effective control measures. Herein, multiple tuberculosis clusters were retrospectively investigated by integrating patients' epidemiological and clinical information with median-joining networks recreated based on whole genome sequencing (WGS) data of Mycobacterium tuberculosis isolates. Epidemiologically linked tuberculosis patient clusters were identified during the source case investigation for pediatric tuberculosis patients. Only M. tuberculosis isolate DNA samples with previously determined spoligotypes identical within clusters were subjected to WGS and further median-joining network recreation. Relevant clinical and epidemiological data were obtained from patient medical records. We investigated 18 clusters comprising 100 active tuberculosis patients 29 of whom were children at the time of diagnosis; nine patients experienced recurrent episodes. M. tuberculosis isolates of studied clusters belonged to Lineages 2 (sub-lineage 2.2.1) and 4 (sub-lineages 4.3.3, 4.1.2.1, 4.8, and 4.2.1), while sub-lineage 4.3.3 (LAM) was the most abundant. Isolates of six clusters were drug-resistant. Within clusters, the maximum genetic distance between closely related isolates was only 5-11 single nucleotide variants (SNVs). Recreated median-joining networks, integrated with patients' diagnoses, specimen collection dates, sputum smear microscopy, and epidemiological investigation results indicated transmission directions within clusters and long periods of latent infection. It also facilitated the identification of potential infection sources for pediatric patients and recurrent active tuberculosis episodes refuting the reactivation possibility despite the small genetic distance of ≤5 SNVs between isolates. However, unidentified active tuberculosis cases within the cluster, the variable mycobacterial mutation rate in dormant and active states, and low M. tuberculosis genetic variability inferred precise transmission chain delineation. In some cases, heterozygous SNVs with an allelic frequency of 10-73% proved valuable in identifying direct transmission events. The complex approach of integrating tuberculosis cluster WGS-data-based median-joining networks with relevant epidemiological and clinical data proved valuable in delineating epidemiologically linked patient transmission chains and deciphering causes of recurrent tuberculosis episodes within clusters.