High-risk Subgroups Research Articles

Risk of Atherosclerotic Cardiovascular Disease Hospitalizations after Chronic Obstructive Pulmonary Disease Hospitalization among Older Adults.

Rationale: Meta-analyses have suggested the risk of cardiovascular disease (CVD) events is significantly higher after a chronic obstructive pulmonary disease (COPD) exacerbation. However, many of these studies have included a broad array of CVD events or have been limited to highly selected patient populations potentially not generalizable to the broader population of COPD. Objectives and Methods: We assessed the risk of atherosclerotic cardiovascular disease (ASCVD) hospitalizations after COPD hospitalization compared with before COPD hospitalization and identified patient factors associated with ASCVD hospitalizations after COPD hospitalization. This retrospective cohort study used claims data from 920,550 Medicare beneficiaries hospitalized for COPD from 2016 to 2019 in the United States. The primary outcome was risk of an ASCVD hospitalization composite outcome (myocardial infarction, percutaneous coronary intervention, coronary artery bypass graft surgery, stroke, or transient ischemic attack) in the 30 days and 1 year after COPD hospitalization relative to the same time period before COPD hospitalization. Time in the before and after COPD hospitalization time periods to a composite ASCVD hospitalization outcome were modeled using an extension of the Cox proportional hazards model, the Anderson-Gill model, with adjustment for patient characteristics. Additional analyses evaluated for interactions in subgroups associated with the composite ASCVD hospitalization outcome. Results: Among 920,550 patients in the 30-day and 1-year cohorts (mean age, 73-74 yr) the hazard ratio estimate (95% confidence interval) for the composite ASCVD hospitalization outcome after COPD hospitalization versus before COPD hospitalization for the 30-day cohort was 0.99 (0.93, 1.05; P = 0.67), and for the 1-year cohort, it was 0.99 (0.97, 1.02; P = 0.53) after adjustment. We observed three subgroups that were significantly associated with higher risk for ASCVD hospitalizations 1 year after COPD hospitalization: 76+ years old, women, and COPD hospitalization severity. Conclusions: Among Medicare beneficiaries hospitalized for COPD, the risk of ASCVD hospitalization was not significantly increased 30 days or 1 year after COPD hospitalization relative to before COPD hospitalization. In subgroup analyses, we identified age 76+ years old, female sex, and COPD hospitalization severity as high-risk subgroups with increased risk of ASCVD events 1 year after COPD hospitalization. Further research is needed to characterize the COPD exacerbation populations at highest ASCVD hospitalization risk.

Predictive enrichment for the need of renal replacement in sepsis-associated acute kidney injury: combination of furosemide stress test and urinary biomarkers TIMP-2 and IGFBP-7

BackgroundIn sepsis, initial resuscitation with fluids is followed by efforts to achieve a negative fluid balance. However, patients with sepsis-associated acute kidney injury (SA-AKI) often need diuretic or renal replacement therapy (RRT). The dilemma is to predict whether early RRT might be advantageous or diuretics will suffice. Both the Furosemide Stress Test (FST) and measurements of the urinary biomarkers TIMP-2*IGFBP-7, if applied solely, do not provide sufficient guidance. We tested the hypothesis that a combination of two tests, i.e., an upstream FST combined with downstream measurements of urinary TIMP-2*IGFBP-7 concentrations improves the accuracy in predicting RRT necessity.MethodsIn this prospective, multicenter study 100 patients with sepsis (diagnosed < 48h), AKI stage ≥ 2, and an indication for negative fluid balance were included between 02/2020 and 12/2022. All patients received a standardized FST and urinary biomarkers TIMP-2*IGFBP-7 were serially measured immediately before and up to 12 h after the FST. The primary outcome was the RRT requirement within 7 days after inclusion.Results32% (n = 32/99) of SA-AKI patients eventually required RRT within 7 days. With the FST, urine TIMP-2*IGFBP-7 decreased within 2 h from 3.26 ng2/mL2/1000 (IQR: 1.38–5.53) to 2.36 ng2/mL2/1000 (IQR: 1.61–4.87) in RRT and 1.68 ng2/mL2/1000 (IQR: 0.56–2.94) to 0.27 ng2/mL2/1000 (IQR: 0.12–0.89) and non-RRT patients, respectively. While TIMP-2*IGFBP-7 concentrations remained low for up to 12 h in non-RRT patients, we noted a rebound in RRT patients after 6 h. TIMP-2*IGFBP-7 before FST (accuracy 0.66; 95%-CI 0.55–0.78) and the FST itself (accuracy 0.74; 95%-CI: 0.64–0.82) yielded moderate test accuracies in predicting RRT requirement. In contrast, a two-step approach, utilizing FST as an upstream screening tool followed by TIMP-2*IGFBP-7 quantification after 2 h improved predictive accuracy (0.83; 95%-CI 0.74–0.90, p = 0.03) compared to the FST alone, resulting in a positive predictive value of 0.86 (95%-CI 0.64–0.97), and a specificity of 0.96 (95%-CI 0.88–0.99).ConclusionsThe combined application of an upstream FST followed by urinary TIMP-2*IGFBP-7 measurements supports highly specific identification of SA-AKI patients requiring RRT. Upcoming interventional trials should elucidate if this high-risk SA-AKI subgroup, identified by our predictive enrichment approach, benefits from an early RRT initiation.

Daratumumab in transplant-eligible patients with newly diagnosed multiple myeloma: final analysis of clinically relevant subgroups in GRIFFIN

The randomized, phase 2 GRIFFIN study (NCT02874742) evaluated daratumumab plus lenalidomide/bortezomib/dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM). We present final post hoc analyses (median follow-up, 49.6 months) of clinically relevant subgroups, including patients with high-risk cytogenetic abnormalities (HRCAs) per revised definition (del[17p], t[4;14], t[14;16], t[14;20], and/or gain/amp[1q21]). Patients received 4 induction cycles (D-RVd/RVd), high-dose therapy/transplant, 2 consolidation cycles (D-RVd/RVd), and lenalidomide±daratumumab maintenance (≤ 2 years). Minimal residual disease–negativity (10−5) rates were higher for D-RVd versus RVd in patients ≥ 65 years (67.9% vs 17.9%), with HRCAs (54.8% vs 32.4%), and with gain/amp(1q21) (61.8% vs 28.6%). D-RVd showed a trend toward improved progression-free survival versus RVd (hazard ratio [95% confidence interval]) in patients ≥ 65 years (0.29 [0.06–1.48]), with HRCAs (0.38 [0.14–1.01]), and with gain/amp(1q21) (0.42 [0.14–1.27]). In the functional high-risk subgroup (not MRD negative at the end of consolidation), the hazard ratio was 0.82 (0.35–1.89). Among patients ≥ 65 years, grade 3/4 treatment-emergent adverse event (TEAE) rates were higher for D-RVd versus RVd (88.9% vs 77.8%), as were TEAEs leading to discontinuation of ≥ 1 treatment component (37.0% vs 25.9%). One D-RVd patient died due to an unrelated TEAE. These results support the addition of daratumumab to RVd in transplant-eligible patients with high-risk NDMM.Video -YjyZJrsb3fs1sAVfK2kfK

The clinical impact of estimating low-density lipoprotein cholesterol (LDL-C) using different equations in the general population

BackgroundLow-density lipoprotein cholesterol (LDL-C) is associated with atherosclerotic cardiovascular disease (ASCVD). Friedewald, Sampson, and Martin-Hopkins equations are used to calculate LDL-C. This study compares the impact of switching between these equations in a large geographically defined population.Materials and methodsData for individuals who had a lipid panel ordered clinically between 2010 and 2019 were included. Comparisons were made across groups using the two-sample t-test or chi-square test as appropriate. Discordances between LDL measures based on clinically actionable thresholds were summarized using contingency tables.ResultsThe cohort included 198,166 patients (mean age 54 years, 54% female). The equations perform similarly at the lower range of triglycerides but began to diverge at a triglyceride level of 125 mg/dL. However, at triglycerides of 175 mg/dL and higher, the Martin-Hopkins equation estimated higher LDL-C values than the Samson equation. This discordance was further exasperated at triglyceride values of 400 to 800 mg/dL. When comparing the Sampson and Friedewald equations, at triglycerides are below 175 mg/dL, 9% of patients were discordant at the 70 mg/dL cutpoint, whereas 42.4% were discordant when triglycerides are between 175 and 400 mg/dL. Discordance was observed at the clinically actionable LDL-C cutpoint of 190 mg/dL with the Friedewald equation estimating lower LDL-C than the other equations. In a high-risk subgroup (ASCVD risk score > 20%), 16.3% of patients were discordant at the clinical cutpoint of LDL-C < 70 mg/dL between the Sampson and Friedewald equations.ConclusionsDiscordance at clinically significant LDL-C cutpoints in both the general population and high-risk subgroups were observed across the three equations. These results show that using different methods of LDL-C calculation or switching between different methods could have clinical implications for many patients.

The Hidden Hunger among Nepalese Non-Pregnant Women Aged 15-49 Years: The Role of Individual, Household, and Community-Level Factors.

Micronutrient deficiencies remain a public health burden among non-pregnant women in developing countries, including Nepal. Hence, this study examined micronutrient deficiencies among non-pregnant Nepalese women aged 15-49 using the 2016 Nepal National Micronutrient Status Survey (NNMSS). Data for 2143 non-pregnant women was extracted from the 2016 NNMSS. The study analysed the levels of ferritin, soluble transferrin receptor (sTfR), red blood cell (RBC) folate, and zinc of the participants. Multivariable logistic analysis was carried out to assess factors associated with micronutrient deficiencies. The prevalence of ferritin, sTfR, folate, and zinc was observed to be 19%, 13%, 16%, and 21%, respectively. Non-pregnant women from the Janajati region were significantly less prone to high levels of ferritin [adjusted odds ratio (AOR): 0.45; 95% confidence interval (CI): 0.25, 0.80], and those who had body mass index (BMI) of 25 kg/m2 or higher had significantly elevated ferritin levels [AOR: 2.69; 95% CI: 1.01, 7.17]. Non-pregnant women aged 35-49 years were significantly less predisposed to folate deficiency [AOR: 0.58; 95% CI: 0.40, 0.83], and the odds of zinc deficiency were significantly lower among non-pregnant women from wealthier households [AOR: 0.48; 95% CI: 0.31, 0.76]. This study provides further insight into screening high-risk subgroups and instituting public health interventions to address the prevailing micronutrient deficiencies among non-pregnant Nepalese women.

Underuse of Postoperative Radiation After Nipple-Sparing Mastectomy for Standard Radiation Indications

BackgroundNipple areola complex-sparing surgeries, such as nipple-sparing mastectomy (NSM), are increasingly utilized for women with early-stage breast cancer. In the post-operative setting, two major indications for post-operative radiation (PORT) with/without regional nodal irradiation (RNI) are positive margins (margin+) and pathologically involved lymph nodes (pN+), though the frequency of these adverse pathologic features and the rate of indicated PORT use following NSM is unknown. We determined the frequency of margin+ and pN+ following NSM compared to nipple-sparing lumpectomy (BCS) and identified trends in appropriate PORT administration for these standard indications in the NSM setting. MethodsUsing the National Cancer Database, women diagnosed with cT1-3N0M0 invasive carcinoma between 2004-2017 who received NSM were compared to those who received BCS with nipple preservation. The frequencies of margin+ and pN+ by surgical subtype and utilization of PORT with/without RNI were assessed by cohort to determine if the type of surgery was associated with radiation delivery. Overall survival between the two cohorts was also compared. We performed univariable/multivariable logistic & Cox regression (MVA) with odds ratios to control for confounders. ResultsOf 624,075 women included, 611,907 had BCS and 12,168 had NSM. The surgical margin+ rate was significantly higher for NSM at 4.5% (n=544) than 3.7% for BCS (n=22,449) (p<0.001), and remained significant on MVA (OR 1.13 CI 1.03-1.25, p= 0.012). Utilization of PORT for margins+ was significantly lower by MVA after NSM (OR 0.07 CI 0.06-0.09, p<0.001). Similarly, pN+ rate was significantly higher for NSM at 22.5% (n=2,740) versus BCS 13.5% (n=82,288)(p<0.001), retaining significance on MVA (OR 1.12 CI 1.06-1.19, p<0.001). PORT with RNI for pN+ occurred less often for NSM on multivariable analysis (OR 0.73, CI 0.67-0.81, p<0.001). Neither high-risk subgroup had differences in overall survival on MVA. DiscussionNSM is associated with a higher rate of margin+ and pN+ versus BCS. Radiation is underutilized after NSM for these standard indications. Our results highlight the need to further refine patient selection for NSM, and the importance of communicating the higher potential for adverse pathologic features (and thus the potential need for radiation) to patients undergoing NSM.

Magnetic resonance imaging-based prognostic model for subsequent distant metastasis in patients with ipsilateral breast tumor recurrence following breast-conserving surgery.

Ipsilateral breast tumor recurrence (IBTR) following breast-conserving surgery (BCS) has been considered a risk factor for distant metastasis (DM). Limited data are available regarding the subsequent outcomes after IBTR. Therefore, this study aimed to determine the clinical course after IBTR and develop a magnetic resonance imaging (MRI)-based predictive model for subsequent DM. We retrospectively extracted quantitative features from MRI to construct a radiomics cohort, with all eligible patients undergoing preoperative MRI at time of primary tumor and IBTR between 2010 and 2018. Multivariate Cox analysis was performed to identify factors associated with DM. Three models were constructed using different sets of clinicopathological, qualitative, and quantitative MRI features and compared. Additionally, Kaplan-Meier analysis was performed to assess the prognostic value of the optimal model. Among the 183 patients who experienced IBTR, 47 who underwent MRI for both primary and recurrent tumors were enrolled. Multivariate analysis demonstrated that the independent prognostic factors were human epidermal growth factor receptor 2 (HER2) status [hazard ratio (HR) =5.40] and background parenchymal enhancement (BPE) (HR =7.94) (all P values <0.01). Furthermore, four quantitative MRI features of recurrent tumors were selected through the least absolute shrinkage and selection operator (LASSO) method. The combined model exhibited superior performance [concordance index (C-index) 0.77] compared to the clinicoradiological model (C-index 0.71; P=0.006) and radiomics model (C-index 0.70; and P=0.01). Furthermore, the combined model successfully categorized patients into low- and high-risk subgroups with distinct prognoses (P<0.001). The clinicopathological and MRI features of IBTR were associated with secondary events following surgery. Additionally, the MRI-based combined model exhibited the highest predictive efficacy. These findings could be helpful in risk stratification and tailoring follow-up strategies in patients with IBTR.

Cervicovaginal specimen biomarkers for early detection of ovarian and endometrial cancer: A review.

In the last decade, technical innovations have resulted in the development of several minimally invasive diagnostic cancer tools. Within women at high risk of developing ovarian or endometrial cancer (EC) due to hereditary cancer syndrome, there is an urgent need for minimally invasive and patient-friendly methods to detect ovarian cancer and EC at an early stage. We performed a systematic search of studies using DNA methylation or mutation analysis, microbiome, or proteomics performed on cervicovaginal specimens (smear, swab, or tampon) intended to detect ovarian and EC published until January 2024. Included studies (n = 36) showed high heterogeneity in terms of biomarkers used and outcomes, and only a few studies reported on the detection of biomarkers in high-risk subgroups. Based on the findings in this review, DNA methylation techniques seem to be the most promising for detecting ovarian and EC at early stages in the general population. Future validation of cervicovaginal DNA methylation techniques is needed to determine whether this technique might be beneficial in hereditary high-risk subgroups.

Dendritic cell-related hub genes in head-and-neck squamous cell carcinoma: implications for prognosis and immunotherapy.

In the context of head-and-neck squamous cell carcinoma (HNSCC), dendritic cells (DCs) assume pivotal responsibilities, acting as architects of antigen presentation and conductors of immune checkpoint modulation. In this study, we aimed to identify hub genes associated with DCs in HNSCC and explore their prognostic significance and implications for immunotherapy. Integrated clinical datasets from The Cancer Genome Atlas (TCGA)-HNSCC and GSE65858 cohorts underwent meticulous analysis. Employing weighted gene co-expression network analysis (WGCNA), we delineated candidate genes pertinent to DCs. Through the application of random survival forest and least absolute shrinkage and selection operator (LASSO) Cox's regression, we derived key genes of significance. Lisa (epigenetic Landscape In Silico deletion Analysis and the second descendent of MARGE) highlighted transcription factors, with Dual-luciferase assays confirming their regulatory role. Furthermore, immunotherapeutic sensitivity was assessed utilizing the Tumor Immune Dysfunction and Exclusion online tool. This study illuminated the functional intricacies of HNSCC DC subsets to tailor innovative therapeutic strategies. We leveraged clinical data from the TCGA-HNSCC and GSE65858 cohorts. We subjected the data to advanced analysis, including WGCNA, which revealed 222 DC-related candidate genes. Following this, a discerning approach utilizing random survival forest analysis and LASSO Cox's regression unveiled seven genes associated with the prognostic impact of DCs, notably ACP2 and CPVL, associated with poor overall survival. Differential gene expression analysis between ACP2 + and ACP2 - DC cells revealed 208 differential expressed genes. Lisa analysis identified the top five significant transcription factors as STAT1, SPI1, SMAD1, CEBPB, and IRF1. The correlation between STAT1 and ACP2 was confirmed through quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Dual-luciferase assays in HEK293T cells. Additionally, TP53 and FAT1 mutations were more common in high-risk DC subgroups. Importantly, the sensitivity to immunotherapy differed among the risk clusters. The low-risk cohorts were anticipated to exhibit favorable responses to immunotherapy, marked by heightened expressions of immune system-related markers. In contrast, the high-risk group displayed augmented proportions of immunosuppressive cells, suggesting a less conducive environment for immunotherapeutic interventions. Our research may yield a robust DC-based prognostic system for HNSCC; this will aid personalized treatment and improve clinical outcomes as the battle against this challenging cancer continues.

Identification and experimental validation of m7G-related molecular subtypes, immune signature, and feature genes in Alzheimer's disease

BackgroundStudies has shown that N7-methylguanosine (m7G) modification plays a critical role in neurological diseases. However, the exact role and association of m7G with the immune microenvironment in Alzheimer's disease (AD) remain largely unknown and unexplored. MethodsThe study datasets comprised 667 AD samples and 503 control samples selected from eight datasets in the Gene Expression Omnibus database; m7G regulator genes were obtained from previous literature. The AD subtypes were identified by consensus clustering analysis according to m7G regulator genes. The clinical characteristics, immune infiltration, and biological functions of the AD subgroups were evaluated. A combination of different types of machine-learning algorithms were used for the identification of AD genes. We also assessed and validated the diagnostic performance of the identified genes via qRT-PCR, immunofluorescence, and immunohistochemical analyses. ResultsTwo AD distinct subgroups, namely cluster A and cluster B, were identified. Cluster A had poor pathological progression and immune infiltration, representing a high-risk subgroup for AD. The differentially expressed genes of cluster A were enriched in immune and synapse-related pathways, suggesting that these genes probably contribute to AD progression by regulating immune-related pathways. Additionally, five feature genes (AEBP1, CARTPT, AK5, NPTX2, and COPG2IT1) were identified, which were used to construct a nomogram model with good ability to predict AD. The animal experiment analyses further confirmed that these feature genes were associated with AD development. ConclusionTo the best of our knowledge, this is the first study to reveal close correlations among m7G RNA modification, the immune microenvironment, and the pathogenesis of AD. We also identified five feature genes associated with AD, further contributing to our understanding of the underlying mechanisms and potential therapeutic targets for AD.

The prognostic value of immune escape-related genes in lung adenocarcinoma.

Lung cancer is one of the most common cancers in humans, and lung adenocarcinoma (LUAD) has become the most common histological type of lung cancer. Immune escape promotes progression of LUAD from the early to metastatic late stages and is one of the main obstacles to improving clinical outcomes for immunotherapy targeting immune detection points. Our study aims to explore the immune escape related genes that are abnormally expressed in lung adenocarcinoma, providing assistance in predicting the prognosis of lung adenocarcinoma and targeted. RNA data and related clinical details of patients with LUAD were obtained from The Cancer Genome Atlas (TCGA) database. Through weighted gene coexpression network analysis (WGCNA), 3112 key genes were screened and intersected with 182 immune escape genes obtained from a previous study to identify the immune escape-related genes (IERGs). The role of IERGs in LUAD was systematically explored through gene ontology (GO) and Kyoto Encyclopedia of Genes and Genome (KEGG) analyses, which were used to enrich the relevant pathways of IERGs. The least absolute shrinkage and selection operator (LASSO) algorithm and multivariate Cox regression analysis were used to identify the key prognostic genes, and a prognostic risk model was constructed. Estimation of Stromal and Immune Cells in Malignant Tumor Tissues Using Expression Data (ESTIMATE) and microenvironment cell populations (MCP) counter methods (which can accurately assess the amount of eight immune cell populations and two stromal cell groups) were used to analyze the tumor immune status of the high and low risk subgroups. The protein expression level of the differentially expressed genes in lung cancer samples was determined by using the Human Protein Atlas (HPA) database. A nomogram was constructed, and the prognostic risk model was verified via the Gene Expression Omnibus (GEO) datasets GSE72094 and GSE30219. Twenty differentially expressed IERGs were obtained. GO analysis of these 20 IERGs revealed that they were mainly associated with the regulation of immune system processes, immune responses, and interferon-γ enrichment in mediating signaling pathways and apoptotic signaling pathways; meanwhile, KEGG analysis revealed that IERGs were associated with necroptosis, antigen processing and presentation, programmed cell death ligand 1 (PD-L1) expression and programmed cell death 1 (PD-1) pathway in tumors, cytokine-cytokine receptor interactions, T helper cell 1 (Th1) and Th2 differentiation, and tumor necrosis factor signaling pathways. Using LASSO and Cox regression analysis, we constructed a four-gene model that could predict the prognosis of patients with LUAD, and the model was validated with a validation cohort. The immunohistochemical results of the HPA database showed that AHSA1 and CEP55 had low expression in normal lung tissue but high expression in lung cancer tissue. We constructed an IERG-based model for predicting the prognosis of LUAD. Among the genes identified, CEP55 and AHSA1 may be potential prognostic and therapeutic targets, and reducing their expression may represent a novel approach in the treatment of LUAD.

NOTCH1 fusions in pediatric T-cell lymphoblastic lymphoma: Ahigh-risk subgroup with CCL17 (TARC) levels as diagnostic biomarker.

Twenty percent of children with T-cell lymphoblastic lymphoma (T-LBL) will relapse and have an extremely poor outcome. Currently, we can identify a genetically low-risk subgroup in pediatric T-LBL, yet these high-risk patients who need intensified or alternative treatment options remain undetected. Therefore, there is an urgent need to recognize these high-risk T-LBL patients through identification of molecular characteristics and biomarkers. By using RNA sequencing which was performed in 29/49 T-LBL patients who were diagnosed in the Princess Maxima Center for Pediatric Oncology between 2018 and 2023, we discovered a previously unknown high-risk biological subgroup of children with T-LBL. This subgroup is characterized by NOTCH1 gene fusions, found in 21% of our T-LBL cohort (6/29). All patients presented with a large mediastinal mass, pleural/pericardial effusions, and absence of blasts in the bone marrow, blood, and central nervous system. Blood CCL17 (C-C Motif Chemokine Ligand 17, TARC) levels were measured at diagnosis in 26/29 patients, and all six patients with NOTCH1 gene fusions patients exclusively expressed highly elevated blood CCL17 levels, defining a novel and previously not known clinically relevant biomarker for T-cell lymphoblastic lymphoma. Four out of these six patients relapsed during therapy, a fifth developed a therapy-related acute myeloid leukemia during maintenance therapy. These data indicate that T-LBL patients with a NOTCH1 fusion have a high risk of relapse which can be easily identified using a blood CCL17 screening at diagnosis. Further molecular characterization through NOTCH1 gene fusion analysis offers these patients the opportunity for treatment intensification or new treatment strategies.

Disposable e-cigarette use and associated factors in US middle and high school students, 2021-2022.

Disposable e-cigarettes are the predominant type of vaping product used by adolescents and pose a significant public health concern. Identifying factors contributing to this growing trend is essential to curbing the vaping epidemic among youths. This study aims to investigate the growing prevalence and correlates of disposable e-cigarette use among US students. Data from 48437 US middle and high school students from the 2021 and 2022 National Youth Tobacco Survey (NYTS) were analyzed using logistic and ordinal regression models to evaluate disposable e-cigarette use and frequency of use (low, medium, and high) with demographic and psychosocial factors. Weighted prevalence of current e-cigarette use with 95% CIs by device types in 2021 and 2022, were calculated. Odds ratios (ORs) of correlations of disposable e-cigarette use and frequency of use with demographic and psychosocial factors were analyzed. Disposable e-cigarette use increased from 3.9% (95% CI: 3.3-4.7) in 2021 to 5.1% (95% CI: 4.2-6.1) in 2022, and was associated with being female (OR=1.57; 95% CI: 1.29-1.91 vs male), high schoolers (OR=5.14; 95% CI: 3.96-6.67 vs middle schoolers), having low harm perceptions of e-cigarettes (OR=7.75; 95% CI: 5.58-10.75 vs lot of harm), and high exposure to marketing (OR=1.57; 95% CI: 1.05-2.35 vs low exposure). Identifying as LGBTQ (OR=1.41; 95% CI: 1.00-2.00 vs straight), having low academic performance (OR=2.16; 95% CI: 1.15-4.07, D vs A grades), and having psychological distress (OR=2.01; 95% CI: 1.64-2.47, severe vs none) were also linked to increased frequency of use. This study underscores increasing disposable e-cigarette use among US students, noting existing disparities. It identifies high-risk adolescent subgroups vulnerable to disposable e-cigarette use. These findings emphasize the urgency of targeted prevention and stricter regulations on disposable e-cigarettes to combat nicotine addiction among youths.

Vaccinations, cardiovascular drugs, hospitalization, and mortality in COVID-19 and Long COVID

ObjectiveTo identify highest-risk subgroups for COVID-19 and Long COVID(LC), particularly in contexts of influenza and cardiovascular disease(CVD). MethodsUsing national, linked electronic health records for England (NHS England Secure Data Environment via CVD-COVID-UK/COVID-IMPACT Consortium), we studied individuals (of all ages) with COVID-19 and LC (2020-2023). We compared all-cause hospitalization and mortality by prior CVD, high CV risk, vaccination status (COVID-19/influenza), and CVD drugs, investigating impact of vaccination and CVD prevention using population preventable fractions. ResultsHospitalization and mortality were 15.3% and 2.0% among 17,373,850 individuals with COVID-19 (LC rate 1.3%), and 16.8% and 1.4% among 301,115 with LC. Adjusted risk of mortality and hospitalization were reduced with COVID-19 vaccination ≥ 2 doses(COVID-19:HR 0.36 and 0.69; LC:0.44 and 0.90). With influenza vaccination, mortality was reduced, but not hospitalization (COVID-19:0.86 and 1.01, and LC:0.72 and 1.05). Mortality and hospitalization were reduced by CVD prevention in those with CVD, e.g., anticoagulants- COVID:19:0.69 and 0.92; LC:0.59 and 0.88; lipid lowering- COVID-19:0.69 and 0.86; LC:0.68 and 0.90. COVID-19 vaccination averted 245044 of 321383 and 7586 of 8738 preventable deaths after COVID-19 and LC, respectively. InterpretationPrior CVD and high CV risk are associated with increased hospitalization and mortality in COVID-19 and LC. Targeted COVID-19 vaccination and CVD prevention are priority interventions. FundingNIHR. HDR UK.

MDB-46. ARE RAB40 SMALL GTPASES DRIVERS OF MEDULLOBLASTOMA PATHOGENESIS?

Abstract BACKGROUND Medulloblastoma is the most common solid paediatric neoplasm and is among the leading causes of cancer-related deaths in children. Patients associated with high-risk molecular subgroups convey poor outcomes due to frequent relapse and metastasis, with two thirds of survivors experiencing life-changing developmental deficits. Poor patient outcomes and significant co-morbidities highlight an urgent need for specific, molecularly targeted therapies. The RAB40 subfamily of atypical small GTPases regulate cytoskeletal structure and cell adhesion via their ubiquitin ligase activity. Although previous studies have linked the RAB40 subfamily with cell invasiveness, their role in paediatric brain cancer remains undefined. METHODS Patient methylation and survival data from Cavalli et. al (2017) was analysed via the R2 Genomics Analysis and Visualisation Platform. RAB40 gene and protein expression were determined in eight in vitro models of medulloblastoma via qRT-PCR and western blotting. Cells were transfected with EGFP-Cas9 mRNA and RAB40-targeted CRISPR sgRNA and seeded singly using fluorescence-activated cell sorting. RAB40 knockout clones were identified via western blot and Sanger sequencing. RESULTS Patient data demonstrated that higher RAB40 gene expression correlates with worse outcomes in group 3 and 4 medulloblastoma. RAB40 genes were also significantly more highly expressed in high-risk groups 3 and 4 compared to low-risk WNT group medulloblastoma. RAB40 mRNA was enriched in cell lines derived from high-risk group 3 and 4 medulloblastoma relative to SHH controls. RAB40 knockout models were subsequently generated in HD-MB03, an in vitro model of metastatic Group 3 medulloblastoma using CRISPR/Cas9. CONCLUSIONS Our data supports the hypothesis that RAB40 small GTPases are enriched in high-risk medulloblastoma subgroups, and that their expression correlates with worse patient outcomes. We have generated knockout models which will be used to characterise the impact of RAB40 GTPases on cell growth, adhesion, invasiveness, and chemotherapeutic tolerance.

MDB-04. LONG-TERM OUTCOME OF THE MILANO STRATEGY FOR HIGH-RISK MEDULLOBLASTOMA, INCLUDING THE IMPACT OF MOLECULAR SUBTYPE

Abstract BACKGROUND Since 2008 we have been using the same strategy as for M+ medulloblastoma for all other high-risk subgroups(LC/A histology,TP53 mutations,and/or MYC/MYCN amplification). METHODS After surgery,patients &amp;gt;3-year-old received staging/histo-biological revision and sequential HD-methotrexate,HD-VP16,HD-Cyclo,HD-Carbo.HART-CSI,in two daily 1.3 Gy-fractions/5-days-a-week, reached doses tailored to age and pre-radiation response to chemotherapy:31.2 Gy under 10 years-old if CR+PR or no metastases,39 Gy in other/older patients.Boosts to posterior fossa/residual M+ deposits were given reaching total doses of 59.7–60 Gy and 9 Gy,respectively and avoided if metastatic nodules very big or patients very young.Two courses of high-dose thiotepa were delivered in case of not-optimal response after pre-RT phase and in all M0 patients either in pre/post-RT phase.Subgrouping was obtained through IHC and methylation EPICv2.0 in rescued samples. RESULTS Patients were 89,median age 8.8 years,64 males,median fup 136 months. OS/PFS/EFS at 5/15-years were 75.9/66.5%,71.1/69.8%,68.2/65.3%,respectively; 6/28 fatal events were not correlated to medulloblastoma relapse(four 2nd tumors).Sex,age below 10/over 15 years, post-sugical residues,histological subtype(#24 LC/A,#57 classic,#7 nodular-desmoplastic),MYC amplification(#17),CSI dose reduction(#31),absence of boosts(#16),use of myeloablative courses(#45),presence/absence of metastases(#77 M+) did not impact prognosis.Patients progressing after pre-HART chemotherapy(#14) and SD+PD after HART(# 10) did significantly worse(P&amp;lt;0.001)with 1/0 survivors, respectively.Subgrouping done in 44/89 patients so far,showed significant worse PFS/EFS for patients with SHH-tumors(#11, 2 with constitutional Tp53-mutations) vs. groups3 and 4(11 and 22 patients, respectively).Patients younger than 10 had worse response to CT and less boosts (P=0.03 in both) but could receive lower CSI-doses if stratified according to CT-response. CONCLUSIONS This strategy, partly adopted in the ongoing SIOPE protocol, confirmed satisfying results in all high-risk categories; SHH tumors appeared the most aggressive in this context.

Pulmonary hypertension and chronic kidney disease: prevalence, pathophysiology and outcomes.

Pulmonary hypertension (PH) is common in patients with chronic kidney disease (CKD) or kidney failure, with an estimated prevalence of up to 78% in those referred for right-heart catheterization. PH is independently associated with adverse outcomes in CKD, raising the possibility that early detection and appropriate management of PH might improve outcomes in at-risk patients. Among patients with PH, the prevalence of CKD stages 3 and 4 is estimated to be as high as 36%, and CKD is also independently associated with adverse outcomes. However, the complex, heterogenous pathophysiology and clinical profile of CKD-PH requires further characterization. CKD is often associated with elevated left ventricular filling pressure and volume overload, which presumably leads to pulmonary vascular stiffening and post-capillary PH. By contrast, a distinct subgroup of patientsat high risk is characterized by elevated pulmonary vascular resistance and right ventricular dysfunction in the absence of pulmonary venous hypertension, which may represent a right-sided cardiorenal syndrome defined in principle by hypervolaemia, salt avidity, low cardiac output and normal left ventricular function. Current understanding of CKD-PH is limited, despite its potentially important ramifications for clinical decision making. In particular, whether PH should be considered when determining the suitability and timing of kidney replacement therapy or kidney transplantation is unclear. More research is urgently needed to address these knowledge gaps and improve the outcomes of patients with or at risk of CKD-PH.

EPEN-27. GAINING A CLUE FROM 1Q: A HIGH-RISK CHROMOSOMAL GAIN IN PEDIATRIC POSTERIOR FOSSA EPENDYMOMA

Abstract BACKGROUND Ependymomas are neuroepithelial tumours that can be classified into distinct molecular subgroups, each exhibiting a unique clinical outcome. Therapeutic efforts against the most aggressive and abundant subgroup of pediatric ependymoma (posterior fossa group A, PFA) have traditionally been hampered by a lack of known recurrent driver mutations. However, approximately 25% of PFA tumours exhibit gains of the chromosome arm 1q which is associated with an extremely poor prognosis despite aggressive treatment. By interrogating the multi-omic landscape of PFAs harbouring this copy number variation, we aimed to uncover genetic dependencies from which actionable therapeutics could be derived. METHODS Transcriptomic (bulk/single-cell RNA sequencing), proteomic (LC-MS/MS) and phosphoproteomic analyses were conducted on patient tissues and primary patient-derived cell lines to gain insight into the pathways that drive 1q gain pathogenesis. Chromatin immunoprecipitation sequencing of H3K27me3 and H3K27ac marked histones was carried out to profile the epigenetic landscape of these tumours, and whole genome CRISPR knockout screens were performed to reveal the contribution of essential genes unique to tumours harboring 1q gains. RESULTS Through the comparison of 1q gain and balanced PFA samples, our multi-omic analyses identified the up-regulation and essentiality of known glioma oncogenic drivers previously uncharacterized in PFA. The investigation of essential candidate genes showed a convergence on pathways related to ciliogenesis, with genetic vulnerabilities informing in vitro drug screening. Candidate genes were further validated by in vivo knockdown using established xenograft mouse models for pre-clinical testing. CONCLUSIONS This combined approach has allowed for the derivation of a functional cancer signature underlying 1q gains in PFA and presents novel therapeutic targets for this high-risk subgroup. PFA ependymoma is a deadly malignancy whose complex biology has so far eluded therapy, and new insights from this project will help to identify the first effective therapies for this vulnerable patient population.

MODL-16. CRANIOSPINAL RADIOTHERAPY IN COMBINATION WITH DNA-DAMAGE RESPONSE INHIBITORS IN PATIENT-DERIVED ORTHOTOPIC XENOGRAFT MODELS OF MEDULLOBLASTOMA

Abstract BACKGROUND Despite treatment intensification, survival for high-risk subgroups of medulloblastoma (MB) such as MYC-amplified Group 3 (Gr3-II) and p53-mutant SHH (SHH-3p53mut) have remained dismal with overall survival around 40% and 20% respectively. Our previous studies have shown that the DNA-damage response inhibitors (DDRis) prexasertib and ceralasertib enhance the effects of CSI using medulloblastoma cell line-derived orthotopic mouse models. However, patient-derived orthotopic xenografts (PDOXs) are considered superior models for preclinical testing compared to immortalised cell lines. Here, we developed a CSI protocol for multiple PDOX models of high-risk medulloblastoma and tested the optimal protocol with concurrent DDRis. METHOD For our CSI optimisation studies, MED211FH (Gr3-II) or MED813FH (SHH-3p53mut) tumour-bearing mice were monitored for clinical symptoms of tumour before commencing treatment. Multiple, fractionated CSI dosing schedules using a 5-days-on, 2-days-off treatment cycle were trialled based on our lab’s previously established CSI protocols before a schedule of 10 x 0.5 Gy fractions (5.0 Gy total) proved optimal. This schedule was then used in both PDOX models plus an additional SHH-3p53mut model (MED314mCLFH), either alone or in combination with concurrent prexasertib or ceralasertib. RESULTS MED211FH and MED813FH mice treated with 5.0 Gy CSI alone resulted in significantly improved median survival compared to control mice (p&amp;lt;0.0001 and p&amp;lt;0.005 respectively) While 5.0 Gy CSI plus concurrent prexasertib or ceralasertib showed significantly improved survival when compared to CSI alone for each model used. MED211FH: p&amp;lt;0.01 and p&amp;lt;0.001 respectively, MED813FH: p&amp;lt;0.05 and p&amp;lt;0.01 respectively and MED314mCLFH: p&amp;lt;0.05 for both DDRi combination groups. CONCLUSION Remarkably, concurrent use of prexasertib or ceralasertib with CSI significantly improved survival in fatal Gr3-II and SHH-3p53mut models. With these results, we provide robust preclinical evidence for radiosensitising use of DDRi in paediatric high-risk MB and recommend swift clinical translation.

EE88 Cost-Effectiveness of Apixaban Compared to Warfarin, Dabigatran and Rivaroxaban in Patients with Nonvalvular Atrial Fibrillation: Results for High-Risk Patient Subgroups Based on the Aristophanes Real-World Evidence Study

EE88 Cost-Effectiveness of Apixaban Compared to Warfarin, Dabigatran and Rivaroxaban in Patients with Nonvalvular Atrial Fibrillation: Results for High-Risk Patient Subgroups Based on the Aristophanes Real-World Evidence Study