Multivariate Cox Regression Model Research Articles

Mortality and patient stratification 30 days after Staphylococcus aureus bacteraemia in patients with cardiac implantable electronic devices - a Danish nationwide cohort study

Abstract Background Staphylococcus aureus bacteraemia (SAB) is a high-risk condition with a reported 30-day mortality of up to 25% even with timely and correct treatment. Patients with cardiac implantable electronic devices (CIEDs) are at increased risk of a complicated course of disease due to the risk of device infection. Purpose We aimed to estimate the 30-day mortality rate following SAB among adult Danish patients with a de novo CIED. Furthermore, we aimed to identify patients with low, intermediate, and high mortality risk following SAB. Methods Using The National Danish Staphylococcus Aureus Bacteriemia Database and The Danish Pacemaker and ICD Register, we identified all Danish patients aged 18 to 99 years with a de novo CIED implantation between 2000 and 2020, and subsequently positive Staphylococcus aureus blood culture. The primary outcome was 30-day all-cause mortality from date of SAB. Clinical variables significantly associated with increased 30-day mortality following SAB were identified (p<0.05 and 95% CI not including 1) using adjusted multivariable Cox regression modelling. We tested variables related to age, sex, calendar year of SAB, device type, timing of infection, previous SAB, concomitant medication, and clinically relevant pre-existing co-morbidities including valvular replacement, recent surgery, and renal dialysis. Patients were awarded 1 point for each of the significant variables present, and the sum was used to stratify into low-, intermediate-, and high-risk groups. The cut-offs between the groups were set at 0 and 2 points (0 points = low risk, 1-2 points = intermediate risk, ≥3 = high risk). Results We identified 1,393 patients with de novo CIED (pacemaker: n=983, implantable cardioverter defibrillator: n=230, cardiac resynchronization therapy w/wo defibrillator capacity: n=180) and subsequent SAB (median time to SAB from CIED implantation: 679 days [IQR 168-1,525]). Median age at the time of SAB diagnosis was 77 years [IQR 68-84] with 72.4% being males. In total, 469 patients died within the first 30 days from SAB, equivalent to an overall 30-day mortality rate of 33.7% (95% CI 31.2-36.2). We identified high age, left sided valvular disease, use of systemic corticosteroids, and SAB occurring >6 months from CIED implantation to be associated with an increased hazard of 30-day mortality following the SAB diagnosis (Fig. 1). The median total sum obtained from the stratification model was 2 points [IQR 1-2]. 30-day all-cause mortality was estimated to 16.2%, 31.6% and 54.9% for the low-, intermediate- and high-risk groups, respectively (Fig. 2). Conclusions In patients with a de novo cardiac implantable electronic device and subsequent Staphylococcus aureus bacteraemia the overall 30-day mortality from date of SAB was 33.7%. Patients with high age, recent surgery, left sided valvular disease, and use of systemic corticosteroids were particularly at risk.Fig. 1.Simplified stratification modelFig. 2.30-day mortality following SAB

Permanent pacemaker implantation is associated with an increased risk of heart failure hospitalization in transcatheter aortic valve implantation patients with reduced systolic function

Abstract Background The impact of permanent pacemaker implantation (PPI) on outcome of patients following transcatheter aortic valve implantation (TAVI) is not fully understood. Purpose This study aimed to assess the impact of PPI on risk of two-year mortality and hospitalization due to heart failure (HF) in TAVI patients. Methods A total of 1275 consecutive patients who underwent TAVI at our hospital between 2009 and 2021 were enrolled in this study (mean age 81.4±5.6 years, 51.8% male). The primary endpoint was defined as two-year all-cause death after TAVI. The second endpoints included cardiovascular (CV) death and HF related hospitalization after TAVI. Results Among the 1275 patients following TAVI, 297 (23.3%) patients received PPI, with 134 receiving PPI before TAVI and 163 receiving PPI after TAVI. The patients were categorized into two groups: no PPI group (n=978) and PPI group (n=297). Compared to patients without PPI, patients who received PPI were more likely to be male (60.9% vs. 49.1%, P<0.001), higher prevalence of atrial fibrillation (51.2% vs. 43.3%, P=0.016), coronary artery disease (61.6% vs. 53.8%, P=0.017), use aldosterone receptor antagonists (MRAs, 25.3% vs. 15.2%, P<0.001), and lower left ventricular ejection fraction (LVEF, 54.9±13.1% vs. 57.5±11.4%, P<0.001). There were no significant differences in all-cause mortality (16.6% vs. 18.5%), CV mortality (11.3% vs. 13.5%), as well as HF hospitalization rate (18.5% vs, 21.2%) between the two groups (P>0.05). In this cohort, 1012 (79.4%) TAVI patients had a preserved LVEF (≥50%), 122 (9.6%) had a mildly reduced LVEF (41-49%), and 141 (11.1%) had reduced LVEF (≤40%). Their primary and secondary outcomes were similar among LVEF subgroups (all P>0.05). In the subgroup of reduced LVEF, the HF related hospitalization rate after TAVI was significantly higher in TAVI patients with PPI compared to those without PPI (30.6% vs. 13.0%, P=0.003). Multivariable Cox regression models demonstrated a 3-fold increased risk of HF related hospitalization in TAVI patients with PPI in comparison to those without PPI in the subgroup of LVEF≤40% (HR 3.057, 95% CI 1.311-7.130, P=0.010) after adjusting for age, sex, TAVI approach, atrial fibrillation, coronary artery disease, and the use of MRAs. Conclusion All-cause mortality and CV mortality are similar between TAVI patients with and without PPI. However, in the subset of TAVI patients with reduced LVEF (≤40%), PPI is associated with an increased risk of HF hospitalization. Efforts are thus needed to reduce the risk of HF hospitalization in these patients.

Prognostic value of circulating glypican-4 in patients with chronic heart failure with reduced ejection fraction

Abstract Background Chronic heart failure is one of the leading causes of hospitalization and mortality worldwide, with an ever-increasing prevalence. Glypican-4 (GPC4) is a cell surface protein part of the endothelial glycocalyx which is actively released into the circulation in the context of ischemia, inflammation, neurohumoral activity, and shear stress. The current literature on the association between circulating GPC4 and heart failure is limited and its prognostic value on top of established risk markers in chronic heart failure is unknown. Purpose In the present study, we aim to investigate the prognostic value of circulating GPC4 on clinical outcomes in a contemporary cohort of patients with stable chronic heart failure with reduced ejection fraction (HFrEF). Methods Symptomatic outpatients with stable chronic HFrEF were consecutively enrolled in a prospective cohort study. Circulating serum GPC4 levels were assessed using an enzyme-linked immunosorbent at baseline. Patient outcomes were retrieved from medical and health insurance records. Results We enrolled 205 patients with a median (interquartile range) age of 66 (59-74) years, with 22% females. Median left ventricular ejection fraction (LVEF) was 37 (30-43)%, median estimated glomerular filtration rate (eGFR) was 64 (48-80) ml/min/1,73 m2, median N-terminal pro-brain natriuretic peptide (NT-proBNP) was 964 (336-2173) pg/ml, median interleukin 6 (IL6) was 4.7 (3.2-7.9) pg/ml, and median GPC4 was 1553 (1034-1950) pg/ml. During a median follow-up of 4.7 (4.0-5.3) years, 46 patients (22%) were hospitalized due to worsening heart failure (WHF), 18 patients (9%) died of cardiovascular (CV) cause, and 58 patients (28%) died of any cause. In univariate Cox-regression, serum GPC4 levels predicted WHF (HR 1.57, 95%CI 1.29-1.92, p<0.001), CV death (HR 2.07, 95%CI 1.56-2.74, p<0.001), and all-cause mortality (HR 1.93, 95%CI 1.59-2.34, p<0.001). The association between serum GPC4 levels and both, CV death (HR 1.69, 95%CI 1.04-2.86, p=0.048) and all-cause mortality (HR 1.56, 95%CI 1.14-2.14, p=0.006) remained significant in a multivariable Cox-regression model adjusted for age, sex, eGFR, IL6, NT-proBNP, and LVEF. Conclusion In patients with stable chronic HFrEF, circulating GPC4 is significantly associated with cardiovascular outcome and is an independent predictor of all-cause mortality. The potential prognostic value in clinical routine of GPC4 should be addressed in prospective studies.

Insurance remains a major source of disparity for patients with testicular cancer: call for advocacy.

To evaluate the effects of socioeconomic factors, including insurance status, on treatment and survival for patients with testicular cancer. We extracted a retrospective cohort from the National Cancer Database that included patients diagnosed with testicular cancer 2004-2020. Competing-risks and Cox regression multivariate models including demographic, pathological, and socioeconomic covariates were constructed to evaluate receipt of treatment and death, respectively. A total of 95 955 patients with testicular cancer were identified. Compared with private insurance, Medicaid (sub-distribution hazard ratio [SHR] 0.70, P < 0.001), Medicare (SHR 0.73, P < 0.001), and uninsured (SHR 0.72, P < 0.001) patients were associated with decreased likelihood of receiving chemotherapy. Compared with private insurance, Medicaid (SHR 0.55, P < 0.001), Medicare (SHR 0.76, P-value <0.001), uninsured (SHR 0.63, P-value < 0.001), and other government insurance (SHR 0.71, P = 0.010) was associated with decreased likelihood of receiving radiation. Medicaid insurance status (reference private, HR 2.60, P < 0.001) conferred the second largest hazard of death, behind having Stage III disease (reference Stage 0). Compared with private insurance, Medicare (HR 2.20, P < 0.001), no insurance (HR 2.32, P < 0.001), and other government insurance (HR 1.53, P = 0.027) statuses had higher risk of death. Patients diagnosed in Medicaid-expansion states had lower all-cause mortality (11.4% vs 13.6%, P < 0.001). Testicular cancer care relies on early diagnosis and treatment. It is critically important to have a healthcare system where individuals have access to insurance and are served equitably.

Life Expectancy in High-Grade Incidental Prostate Cancer Patients Versus Population-Based Controls According to Treatment Type.

To quantify the differences in 5-year overall survival (OS) between high-grade (Gleason sum 8-10) incidental prostate cancer (IPCa) patients and age-matched male population-based controls, according to treatment type: no active versus active treatment. We relied on the Surveillance, Epidemiology, and End Results (SEER) database (2004-2015) to identify not actively treated and actively treated high-grade IPCa patients. For each case, we simulated an age-matched male control (Monte Carlo simulation), relying on Social Security Administration Life Tables (2004-2020) with 5 years of follow-up. Additionally, we relied on Kaplan-Meier plots to display OS for each treatment type. Multivariable Cox regression models were fitted to predict overall mortality (OM). Of 564 high-grade IPCa patients, 345 (61%) were not actively treated versus 219 (39%) were actively treated, either with radical prostatectomy or radiotherapy. Median OS was 3 years for not actively treated high-grade IPCa patients, with OS difference at 5 years follow-up of 27% relative to their age-matched male population-based controls (37% vs. 64%). Median OS was 8 years for actively treated high-grade IPCa patients, with OS difference at 5 years follow-up of 6% relative to their age-matched male population-based controls (68% vs. 74%). In the multivariable Cox regression model, active treatment independently predicted lower OM (hazard ratio = 0.6; 95% confidence interval = 0.4-0.8; p < 0.001). Relative to Life Tables' derived age-matched male controls, not actively treated high-grade IPCa patients exhibit drastically worse OS than their actively treated counterparts. These observations may encourage clinicians to consider active treatment in newly diagnosed high-grade IPCa patients.

Construction of Survival Nomogram for Ventilator-Associated Pneumonia Patients: Based on MIMIC Database.

Objective: To construct and validate a predictive nomogram model for the survival of patients with ventilator-associated pneumonia (VAP) to enhance prediction of 28-day survival rate in critically ill patients with VAP. Methods: A total of 1,438 intensive care unit (ICU) patients with VAP were screened through Medical Information Mart for Intensive Care (MIMIC)-IV. On the basis of multi-variable Cox regression analysis data, nomogram performance in predicting survival status of patients with VAP at ICU admission for 7, 14, and 28 days was evaluated using the C-index and area under the curve (AUC). Calibration and decision curve analysis curves were generated to assess clinical value and effectiveness of model, and risk stratification was performed for patients with VAP. Result: Through stepwise regression screening of uni-variable and multi-variable Cox regression models, independent prognostic factors for predicting nomogram were determined, including age, race, body temperature, Sequential Organ Failure Assessment score, anion gap, bicarbonate concentration, partial pressure of carbon dioxide, mean corpuscular hemoglobin, and liver disease. The model had C-index values of 0.748 and 0.628 in the train and test sets, respectively. The receiver operating characteristic curve showed that nomogram had better performance in predicting 28-day survival status in the train set (AUC = 0.74), whereas it decreased in the test set (AUC = 0.66). Calibration and decision curve analysis curve results suggested that nomogram had favorable predictive performance and clinical efficacy. Kaplan-Meier curves showed significant differences in survival between low, medium, and high-risk groups in the total set and training set (log-rank p < 0.05), further validating the effectiveness of the model. Conclusion: The VAP patient admission ICU 7, 14, and 28-day survival prediction nomogram was constructed, contributing to risk stratification and decision-making for such patients. The model is expected to play a positive role in supporting personalized treatment and management of VAP.

Prognosis of different hemodynamic classifications in patients with pulmonary hypertension due to left heart disease

Objective: To compare the prognostic values of different classification by using transpulmonary pressure gradient (TPG), diastolic pressure gradient (DPG) and pulmonary vascular resistance (PVR) in patients with pulmonary hypertension due to left heart disease (PH-LHD), and investigated hemodynamic and clinical factors associated with mortality in patients with PH-LHD. Methods: This was a single-center prospective cohort study. In-hospital patients diagnosed with PH-LHD via right heart catheterization at the Department of Cardiology, the First Affiliated Hospital of Nanjing Medical University, from September 2013 to December 2019 were enrolled. Patients were divided according to TPG (cutoff value 12 mmHg; 1 mmHg=0.133 kPa), DPG (cutoff value 7 mmHg), PVR (cutoff value 3 Wood Units), and the combination of TPG and PVR. Baseline characteristic was recorded. All patients were followed up until the occurrence of endpoint event, defined as all-cause death that occurred during the follow-up period, or until April 18, 2022. Receiver operating characteristic curves were used to compare the predictive value of 3 classification methods for all-cause death in PH-LHD patients. The optimal cutoff values were calculated using Jorden index. Survival analysis was performed using Kaplan-Meier analysis, and log-rank test was used to compare the predictive efficacy of classification methods based on optimal cutoff values or guidance-recommended thresholds for the survival of PH-LHD patients. Variables showing statistical significance in the univariate analysis were incorporated into multivariate Cox regression model to analyze the independent risk factors for all-cause mortality. Results: A total of 243 patients were enrolled, aged (54.9±12.7) years old, including 169 (69.5%) males. During a median follow-up of 57 months, there were 101 (41.6%) deaths occurred. Grouping results were as follows: (1) TPG: TPG≤12 mmHg group 115 patients, TPG>12 mmHg group 128 patients; (2) DPG: DPG<7 mmHg group 193 patients, DPG≥7 mmHg group 50 patients; (3) PVR: PVR≤3 Wood Units group 108 patients, PVR>3 Wood Units group 135 patients; (4) TPG and PVR: TPG≤12 mmHg and PVR≤3 Wood Units group 89 patients, TPG>12 mmHg and PVR>3 Wood Units group 109 patients. PVR (AUC=0. 698,95%CI:0.631-0.766) had better predictive value for all-cause mortality than TPG (AUC=0.596, 95%CI: 0.523-0.669) and DPG (AUC=0.526, 95%CI: 0.452-0.601) (all P<0.05). The optimal cutoff values for TPG, DPG, and PVR were13.9 mmHg, 2.8 mmHg, and 3.8 Wood Units, respectively. Kaplan-Meier analysis based on the optimal cutoff values or guidance-recommended thresholds showed that PVR and TPG were the predictors of survival (P<0.05), while DPG did not showed significance (P>0.05). Multivariate Cox regression analysis showed that age, PVR and log2N-terminal pro-B-type natriuretic peptide were independent risk factors for all-cause mortality in PH-LHD patients (all P<0.05). Conclusion: Classification according to PVR was most valuable in predicting all-cause death in PH-LHD patients, while TPG showed moderate predictive ability and DPG had no predictive value.

Neutrophil-lymphocyte ratio is a predictor for all-cause and cardiovascular mortality in individuals with prediabetes in a National study.

We aimed to investigate the value of the neutrophil-lymphocyte ratio (NLR) in predicting the all-cause and cardiovascular mortality risk of individuals with prediabetes. A total of 11,504 prediabetic patients from the National Health and Nutrition Examination Survey (NHANES) 2003-2016 were included in the present study. Mortality and the underlying cause of death were ascertained by linkage to National Death Index records through December 31, 2019. Restricted cubic spline (RCS) analysis was conducted to visualize the association between the NLR and mortality risk. The optimal NLR cutoff value corresponding to the most significant correlation with survival outcomes was calculated by the maximally selected rank statistics method (MSRSM). Weighted multivariable Cox regression models and subgroup analyses were used to calculate HRs and 95% CIs for all-cause and cardiovascular mortality. During a median follow-up of 101 months (interquartile range, 64.0-138.0 months), 1654 (14.38%) deaths were documented, including 422 (3.67%) and 1232 (10.71%) due to cardiovascular and non-cardiovascular events, respectively. RCS regression analysis indicated that the NLR was positively associated with all-cause and cardiovascular mortality. Individuals were divided into lower (≤2.94) and higher (>2.94) NLR groups using the MSRSM. In the multivariable-adjusted model, compared with the lower NLR group, the higher NLR group had a HR of 1.63 (95% CI, 1.38-1.93) and 2.19 (95% CI, 1.55-3.01) for all-cause and cardiovascular mortality, respectively. The NLR was a valuable marker for predicting all-cause and cardiovascular mortality risk in prediabetic patients.

Independent and joint influence of depression and advanced lung cancer inflammation index on mortality among individuals with chronic kidney disease.

The combined effect of depression and nutritional-inflammatory status on mortality in the chronic kidney disease (CKD) population is unclear. We prospectively analyzed 3,934 (weighted population: 22,611,423) CKD participants from the National Health and Nutrition Examination Survey (2007-2018). Depression and nutritional-inflammatory status were assessed with Patient Health Questionnaire 9 (PHQ-9) and Advanced Lung Cancer Inflammation Index (ALI), respectively. Weighted multivariate COX regression models, restricted cubic splines (RCS) models, and stratified analyses were used to investigate the association of PHQ-9 scores and ALI with all-cause mortality. During a median follow-up of 5.8 years (interquartile range 3.4-8.6 years), a total of 985 patients died (25.0%). Each point increase in a patient's PHQ-9 score increased the risk of all-cause mortality by 4% (HR, 1.04; 95% CI, 1.02-1.06; p < 0.001), in the full adjusted model. However, an increase in ALI levels was associated with a decreased risk. HRs (95% CI) of 0.76 (0.65-0.90), 0.70 (0.57-0.86), and 0.51 (0.41-0.64) in the Q2, Q3, and Q4 of ALI compared with the Q1 of ALI, respectively. In addition, the joint analysis showed that CKD patients without depression and with higher ALI were associated with a reduced risk of all-cause mortality. Namely, patients in the highest ALI group (Q4) without depression had the lowest risk (HR, 0.32; 95% CI, 0.21-0.48). Furthermore, this combined effect was consistent across all subgroups, and no significant interaction was found (p > 0.05 for interaction). In a nationally representative sample of US patients with CKD, coexisting depression and poorer nutrition-inflammation were associated with a significantly increased risk of all-cause mortality.

Grip strength, genetic predisposition, and Incident Parkinson's disease: a prospective cohort study in the UK Biobank.

To examine the association and modifiable risk factors between grip strength (GS) and Parkinson's disease (PD) incidence considering genetic factors, a total of 411,648 individuals without PD at baseline from the UK Biobank were included. GS was measured by a hydraulic dynamometer. The polygenic risk score assessed the genetic predisposition. Multivariable Cox regression models were performed. During a median follow-up of 12.3 years, 2409 individuals developed PD. Compared with those with high GS, low-GS individuals had a 58.5% increased risk of PD (42.7%-76.1%), and 16.3% of this excess risk could be explained by adjusted risk factors. Low GS and high genetic predisposition contribute to the highest PD risk in an additive interaction. We observed that low GS was associated with higher PD incidence, particularly among individuals with high genetic predisposition. In addition to enhancing GS, interventions targeting risk factors (e.g., unhealthy lifestyles) might also reduce the excess risk.

Left atrial volume assessed by echocardiography identifies patients with high risk of adverse outcome after acute myocardial infarction

BackgroundThe left atrial (LA) volume has been demonstrated to be an important predictor of adverse outcome in patients with various cardiac conditions, including acute myocardial infarction (AMI). However, new treatment strategies in patients with AMI have led to better patient outcomes. We hypothesised that increased LA size could still predict mortality in patients with AMI despite improved treatment strategies.MethodsWe included patients with AMI in a prospective multicenter cohort study and the study patients were enrolled from 2014 to 2022. We recorded echocardiographic and clinical data during their index hospitalisation. Indexed LA volume (LAVi) was assessed in all patients and was used as a continuous variable in the univariate and multivariate Cox regression analysis. The study took place over a period of five years and median follow-up time was 3.8 years (range 3.1 to 5.0 years). The primary study outcomes were all-cause mortality and major adverse cardiac events (MACE). MACE was defined as hospital readmission due to myocardial infarction, cardiac arrest, stroke, heart failure, or onset of new atrial fibrillation.ResultsWe included 487 patients (69 ± 12 years old, 26% female) with AMI. During the follow-up period all-cause mortality was 50 (10.3%) and patients who reached the primary outcomes were 153 (31.4%). The deceased patients had higher LAVi compared to survivors (40.0 ± 12.9 mL/m2 vs. 29.7 ± 11.2 mL/m2, p < 0.001). Factors associated with all-cause mortality and MACE were age, year of enrollment, left ventricular (LV) ejection fraction, LV global longitudinal strain (GLS), LV filling pressure, moderate or severe mitral regurgitation and LAVi. GLS and EF were segregated into two distinct models due to their moderately high correlation (r = 0.57, p < 0.001). LAVi remained as an independent echocardiographic predictor of primary outcomes after adjusting for the covariates above in two separates multivariable Cox regression models (hazard ratio 1.02/1.02 mL/m2 [95% CI 1.01–1.03/1.01–1.03], p = 0.006/0.003).ConclusionsOur study demonstrated that LA dilatation is an independent echocardiographic predictor of mortality and MACE in patients with AMI despite improved treatment strategies. This finding highlights the potential of using LAVi as a marker for prognostication in these patients.

Optimizing risk stratification for intermediate-risk prostate cancer – the prognostic value of baseline health-related quality of life

ObjectiveTo investigate the prognostic value of baseline health-related quality of life (HRQOL) for patients with intermediate-risk localized prostate cancer (IR-PCa) undergoing radical prostatectomy (RP).Methods4780 patients with IR-PCa according to NCCN risk stratification were identified from a prospectively maintained database. All patients were treated with RP and had prospectively assessed baseline HRQOL. Main outcomes were oncologic endpoints metastasis-free survival (MFS); biochemical recurrence free survival (BRFS) and overall survival (OS). Multivariable Cox regression models assessed prognostic significance of baseline global health status (GHS) on survival outcomes. Harrell’s discrimination C-index was applied to calculate the predictive accuracy of the model. Decision curve analysis (DCA) tested the clinical net benefit associated with adding the GHS domain to our multivariable model (p < 0.05).ResultsMedian follow-up was 51 months. Multivariable analysis confirmed baseline GHS as an independent predictor for increased MFS (HR 0.976, 95%CI 0.96–0.99; p < 0.001), increased BRFS (HR 0.993, 95%CI 0.99–1.00; p = 0.027) and increased OS (HR 0.969, 95%CI 0.95–0.99; p = 0.002), indicating a relative risk reduction of 2.4% for MFS, 0.7% for BRFS and 3.1% for OS per 1-point increase of baseline GHS. Baseline HRQOL improved discrimination in predicting MFS, BRFS and OS. DCA revealed a net benefit over all threshold probabilities.ConclusionsWe found baseline HRQOL to substantially improve risk stratification for the heterogeneous cohort of IR-PCa. Baseline HRQOL accurately predicts increased MFS, BRFS and OS. Our findings therefore support the role of preoperative HRQOL as an adjunct to established prognosticators for IR-PCa, potentially facilitating guidance of therapy.

Shorter Leukocyte Telomere Length Is Associated with Increased Major Adverse Cardiovascular Events or Mortality in Patients with Essential Hypertension.

The association between leukocyte telomere length (LTL) alteration and major adverse cardiovascular events (MACE) or mortality in patients with hypertension is still unclear. 20,034 patients with essential hypertension were enrolled from UK biobank. Multivariable COX regression models were performed to assess the association. LTL was shorter in hypertensive patients with MACE compared to those without MACE. Hypertensive patients in the lowest LTL quartile were at higher risk to develop MACE (adjusted HR 1.15 [95%CI 1.02-1.29], vs top LTL quartile, p-trend = 0.03). Similarly, shorter LTL was related with increased mortality (adjusted HR 1.18[95% CI 1.06-1.3], lowest vs top LTL quartile, p-trend < 0.001). This investigation demonstrated that shorter LTL is associated with increased risk of MACE or mortality in patients with essential hypertension, which indicates that LTL may be a potential predictor of prognosis or underlying therapeutic target for hypertension.

TGFB2 mRNA Levels Prognostically Interact with Interferon-Alpha Receptor Activation of IRF9 and IFI27, and an Immune Checkpoint LGALS9 to Impact Overall Survival in Pancreatic Ductal Adenocarcinoma

The treatment of pancreatic ductal adenocarcinoma (PDAC) is an unmet challenge, with the median overall survival rate remaining less than a year, even with the use of FOLFIRINOX-based therapies. This study analyzed archived macrophage-associated mRNA expression using datasets deposited in the UCSC Xena web platform to compare normal pancreatic tissue and PDAC tumor samples. The TGFB2 gene exhibited low mRNA expression levels in normal tissue, with less than one TPM. In contrast, in tumor tissue, TGFB2 expression levels exhibited a 7.9-fold increase in mRNA expression relative to normal tissue (p &lt; 0.0001). Additionally, components of the type-I interferon signaling pathway exhibited significant upregulation of mRNA levels in tumor tissue, including Interferon alpha/beta receptor 1 (IFNAR1; 3.4-fold increase, p &lt; 0.0001), Interferon regulatory factor 9 (IRF9; 4.2-fold increase, p &lt; 0.0001), Signal transducer and activator of transcription 1 (STAT1; 7.1-fold increase, p &lt; 0.0001), and Interferon Alpha Inducible Protein 27 (IFI27; 66.3-fold increase, p &lt; 0.0001). We also utilized TCGA datasets deposited in cBioportal and KMplotter to relate mRNA expression levels to overall survival outcomes. These increased levels of mRNA expression were found to be prognostically significant, whereby patients with high expression levels of either TGFB2, IRF9, or IFI27 showed median OS times ranging from 16 to 20 months (p &lt; 0.01 compared to 72 months for patients with low levels of expression for both TGFB2 and either IRF9 or IFI27). Examination of the KMplotter database determined the prognostic impact of TGFB2 mRNA expression levels by comparing patients expressing high versus low levels of TGFB2 (50th percentile cut-off) in low macrophage TME. In TME with low macrophage levels, patients with high levels of TGFB2 mRNA exhibited significantly shorter OS outcomes than patients with low TGFB2 mRNA levels (Median OS of 15.3 versus 72.7 months, p &lt; 0.0001). Furthermore, multivariate Cox regression models were applied to control for age at diagnosis. Nine genes exhibited significant increases in hazard ratios for TGFB2 mRNA expression, marker gene mRNA expression, and a significant interaction term between TGFB2 and marker gene expression (mRNA for markers: C1QA, CD74, HLA-DQB1, HLA-DRB1, HLA-F, IFI27, IRF9, LGALS9, MARCO). The results of our study suggest that a combination of pharmacological tools can be used in treating PDAC patients, targeting both TGFB2 and the components of the type-I interferon signaling pathway. The significant statistical interaction between TGFB2 and the nine marker genes suggests that TGFB2 is a negative prognostic indicator at low levels of the IFN-I activated genes and TAM marker expression, including the immune checkpoint LGALS9 (upregulated 16.5-fold in tumor tissue; p &lt; 0.0001).

Dimensional assessment on baseline MRI of soft-tissue sarcomas: longest diameter, sum and product of diameters, and volume-which is the best measurement method to predict patients' outcomes?

The longest diameter (LD) is a strong prognostic factor for patients with soft-tissue sarcoma (STS). Other dimensional assessments, such as the sum of diameters (SoD), product of diameters (PoD), and volume (3D-COG - proposed by the Children Oncology Group), can be rapidly performed; however, their prognostic values have never been compared to LD. Our goal was to investigate their performance in improving patients' prognostication for STS of the lower limbs. All consecutive adults managed with curative intent at our sarcoma reference center for a newly diagnosed STS of the lower limbs between 2000 and 2017, with pre-treatment MRI, were included in this retrospective study. Multivariable Cox regression models were trained to predict metastasis-free survival (MFS) in a Training cohort of 66.7% patients based on LD, PoD, SoD, or 3D-COG (and systematically including age, histologic grade, histotype, radiotherapy, chemotherapy, and surgical margins as covariables). The models were then compared on a validation cohort of 33.3% patients using concordance indices (c-index). The same approach was applied for overall survival (OS) and local relapse-free survival (LFS). Measurement reproducibility among three readers was evaluated with an intraclass correlation coefficient (ICC). 382 patients were included in the survival modeling (72/253 [28.5%] metastatic relapses in Training and 36/129 [27.9%] metastatic relapses in Validation). Higher dimensions were associated with lower MFS (multivariable hazard ratio [HR] = 2.44 and P = 0.0018 for LD; HR = 1.88 and P = 0.0009 for PoD, HR = 1.52 and P = 0.0041 for SoD; and HR = 1.08 and P = 0.0195 for 3D-COG). Higher c-indices were obtained with PoD model in Training (c-index = 0.772) and Validation (c-index = 0.688), but they were not significantly higher thanthose obtained with LD model. None of the measurements was associated with LFS or OS. All measurements demonstrated excellent ICC (> 0.95). Regarding its simplicity and good performance, LD appeared as the best metric to incorporate in prognostic models and nomograms for MFS.

Drug overdose deaths among homeless veterans in the United States Department of Veterans Affairs healthcare system.

With an epidemic of drug overdoses, contemporary research is needed to examine drug overdose deaths among homeless populations. This study measured rates, types and correlates of drug overdose deaths occurring over a 5-year study period among veterans experiencing homelessness (VEH) and non-homeless veterans (NHV) in the US Department of Veterans Affairs (VA) healthcare system. Retrospective cohort study. USA. A total of 6 128 921 veterans. We followed 399 125 VEH and 5 729 796 NHV between 2017 and 2021 using linked administrative VA and National Death Index data. Multivariable Cox regression models were constructed to estimate hazard ratios (HRs) for homelessness as a predictor of time-to-occurrence of overdose deaths with 95% confidence interval (CIs), sequentially controlling for demographic, medical, substance use and mental health characteristics. Among overdose deaths, 8653 [93.7%, 95% confidence interval (CI) = 93.2-94.2%] were unintentional and 5378 (57.8%, 95% CI = 56.8-58.8%) involved opioids. The overdose-specific mortality rate (per 100 000 person-years) was 227.3 among VEH and 23.2 among NHV (HR = 9.76, 95% CI = 9.36, 10.16), with rates 7-14 times higher among VEH than NHV, depending on the drug involved. In fully adjusted models, homelessness was associated with greater risk of drug overdose death (HR = 3.33, 95% CI = 3.18, 3.49), with the greatest risk involving psychostimulants (HR = 4.19), followed by antiepileptic/sedative/hypnotic drugs (HR = 3.69), synthetic opioids (HR = 3.50) and natural and semi-synthetic opioids (HR = 2.79). US veterans experiencing homelessness appear to have three times the risk for drug overdose deaths than non-homeless veterans. There may be specific risks associated with psychostimulant, antiepileptic, sedative and hypnotic drugs in this population that deserve greater attention.

Soluble Urokinase Plasminogen Activator Receptor as a Predictor of All-Cause Death in Patients Undergoing Coronary Angiography at 10-Year Follow-Up.

Background: We aimed to explore the predictive role of soluble urokinase plasminogen activator receptor (suPAR) in patients undergoing coronary angiography by systematically evaluating its association with adverse cardiovascular events at 10 years follow-up. Methods: The KORONEF study was a single-center, observational, prospective study with 492 subjects included. In the multivariable Cox regression model, we checked the impact of suPAR, neutrophil elastase, myeloperoxidase, and DNase 1 on long-term outcomes. Results: The mean study population age was 64.4 ± 9.9 years, and there were 37.2% women. We divided the population into tertiles of suPAR levels (T1 0.793-2.135 ng/mL; T2 2.136-2.868 ng/mL; and T3 2.872-8.677 ng/mL). Patients with higher suPAR concentrations were more often females (tertile 1 vs. tertile 3: 27.4% vs. 50.6%, p < 0.001) and older age (60.8 ± 8.7 years vs. 68.8 ± 9.5 years, p < 0.001). They also characterized higher incidence of diabetes (17.7% vs. 38.0%, p < 0.001), previous myocardial infarction (22% vs. 44.8%, p < 0.001), and chronic kidney disease (3% vs. 18.4%, p < 0.001), but lower incidence of dyslipidemia (54.3% vs. 35.6%). The 10-year all-cause death rates were 14.6% vs. 34.1%, HR 2.68, 95% CI 1.66-4.33, p < 0.001 for tertile 2, and 14.6% vs. 39.9%, HR 3.24, 95% CI 2.03-5.17, p < 0.001 for tertile 3. The optimal cut-off suPAR value of 2.39 ng/mL provided a sensitivity of 66.9% and a specificity of 54.6% in predicting all-cause death. Conclusions: The association of elevated suPAR with increased mortality risk suggests its potential relevance in predicting long-term outcomes and may help inform more individualized management strategies for high-risk patients.

Evaluation of Physiological Variables Determining Time-to-Mortality after Stroke-Associated Pneumonia

Introduction: Stroke-associated pneumonia (SAP) frequently complicates stroke and is associated with significant mortality. Clinicians often use physiological variables within the National Early Warning Score (NEWS) when diagnosing and prescribing antibiotics for SAP, but little is known of its association with mortality. We investigated the relationship of the NEWS 2 score and its components (respiratory rate, heart rate, temperature, oxygen requirement, oxygen saturation, and alertness level) prior to antibiotic initiation, with time-to-mortality in SAP. Methods: We included patients with SAP (n = 389) from a single hyperacute stroke unit. Diagnosis of SAP was made if pneumonia occurred within 7 days of hospital admission. Kaplan-Meier survival curves were generated to assess NEWS 2 parameters influencing survival at pre-defined time periods (1 year and 5 years). The association of these parameters on time-to-mortality were analysed using multivariable Cox-regression models to account for a set of pre-specified potential confounders. Results: The median age was 80 years (71–87 years) and median NIHSS was 7 (IQR 4–17). Mortality within 1 year was 52.4% and 65.8% within 5 years. In the multivariable analyses, time-to-mortality was independently associated with respiratory rate (heart rate [HR] 1.04, 95% confidence intervals [CI] 1.01–1.08, p = 0.009) and total NEWS 2 score (HR 1.13, 95% CI 1.06–1.21, p < 0.001). Conclusions: In patients with SAP, higher respiratory rate and total NEWS 2 score prior to antibiotic initiation were independently associated with time-to-mortality. Further studies are warranted to identify potential opportunities for intervention and ultimately guide treatment to improve outcomes in SAP patients.

Triple combination of vemurafenib, cobimetinib, and atezolizumab in real clinical practice in the Russian Federation: results of the A1 cohort of the ISABELLA study.

Among several treatment options for BRAF-mutant metastatic melanoma, a combination of BRAF inhibitor, MEK inhibitor, and anti-PDL1 antibody seems to be a new emergent approach recently registered in the Russian Federation. It is still not clear which patient population benefits more from this simultaneous use of three drugs instead of its sequencing. This study aimed to evaluate patients' characteristics treated in real practice in 14 Russian regions by triple combination and to analyze their outcomes depending on biomarkers (PD-L1 expression). This was a part (cohort A1) of a prospective non-interventional study of clinical outcomes and biomarkers in patients with skin melanoma. Patients were included in cohort A1 if combination treatment with vemurafenib (vem) + cobimetinib (cobi) + atezolizumab (atezo) was initiated no earlier than 12 weeks (84 days) prior to written informed consent to participate in this study. The index event was the initiation of therapy with all three drugs vem + cobi + atezo (i.e., triple combination). The primary efficacy endpoint of the study was the 24-month overall survival (OS), defined as the time from the index date to the date of death from any cause. If the patient did not experience an event, the OS will be censored at the date of the last contact. Objective response rate (ORR), duration of response (DoR), and progression-free survival (PFS) in the Intention to treat (ITT) population, in biomarker positive population, and in population with brain metastases were also evaluated. Quality of life questionnaires were pre-planned by protocol if it was a part of routine practice. Adverse events were also collected. Between March 2021 and May 2023, 59 patients were enrolled in 19 centers from 14 regions of Russia. Thirty-one of 59 (52.4%) patients had central nervous system metastases, and 18 of 31 (58.4%) were symptomatic. Forty of 59 patients (68%) received the triple combination as the first-line treatment. The median follow-up period was 16.83 [95% confidence interval (CI) 13.8-19.8] months. The mean duration of therapy with this regimen was 9.95 months (95% CI 7.48-13.8). ORR was 55.1%; progression as the best outcome was seen in 16.3%. The median DoR was 12.95 months (95% CI 11.0-14.8 months), with a median of 20.3 months (95% CI 9.1-31.5 months) when triple therapy was administered in the first-line treatment. In patients with brain metastases (N = 31), ORR was 45.1%; the median DoR was 12.95 (95% CI 11.0-14.8 months). The median PFS in the entire population was 13.6 months (95% CI 8.6-18.6); the 24-month PFS was 22%. The estimated median OS in the entire population was 15.8 months (95% CI NA); 24-month OS was 45% (95% CI 0.32-0.64). In multivariate Cox regression model, biomarkers of interest [lactate dehydrogenase, Programmed cell death ligand-1 (PD-L1)] did not have statistically significant impact on PFS, OS, or DoR probably due to high data missing rate. No unexpected adverse events were reported. Grades 3-4 AEs were seen in 23 of 59 patients (38%) with most common were skin and liver toxicity. Triple combination of atezolizumab, vemurafenib, and cobimetinib had proven its efficacy and tolerability in real settings. No impact of potential predictive biomarkers was seen (NCT05402059).

Covid-19 mortality risk factors: Survival analysis of the hospitalized cohort in Sahloul university hospital in Tunisia

Background Tunisia was one of the most affected nations with COVID-19 disease. The clinical features of this illness range from asymptomatic illness to death. Aim To analyse the survival of patients admitted to a Tunisian tertiary care center (Sahloul University Hospital) and identify independent predictive factors for hospital COVID-19 mortality. Methods A longitudinal study was conducted among confirmed COVID-19 patients hospitalized in Sahloul University Hospital between September 2020 and September 2022. Cox univariate regression was used to calculate the Hazard Ratio (HR) of death for patient characteristics regarding the time at risk. Risk factors with a p value of 0.2 or less in the univariate analysis were initially included in the multivariate Cox regression models. Results During the study at Sahloul Hospital, 1978 patients were hospitalized, averaging 55.65 years in age (± 21.39). Among them, 417 deaths occurred, with a median survival of 30 days (± 3.11) [23.904-36.096]. Factors significantly affecting the survival curve were: Age, male gender, comorbidities, diabetes, hypertension, endocrine diseases, obesity, intubation, and ICU admission Multilevel survival analyses revealed that hypertension (aHR 1.24; CI [1.02-1.52]; p=0.028), ICU admission (aHR 12.20- CI [9.56-15.57]; p&lt;10-3), and male gender (HR 1.19; CI [0.98-1.46]; p=0.076) were independent factors associated with COVID-19 mortality. Conclusion Our study concluded the importance of the early identification of high-risk COVID-19 patients to decrease this virus mortality. A good understanding of the possible clinical factors associated with COVID-19 severity is helpful for clinicians in identifying patients who are at high risk and require prioritized treatment to minimize death.