Adjustment For Sex Research Articles

#853 Kidney-protective medication and risk of adverse clinical outcomes in patients with chronic kidney disease: preliminary findings from DISCOVER CKD

Abstract Background and Aims Renin-angiotensin-system inhibitors (RASi) have been a foundational therapy in chronic kidney disease (CKD) for several decades. Sodium-glucose co-transporter-2 inhibitors (SGLT2i) have also emerged as a critical disease-modifying therapy in CKD, with contemporary data from trials showing SGLT2i to significantly improve kidney and cardiovascular (CV) outcomes in patients with or without diabetes. Nonetheless, several studies have revealed sub-optimal prescribing of RASi and/or SGLT2i therapy (both herein referred to as kidney-protective medication) in patients with CKD. Using prospective data from the DISCOVER CKD study, we conducted an exploratory analysis to assess the association of kidney-protective medication real-world use with mortality risk, CV events (fatal and non-fatal), and hospitalisation in patients with CKD. Method DISCOVER CKD (NCT04034992) is a multi-country, non-interventional cohort study designed to characterise the epidemiology of CKD, including describing patient characteristics, disease progression, clinical outcomes, patient journey, practice patterns, and clinical management. In the prospective phase, patients with CKD were recruited from the UK, USA, Spain, Italy, Sweden and Japan between September 2019 and June 2022. Clinical data were extracted manually from patients’ health records into a standardised case report form. The current analysis includes 12 months’ follow-up data. A Cox proportional hazards model was used to compare the risk of all-cause mortality and CV events and a negative binomial regression model was used to compare the risk of all-cause hospitalisation between patients receiving and not receiving kidney-protective medication at baseline, with adjustments for age, sex, CKD stage, diabetes mellitus, hyperkalaemia, and heart failure. DISCOVER CKD received research ethics board approval, and informed consent was obtained from all patients. Results Of the 1052 patients enrolled in DISCOVER CKD, 643 (61.1%) were receiving kidney-protective medication in the form of RASi (n = 618) and SGLT2i (n = 147) at baseline. The mean age of participants receiving and not receiving kidney-protective medication was 62.4 years and 62.7 years, respectively; 34.4% and 40.8%, respectively, were female. Most patients had CKD stage 3A (n = 332, 31.6%) or 3B (n = 308, 29.3%), and 8.4% (n = 88) had ongoing dialysis. Body mass index (30.4 vs 29.4 kg/m2) and blood pressure were similar for those receiving kidney-protective medication versus those who were not. Laboratory assessments were also generally similar, although estimated glomerular filtration rate (eGFR; 40.9 vs 33.7 mL/min/1.73 m2) and haemoglobin (132.0 g/L vs 124.0 g/L) were higher in patients receiving kidney-protective medication versus those not. During the follow-up, patients receiving kidney-protective medication had a 67% lower risk of all-cause mortality (hazard ratio [HR] 0.33; 95% confidence interval [CI] 0.12–0.80, p = 0.019), and a 20% lower risk of all-cause hospitalisation (HR, 0.80; 95% CI 0.64–0.99, p = 0.042) compared with patients not receiving kidney-protective medication. In the population without pre-existing CV disease, a trend towards a lower rate of CV events was observed in patients with kidney-protective medication (CV events rates: 2.2 vs 3.2 per 100 person-years; HR, 0.38; 95% CI 0.12–1.08, p = 0.074 (Figure). Conclusion In this multinational CKD cohort, preliminary analysis indicates that using kidney-protective medication was associated with lower risks of adverse outcomes including death. Further analysis to mitigate potential confounding will be performed to confirm these preliminary findings.

#1910 Echocardiographic findings in patients with advanced diabetic kidney disease and obstructive sleep apnea

Abstract Background and Aims Obstructive sleep apnea (OSA) is associated with accelerated development of cardiovascular disease. The prevalence of OSA is increased in both type 2 diabetes (DM2) and in chronic kidney disease, and is very high in patients with diabetic kidney disease. However, the contribution of OSA to alterations in cardiac structure and function in diabetic kidney disease remains unknown. We therefore compared cardiac structure and function in diabetic kidney disease patients with or without OSA. Method In a cross-sectional study, 120 patients with DM2, a urine albumin-creatinine ratio (UACR) > 30 mg/g and an estimated glomerular filtration rate (eGFR) < 60 ml/min/1.73 m2 were tested for OSA. OSA severity was quantified by the apnea-hypopnea-index (AHI). Patients without OSA (AHI < 5 events/hour) were compared to patients with moderate (AHI 15-29 events/hour) or severe OSA (AHI ≥30 events/hour). Transthoracic echocardiography was conducted in all patients to evaluate cardiac structure and function. Linear regression analyses were used to assess the associations between OSA and echocardiographic parameters. Results AHI-data were available for 114 patients; 43 had no OSA, 33 had mild OSA and 38 had moderate-severe OSA. A total of 74 patients (73% men), 39 with no OSA and 35 with moderate-severe OSA, had complete data for both echocardiography and OSA. Their mean age was 71.5 ± 9.4 years, mean eGFR was 32.2 ± 12.3 mL/min/1.73 m2 and the median UACR of 533 (192–1707) mg/g. Age, smoking status, diabetes duration, eGFR, blood pressure, antihypertensive medicine, chronic obstructive pulmonary disease and atrial fibrillation were not significantly different between patients with and without OSA. Patients with moderate-severe OSA had significantly larger left atrial volume index (LAVI) (39.0 ± 19.6 vs. 28.1 ± 10.5 mL/m2, P = 0.0035), left ventricular mass index (LVMI) (49.2 ± 12.0 vs. 41.8 ± 9.7, g/m2, P = 0.0043), and right ventricular diameter (34.3 ± 5.8 vs. 28.4 ± 4.4 mm, P < 0.0001) compared to those without OSA (Fig. 1). Global longitudinal strain (GLS) was significantly reduced in OSA patients (−14.9 ± 3.1 vs. −16.6 ± 2.8, P = 0.0196), while no difference was observed in LV ejection fraction (54.4 ± 8.1 vs. 56.5 ± 6.2, p = 0.21). The association between OSA and LAVI, LVMI, right ventricular diameter and GLS remained significant after adjustment for age, sex, eGFR and mean arterial pressure. Conclusion Moderate-severe OSA is independently associated with alterations in cardiac structure and function in patients with diabetic kidney disease and reduced renal function. OSA could be an independent contributor to the development of heart failure in patients with diabetic kidney disease.

#1430 Acid excretion is disturbed in calcium oxalate and calcium phosphate stone formers in the Swiss kidney stone cohort

Abstract Background and Aims Kidney stone is a highly prevalent disease worldwide that causes high morbidity and may increase the risk for chronic kidney disease. Urine pH influences the crystallization of some types of kidney stones, such as calcium phosphate and uric acid. This study aimed to identify whether other acid-base parameters are associated with stone formation in the Swiss kidney stone cohort. Method Urinary, serum, clinical, and anthropomorphic baseline data were obtained from the Swiss Kidney Stone Cohort, a prospective, longitudinal, and multi-centric observational study. We included 200 non-stone formers (NSF, determined by CT scan), and 265 calcium oxalate (CaOx) and 113 calcium phosphate (CaP) stone formers with complete data for urine pH (collected under oil). Titratable acids were calculated based on urine phosphate and creatinine levels and urine bicarbonate based on urine pH. Net acid excretion (NAE) was calculated and NAE capacity (NAEC), the NAE for a given urine pH, which reveals the ability of kidneys to excrete acids, was calculated from the residuals of the relation between urine pH and NAE. Logistic regression analyses were used to estimate the potential contributions of various acid-base variables to the occurrence of CaOx or CaP kidney stones. Odds ratio (OR) are reported as “OR [95% confidence interval]” Results CaOx stone formers were slightly older than NSF individuals and CaP stone formers (NSF = 42.9 ± 13.6 y.o., CaOx = 47.3 ± 14.3 y.o., CaP = 43.3 ± 12.9 y.o.), slightly more overweight (NSF = 25.0 ± 4.15, CaOx = 27.1 ± 4.72, CaP = 25.9 ± 4.55), and had a higher prevalence of males (NSF = 56.0%, CaOx= 72.1%, CaP = 59.3%), but had similar baseline estimated glomerular filtration rate (NSF = 97.1 ± 16.5, CaOx = 96.3 ± 18.3, CaP = 99.5 ± 18.0 ml/min/1.73 m2). Hypertension, type 2 diabetes, pyelonephritis, and nephrocalcinosis were more prevalent among people with either type of kidney stones in comparison with NSFs, while inflammatory bowel disease was more common among CaOx stone formers in comparison with NSF individuals. CaOx and CaP stone formers showed disturbed capacity of excreting acids in relation to NSF (NAEC NSF = 1.81 ± 8.21 µmol/min; CaOx = −1.35 ± 8.45, P < .001; CaP = −0.89 ± 7.66, P = .016) and lower 24 h urine excretion of ammonium (NSF = 19.8 ± 8.70 µmol/min; CaOx = 17.4 ± 8.54, P = .012; CaP = 16.5 ± 8.23, P = .005), but also of citrate, oxalate, and potassium (Table 1). In addition, CaOx exhibited a lower urine volume. In contrast, both CaOx and CaP excreted more calcium (NSF = 3.12 ± 1.85 µmol/min; CaOx = 3.82 ± 1.91 p <0.001; CaP = 4.63 ± 2.27, p <0.001). Urine pH was more acidic in CaOx (p < 0.001) in comparison with NSFs and CaP (P = .004), NSF = 6.05 ± 0.51; CaOx = 5.86 ± 0.53; CaP = 6.16 ± 0.62. The correlations between urine pH and both urine calcium and ammonium were disturbed in CaOx stone formers and shifted in CaP stone formers (Fig. 1). Logistic models including urine ammonium, pH, citrate, phosphate, potassium, calcium, magnesium, oxalate, protein, and volume showed that ammonium is negatively associated with both CaOx and CaP stone formation (unadjusted model OR 0.41[0.26-0.57], p< 0.001 for CaOx and OR 0.42[0.26–0.67], P < .001 for CaP) and urine calcium is positively associated with kidney stones (OR 2.37 [1.72-3.43], P < .001 for CaOx and OR 5.82 [3.6–10.1], P < .001 for CaP). Similar results were obtained after adjustment for age, sex, and BMI. Removing urine ammonium, pH, and phosphate from our logistic model and adding NAEC rendered comparable goodness of fit and model complexity. Holding all other independent variables constant, the odds of CaOx associated with NAEC were 0.45 [0.33–0.61], P < .001 and with calcium of 2.6 [1.91–3.64], P < .001. For CaP, NAEC was still associated with it, but urine magnesium showed a lower odds ratio value (0.44 [0.27–0.72], P = .001 vs 0.54 [0.36–0.80], P = .003). Urine citrate was only associated with CaOx stones. Conclusion Baseline urine ammonium and net acid excretion capacity are strongly associated with the occurrence of CaOx and CaP kidney stones. Reduced NAEC indicates that poor control of ammonium excretion is a hallmark of both types of kidney stones, although more strongly apparent in CaOx.

#1680 Cardiovascular disease in kidney transplant recipients with post-transplant diabetes mellitus—retrospective analysis from a randomized trial

Abstract Background and Aims Kidney transplant recipients are at risk for glucometabolic deterioration. While many individuals recover their glycemic profiles, some develop posttransplant diabetes mellitus (PTDM). Previous reports have shown that PTDM is associated with increased risk for cardiovascular disease (CVD) and mortality. Here we aimed at assessing the association of PTDM with the development of CVD in kidney transplant recipients from a randomized trial. Method CVD with functioning graft (WFG), all-cause death WFG and death-censored graft loss were retrospectively investigated in N = 263 participants from the Insulin Therapy for the Prevention of New Onset Diabetes after Transplantation multicenter randomized-controlled trial (ITP-NODAT, ClinicalTrials.gov NCT03507829). The clinical trial was conducted from November 2012 through May 2018; kidney transplant recipients without previous diabetes diagnosis had received basal insulin therapy or control for afternoon hyperglycemia. For the current analysis, CVD was defined as a composite of cerebrovascular disease (stroke, transient ischemic attack), coronary artery disease (myocardial infarction, revascularization, stenting), hospitalization for heart failure and vascular/peripheral arterial disease interventions. Participants were to perform three OGTTs at 6, 12 and 24 months posttransplant, which we handled as landmarks in our present analysis. Besides PTDM versus NON-PTDM, we stratified according to basal insulin intervention and control. Cox proportional hazard models were presented unadjusted and adjusted for age, sex and pre-transplant CVD. All patients gave informed consent to participate in the trial and we obtained institutional review board approval for the present analysis. Results Cumulative incidence curves for CVD WFG are presented in Fig. 1. The associated risk of PTDM at 6, 12 and 24 months for CVD WFG tended to be higher in PTDM versus NON-PTDM. At the respective timepoints, the control versus basal insulin groups were similar (Fig. 1). Cause-specific hazard ratios for CVD WFG, all-cause death WFG and death-censored graft loss are presented in Table 1. PTDM was associated with CVD WFG in the univariable models. Corresponding Hazard Ratios (with 95% Confidence Intervals) at 6, 12 and 24 months were 2.53 (1.23, 5.18), 3.19 (1.51, 6.78) and 4.28 (1.94, 9.48), respectively. After adjustment for age, sex and pre-transplant history of CVD, corresponding HRs (95% CIs) were 1.37 (0.64, 2.91), 1.37 (0.61, 3.06) and 3.01 (1.26, 7.22), respectively. PTDM was not associated with all-cause death WFG in the univariable models. Corresponding HRs (95% CIs) at 6, 12 and 24 months were 1.97 (0.82, 4.75), 2.44 (0.95, 6.25) and 2.32 (0.89, 6.05), respectively. PTDM was also not associated with death-censored graft loss in the univariable models. Corresponding HRs (95% CIs) at 6, 12 and 24 months were 1.44 (0.62, 3.36), 2.10 (0.89, 4.94) and 1.15 (0.39, 3.37), respectively. PTDM was neither associated with all-cause death WFG or death-censored graft loss in the adjusted models. Conclusion PTDM diagnosed by OGTT at month 24 was significantly associated with cardiovascular disease independent of age, sex or pre-transplant CVD. The association, however, was not significant when PTDM was diagnosed before month 24. It is possible that transient PTDM diagnosis, early CVD events and study discontinuations before month 24 may have contributed to the differing results over time. Timely PTDM diagnosis may open a window of opportunity for interventions, such as in the form of novel glucose-lowering agents, that may reduce cardiovascular risk in kidney transplant recipients.

#2213 APOL1 high-risk genotype in in a Dutch multi-ethnic population

Abstract Background and Aims The presence of 2 APOL1 high-risk alleles (high-risk APOL1 genotype) is associated with an increased risk of ESKD. In the USA, the prevalence of these high-risk alleles is high in people of West African descent and almost absent in patients from European descent. In Amsterdam, there is a significant number of people from Surinam, and (West-) Africa. A big group of Surinamese individuals have a West African heritage. The prevalence, however, of high-risk APOL1 genotype in the Netherlands and thereby the significance is unknown. The aim of this research was to investigate the prevalence of the APOL1 risk alleles in a multi-ethnic cohort of the Amsterdam general population consisting of individuals of African Surinamese, Ghanaian, Moroccan and Dutch origin. Second we correlate the presence of these risk alleles to blood pressure, kidney function and proteinuria. Method HELIUS is a multi-ethnic prospective cohort study including people aged 18-70 who were randomly selected, stratified by ethnic origin, from the Amsterdam general population. Baseline examination took place tween 2011 and 2015. We analysed a population of 5971 individuals with available genotype data, of whom 1287 were of Dutch, 3048 of Moroccan, 1156 of African Suriname and 480 of Ghanaian descent. APOL1 risk was determined by genotyping two APOL1 missense variants, rs73885319A>G, S342G; rs60910145T>G, I384M, together constitute the G1 high-risk allele and the 6-base pair deletion allele, rs71785313 RRRATAA/−, N388Y399/−−, is the G2 high risk allele. Logistic regression analyses were performed to determine correlation between creatinine, eGFR, and systolic blood pressure and apol1 high risk genotype, with additional adjustments for age, sex, and BMI. Results The prevalence of high-risk APOL1 genotype was 4.17% in the total sample, in African Surinamese 9.5%, and in the Ghanaian 29.0%. There were no individuals with high risk genotype in the Moroccan or Dutch descent population. The presence of high risk APOL1 genotype was associated with an elevated creatinine level of 10.68 µmol/L (SD 0.91) in the whole cohort. Also, in the Surinamese and Ghanaian populations population the presence of the high-risk APOL1 genotype was associated with an increased creatinine of 2.6 µmol/L (SD 1.00) as compared to the black population with low-risk APOL1 genotype. People with high-risk APOL1 genotype had significantly higher systolic blood pressure 10.69 mmHg (SD 0.091) than those without. Nevertheless, there was no significant difference in systolic blood pressure in the black population with high-risk APOL1 genotype in comparison with the black population with low-risk APOL1 genotype 1.38 mmHg (SD 1.17). Also, there was no significant difference in eGFR (CKD CKD-EPI 2009) in any analysis and no differences in proteinuria was seen, between those with and without the high-risk APOL1 genotype. Conclusion In this population, the overall prevalence of the APOL1 risk alleles seems to conform to the African American population in the USA. There is however a much higher prevalence of high-risk APOL1 genotype in the Ghanaian in comparison to the African Surinamese. The group with high-risk APOL1 genotype had significantly higher creatinine levels and higher systolic blood pressure. However there was no significant difference in blood pressure within the black population between APOL1 high-risk genotype and low-risk genotype. There was no significant difference in eGFR, possibly because the CKD-EPI 2009 formula was used which overestimates the eGFR in the black population. Better calculation with cysteine C possibly gives different outcomes. In conclusion, this is the first study in Europe investigating the prevalence of APOL1 high-risk genotype in a large population-based cohort. APOL1 risk alleles, and high-risk genotype, are prevalent in our population of African descent. More analysis in this cohort are pending and also longitudinal data will follow.

Age-Related Macular Degeneration and Extramacular Drusen: Genetic Associations in the Coimbra Eye Study.

To explore the association between the genetics of age-related macular degeneration (AMD) and extramacular drusen (EMD) in patients with and without AMD. We included 1753 eyes (912 subjects) with phenotypic characterization regarding AMD and EMD. Genetic sequencing and the genetic risk score (GRS) for AMD were performed according to the EYE-RISK consortium methodology. To test for differences in the GRS from EMD cases, AMD cases, and controls, a clustered Wilcoxon rank-sum test was used. The association of AMD, EMD, and the GRS was evaluated using logistic regression models adjusted for age and sex. Individual associations of common risk variants for AMD with EMD were explored. EMD were found in 755 eyes: 252 (14.4%) with AMD and 503 (28.7%) without. In total, 122 eyes (7.0%) had only AMD, and 876 (50.0%) were controls. EMD were strongly associated with AMD (odds ratio [OR], 3.333; 95% confidence interval [CI], 2.356-4.623; P < 0.001). The GRS was associated with an increased risk of AMD (OR, 1.416; 95% CI, 1.218-1.646; P < 0.001) but not with EMD. Individually, the common risk variants ARMS2 rs10490924 (P = 0.042), C3 rs2230199 (P = 0.042), and CETP rs5817082 (P = 0.042) were associated with EMD, after adjustment for AMD, sex, and age. We found a strong association between EMD and AMD, suggesting a common pathogenesis. The GRS for AMD was not associated with EMD, but a partially overlapping genetic basis was suggested when assessing individual risk variants. We propose that EMD per se do not represent an increase in the global genetic risk for AMD.

Abstract B003: Preliminary machine learning integration of DNA methylation-based tumor immune microenvironment deconvolution with histopathological slides for bladder cancer prognostication

Abstract Background: Analyzing the cellular composition of the tumor microenvironment (TME) is crucial for bladder cancer (BCa) prognosis but is hampered by technical and financial limitations of immunofluorescence, flow cytometry and scRNASeq, primarily due to cell disaggregation challenges, antibody selection and cost/throughput constraints. A DNA methylation-based (DNAm) technique, HiTIMED, was introduced, enabling precise differentiation of 17 unique cell types within solid tumors– including those related to tumor growth, angiogenesis, and immune responses– enhancing our ability to investigate the complex interactions within TME tied to exposures, patient outcomes, and treatment efficacy. Automated morphological identification of cellular signatures on histopathological slides has been fraught with challenges. The potential to identify signatures at higher resolution, beyond immune cells, could improve disease management and application of Whole Slide Imaging (WSI) in clinical research. Our research explores direct estimation of HiTIMED-inferred cellular distributions from WSI and benefits of multimodal integration of WSI with HiTIMED proportions for BCa prognostication. Methods: BCa WSI and Illumina Methylation 450k DNAm data for BCa were obtained from TCGA (MIBC, n=456) and Dartmouth-Hitchcock (NMIBC, n=136), divided into training, validation, and testing sets. HiTIMED deconvolved DNAm into 17 cellular components. Survival, stage, and demographics were incorporated. Graph convolutional networks (GCNs) predicted HiTIMED-derived cellular proportions from WSI (WSI2HiTIMED). Logistic regression and Cox Proportional Hazards (CoxPH) were used to compare how standardized cellular proportions estimated by HiTIMED and WSI2HiTIMED each correlate with advanced T-stage (T&amp;gt;2) and survival with age and sex adjustment. We combined a GCN modeling WSI with a neural network using HiTIMED proportions to predict 10-year survival, adjusting for age and sex with CoxPH. This integrated approach was benchmarked against CoxPH models using only imaging or cellular data. Results: HiTIMED and WSI2HiTIMED demonstrated consistent associations with advanced T-stage, respectively: 1) endothelial cells (OR=2.70, p=0.0095; OR=2.24, p=0.033), 2) epithelial cells (OR=0.02, p=0.0005; OR=0.51, p=0.112), 3) lymphocytes (OR=2.04, p=0.0635; OR=2.13, p=0.041), 4) stromal cells (OR=4.30, p=0.001; OR=2.32, p=0.0235), and 5) tumor cells (OR=0.41, p=0.0165; OR=0.42, p=0.020). The prognostic value for survival based on endothelial cell estimates from HiTIMED and WSI2HiTIMED was comparable, with p-values of 0.006 and 0.009, respectively. The C-index for BCa survival prediction improved from 0.730 using WSI GCN-derived hazards to 0.766 with HiTIMED proportions. Conclusion: DNAm offers a cost-effective method for improving cell type estimation from WSI and provides complementary information for BCa analysis. Future efforts will focus on enhancing precision across additional cell types with larger cohorts and exploring synergy with pathologist annotations and spatial transcriptomics. Citation Format: Zarif L. Azher, Ze Zhang, Brock C. Christensen, Lucas A. Salas, Margaret R. Karagas, Louis J. Vaickus, Hideki Fuyura, Keluo Yao, Joshua J. Levy. Preliminary machine learning integration of DNA methylation-based tumor immune microenvironment deconvolution with histopathological slides for bladder cancer prognostication [abstract]. In: Proceedings of the AACR Special Conference on Bladder Cancer: Transforming the Field; 2024 May 17-20; Charlotte, NC. Philadelphia (PA): AACR; Clin Cancer Res 2024;30(10_Suppl):Abstract nr B003.

Effects of different treatments for type 2 diabetes mellitus on mortality of coronavirus disease from 2019 to 2021 in China: a multi-institutional retrospective study.

The coronavirus disease (COVID-19) pandemic has continued for 5 years. Sporadic cases continue to occur in different locations. Type 2 diabetes mellitus (T2DM) is associated with a high risk of a poor prognosis in patients with COVID-19. Successful control of blood glucose levels can effectively decrease the risks of severe infections and mortality. However, the effects of different treatments were reported differently and even adversely. This retrospective study included 4,922 patients who have been diagnosed as COVID-19 and T2DM from 138 Hubei hospitals. The clinical characteristics and outcomes were compared and calculated their risk for death using multivariate Cox regression and Kaplan-Meier curves. After adjustment of age, sex, comorbidities, and in-hospital medications, metformin and alpha-glucosidase inhibitor (AGI) use performed lower all-cause mortality (adjusted hazard ratio [HR], 0.41; 95% confidence interval [CI]: 0.24-0.71; p = 0.001 for metformin; 0.53, 0.35-0.80, p = 0.002 for AGIs), while insulin use was associated with increased all-cause mortality (adjusted HR, 2.07, 95% CI, 1.61-2.67, p < 0.001). After propensity score-matched (PSM) analysis, adjusted HRs for insulin, metformin, and AGIs associated with all-cause mortality were 1.32 (95% CI, 1.03-1.81; p = 0.012), 0.48 (95% CI, 0.23-0.83, p = 0.014), and 0.59 (95% CI, 0.35-0.98, p = 0.05). Therefore, metformin and AGIs might be more suitable for patients with COVID-19 and T2DM while insulin might be used with caution.

SERUM OSMOLARITY ON ADMISSION ACUTE HEART FAILURE AND SHORT–TERM MORTALITY

Abstract Background Serum osmolality has been reported to be infuenced by well–known prognostic factors such as arginine vasopressin, the renin–angiotensin–aldosterone system, and natriuretic peptides, which suggest that osmolality itself could be also associated with the prognosis of heart failure. However, previous studies in acute heart failure (AHF) reported conflicting results on the prognostic role of serum osmolality. Methods We conducted a retrospective cohort study in subjects hospitalized with AHF between 2022 and 2023 in order to determine the association between serum osmolality at admission and 90–days mortality using Cox proportional hazard and Kaplen–Meier models. Results The study group consisted of 166 AHF patients (male 51%), mean age of 80 ± 9 years) with serum osmolarity 282± 11 mOsm/L and 90–days mortality equal to 23%. At univariate analysis, osmolality was significantly associated with mortality (HR 0.96, 95% CI 0.94–0.96). The optimal cut–off values for mortality was &amp;lt;280 mOsm/L (AUC 0.61; VPV 33 VPN 84). After adjustment for sex, age, BNP, renal and left ventricular functions, osmolality remained significantly and independently associated with mortality (HR 0.97, 95% CI 0.95–0.99). Conclusions Lower levels of serum osmolality on admission were related to short–term mortality in patients with AHF, suggesting that this could help stratify the risk of early mortality.

IMPACT OF POLYVASCULAR DISEASE ON LONG–TERM PROGNOSIS IN PATIENTS WITH ACUTE CORONARY SYNDROME. A PROSPECTIVE COHORT STUDY IN ITALY

Abstract Background Atherothrombosis should be considered a systemic disease that may involve one or more than one vascular beds. Data on the impact of polyvascular disease on long–term prognosis in patients with acute coronary syndrome (ACS) are still scarce. Aim To assess the prevalence of symptomatic polyvascular disease in a cohort of patients with ACS and to investigate the impact on long–term outcomes of single versus multiple vascular beds involvement. Methods We analyzed a nationwide, comprehensive, and universal administrative database of consecutive patients older than 40 years admitted for a new episode of ACS in 2013–14 in Italy. Patients with ACS were stratified according to the presence of Peripheral Arterial Disease (PAD) only, Cerebrovascular Disease (CeVD) only, PAD and CeVD (PAD+CeVD) or neither (noPAD/noCeVD). A Cox proportional hazard multivariate model was used to evaluate the impact of PAD only, CeVD only and PAD+CeVD on 5–year MACCE. Results 331320 new episode of ACS were identified. Among them, 24491 (7.4%) were patients with PAD only, 16269 (4.9%) with CeVD only and 4710 (1.4%) with PAD+CeVD. The 5 years MACCE was 42.6%, 64.7%, 66.1 and 72.2 (p&amp;lt;0.001) for noPAD/noCeVD, PAD only, CeVD only and PAD+CeVD, respectivelly. After adjustment for age, sex, and comorbidities, the hazard ratio (HR) for 5–year MACCE was 1.30 (p&amp;lt;0.0001), 1.39 (p&amp;lt;0.0001), and 1.46 (p&amp;lt;0.0001) in patients with PAD only, CeVD only, and PAD+CeVD, respectively, as compared with patients without PAD and CeVD. Conclusion Polyvascular disease represents a major risk factor in patients with ACS. The simultaneous involvement of three vascular beds further increases the risk of long–term outcomes. Greater effort should be directed toward identification of subclinical/clinical atherosclerosis of beds different from coronary for a better risk stratification.

IMPACT OF DISCHARGE FROM A CARDIOLOGY UNIT ON OUTCOMES IN NON–ST ELEVATION MYOCARDIAL INFARCTION: AN ANALYSIS OF A NATIONWIDE ADMINISTRATIVE DATABASE

Abstract Background Current data on the prognostic impact of a specialist management of patients with acute coronary syndromes are scarce. Aim To evaluate the impact of the discharge of revascularized patients with Non–ST elevation myocardial infarction (NSTEMI) from a cardiology unit on their 1–year prognosis and to evaluate the differences in terms of effectiveness between discharge from a cardiology and non–cardiology unit and the whole management of the index hospitalization in a cardiology unit. Methods Retrospective nationwide cohort study enrolling consecutive patients older than 18 years admitted in 2019–2020 in Italy for a NSTEMI and undergoing percutaneous coronary intervention (PCI) within 48 hours from the index admission. Patients died within 30 days from the index admission were excluded from the analysis. Enrolled patients were classified based on the management department into: patients not discharged from a cardiology unit (group 1); patients not admitted but discharged from a cardiology unit (group 2); patients completely managed (admitted and discharged) in a cardiology unit (group 3). The outcome of interest was 1–year all–cause mortality. A Cox multivariate regression model was used to evaluate the impact of the management department on 1–year mortality. Results The study cohort consisted of 31950 NSTEMI events. Among them, 534 (1.6%) were allocated in group 1, 1160 (3.6%) in group 2 and 30256 (94.7%) in group 3. Patients completely managed by a cardiology unit were younger and less likely to be female than patients in other groups. The 1–year mortality was 14.4%, 8.4% and 3.8% (p&amp;lt;0.001) for group 1, group 2 and group 3, respectively (Figure). After adjustment for age, sex, and comorbidities, the hazard ratio (HR) for 1–year mortality was 2.4 (p&amp;lt;0.0001) and 1.7 (p&amp;lt;0.0001), in patients in group 1 and group 2, respectively, as compared with patients completely managed in a cardiology unit (group 3). Conclusion Complete management of index hospitalization or hospital discharge from a specialist unit alone improves the one–year prognosis of patients hospitalized with a diagnosis of NSTEMI in Italy.

Coexisting RET/PTC and TERT Promoter Mutation Predict Poor Prognosis but Effective RET and MEK Targets in Thyroid Cancer.

To investigate the role of coexisting RET/PTC rearrangement and TERT promoter mutation in the prognosis and therapeutic targeting in papillary thyroid cancer (PTC). A total of 669 PTC patients with complete clinical follow-up and genetic data were pooled from thyroid cancer datasets TCGA, MSK MetTropism, and MSK-IMPACT, from whom 163 patients (112 women and 47 men, 4 unknown) with wild-type BRAF/RAS were identified, with median age (IQR) of 46.00 (33.00, 61.00) years and median follow-up time (IQR) of 16.13 (8.09, 27.91) months for comparative genotype cohort analysis of mortality. There was a significant concurrence index between RET/PTC and TERT promoter mutations, being 2.040 (95% CI 1.110-3.747, P = 0.023). Mortality occurred in 5/100 (5%) patients harboring neither mutation, 2/18 (11.1%) patients harboring TERT promoter mutation alone, 0/31 (0%) patients harboring RET/PTC alone, and 7/14 (50%) patients harboring both genetic alterations, corresponding to HRs (95% CI) of 1 (Reference), 2.469 (0.405-14.02), 3.296e-09 (0-inf), and 9.019 (2.635-30.87), respectively, which remained essentially unchanged after adjustment for patient race, sex, and age. Similar results were observed with BRAF/RAS and TERT promoter mutations. Mechanistically, RET/PTC used the MAP kinase pathway to upregulate the mutated TERT, but not the wild-type TERT, and, correspondingly, targeting RET and MEK could suppress mutated TERT but not the wild-type TERT. Coexisting RET/PTC and TERT promoter mutation identify PTC as a unique clinical entity with high mortality, providing new implications for genetic-based prognostication and potential therapeutic targeting of RET and MEK guided by RET/PTC and TERT status.

Long-term sustained effects of the Look AHEAD lifestyle intervention on body composition among adults with type 2 diabetes.

The objective of the study was to test whether there are sustained effects of the Look AHEAD intensive lifestyle intervention (ILI), versus diabetes support and education (DSE), on weight and body composition 12 to 16 years after randomization. Participants were a subset of enrollees in the Look AHEAD dual-energy x-ray absorptiometry substudy who completed the final visit, composed of men (DSE = 99; ILI = 94) and women (DSE = 134; ILI = 135) with type 2 diabetes and mean (SD) age 57.2 (6.4) years and BMI 34.9 (5.1) kg/m2 at randomization. Dual-energy x-ray absorptiometry measured total and regional fat and lean masses at randomization, at Years 1, 4, and 8, and at the final visit. Linear mixed-effects regressions were applied with adjustment for group, clinic, sex, age, race/ethnicity, and baseline body composition. Weight and most body compartments were reduced by 2% to 8% (and BMI 4%) in ILI versus DSE in men but not women. ILI-induced loss of lean tissue did not show a lower percent lean mass versus DSE at 16 years after randomization. ILI-related changes in weight, fat, and lean mass were detectable 12 to 16 years after randomization in men but, for unknown reasons, not in women. There was no evidence that the intervention led to a disproportionate loss of lean mass by the end of the study.

Metabolomic pattern associated with physical sequelae in patients presenting with respiratory symptoms validates the aestivation concept in dehydrated patients.

Hypertonic dehydration is associated with muscle wasting and synthesis of organic osmolytes. We recently showed a metabolic shift to amino acid production and urea cycle activation in coronavirus-2019 (COVID-19), consistent with the aestivation response. The aim of the present investigation was to validate the metabolic shift and development of long-term physical outcomes in the non-COVID cohort of the Biobanque Québécoise de la COVID-19 (BQC19). We included 824 patients from BQC19, where 571 patients had data of dehydration in the form of estimated osmolality (eOSM = 2Na + 2K + glucose + urea), and 284 patients had metabolome data and long-term follow-up. We correlated the degree of dehydration to mortality, invasive mechanical ventilation, acute kidney injury, and long-term symptoms. As found in the COVID cohort, higher eOSM correlated with a higher proportion of urea and glucose of total eOSM, and an enrichment of amino acids compared with other metabolites. Sex-stratified analysis indicated that women may show a weaker aestivation response. More severe dehydration was associated with mortality, invasive mechanical ventilation, and acute kidney injury during the acute illness. Importantly, more severe dehydration was associated with physical long-term symptoms but not mental long-term symptoms after adjustment for age, sex, and disease severity. Patients with water deficit in the form of increased eOSM tend to have more severe disease and experience more physical symptoms after an acute episode of care. This is associated with amino acid and urea production, indicating dehydration-induced muscle wasting.NEW & NOTEWORTHY We have previously shown that humans exhibit an aestivation-like response where dehydration leads to a metabolic shift to urea synthesis, which is associated with long-term weakness indicating muscle wasting. In the present study, we validate this response in a new cohort and present a deeper metabolomic analysis and pathway analysis. Finally, we present a sex-stratified analysis suggesting weaker aestivation in women. However, women show less dehydration, so the association warrants further study.

Social Determinants of Health and Delivery of Rehabilitation to Older Adults During ICU Hospitalization

Older adults with socioeconomic disadvantage develop a greater burden of disability after critical illness than those without socioeconomic disadvantage. The delivery of in-hospital rehabilitation that can mitigate functional decline may be influenced by social determinants of health (SDOH). Whether rehabilitation delivery differs by SDOH during critical illness hospitalization is not known. To evaluate whether SDOH are associated with the delivery of skilled rehabilitation during critical illness hospitalization among older adults. This cohort study used data from the National Health and Aging Trends Study linked with Medicare claims (2011-2018). Participants included older adults hospitalized with a stay in the intensive care unit (ICU). Data were analyzed from August 2022 to September 2023. Dual eligibility for Medicare and Medicaid, education, income, limited English proficiency (LEP), and rural residence. The primary outcome was delivery of physical therapy (PT) and/or occupational therapy (OT) during ICU hospitalization, characterized as any in-hospital PT or OT and rate of in-hospital PT or OT, calculated as total number of units divided by length of stay. In the sample of 1618 ICU hospitalizations (median [IQR] patient age, 81.0 [75.0-86.0] years; 842 [52.0%] female), 371 hospitalizations (22.9%) were among patients with dual Medicare and Medicaid eligibility, 523 hospitalizations (32.6%) were among patients with less than high school education, 320 hospitalizations (19.8%) were for patients with rural residence, and 56 hospitalizations (3.5%) were among patients with LEP. A total of 1076 hospitalized patients (68.5%) received any PT or OT, with a mean rate of 0.94 (95% CI, 0.86-1.02) units/d. After adjustment for age, sex, prehospitalization disability, mechanical ventilation, and organ dysfunction, factors associated with lower odds of receipt of PT or OT included dual Medicare and Medicaid eligibility (adjusted odds ratio, 0.70 [95% CI, 0.50-0.97]) and rural residence (adjusted odds ratio, 0.65 [95% CI, 0.48-0.87]). LEP was associated with a lower rate of PT or OT (adjusted rate ratio, 0.55 [95% CI, 0.32-0.94]). These findings highlight the need to consider SDOH in efforts to promote rehabilitation delivery during ICU hospitalization and to investigate factors underlying inequities in this practice.

Markers of hemophagocytic lymphohistiocytosis are associated with survival in critically ill patients

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): This work was supported by the Association for the Promotion of Research on Arteriosclerosis, Thrombosis and Vascular Biology (ATVB) and the Ludwig Boltzmann Cluster for Cardiovascular Research Background/Introduction Patients admitted to the intensive care unit (ICU) often show systemic immune dysregulation paired with significantly increased inflammatory activity. Haemophagocytic lymphohistiocytosis (HLH) represents a rare syndrome characterized by fever, inflammation, cytopenia, and organ dysfunction. Inappropriate survival of cytotoxic T cells as well as histiocytes triggers cytokine storm, accompanied by the occurrence of hemophagocytosis and multi-organ failure. prevalence of HLH in critical illness continues to be a topic of discussion but most certainly remains underreported. This circumstance often leads to delays in the necessary immunosuppressive therapy due to difficulty in early diagnosis. Purpose In the present study, we aimed to illuminate the prospective value of the individual HLH criteria in a cohort of critically ill patients. Although the prevalence of this syndrome might be low, isolated markers of HLH could help to assess the extent of inflammatory activation and further be of use in predicting the outcome of patients admitted to the ICU. Methods This was a prospective, observational cohort study. 176 consecutive patients admitted to a cardiac ICU were included over the course of one year. Available HLH criteria were recorded except for biopsy samples of bone marrow and measurements of low or absent natural killer cell activity. For soluble CD25 (sCD25) a specific ELISA kit was used according to the manufacturer's instructions. Results The median age was 67.51 years (IQR: 57.50-77.41) and 38.64% of the included patients were female. The total 30-day mortality was calculated to be 25.57% and positivity for two or more criteria of HLH was found to be associated with depicted mortality (p = 0.033). Analyzing the individual parameters, only sCD25 was found to be a predictor of death within the first 30 days (p &amp;lt; 0.001). The combination of triglycerides and fibrinogen did not predict outcomes. However, low fibrinogen values were found to possess prognostic merit in regard to mortality (p= 0.019). In multivariate analysis, both sCD25 and fibrinogen remained a significant predictor of 30-day survival after adjustment for age, sex, and BMI (sCD25 p &amp;lt; 0.001, fibrinogen p = 0.042). Finally, the addition of fibrinogen was able to improve the prognostic value of the SAPS II score significantly (ROC curve, SAPS II – AUC: 0.790, SAPS II &amp; fibrinogen – AUC: 0.827, p = 0.045). Conclusion We provided evidence for the prognostic value of certain markers of HLH in critically ill patients. Positivity for two or more criteria was found to be associated with an increased 30-day mortality. Moreover, sCD25 and fibrinogen independently predicted outcomes in multivariate analysis after adjustment for age, sex, and BMI. The addition of fibrinogen was able to improve the prognostic properties of the SAPS II score.Figure 1Figure 2

Prognostic evaluation of ST-segment elevation acute myocardial infarction according to lung ultrasound in the acute phase

Abstract Funding Acknowledgements Type of funding sources: Foundation. Main funding source(s): JC-M received an Original Research Projects Grant from the Catalan Society of Cardiology and LR-S received Scholarship for Training and Research from the Association of Ischemic Heart Disease and Cardiological Critical Care of the Spanish Society of Cardiology. Introduction Lung ultrasound (LUS) has emerged as a useful diagnostic and prognostic tool in heart failure (HF) and has shown promise in risk stratification for ST-segment elevation myocardial infarction (STEMI) in the acute phase. These studies consistently indicate that the degree of pulmonary congestion, assessed by the number of B-lines on LUS, is significantly associated with a worse prgnosis during hospitalization and short-term follow-up in STEMI patients. However, this prognostic value has mainly been evaluated during hospital admission or a few days after discharge without a long-term follow-up. Purpose To assess the prognostic value of LUS at one year in patients admitted for STEMI. Methods In a prospective multicenter cohort study involving STEMI patients, an independent operator performed LUS during the first 24 hours after revascularization and offline B-line counting was conducted. LUS results were assessed both as a categorical [wet (at least one site with ³3 B-lines)/dry lung] and continuous variable (total number of B-lines). The primary endpoint was a composite of death or hospitalization for HF, acute coronary syndrome, or stroke within one year. Results A total of 173 patients were included. The composite endpoint occurred in 13.7% of the patients over a median follow-up of 368 days. LUS was able to predict the composite outcome with hazard ratios (HR) of adjusted hazard ratios of 4.85 (95% CI 2.79-8.43) for having a wet lung and 1.13 (95% CI 1.09-1.18) for each B-line. After and adjustment for sex, age, chronic kidney disease, previous atrial fibrillation, Killip class and left ventricular ejection fraction HR was 1.72 (95% CI 0.91-3.28) for having a wet lung and 1.06 (95% CI 1.00-1.11) for each B-line. Conclusion Detecting B-lines on LUS predicts adverse events at one year in STEMI patients.Kaplan-Meier curves

Assessment of EHR Efficiency Tools and Resources Associated with Physician Time Spent on the Inbox

BackgroundPhysicians are experiencing an increasing burden of messaging within the electronic health record (EHR) inbox. Studies have called for the implementation of tools and resources to mitigate this burden, but few studies have evaluated how these interventions impact time spent on inbox activities.ObjectiveExplore the association between existing EHR efficiency tools and clinical resources on primary care physician (PCP) inbox time.DesignRetrospective, cross-sectional study of inbox time among PCPs in network clinics affiliated with an academic health system.ParticipantsOne hundred fifteen community-based PCPs.Main MeasuresInbox time, in hours, normalized to eight physician scheduled hours (IB-Time8).Key ResultsFollowing adjustment for physician sex as well as panel size, age, and morbidity, we observed no significant differences in inbox time for physicians with and without message triage, custom inbox QuickActions, encounter specialists, and message pools. Moreover, IB-Time8 increased by 0.01 inbox hours per eight scheduled hours for each additional staff member resource in a physician’s practice (p = 0.03).ConclusionsPhysician inbox time was not associated with existing EHR efficiency tools evaluated in this study. Yet, there may be a slight increase in inbox time among physicians in practices with larger teams.

Association between age at diagnosis and all-cause mortality in type 2 diabetes: the Renal Insufficiency and Cardiovascular Events (RIACE) Italian Multicenter Study

AimsIt is unclear whether type 2 diabetes diagnosed in young adulthood is associated with increased severity than that occurring later in life beyond longer lifetime exposure to hyperglycemia. This study aimed at assessing the independent association of age at type 2 diabetes diagnosis with all-cause mortality.MethodsThis prospective cohort study enrolled 15,773 Caucasian patients with type 2 diabetes in 19 Italian centers in 2006–2008. Cardiometabolic risk profile and presence of complications and comorbidities were assessed at baseline and participants were stratified by quartiles of age at diabetes diagnosis. All-cause mortality was verified on 31 October 2015.ResultsValid information on vital status was retrieved for 15,656 participants (99.3%). Patients in the lowest quartile had the longest diabetes duration, the worst glycemic control and the highest prevalence of insulin treatment, obesity, atherogenic dyslipidemia, and smoking habits. All complications were inversely associated with age at diabetes diagnosis after adjustment for age and sex, but not after further adjustment for diabetes duration. Percentages of death, Kaplan–Meier estimates, and unadjusted hazard ratios and mortality rates increased from the lowest to the highest quartile. In contrast, when adjusting for age and sex, participants falling in the lowest quartile, showed the highest mortality risk [hazard ratio 1.321 (95% confidence interval 1.196–1.460), P < 0.0001]. However, differences among quartiles disappeared after adjustment for diabetes duration, complications/comorbidities, or other cardiovascular risk factors.ConclusionsType 2 diabetes onset in young adulthood is associated with increased mortality that is mainly driven by longer diabetes duration favoring the development of complications.Trial registration: ClinicalTrials.gov, NCT00715481, retrospectively registered 15 July, 2008.

Association of epicardial adipose tissue volume with heart weight in post-mortem cases.

Epicardial adipose tissue (EAT) deposition has been long associated with heart weight. However, recent research has failed to replicate this association. We aimed to determine the association of EAT volume with heart weight in post-mortem cases and identify potential confounding variables. EAT volume derived from post-mortem computed tomography (PMCT) and heart weight were measured in post-mortem cases (N = 87, age: 56 ± 16years, 28% female). Cases with hypertrophied heart weights (N = 44) were determined from reference tables. Univariable associations were tested using Spearman correlation and simple linear regression. Independence was determined with stepwise regression. In the total cohort, EAT volume (median 66 ± 45 cm3) was positively associated with heart weight (median 435 ± 132g) at the univariable level (r = 0.6, P < 0.0001) and after adjustment for age, female sex, and various body size metrics (R2 adjusted = 0.41-0.57). Median EAT volume was 1.9-fold greater in cases with hypertrophic hearts (P < 0.0001) but with considerably greater variability, especially in cases with extreme EAT volume or heart weight. As such, EAT volume was not associated with heart weight in hypertrophic cases, while a robust independent association was found in non-hypertrophic cases (R2 adjusted = 0.62-0.86). EAT mass estimated from EAT volume found that EAT comprised approximately 13% of overall heart mass in the total cases. This was significantly greater in cases with hypertrophy (median 15.5%; range, 3.6-36.6%) relative to non-hypertrophied cases (12.5%, 3.3-24.3%) (P = 0.04). EAT volume is independently and positively associated with heart weight in post-mortem cases. Excessive heart weight significantly confounded this association.