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Uric acid is an emerging biomarker for cardiovascular morbidity and mortality, but its association with all-cause mortality and ECG findings remains unestablished, specifically among older adults. We aimed to evaluate the association between serum uric acid (SUA) with incidental findings of ECG abnormalities and with long-term all-cause mortality. We conducted a prospective cohort study of 851 community dwelling men and women, who were examined between 1999 and 2008, and followed over 20 years until December 2019 for all-cause mortality. Subjects free of Gout or diuretics treatment at baseline were included. SUA was categorized according to sex-specific tertiles and evaluated against baseline ECG findings and all-cause mortality. Mean baseline age was 72±7 years and 416 (49%) were females. Ischemic changes on ECG were observed in 85 (10.0%) participants, of them 36 (13.5%) belonged to the upper SUA tertile and 49 (8.4%) to the lower ones (p = 0.02). Multivariable logistic regression showed 80% higher odds for ischemic changes on ECG among participants in the high SUA tertile (adjusted-OR = 1.8, 95%CI 1.1-2.9, p = 0.03) compared with the lower SUA two-tertiles. During a median follow-up of 14 years, 380 (44.7%) participants died. SUA ≥5.3 mg/dl for women and ≥ 6.2 mg/dl for men, was associated with a 30% greater risk for all-cause mortality in a multivariable Cox regression model (HR = 1.3, 95%CI: 1.0-1.6, p = 0.03). High SUA level was associated with ischemic changes on ECG and with an increased risk for all-cause mortality over 20 years of follow-up among community dwelling older adults free of Gout. Even lower sex-specific thresholds of SUA were associated with all-cause mortality than previously proposed. SUA should be considered as a biomarker for cardiovascular risk and all-cause mortality.

Background The association between insulin resistance and cancer-mortality is not fully explored. We investigated the association between several insulin sensitivity indices (ISIs) and cancer-mortality over 3.5 decades in a cohort of adult men and women. We hypothesized that higher insulin resistance will be associated with greater cancer-mortality risk. Methods A cohort of 1,612 men and women free of diabetes during baseline were followed since 1979 through 2016 according to level of insulin resistance (IR) for cause specific mortality, as part of the Israel study on Glucose Intolerance, Obesity and Hypertension (GOH). IR was defined according to the Mcauley index (MCAi), calculated by fasting insulin and triglycerides, the Homeostatic Model Assessment (HOMA), the Matsuda Insulin Sensitivity Index (MISI), and the Quantitative Insulin Sensitivity Check Index (QUICKI), calculated by plasma glucose and insulin. Results Mean age at baseline was 51.5 ± 8.0 years, 804 (49.9%) were males and 871 (54.0%) had prediabetes. Mean follow-up was 36.7±0.2 years and 47,191 person years were accrued. Cox proportional hazard model and competing risks analysis adjusted for age, sex, country of origin, BMI, blood pressure, total cholesterol, smoking and glycemic status, revealed an increased risk for cancer-mortality, HR = 1.5 (95% CI: 1.1-2.0, p = 0.005) for the MCAi Q.sub.1 compared with Q.sub.2-4 . No statistically significant associations were observed between the other ISIs and cancer-mortality. Conclusion The MCAi was independently associated with an increased risk for cancer-mortality in adult men and women free of diabetes and should be further studied as an early biomarker for cancer risk.

Background Type 2 Diabetes is a major risk factor for cardiovascular (CV) mortality. Insulin resistance can be evaluated non-invasively by insulin sensitivity indices (ISI) such as the Mcauley index (MCAi), which is a function of the fasting insulin and triglycerides. Currently, the association between ISIs and ECG findings and all-cause and CV mortality is still not established in a large scale and heterogeneous population. Method In a prospective study of the Israel cohort on Glucose Intolerance, Obesity and Hypertension (GOH) second phase (1979–1982) 1830 men and women were followed until December-2016 for CV-mortality and December-2019 for all-cause mortality. ECGs were recorded and OGTTs performed during baseline. ISIs were categorized into quartiles and evaluated against ECG findings and all-cause and CV-mortality. Results Mean age at baseline was 52.0 ± 8.1 years, and 75 (15.2%) and 47 (25.3%) participants in the upper quartiles (Q 2-4 ) and the lower quartile (Q 1 ) of the MCAi, presented with Ischemic changes on ECG respectively ( p  = 0.02). Multivariable analysis showed higher odds for ECG ischemic changes, for individuals in Q 1 -MCAi (adjusted-OR = 1.7, 95% CI 1.02–2.8), compared with Q 2-4 -MCAi, which attenuated when excluding individuals with diabetes (adjusted-OR = 1.6, 95% CI 0.9–2.7, p  = 0.09). Median follow up for all-cause and for cardiovascular mortality was 31 years and 37 years, respectively. Cox proportional-hazards regression showed an increased risk for all-cause mortality for individuals in Q 1 -MCAi (HR = 1.2, 95% CI 1.02–1.3) as well as an increased risk for CV-mortality (HR = 1.4, 95%CI 1.1–1.8) compared with Q 2-4 -MCAi. Individuals in Q 4 -Ln Homeostatic model assessment- Insulin Resistance (HOMA-IR) and Q 1 - Quantitative Insulin Sensitivity Check Index (QUICKI) also presented with increased risk for all-cause-mortality (HR = 1.2, 95%CI 1.04–1.4; and HR = 1.2, 95% CI 1.04–1.4, respectively). Other ISIs did not show significant associations with CV-mortality. Conclusion Higher insulin-resistance, according to the MCAi, associated with ECG-changes, and with greater risk for all-cause and CV-mortality over a 40-year follow-up. The MCAi may be considered as an early predictive and prognostic biomarker for CV-morbidity and mortality in adults.

Background As indications for sodium-glucose co-transporter-2 inhibitors (SGLT2i) are expanding, a growing number of older adults have become candidates for treatment. We studied the safety profile of SGLT2i among older adults. Methods A retrospective, pharmacovigilance study of the FDA’s global database of safety reports. To assess reporting of pre-specified adverse events following SGLT2i among adults (< 75 years) and older adults (≥ 75), we performed a disproportionality analysis using the sex-adjusted reporting odds ratio (adj.ROR). Results We identified safety reports of 129,795 patients who received non-insulin anti-diabetic drugs (NIAD), including 24,253 who were treated with SGLT2i (median age 60 [IQR: 51–68] years, 2,339 [9.6%] aged ≥ 75 years). Compared to other NIAD, SGLT2i were significantly associated with amputations (adj.ROR = 355.1 [95%CI: 258.8 − 487.3] vs adj.ROR = 250.2 [79.3 − 789.5]), Fournier gangrene (adj.ROR = 45.0 [34.5 − 58.8] vs adj.ROR = 88.0 [27.0 − 286.6]), diabetic ketoacidosis (adj.ROR = 32.3 [30.0 − 34.8] vs adj.ROR = 23.3 [19.2 − 28.3]), genitourinary infections (adj.ROR = 10.3 [9.4 − 11.2] vs adj.ROR = 8.6 [7.2 − 10.3]), nocturia (adj.ROR = 5.5 [3.7 − 8.2] vs adj.ROR = 6.7 [2.8 − 15.7]), dehydration (adj.ROR = 2.5 [2.3 − 2.8] vs adj.ROR = 2.6 [2.1 − 3.3]), and fractures (adj.ROR = 1.7 [1.4 − 2.1] vs adj.ROR = 1.5 [1.02 − 2.1]) in both adults and older adults, respectively. None of these safety signals was significantly greater in older adults (P interaction threshold of 0.05). Acute kidney injury was associated with SGLT2i in adults (adj.ROR = 1.97 [1.85 − 2.09]) but not in older adults (adj.ROR = 0.71 [0.59 − 0.84]). Falls, hypotension, and syncope were not associated with SGLT2i among either adults or older adults. Conclusion In this global post-marketing study, none of the adverse events was reported more frequently among older adults. Our findings provide reassurance regarding SGLT2i treatment in older adults, although careful monitoring is warranted.

Background A direct comparison between glycemic-based and lipid-based insulin sensitivity indices (ISIs) for ECG findings and all-cause and cardiovascular mortality is lacking. Methods 963 community-dwelling older adults, examined as part of the third phase of the Glucose intolerance, Obesity, and Hypertension study between 1999 and 2008, were followed until December 2016 and December 2019 for cardiovascular and all-cause mortality, respectively. Eleven different ISIs were calculated and evaluated against ECG findings, all-cause, and cardiovascular mortality with multivariable regression models. The area under the receiver operating curve (AUC) and net reclassification improvement (NRI) analysis were implemented to compare ISIs performance. Results Mean age was 72.3 ± 7 years and 471 (49%) were females. Ischemic ECG changes were observed in 107 (11.2%) individuals. Upper quartile (Q 4 ) of triglyceride-glucose waist-to-height ratio (TyG-WTHR) was associated with 220% greater odds for ischemic changes on ECG compared with lower quartiles (Q 1-3 ) (95%CI:1.3–3.7, p = 0.004), an association that was not observed with other ISIs. During a median follow-up of 13 [IQR-8] and 11 [IQR-6] years for all-cause and CV mortality, respectively, 466 (48.4%) participants died, of them, 179 (38.4%) were attributed to cardiovascular causes. TyG-WTHR was the only ISI that was associated with both all-cause (HR = 1.3, 95%CI:1.0–1.6, p = 0.04) and cardiovascular (HR = 1.7, 95%CI:1.2–2.4, p = 0.004) mortality. Lipid based and glycemic ISIs showed similar predicative ability with slightly better predictive performance for TyG-WTHR for all-cause mortality (AUC = 0.46, 95%CI:0.4–0.5, p = 0.02). The NRI analysis revealed better reclassification ability for triglyceride-high-density-lipoprotein ratio (95%CI: 0.02–0.27, p = 0.03) and TyG-WTHR (95%CI: 0.0004–0.01, p = 0.03) for all-cause mortality while TyG-WTHR-based model correctly reclassified 19% of participants (95%CI: 0.02–0.36, p = 0.03) for cardiovascular mortality compared with model unadjusted for any ISIs and correctly reclassified 3% (95%CI:0.003–0.05, p = 0.02) compared with QUICKI based-model for all-cause mortality. Conclusions TyG-WTHR was the only ISI associated with ischemic changes on ECG and all-cause and cardiovascular mortality and significantly improved the predictive performance for all-cause cardiovascular mortality. While most glycemic-based and lipid-based ISIs showed similar predictive ability, TyG-WTHR stands as the preferred ISI and should be considered for screening at-risk individuals for cardiovascular morbidity and mortality. Graphical Abstract

BackgroundCardiotoxicity is a leading cause of morbidity and mortality among patients receiving cancer therapy. The most commonly used definition is cancer therapy-related cardiac dysfunction (CTRCD) defined by a left ventricular ejection fraction reduction. Global longitudinal strain (GLS) has been implied to be superior in detecting early subclinical dysfunction.ObjectivesEvaluate the prevalence of reduced GLS and whether it is associated with CTRCD development among patients receiving cancer therapy.MethodsData were collected as part of the Israel Cardio-Oncology Registry (ICOR), a prospective registry enrolling all adult patients receiving different types of cancer therapy, who were referred to the cardio-oncology clinic. Patients were divided into two groups—reduced GLS (> − 17%) vs. preserved GLS (≤ − 17%). Multivariable analyses were adjusted for a propensity score for baseline characteristics.ResultsAmong 291 consecutive patients, 48 (16%) patients were included in the reduced GLS group. Overall, 11 (5%) patients developed CTRCD at following echocardiogram evaluation. Patients with preserved GLS had a significantly lower risk for CTRCD development [odds ratio (OR) 0.11, 95% confidence interval (CI) 0.03–0.41, p = 0.001], with every 1-unit improvement of GLS the risk of CTRCD decreased by 16% (OR 0.84, 95%CI 0.73–0.95, p = 0.007). After adjustment for baseline characteristics, including cardiovascular risk factors and systolic function, preserved GLS remained significantly associated with a lower risk for CTRCD development (OR 0.11, 95%CI 0.02–0.64, p = 0.014), with every 1-unit improvement lowering the risk by 19% (OR 0.81, 95%CI 0.67–0.98, p = 0.032).ConclusionsReduced GLS is common among patients receiving cancer therapy and may identify patients at increased risk for CTRCD development.Graphic abstract

Background Chemotherapy induced cardio-toxicity has been recognized as a serious side effect since the first introduction to anthracyclines (ANT). Cardio-toxicity among patients with breast cancer is well studied but the impact on patients with sarcoma is limited, even though they are exposed to higher ANT doses. The commonly used term for cardio-toxicity is cancer therapeutics related cardiac dysfunction (CTRCD), defined as a left ventricular ejection fraction (LVEF) reduction of > 10%, to a value below 53%. The aim of our study was to estimate the prevalence of CTRCD in patients diagnosed with sarcoma and to describe the baseline risk factors and echocardiography parameters among that population. Methods Data were collected as part of the Israel Cardio-Oncology Registry (ICOR), enrolling all patients evaluated in the cardio-oncology clinic at our institution. The registry was approved by the local ethics committee and is registered in clinicaltrials.gov (Identifier: NCT02818517). All sarcoma patients were enrolled and divided into two groups - CTRCD group vs. non-CTRCD group. Results Among 43 consecutive patients, 6 (14%) developed CTRCD. Baseline cardiac risk factors were more frequent among the non-CTRCD group. Elevated left ventricular end systolic diameter and reduced Global Longitudinal Strain were observed among the CTRCD group. During follow-up, 2 (33%) patients died in the CTRCD group vs. 3 (8.1%) patients in the non-CTRCD group. Conclusions CTRCD is an important concern among patients with sarcoma, regardless of baseline risk factors. Echocardiography parameters may provide an early diagnosis of cardio-toxicity.

Background Pneumonia remains a leading cause of morbidity and mortality globally, necessitating reliable clinical prediction tools to guide medical management decisions. The Pneumonia Severity Index (PSI), CURB-65, and CRB-65 are clinical scoring tools used to assess the severity of community-acquired pneumonia (CAP), aiding in risk stratification and guiding decisions on hospitalization, level of care and prognosis. Comparative data on their utility, specifically in immunocompetent patients hospitalized in internal medicine wards, are limited. This study aimed to evaluate the predictive capabilities of these scoring tools for mortality and intensive care unit (ICU) transfers in a large cohort of hospitalized patients. Methods We conducted a retrospective, single-center cohort study including 12,670 immunocompetent patients hospitalized with pneumonia in the internal medicine division. PSI, CURB-65, and CRB-65 performance was compared across multiple outcomes, including in-hospital mortality, 30-, 60-, 90-day mortality, and ICU transfer from ward. Subgroup analyses were performed for key comorbidities (chronic obstructive pulmonary disease [COPD], congestive heart failure [CHF], diabetes, chronic kidney disease [CKD] and hypertension). Results PSI consistently demonstrated significantly superior discrimination between survivors and non-survivors across all mortality outcomes with AUC range of 0.73–0.75 ( p  < 0.001, FDR-corrected). In the subgroup analysis by comorbidities, PSI was significantly superior to the other scoring systems only in diabetes patients in 60 and 90-day mortality (AUC = 0.70–0.71). CURB-65 performed comparably to PSI in most of the cases and was superior to CRB-65 only in diabetes and hypertension patients. When predicting ICU transfer during hospitalization, there were no significant differences between the scoring tools, and all demonstrated low predictive capability. Conclusion The PSI demonstrates superior discriminative ability in immunocompetent patients hospitalized with pneumonia. However, its greater complexity should be considered when evaluating its practicality for routine use.

BackgroundImmune checkpoint inhibitors (ICI) have transformed the standard care of cancer treatment. Recent case reports describe ICI-mediated myocarditis with an atypical presentation and fatal potential which lead to permanent interruption of immunotherapy.ObjectivesTo characterize ICI-mediated myocarditis and re-introduction to immunotherapy.MethodsDuring 2019, 849 patients were treated with ICI at Tel Aviv Sourasky Medical Center for the diagnosis of lung adenocarcinoma, gastric adenocarcinoma, urothelial carcinoma, and hepatocellular carcinoma. Overall, seven (0.8%) patients were diagnosed with ICI-mediated myocarditis, according to the European Society of Cardiology guidelines of myocarditis 2013. We retrospectively evaluated their presentation, severity, and clinical outcomes.ResultsAmong the seven patients, only one had a history of cardiac disease. The majority were diagnosed with lung adenocarcinoma and treated with anti-programmed death-1 antibody. All patients were treated with single-agent ICI. Most patients presented with cardiac symptoms, elevated troponin and typical cardiac magnetic resonance; however, only three had reduced ejection fraction. Overall, three patients were chosen for re-introduction with concomitant low dose steroids and weekly troponin follow-up. Two patients diagnosed with grade I and II renewed therapy successfully with no recurrence of symptoms and improvement in disease burden. The one patient diagnosed with grade III developed worsening of cardiac symptoms after the 1st cycle and, therefore, therapy was interrupted permanently.ConclusionsICI-mediated myocarditis is potentially fatal and leads to permanent interruption of life-saving cancer therapy. The current data suggest that re-introduction may be considered in low-grade patients; however, a better definition of the diagnosis and grading is needed.Graphic abstract

Myocardial perfusion defect, assessed with single photon emission computed tomography (SPECT), is useful for patient management and risk stratification. Left ventricle Global Longitudinal Strain (LV GLS) has gained interest for observing subclinical LV dysfunction. We aimed to investigate the utility of LV GLS in evaluating myocardial perfusion defect. A retrospective study of all patients who underwent SPECT and LV GLS at Tel Aviv Sourasky medical center. Overall, 86 patients were included. LV GLS and SPECT correlated in the base and apex sections for infraction, and in the apex only for ischemia. Adjusted analysis showed a significant correlation between LV GLS of both the mid and apical section and infarction by SPECT, but no association with ischemia. No associations were found by arterial supply territory. A sub-analysis of patients without left bundle branch block (LBBB) strengthened the correlations, with a 58–70% higher chance of both fixed and reversible defects for every 1-unit decrease LV GLS in the mid and apical sections. LV GLS effectively evaluated the presence of infarction by SPECT in the mid and apical sections, particularly in patients without LBBB. Due to its high availability, LV GLS may have a role in evaluating myocardial perfusion defect.