Individual Endpoints Research Articles

A Composite Endpoint of Liver Surgery (CELS): Development and Validation of a Clinically Relevant Endpoint Requiring a Smaller Sample Size.

The feasibility of trials in liver surgery using a single-component clinical endpoint is low because single endpoints require large samples due to their low incidence. The current study sought to develop and validate a novel composite endpoint of liver surgery (CELS) to facilitate the generation of more feasible and robust high-level evidence in the field of liver surgery. Patients who underwent curative-intent hepatectomy for hepatocellular carcinoma, intrahepatic cholangiocarcinoma, or colorectal liver metastasis were identified using a multi-institutional database. Components of CELS were selected based on perioperative liver surgery-specific complications using univariable logistic regression models. The association of CELS with prolonged length of stay (LOS) and surgery-related death was evaluated and externally validated. Sample sizes were calculated for both individual outcomes and CELS. Among 1958 patients, 377 (19.3%) met CELS criteria based on postoperative bile leak (n = 221, 11.3%), post-hepatectomy liver failure (n = 71, 3.6%), post-hepatectomy hemorrhage (n = 38, 1.9%), or intraoperative blood loss of 2000 ml or greater (n = 101, 5.2%). CELS demonstrated favorable discriminative accuracy of surgery-related death (analytic cohort: area under the curve [AUC], 0.79 vs external validation cohort: AUC, 0.85). In addition LOS was longer among the patients with a positive CELS (analytic cohort: 14 vs. 9 days [p < 0.001] vs. the validation cohort: 10 vs. 6 days [p < 0.001]). Relative to individual endpoints, CELS allowed a 45.8-91.6% reduction in sample size. CELS effectively predicted surgery-related death and can be used as a standardized, clinically relevant endpoint in prospective trials, facilitating smaller sample sizes and enhancing feasibility compared with single quality outcomemetrics.

Integrating population-level effects into the regulatory assessment of endocrine disrupting substances

Abstract Population modeling, field studies, and monitoring approaches have all been proposed for assessing the relevance of adverse effects of endocrine disrupting chemicals (EDCs) at the population level for nontarget (wild) vertebrates, but how these approaches should be used in the regulatory hazard assessment is unclear and not detailed in the relevant European Guidance Document. A literature review focused on identifying published approaches assessing the population relevance of adverse effects from EDCs was performed, and, subsequently, 47 primary research papers were evaluated. By extracting from these sources, a novel approach was developed with guiding principles for assessing adverse effects of EDCs at the population level considering (i) choice of focal species, scenarios (and models), (ii) the individual level apical endpoints to be considered, (iii) the magnitude of effect to be imposed, (iv) for what duration effects should be imposed, (v) whether individuals repairing the damage from exposure should be included, (vi) the population-level endpoints to be considered, and (vii) what threshold to set for defining an adverse effect at this level. Recommendations for modeling and field and monitoring studies are included. Case studies are also presented to demonstrate how the proposed approach might be implemented. Although some aspects (e.g., choice of focal species, model/experimental scenario, monitoring study assessment) require further consideration, this should not prevent the use of this approach in a regulatory EDC assessment context. As such, we propose that the approach be used immediately to implement population modeling and perform field studies within this regulatory context. We envisage that consistent application of these principles will encourage regulatory developments in this critical area to provide a much needed level of clarity in the EDC assessment for all stakeholders.

Association of radiation-induced normal tissue toxicity with a high genetic risk for rheumatoid arthritis.

Overlapping genes are involved with rheumatoid arthritis (RA) and DNA repair pathways. Therefore, we hypothesised that patients with a high polygenic risk score (PRS) for RA will have an increased risk of radiotherapy (RT) toxicity given the involvement of DNA repair. Primary analysis was performed on 1494 prostate cancer, 483 lung cancer and 1820 breast cancer patients assessed for development of RT toxicity in the REQUITE study. Validation cohorts were available from the Radiogenomics Consortium. All patients had undergone curative-intent radiotherapy and were assessed prospectively for toxicity. Germline genomic data was available for all patients, allowing a PRS to be calculated using 101 RA risk variants. PRS was analysed as a continuous variable and with >90th percentile cut-off. Associations with acute and late standardised total average toxicity (STAT) scores and individual toxicity end-points were analysed in multivariable models with preselected adjustment variables. Increasing PRS for RA did not increase the risk of acute or late STAT in any cohort. There was an increased risk of late oesophagitis in the lung cancer cohort (coefficient 0.018, p = .01), however this was not validated (p = .79). No individual acute or late toxicity endpoints were significantly associated with PRS for the prostate or breast cohorts. No significant results were found in the validation cohorts in multivariable models. Patients with a high genetic risk for RA do not show increased levels of toxicity after radiotherapy suggesting treatment planning does not need to be modified for such patients.

Benefit of Avasopasem Manganese on Severe Oral Mucositis in Head and Neck Cancer in the ROMAN Trial: Unplanned Secondary Analysis

IntroductionOral mucositis is a debilitating side effect of cisplatin and intensity-modulated radiation therapy (IMRT) in patients with head and neck cancer. The phase 3 ROMAN trial showed avasopasem manganese (AVA) significantly decreased individual endpoints of incidence and duration of severe oral mucositis (SOM, World Health Organization [WHO] grade 3-4), with nominal decrease in severity (WHO grade 4) and significant increase in the delay in onset of SOM. We sought to determine the Net Treatment Benefit (NTB) of AVA versus placebo (PBO) using the generalized pairwise comparisons (GPC) method. MethodsGPC is a statistical method that permits simultaneous analysis of several prioritized outcomes, comparing all possible pairs of a patient in the active (i.e., AVA) group and a patient from the control (i.e., PBO) group. NTB is the net benefit across all the outcomes for AVA compared to PBO. Key clinically relevant outcomes from ROMAN were prioritized: 1) WHO grade 4 OM incidence, 2) SOM incidence, 3) days of SOM, 4) days to SOM onset, with 7 days difference defined as the clinical relevance threshold for SOM days and SOM onset. ResultsGPC analysis of 407 patients (AVA = 241, Placebo = 166) stratified by cisplatin schedule and treatment setting resulted in 13,969 pairwise comparisons. AVA showed statistically significant net benefit on all four key outcomes with a 53.9% probability that AVA would benefit patients versus a 35.0% probability that PBO would; the difference between these probabilities was a NTB of 18.9% (p=0.0012), translating to an AVA number needed to treat of 5.3 patients. All outcomes contributed to NTB, reflecting improvements in SOM incidence, onset and duration, and in Grade 4 OM incidence seen in the original ROMAN analysis. ConclusionsThis GPC analysis shows compelling evidence from the ROMAN trial of AVA's clinical benefit across key parameters of SOM burden.

Weighted reverse counting process (WRCP): A novel approach to quantify the overall treatment effect with multiple time-to-event outcomes by adaptive weighting.

In a longitudinal randomized study where multiple time-to-event outcomes are collected, the overall treatment effect may be quantified by a composite endpoint defined as the time to the first occurrence of any of the selected events including death. The reverse counting process (RCP) was recently proposed to extend the restricted mean survival time (RMST) approach with an advantage of utilizing observations of events beyond the "first-occurrence" endpoint. However, the interpretation may be questionable because RCP treats all events equally without considering their different associations with the overall survival. In this work, we propose a novel approach, the weighted reverse counting process (WRCP), to construct a weighted composite endpoint to evaluate the overall treatment effect. A multi-state transition model is used to model the association between events, and an adaptive weighting algorithm is developed to determine the weight for individual endpoints based on the association between the nonfatal endpoints and death using the trial data. Simulation studies are presented to compare the performance of WRCP with RCP, log-rank test and RMST approach. The results show that WRCP is a powerful and robust method to detect the overall treatment effect while controlling the clinically false positive rate well across different simulation scenarios.

Ticagrelor vs Prasugrel for Acute Coronary Syndrome in Routine Care

In patients with acute coronary syndrome (ACS) undergoing invasive treatment, ticagrelor and prasugrel are guideline-recommended P2Y12 receptor inhibitors. The ISAR-REACT5 randomized clinical trial demonstrated superiority for prasugrel, although concerns were raised about the generalizability of some underpowered subgroup analyses. To emulate a randomized clinical trial evaluating the safety and effectiveness of ticagrelor vs prasugrel under the conditions of routine care in individuals with ACS planned to undergo an invasive treatment strategy. This new-user cohort study included secondary data from a German statutory health insurance claims database between January 2012 and December 2021, using 1:1 propensity score nearest-neighbor matching to emulate ISAR-REACT5. Individuals with ACS receiving either ticagrelor or prasugrel treatment after hospital discharge were followed up for 1 year. Eligibility criteria closely emulated those of ISAR-REACT5 and included age of 18 years or older and cardiovascular risk factors. Data were analyzed from May 2023 to May 2024. Outpatient prescription of ticagrelor or prasugrel. The primary end point was the composite of all-cause mortality, myocardial infarction (MI), or stroke within 1 year of outpatient treatment initiation. Secondary end points included individual components of the primary end point and stent thrombosis. The safety end point was major bleeding. A Cox proportional hazards regression model was fitted to the overall cohort. Of 17 642 propensity score-matched individuals (mean [SD] age, 63.1 [10.9] years; 73.9% male), 8821 received ticagrelor and 8821 received prasugrel. Agreement was met in 11 of 12 predefined agreement metrics when comparing the results with ISAR-REACT5. The primary composite end point of all-cause mortality, MI, or stroke occurred in 815 individuals (9.2%) receiving ticagrelor and 663 (7.5%) receiving prasugrel (hazard ratio [HR], 1.24; 95% CI, 1.12-1.37). Myocardial infarction (HR, 1.20; 95% CI, 1.06-1.36) and stroke (HR, 1.33; 95% CI, 1.02-1.74) each occurred significantly more often in the ticagrelor group. Analysis of all-cause mortality (HR, 1.27; 95% CI, 0.99-1.64), stent thrombosis (HR, 1.11; 95% CI, 0.89-1.30), and major bleeding (HR, 1.12; 95% CI, 0.96-1.32) revealed no significant differences between treatment groups. Subgroup analysis showed that prasugrel was associated with the primary composite end point in fewer individuals with ST-segment elevation MI (338 of 4941 [6.8%] vs 451 of 4852 [9.3%]). This cohort study found that prasugrel was associated with lower rates of all-cause mortality, MI, or stroke compared with ticagrelor in individuals with ACS undergoing an invasive treatment strategy in routine care, particularly in individuals with ST-segment elevation MI. The findings suggest that carefully designed database studies can complement and extend findings from randomized clinical trials, informing guidelines and clinical decision-making.

Effects of sodium-glucose co-transporter inhibitors on individual clinical endpoints and quality of life.

Sodium-glucose co-transporter inhibitors (SGLTis) have cardiovascular protective effects. We aimed to assess the effects of SGLTis on individual hard clinical endpoints and quality of life (QoL) in patients with cardiovascular risk factors. Data was searched in PubMed, Embase, Cochrane Library and clinicaltrials.gov databases up to February 2024. Randomized controlled trials (RCTs) comparing SGLTis with placebo were included. The primary outcomes were individual hard clinical endpoints (Subset A) and QoL (Subset B). For Subset A, 13 RCTs including 90413 patients were enrolled (age 66±10.1years, 35.7% female, follow-up 2.4±0.3years); as compared with placebo, SGLTis were associated with significantly lower risk of all-cause mortality [risk ratio (RR): 0.90, 95% confidence interval (CI): 0.86-0.94, P<0.01], cardiovascular mortality (RR: 0.87, 95% CI: 0.82-0.92, P<0.01), hospitalization for heart failure (HF) (RR: 0.72, 95% CI: 0.68-0.76, P<0.01), HF events (RR: 0.72, 95% CI: 0.68-0.75, P<0.01), hospitalization for any cause (RR: 0.91, 95% CI: 0.88-0.93, P<0.01) and myocardial infarction (MI) (RR: 0.92, 95% CI: 0.85-0.99, P=0.03). Notably, the favourable effect of SGLTis on all-cause mortality was more pronounced in younger (<65years) patients (RR: 0.86, 95% CI: 0.81-0.92) and in studies with less female (RR: 0.84, 95% CI: 0.79-0.90). The favourable effect of SGLTis on MI was only observed in patients who received sotagliflozin (RR: 0.47, 95% CI: 0.31-0.73). For Subset B, nine RCTs including 2552 HF patients were enrolled (age 67.8±12.4years, 36.4% female, follow-up 3.4±1.9months); SGLTis were associated with significant improvement in QoL as compared with placebo. In patients with a broad spectrum of cardiovascular risk factors, SGLTis substantially improve individual hard clinical outcomes and QoL.

Abstract 4141439: Catheter ablation and clinical outcomes among older Medicare beneficiaries with atrial fibrillation

Background: Catheter ablation (CA) is increasingly used for treatment of atrial fibrillation (AF). However, CA has not been widely adopted in the older population with AF. The aim of this study is to examine the risks of adverse outcomes following CA in older people with AF. Methods: Using 2014-2019 Medicare claims, we conducted a propensity score analysis of patients treated with CA within 6 months of new AF diagnosis to patients treated with only antiarrhythmic therapy in the 6-month period. The outcome follow-up began after the 6-month period. Cox proportional hazards models were used to estimate hazard ratios (HR) for the composite and individual endpoints from CABANA trial (death, stroke, major bleeding or cardiac arrest) and CASTLE-AF trial (death or heart failure). Subgroup analyses were performed by sex, race-ethnicity, social deprivation index, frailty and dementia. Results: The study population comprised of 14623 AF patients (mean age, 76.1±7.6 years; 55% female, 28% frailty, 13% dementia), including 8% receiving CA. The mean follow-up was 1.8 years. Compared to patients with only antiarrhythmic therapy, patients treated with CA had lower rates of CABANA endpoints (CA vs antiarrhythmic therapy: 5.6 vs 11.7 per 100 person-years; HR:0.72, 95%CI:0.66-0.77) and CASTLE-AF endpoints (6.5 vs 13.8 per 100 person-years; HR:0.72, 95%CI:0.67-0.78). The benefits of CA were consistent in both female and male for CABANA endpoints (female: HR:0.71, 95%CI:0.64-0.79 and male: HR:0.72, 95%CI:0.65-0.81) and CASTLE-AF endpoints (female: HR:0.65, 95%CI:0.59-0.73 and male: HR:0.78, 95%CI:0.71-0.87), and in both frail and non-frail patients for CABANA endpoints (frail: HR:0.72, 95%CI:0.66-0.80 and non-frail: HR:0.70, 95%CI:0.63-0.77) and CASTLE-AF endpoints (frail: HR:0.89, 95%CI:0.81-0.97 and non-frail: HR:0.69, 95%CI:0.63-0.75). Similar trends were observed for subgroups defined by race-ethnicity, social deprivation index, and dementia. Conclusions: These findings suggest that CA may be beneficial for older AF patients. Nonetheless, further investigation of the safety and efficacy of CA given to older patients in well-designed interventional trials are warranted.

Invasive Versus Conservative Strategy in Older Adults ≥75 Years of Age With Non-ST-segment-Elevation Acute Coronary Syndrome: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Older adults with non-ST-segment-elevation acute coronary syndrome are less likely to undergo an invasive strategy compared with younger patients. Randomized controlled trials traditionally exclude older adults because of their high burden of geriatric conditions. We searched for randomized controlled trials comparing invasive versus medical management or a selective invasive (conservative) strategy for older patients (age≥75 years) with non-ST-segment-elevation acute coronary syndrome. Fixed effects meta-analysis was conducted to estimate the odds ratio (OR) with 95% CI for the composite of death or myocardial infarction (MI) and individual secondary end points of all-cause death, cardiovascular death, MI, revascularization, stroke, and major bleeding. Nine studies with 2429 patients (invasive: 1228 versus control: 1201) with a mean follow-up of 21 months were included. An invasive strategy was associated with a significantly decreased risk of a composite of death and MI (OR, 0.67 [95% CI, 0.54-0.83], P<0.001), MI (OR, 0.56 [95% CI, 0.45-0.70], P<0.001) and subsequent revascularization (OR, 0.27 [95% CI, 0.16-0.48], P<0.001). There was no difference in all-cause death (OR, 0.84 [95% CI, 0.65-1.10], P=0.21), cardiovascular death (OR, 0.85 [95% CI, 0.63-1.15], P=0.30), stroke (OR, 0.74 [95% CI, 0.38-1.47], P=0.39), or major bleeding (OR, 1.24 [95% CI, 0.42-3.66], P=0.70). In older patients ≥75 years old with non-ST-segment-elevation acute coronary syndrome, an invasive strategy reduced the risk of a composite of death and MI, MI, and subsequent revascularization compared with a conservative strategy alone. Older adults with higher burden of geriatric conditions should be included in future trials to improve generalizability to this growing population.

A randomised trial of sirolimus- versus paclitaxel-coated balloons for de novo coronary lesions.

Paclitaxel-coated balloons (PCB) are a viable alternative to drug-eluting stents in the treatment of de novo coronary lesions. Whether sirolimus represents an alternative to paclitaxel for drug-coated balloons remains elusive. This randomised, controlled, multicentre, non-inferiority trial investigated a novel sirolimus-coated balloon (SCB) with a crystalline coating versus a PCB in de novo coronary lesions. To compare a novel SCB with a clinically proven PCB, 70 patients with de novo coronary lesions were enrolled at 4 centres in Germany and Switzerland. The primary endpoint was non-inferiority regarding angiographic late lumen loss (LLL) at 6 months, with a predefined margin of δ=0.35 mm. Secondary endpoints included procedural success, major adverse cardiac events, and individual clinical endpoints. Quantitative coronary angiography revealed no differences in baseline parameters. At 6 months, in-segment LLL was 0.04±0.39 mm in the PCB group versus 0.11±0.37 mm in the SCB group (non-significant), respectively. The mean difference between SCB and PCB was 0.07 mm (95% confidence interval: -0.12 to 0.26). Non-inferiority at the predefined margin of 0.35 was shown. Clinical event rates up to 12 months were not different between the groups (3 target lesion revascularisations in the PCB group versus 2 in the SCB group, no myocardial infarctions, no deaths). The novel SCB showed similar angiographic outcomes in the treatment of de novo coronary disease as compared with a clinically proven PCB (ClinicalTrials.gov: NCT03908450).

Incidence and outcomes of transient new-onset atrial fibrillation complicating acute coronary syndromes: results from a systematic review and meta-analysis.

The overall risk of long-term adverse events of a transient episode of new-onset atrial fibrillation (AF) in patients with acute coronary syndrome (ACS) remains uncertain. This meta-analysis aimed to assess the prognostic impact of transient new-onset AF complicating ACS. Cohort studies examining the risk of adverse events in patients with transient new-onset AF compared to those in sinus rhythm after ACS were identified through a comprehensive search of MEDLINE, Scopus, Cochrane, and Google Scholar Library. Studies reporting the incidence of ischaemic stroke events, recurrent AF, or all-cause mortality at the longest follow-up were included. Adjusted hazard ratios (aHRs) with 95% confidence intervals (CI) were synthesized using inverse variance-weighted random-effects meta-analysis. In the seven observational studies included, comprising 151 735 patients, 6 597 (4.3%) experienced transient new-onset AF, which was associated with an increased risk of ischaemic stroke, recurrent AF, or all-cause mortality (HR: 2.24, 95% CI: 1.75-2.85; P<0.0001; I2=30.76%; seven studies). The results remained consistent across each individual endpoint, including ischaemic stroke (HR 2.38, 95% CI: 1.64-3.44; P<0.01; I2=50.2%; five studies), recurrent AF (HR 4.68, 95% CI: 2.07-10.59; P=0.0002; I2=50.2%; four studies), and all-cause mortality (HR 1.36, 95% CI: 1.08-1.71; P=0.0089; I2=53.25%; four studies). Meta-regression analyses revealed a significant increase in these adverse events associated with ST-elevation myocardial infarction (P=0.001), while there was a tendency for their decrease associated with oral anticoagulant prescription at discharge (P=0.07). The occurrence of transient new-onset AF is associated with an elevated long-term risk of stroke, recurrent AF, and all-cause mortality in patients with ACS. Consequently, these data urge randomized clinical trials to assess the best antithrombotic regimen while potentially helping the current treatment decision-making process for these patients.

Informing healthy urban policy making through quantitative health impact appraisal – a co-designed approach

Abstract Quantitative health impact appraisal for land use development is currently challenging. We show how a co-designed process between urban decision makers and academics can help to improve ways of deriving evidence for creating healthier cities. The Health Appraisal of Urban Systems (HAUS) economic valuation model was developed with local partners to inform a strategic framework for a UK urban regeneration site. HAUS is a comparative risk assessment model which allows the user to understand mechanisms for change through applying an impact-pathway approach to quantify changes in health. It is informed by systematic reviews of epidemiology and societal costs of 85 individual health end-points. Scenarios combined a range of characteristics including air and noise pollution, green space, crime, walkability, food environment and transport. Health outcomes include morbidity and mortality impacts. Results show the value of a holistic approach to comparing health risks in designing urban living. By monetising outcomes, practitioners were able to understand the relative magnitude of risk within a specific area and compare alternate urban development scenarios. Compared to an unmanaged development, the Strategic Framework can mitigate health risks by improving safety and quality of the public realm and add health benefits by encouraging activity and active commuting. Flood risks are managed, and green infrastructure improved and extended. These benefits extend to communities outside the site boundaries. Over 25 years, the PV benefits are £60 - 80 million in averted health costs. Strategic planning for urban areas can unlock the potential of the public realm to tackle health inequalities and mitigate serious risks to public health. Timely access to quantitative information on health can help inform understanding of unhealthy environments, strengthen arguments for good design, reinforce capacity of planning teams and so improve the quality of urban developments. Speakers/Panelists Odile Mekel NRW Centre for Health, Bochum, Germany

Comparison of cardiovascular outcomes in patients with diabetes treated with tirzepatide versus semaglutide: a multi-institutional analysis

Abstract Introduction Glucagon-like-peptide-1 (GLP-1) receptor agonists have been demonstrated to have cardiovascular benefits in patients with diabetes. Two of the most prescribed medications in this class are tirzepatide and semaglutide. Tirzepatide is a dual glucose-dependent insulinotropic polypeptide and GLP-1 receptor agonist, while semaglutide is a selective GLP-1 receptor agonist. Tirzepatide and semaglutide have previously been directly compared to assess efficacy in glycemic control as the primary endpoint. However, there is limited data directly comparing cardiovascular outcomes between the two medications in patients with diabetes. This retrospective cohort study compares the incidence of major adverse cardiovascular events (MACE) in patients with diabetes treated with tirzepatide or semaglutide. Purpose The purpose of this study is to identify differences in cardiovascular outcomes between patients with diabetes treated with tirzepatide as compared to semaglutide. Materials and Methods The TriNetX research network was used for this study. Two patient cohorts were generated using International Classification of Disease 10 (ICD-10) codes and medication codes in the TriNetX system. Both cohorts of patients had a history of diabetes (E08-E13) and no prior history of cerebral vascular accident (I63) or myocardial infarction (I21). One cohort received semaglutide and the other tirzepatide. Each cohort was prohibited from receiving the other agent. The cohorts were balanced for age, race, gender, and ethnicity by propensity score matching and the greedy nearest neighbor algorithm resulting in 36,212 patients in each arm. They were then evaluated for the 3-year outcomes of major adverse cardiovascular events (myocardial infarction, cerebral vascular accident, and death). Results Tirzepatide was associated with statistically significantly fewer MACE outcomes compared to semaglutide for each of the individual endpoints as well as the overall composite endpoint over the 3 year follow up period. Table 1. MACE events for semaglutide and tirzepatide. Table 2. Relative risks for semaglutide MACE endpoints compared to tirzepatide. Conclusions In this retrospective cohort study, tirzepatide was associated with a lower incidence of major adverse cardiovascular events compared to semaglutide in patients with diabetes. These findings suggest that tirzepatide offers superior cardiovascular protection for primary prevention compared to semaglutide and warrant further investigation in future studies and clinical trials.Table 1Table 2

Long-term efficacy and safety of ablation for atrial fibrillation in patients with hypertrophic cardiomyopathy

Abstract Background Hypertrophic cardiomyopathy (HCM) is often accompanied by atrial fibrillation (AF) but data on safety and long-term outcomes after catheter ablation for AF in HCM are scarce. Purpose To investigate safety, long-term efficacy and clinical outcomes following AF ablation in patients with HCM and in matched controls. Methods Patients with HCM (n=76) undergoing a first catheter ablation for AF or atrial flutter between 1999 and 2022 at a University Hospital in Sweden were included (age 64±12 years, 43% female). Diagnosis of HCM was based on the European Society of Cardiology definition (left ventricular wall thickness ≥15 mm or ≥13 mm not solely explained by abnormal loading conditions, and combined with family history, genetic components and/or electrocardiogram abnormalities). Patients with HCM were matched with controls (n=152) based on age, gender, ablation type and intervention-year. Patients were followed for a mean of 5 years and study endpoints included heart failure hospitalization (HFH), stroke and mortality. Cox regression analyses were performed for the association between HCM and the endpoints. Results Among the overall population, 121 (53%) underwent pulmonary vein isolation (PVI), 62 (27%) isthmus ablation and 45 (20%) His-Bundle ablation. Patients with HCM had a shorter mean duration of AF before ablation (48 months vs. 66 months; p=0.047) and more severe symptoms as indicated by a higher EHRA class (EHRA class IV: 30% vs. 10%; p&amp;lt;0.01). Procedural success rate of PVI and isthmus ablation was lower in patients with versus without HCM (88% vs. 97%; p=0.02). Procedure related complications (vascular complications, tamponade) were overall similar in both groups (9% in HCM vs. 5% in controls, p=0.17) except for higher rates of pulmonary oedema in patients with HCM (7% vs 1%, p=0.03). There was a nearly two-fold increase in risk of AF recurrence after PVI or isthmus ablation in patients with HCM compared to controls (OR 1.95; 95% CI 1.06-3.58; p=0.03). During follow-up, patients with HCM had an increased risk of HFH (HR 2.55, 95% CI 1.21-5.36, p=0.01) but not of stroke or mortality (Figure 1). Conclusion AF ablation was overall safe in patients with HCM but less effective. Patients with HCM had an increased risk of the individual endpoint of HFH after AF ablation but not stroke or mortality during long-term follow-up.

SGLT2 Inhibitor Use and Risk of Dementia and Parkinson Disease Among Patients With Type 2 Diabetes.

Despite the mechanistic potential of sodium-glucose cotransporter 2 inhibitor (SGLT2i) to improve neurologic outcomes, the efficacy of SGLT2i in neurodegenerative disorders among patients with type 2 diabetes is not well established. This population-based cohort study aimed to investigate the association of SGLT2i use with risks of incident dementia and Parkinson disease (PD) in patients with type 2 diabetes. This was a retrospective examination of data from a cohort of 1,348,362 participants with type 2 diabetes (≥40 years), who started antidiabetic drugs from 2014 to 2019, evaluated using the Korean National Health Insurance Service Database. Propensity score matching (1:1; SGLT2i to other oral antidiabetic drugs [OADs]) produced a cohort of 358,862 participants. Primary outcomes were the individual incidence of Alzheimer disease (AD), vascular dementia (VaD), and PD. Secondary outcomes were all-cause dementia (AD, VaD, and other dementia) and a composite of all-cause dementia and PD. Cox proportional hazards models were used to investigate the association between SGLT2i use and the risks of dementia and PD. From the 358,862 participants analyzed (mean [SD] age, 57.8 [9.6] years; 58.0% male), 6,837 incident dementia or PD events occurred. Regarding the individual endpoints, SGLT2i use was associated with reduced risks of AD (adjusted hazard ratio [aHR] 0.81, 95% CI 0.76-0.87), VaD (aHR 0.69, 95% CI 0.60-0.78), and PD (aHR 0.80, 95% CI 0.69-0.91) with a 6-month drug use lag period. In addition, use of SGLT2i was associated with a 21% lower risk of all-cause dementia (aHR 0.79, 95% CI 0.69-0.90) and a 22% lower risk of all-cause dementia and PD than use of other OADs (aHR 0.78, 95% CI 0.73-0.83). The association between the use of SGLT2i and the lowered risk of these neurodegenerative disorders was not affected by sex, Charlson Comorbidity Index, diabetic complications, comorbidities, and medications. Sensitivity analysis further adjusting for bioclinical variables from health screening tests, including blood pressure, glucose, lipid profiles, and kidney function, yielded generally consistent results. In this nationwide population-based study, SGLT2i use significantly reduced the risks of neurodegenerative disorders in patients with type 2 diabetes independent of various factors including comorbidities and bioclinical parameters. This study provides Class II evidence that SGLT2 antidiabetic drugs decrease the risk of dementia and PD in people with diabetes.

Effect of Prednisone Dosing on Mineralocorticoid-Related Side Effects With Abiraterone in Prostate Cancer.

Abiraterone use for prostate cancer can cause mineralocorticoid excess syndrome (MES; eg, hypertension and hypokalemia). Prednisone mitigates these effects; however, the optimal dose level is unclear. This study examines MES effects from abiraterone with 5 mg of prednisone once daily versus 5 mg twice daily. Data for 1,410 abiraterone-treated patients from 2011 to 2022 were identified from a large academic/community hospital system. Three hundred and fifty-three patients were excluded for missing medication data and use of an alternative steroid; 1,057 patients remained (5 mg once daily, n = 550, 5 mg twice daily, n = 507). Prednisone dose was treated as a time-varying covariate. Hypokalemia and hypertension incidence over 24 weeks after abiraterone initiation was analyzed via Cox proportional hazard models using Common Terminology Criteria for Adverse Events (v5.0) grading via direct clinical measurements and International Classification of Diseases (ICD)-10 code outcomes. Patients receiving 5 mg of prednisone twice daily had a statistically significant decrease in cumulative hazard for experiencing at least one MES event (hypertension and/or hypokalemia) via direct clinical measurement (hazard ratio [HR], 0.79 [CI, 0.68 to 0.91]; P = .002) and by ICD-10 code (HR, 0.65 [CI, 0.54 to 0.79]; P < .001) analysis. This finding was durable with individual end point analysis of hypertension and hypokalemia. There were no changes to BMI or hyperglycemia (>140 mg/dL) between the cohorts. This retrospective analysis shows a decrease in risk for the development of at least one episode of hypertension or hypokalemia with abiraterone using 5 mg twice-daily prednisone in the study population. Assessments of metabolic impacts (BMI, hyperglycemia) did not show differences with prednisone dosing. These findings may merit consideration when determining an optimal prednisone dosing regimen.

The complete blood count and cardiovascular disease: analyses across six cohorts of 23,370 adults.

The complete blood count (CBC) is one of the most commonly performed laboratory studies. Although studies have found associations between the CBC and cardiovascular disease (CVD), there is limited contemporary information regarding the relationship between the CBC and traditional risk factors and their joint association with CVD endpoints. We sought to define the relationships between the CBC and traditional CVD risk factors and their joint association with CVD endpoints in diverse adult populations. We first examined the relationships between the CBC variables (directly and their principal components), traditional CVD risk factors, and mortality in NHANES (n=7843). Next, we validated and extended these findings to more refined CVD endpoints in five additional cohorts (n=15,527). We first examined the variance accounted for by common laboratory studies (lipid panel, HbA1c, hs-CRP, and basic metabolic panel) by traditional risk factors in NHANES. With the exception of hemoglobin (Hb)-related components, we found that traditional risk factors accounted for less than 20% of the variance in CBC values, similar to that of lipid parameters. Additionally, in the clinically adjusted model, the CBC was more strongly associated with all-cause mortality than the lipid panel or CRP (p<0.0001). Next, we validated and extended these findings across five additional longitudinal cohorts with a mean follow-up of 16 years to evaluate the association of individual CBC parameters and their principal components with refined CVD endpoints. In the fully adjusted meta-analyses across the five cohorts, several CBC components including the white blood cell (WBC) count, neutrophil (PMN) count, hemoglobin (Hb) level, and an integrated immune cell score, were associated with individual CVD endpoints and a composite CV endpoint (MACE3: incident stroke, MI, and revascularization) with standardized hazard ratios of 1.13 (p=0.002), 1.15 (p=0.0006), 0.82 (p<0.0001), and 2.16 (p<0.0001) respectively. This study represents the first systematic examination of the relationship between CBC features and established risk factors, as well as numerous CVD endpoints, in a diverse cohort of 23,370 adults. The findings of this study underscore the potential utility of integrating CBC features into CVD risk assessment and suggest important mechanistic insights into the association between individual CBC components and the genesis of CVD.

Microplastics originated from Plasmix-based materials caused biochemical and behavioral adverse effects on Daphnia magna

The implementation of advanced recycling techniques represents a key strategy for mitigating the mismanagement and the environmental impact of plastic waste. A limited array of plastic polymers can be efficiently recycled, while a notable portion of plastic waste remains unrecyclable. In Italy, this residual, heterogeneous fraction is referred to as Plasmix. Because of its complexity and non-homogeneous composition, Plasmix is primarily directed towards low-value applications. However, recent developments in laboratory-scale mechanical recycling have enabled the creation of new plastic materials from Plasmix. Prior to their application, these materials must undergo rigorous eco-safety evaluation. The present study aims to assess the potential toxicity of microplastics (MPs) from Plasmix-based materials on the freshwater crustacean Daphnia magna. Specifically, this study investigated sub-individual and individual effects induced by a 21-day exposure to different concentrations of MPs generated from the grinding of naïve and Additivated Plasmix-based materials (hereafter referred to as Px-MPs and APx-MPs, respectively). Sub-individual endpoints focused on changes in oxidative status, including the modulation of antioxidant and detoxifying enzyme activities, as well as oxidative damage, such as lipid peroxidation. Individual level endpoints included alterations in survival and reproduction. Microscopy analyses confirmed the ingestion of both Px-MPs and APx-MPs by D. magna individuals. An oxidative stress condition raised in organisms exposed to Px-MPs, whereas no effect was observed in individuals exposed to APx-MPs. Although survival was not affected, a significant impairment in reproductive output was detected at the end of exposure to all the concentrations of both MP types. These findings suggest that even low concentrations of Px-MPs and APx-MPs could negatively affect the health status of D. magna, underscoring the need for further research to complete the risk assessment of Plasmix-based materials prior to their use in consumer products.

In silico occupational exposure banding framework for data poor compounds in biotechnology.

Occupational exposure limits (OELs) and occupational exposure bands (OEBs) provide quantitative benchmarks for worker health protection. If empirical toxicology data are insufficient to derive an OEL, an OEB is often assigned using partial toxicology data along with other relevant hazard information. There is no consensus methodology to assign OEBs for chemicals lacking any empirical toxicology data. Thus, this study developed an in silico framework for OEB assignment of data poor compounds. It relies upon computational tools to evaluate standard toxicological end points and to assign reliability ratings, which are then used to assign Global Harmonization System (GHS) hazard categories. Subsequently, the hazard categories are entered into the National Institute for Occupational Safety and Health (NIOSH) occupational exposure banding tool to assign bands for individual end points as well as an overall OEB. As a proof-of-concept, five compounds with established OELs (i.e., "knowns") were evaluated. The knowns were assigned to overall OEBs C, D, or E, four of which were equal to or lower than the OEBs based on actual harmonized GHS categories as well as established OELs, indicating that the OEBs assigned using this framework are likely to be protective. Subsequently, five compounds with little to no experimental data and no established OELs from any U.S. agency or consensus OEL-setting organizations were evaluated (i.e., "unknowns"). The unknowns were assigned to overall OEBs D or E. It was concluded that the proposed framework can be used to assign protective OEBs to compounds with little to no toxicology testing data. As additional data become available, the compound may be de-risked, and a precautionary OEB (or an OEL) can be assigned. The proposed framework provides an example of a practical methodology to evaluate data poor compounds and shows that the output of this framework is expected to be protective of worker health.

Towards an environmental quality standard (EQS) for lithium in fresh water

Lithium (Li), because of its widespread and increasing use in Li-ion batteries, is an element of vital importance to the energy transition away from fossil fuels and toward clean, renewable energy (green energy). Extraction and refining operations, as well as utilisation in a growing number of applications, are expanding and thus increasing the environmental releases of Li. In order to evaluate consequences of such releases, and to risk assess the accumulation of Li in aquatic ecosystems, environmental quality standards (EQS) are needed so that measured concentrations can be evaluated. Satisfactory EQS for Li are yet to be established and therefore derivation of Predicted No Effect Concentrations (PNECs), or interim EQS, are vital for environmental protection. This study compiled Li freshwater ecotoxicology data from global literature, screened and evaluated it, and then employed it to derive PNECs for short term exposures (i.e. concentrations unlikely to cause harm if their duration is short) and PNECs for standard condition exposures (i.e. concentrations unlikely to cause harm if their duration is continuous) in freshwater ecosystems. The generated dataset comprised 194 individual ecotox endpoints from 31 reference sources, spanning 28 species from 10 separate taxonomic groups (broad organism types). The derived PNECs recommended for consideration in environmental regulation are 0.622 mg/L for short term exposures and 15.2 μg/L for standard condition exposures, but with potential adjustment for site specific water conditions incorporating water hardness, dissolved organic carbon concentration and pH.