25th-75th Percentile Research Articles

Exploiting blood-based biomarkers to align preclinical models with human traumatic brain injury.

Rodent models are important research tools for studying the pathophysiology of traumatic brain injury (TBI) and developing new therapeutic interventions for this devastating neurological disorder. However, the failure rate for the translation of drugs from animal testing to human treatments for TBI is 100%. While there are several potential explanations for this, previous clinical trials have relied on extrapolation from preclinical studies for critical design considerations, including drug dose optimization, post-injury drug treatment initiation and duration. Incorporating clinically relevant biomarkers in preclinical studies may provide an opportunity to calibrate preclinical models to identical (or similar) measurements in humans, link to human TBI biomechanics and pathophysiology, and guide therapeutic decisions. To support this translational goal, we conducted a systematic literature review of preclinical TBI studies in rodents measuring blood levels of clinically used GFAP, UCH-L1, NfL, t-Tau, or p-Tau, published in PubMed/EMBASE up to April 10th, 2024. Although many factors influence clinical TBI outcomes, many of those cannot routinely be assessed in rodent studies (e.g., ICP monitoring), thus we focused on blood biomarkers' temporal trajectories and discuss our findings in the context of the latest clinical TBI biomarker data. Out of the 805 original preclinical studies, 74 met the inclusion criteria, with a median quality score of 5 (25th-75th percentiles: 4-7) on the CAMARADES checklist. GFAP was measured in 43 studies, UCH-L1 in 21, NfL in 20, t-Tau in 19, and p-Tau in seven. Data in rodent models indicate that all biomarkers exhibited injury severity-dependent elevations with distinct temporal profiles. GFAP and UCH-L1 peaked within the first day after TBI (30- and 4-fold increases, respectively, in moderate-to-severe TBI versus sham) with the highest levels observed in the contusion TBI model. NfL peaked within days (18-fold increase) and remained elevated up to 6 months post-injury. GFAP and NfL show a pharmacodynamic response in 64.7% and 60%, respectively, of studies evaluating neuroprotective therapies in preclinical models. However, GFAP's rapid decline post-injury may limit its utility for understanding the response to new therapeutics beyond the hyperacute phase after experimental TBI. Furthermore, as in humans, subacute NfL levels inform on chronic white matter loss after TBI. t-Tau and p-Tau levels increased over weeks after TBI (up to 6- and 16-fold, respectively); however, their relationship with underlying neurodegeneration has yet to be addressed. Further investigation into biomarker levels in the subacute and chronic phases after TBI will be needed to fully understand the pathomechanisms underpinning blood biomarkers' trajectories and select the most suitable experimental model to optimally relate preclinical mechanistic studies to clinical observations in humans. This new approach could accelerate the translation of neuroprotective treatments from laboratory experiments to real-world clinical practices.

Simulation of focal boosting in online adaptive MRI-guided SBRT for patients with locally advanced prostate cancer with seminal vesicle involvement

To evaluate the feasibility and accuracy of focal boosting in online adaptive MRI-guided stereotactic body radiation therapy (SBRT) for patients with prostate cancer (PCa) with seminal vesicle invasion (T3b) by analyzing the impact of intra-fraction motion on the dose planned to the gross tumor volume (GTV) and clinical target volume (CTV). Data of 23 patients with T1-T3a PCa who received focal boosting SBRT on a 1.5T MR-Linac was used. A radiation oncologist replaced clinical GTVs with artificial GTVs representative for T3b tumor(s). For each MRI used for daily adaptation (MRIadapt) an automated treatment plan was generated (Df1-5) using the adapted contours. Patients were planned to receive 35 Gy to the CTV, with an isotoxic focal boost to the GTV up to 50 Gy. During each fraction an additional MRI was acquired to assess intra-fraction motion (MRIduring). Dose accumulation of all fractions was performed by deformable registration of MRIadapt, f2-5 to MRIadapt, f1 (DACC, planned). The Df1-5 were projected to their corresponding MRIduring, which were used to reconstruct DACC, delivered, likewise. Our results were compared to patients with tumor(s) without seminal vesicle invasion (T1-T3a). The median (10th-90th percentile) D98%ACC, planned to the GTV, which correlates most strongly with outcome, was 41.1 Gy (40.1 - 43.0 Gy) in the plans for patients with artificial T3b tumors, compared to 43.0 Gy (40.4 - 47.2 Gy) in the plans for patients with T1-T3a tumors. The D98%ACC, delivered to the GTV, taking into account intra-fraction motion, was 41.0 Gy (39.3 - 42.6 Gy) and 42.5 Gy (40.0 - 46.6 Gy) in the plans for the artificial and clinical GTVs, respectively. MRI-guidance can ensure high accuracy of focal boosting in patients with T3b disease. Due to the unfavorable location of the GTV, a lower boost dose was feasible compared to patients with T1-T3a PCa.

Dapagliflozin versus empagliflozin and major adverse cardiovascular events in type 2 diabetes: a nationwide cohort study

Abstract Background Large randomized clinical trials have shown that sodium-glucose co-transporter-2 (SGLT2) inhibitors reduce the risk of adverse kidney and cardiovascular outcomes in patients with heart failure, chronic kidney disease, or type 2 diabetes mellitus (T2DM) at high risk of atherosclerotic cardiovascular disease. Whether these effects might differ between individual SGLT2-inhbitors remain unclear given the lack of head-to-head comparisons. Purpose To examine the association between treatment with dapagliflozin versus empagliflozin and the long-term rate of major adverse cardiovascular events (MACE) in patients with T2DM. Methods Using nationwide registries, all Danish residents with T2DM, who initiated treatment with dapagliflozin or empagliflozin from 2015 to 2020, were identified. Only treatment with dapagliflozin or empagliflozin was considered in the present analysis, since approximately 3% initiated treatment with other SGLT2-inhibitors (i.e., canagliflozin and ertugliflozin). Patients were followed from date of the first claimed prescription of dapagliflozin or empagliflozin until the outcome of interest, emigration, death, or end of study (December 31, 2021). The primary outcome was a composite endpoint of major adverse cardiovascular events (i.e., time to first heart failure hospitalisation, acute myocardial infarction (AMI), stroke, or all-cause mortality). The primary outcome was compared between the dapagliflozin and empagliflozin group, overall and in prespecified subgroups of interest, with multivariable Cox proportional hazards regression models. Results In total, 61,031 patients with T2DM initiated treatment with dapagliflozin (N=21,028; 34.5%) or empagliflozin (N=40,003; 65.5%). The median age of study population was 62.6 years (25th-75th percentile, 54.2-70.8 years), and 62.6% were men. There were no clinically significant differences between the dapagliflozin and empagliflozin group with respect to age, sex, and clinical characteristics. The median follow-up was 3.1 years (25th-75th percentile, 1.9-4.5 years). The adjusted long-term hazard ratios of the primary outcome, overall and in prespecified subgroups of interest, are displayed in the Figure. Compared with empagliflozin, treatment with dapagliflozin was not associated with a significantly different rate of the primary outcome (HR 1.02 [95% CI, 0.97-1.07]). The observed association was consistent across clinically relevant subgroups, including in patients with and without heart failure, chronic kidney disease, and atherosclerotic cardiovascular disease. Conclusion In a large, nationwide cohort of patients with T2DM, treatment with dapagliflozin was associated with a similar rate of major adverse cardiovascular outcomes compared with empagliflozin, and this association was consistent across clinically relevant subgroups. These findings suggest that the benefits of SGLT2-inhibitors can be characterized as a class-effect.

Identifying low-risk chest pain in out-of-hours primary care: the diagnostic performance of preHEAR and preHEART scores based on two European cohorts

Abstract Background Distinguishing cardiac from non-cardiac acute chest pain presents a diagnostic challenge. Risk stratification tools, such as the HEART score, have been developed for decision support for hospital-based settings. For prehospital settings, the preHEART score was developed as an alternative to the HEART score, with refinements made to meet prehospital conditions, as illustrated in Figure 1. While promising for use by emergency medical services, the diagnostic performance in primary care is unknown. Purpose In this study, we aim to evaluate the preHEART score (with and without high-sensitivity cardiac troponin (hs-cTn)) as a risk stratification tool to rule out acute myocardial infarction (MI) in patients evaluated in out-of-hours primary care. Methods We relied on retrospective data from two cohorts, namely, the OUT-ACS study involving 1,711 consecutive patients (47.7% female, median age: 56 (25th-75th percentiles: 45-68)) evaluated at a Norwegian primary care emergency centre from 2016-2018; and the TRACE study involving 664 consecutive patients (56.9% female, median age: 48 (25th-75th percentiles: 32-67) from a Dutch primary care emergency centre in 2017. We evaluated the preHEAR (OUT-ACS & TRACE without hs-cTn) and preHEART scores (OUT-ACS). The threshold of ≤3 points was considered low-risk and previously determined as optimal for rule-out purposes. The primary outcome was the diagnostic performance for ruling out MI at the index episode, and the secondary outcome was the composite of 90-day all-cause death or MI. Results In the OUT-ACS cohort, 61 (3.6%) patients were diagnosed with an MI; for the TRACE study, MI was diagnosed in 20 (3.0%) patients. The percentage of patients deemed at low risk by preHEAR was 49.3% (n=843) and 82.7% (n=549) for OUT-ACS and TRACE, respectively. For preHEART, only 33.6% (n=575) of OUT-ACS patients were deemed low-risk. As shown in Figure 2, the corresponding sensitivity/specificity indices for index MI were 63.9%/49.8% (OUT-ACS) and 65.0%/84.2% (TRACE) for preHEAR and 93.4%/34.6% for preHEART. Positive predictive values were low (preHEAR 5.0-11.3%, preHEART 5.0%), whereas negative predictive values were high (preHEAR 97.4-98.7%, preHEART 99.3%). For the secondary outcome, similar diagnostic performance metrics were found. All missed MI cases (n=4) in the low-risk preHEART group were female. Conclusion The preHEAR and preHEART scores did not result in adequate rule-out safety for an emergency primary care setting despite a low a priori MI risk. Moreover, the score appears to underestimate the risk for MI in females.preHEAR(T) risk scoresPerformance of the risk scores

Safety and efficiency of modified HEART scores without troponin or electrocardiography: an analysis based on two European out-of-hours primary care cohorts

Abstract Background Differentiating between acute chest pain of cardiac versus non-cardiac origin poses a diagnostic challenge. Risk stratification tools, such as the HEART (History, ECG, Age, Risk and Troponin) score, have been developed to aid in decision-making. These scores typically rely on troponin or electrocardiography (ECG), often unavailable in (low-resource) community-based healthcare settings. Purpose We evaluated the diagnostic performance of the HEART score in a low-risk setting when one of its five metrics is missing Methods We relied on data from two cohorts, OUT-ACS (n=1,711; for analyses with and without troponin) and TRACE (n=664; for analyses without troponin) of consecutive patients evaluated at primary care emergency clinics in respectively Norway (2016-2018; 47.7% female, median age: 56, 25th-75th percentiles:45-68) and the Netherlands (2017, 56.9% female, median age: 48, 25th-75th percentiles:32-67). We evaluated the HEAR score (all elements except troponin) and the HART score (all elements except ECG). The primary outcome was the diagnostic performance for ruling out myocardial infarction (MI) at index presentation, with a secondary outcome consisting of the composite of all-cause death or MI at 90-day follow-up. Results Among study participants, 61 (3.6%) were diagnosed with an MI in the OUT-ACS and 20 (3.0%) in the TRACE cohort. The percentages of patients deemed at low risk by HEAR (<=3) were 925 (54.1%) and 527 (79.4%) in OUT-ACS and TRACE, respectively. Sensitivity and specificity were 70.5% (95 % confidence interval 57.4-81.5) and 55.0% (52.5-57.4), and 75.0% (50.9-91.3) and 81.1% (77.8-84.0) for HEAR in the two respective cohorts. For the HART score, low risk was found in 696 (40.7%) OUT-ACS participants, with a respective sensitivity and specificity of 96.7% (88.7-99.6) and 42.1% (39.7-44.5), Positive predictive values ranged from 5.5-15.3%, whilst negative predictive values were 98.1-99.1% for HEAR and 99.7% for HART. By comparison, the HEART score determined 639 (37.3%) patients as low risk, had a sensitivity and specificity of 98.4% (91.2-100) and 38.7% (36.3-41.1), and positive and negative predictive values of 5.6% (5.3-5.9) and 99.8% (98.9-100). Similar findings were found for analyses using the secondary outcome. Conclusion HEART score variants in which troponin or ECG are omitted have higher efficiency but at the cost of decreased safety, particularly when leaving out troponin. Therefore, these biomarkers are paramount for adequate safety, despite the overall high negative predictive values in this low-prevalence primary care setting.

Clinical value of multiple sensors contributing to a composite heart failure ICD monitoring index

Abstract Background The HeartLogic algorithm integrates data from various implantable defibrillator (ICD) sensors to predict impending heart failure (HF) decompensation. The algorithm computes worsening in its sensors and weighs them based on a risk level. These sensors include accelerometer-based first (S1) and third (S3) heart sounds, intrathoracic impedance (TI), respiration rate (RR), the ratio of respiration rate to tidal volume (RSBI), and night heart rate (NHR). Objective This study assessed the relative worsening of ICD sensors at the onset of HeartLogic alerts, their association with patient characteristics and subsequent outcomes. Methods The HeartLogic feature was activated in 568 ICD patients (410 with CRT-D) across 26 centers, with a median follow-up of 26 months [25th–75th percentile: 16–37]. Results During the follow-up, 1200 HeartLogic alerts were recorded in 370 patients. The sensor with the highest worsening (SHW) at the alert onset was S3 (27% of alerts), followed by S3/S1 (25%), TI (16%), RR (15%), and NHR (11%), RSBI (6%). Patients with atrial fibrillation (AF) at implantation and those with chronic kidney disease (CKD) had higher alert prevalence (AF 84% vs. no-AF 58%, CKD 72% vs. no-CKD 59%; both p <0.05) and higher alert rates (AF 1.51/patient-year vs. no-AF 0.88/patient-year, CKD 1.30/patient-year vs. no-CKD 0.89/patient-year; both p <0.05). AF patients had alerts with every sensor as SHW, while CKD patients had alerts primarily with TI, RR, and RSBI as SHW (Figure). In 85% of cases among 247 patients with >1 alert, the SHW changed between successive alerts. Of the 88 (7%) alerts resulting in HF hospitalizations or deaths, a greater proportion featured RR or RSBI (11%) and NHR (11%) as SHW, followed by heart sounds (5%) (both p <0.05). Clinical events were more common with the first alert (12.6%) than subsequent alerts (5.2%, p <0.001). Conclusion HeartLogic alerts are predominantly associated with the highest worsening in heart sounds. Nevertheless, recurrent alerts often involve other sensors, suggesting varied HF progression mechanisms and potential divergent outcomes. The frequency of alerts and the pattern of worsening in ICD sensors are linked to patient characteristics.

Assessing adherence to remote monitoring recommendations for cardiovascular implantable electronic devices: a retrospective analysis

Abstract Background The recently published Expert Consensus Statement on the Practical Management of Remote Device Clinic offers evidence-based recommendations for managing patients with cardiovascular implantable electronic devices (CIEDs). Purpose This study evaluates adherence to remote monitoring (RM) recommendations in current clinical practice using data from a RM database. Methods According to RM guidelines, patient connectivity should be maintained. If continuous connection is ensured, it is reasonable to schedule in-person visits every 24 months, with alert-based RM potentially replacing structured intermittent device follow-up. Data from 6553 CIED patients followed on the LATITUDE (Boston Scientific) remote network at 26 Italian centers between 2010 and 2023 were analyzed. Median RM duration was 40 months (25th-75th percentile: 23-67). Results Enrollment of patients at centers significantly increased over the observation period (Figure). As of the January 2024 data extraction, 4723 patients had transmitted data in the last 12 months. Among these, 639 (14%) were NOT MONITORED (i.e. interrupted connectivity), with no significant differences among CIED types (Pacemaker: 13%; ICD: 12%; CRT-P: 7%; CRT-D: 13%; S-ICD: 18%). Scheduled device transmissions occurred at least once every 3 months in 96% of patients. The volume of in-office device interrogations and remote transmissions is detailed in Figure. In 2023, among the 4084 MONITORED patients, 6600 in-office device interrogations were conducted, and 64296 remote transmissions were reviewed. Of these, 34267 (53%) were scheduled, 15091 (24%) were patient-initiated, and only 14938 (23%) were triggered by alerts. Conclusions In current clinical practice, RM adoption is increasing, alongside the volume of in-office and remote visits. Solutions must be implemented to ensure transmission continuity in a substantial percentage of patients. Additionally, there persists a significant reliance on frequent scheduled transmissions and in-office visits. Centers stand to gain from implementing the guideline-recommended alert-based RM strategy, reducing the considerable burden of nonactionable remote and in-office visits among patients with continuous connectivity.

Postoperative heart valve infection, when and which bacteria: a nationwide cohort study

Abstract Background In patients undergoing heart valve surgery, subsequent bacteremia and infective endocarditis are feared events due to the associated high mortality. Knowledge on the incidence and specification of bacteremia following left-sided valve surgery are sparse and may have implications for prophylactic strategies and follow-up. Purpose To examine the six months incidence of bacteremia and infective endocarditis following left-sided heart valve surgery. Methods In the period from January 2010 to December 2021 all patients undergoing left-sided valve surgery were identified using Danish nationwide registries. Patients were followed until a maximum of six months, end of study, emigration, death, or outcome of interest (i.e., bacteremia or infective endocarditis). Cumulative incidence curves were computed with death as a competing risk stratified on bacterial species and for subgroups of interest: type of valve surgery, age, and sex. Results A total of 14,305 patients were included in the study. The majority of the study population were male (68.6%), and the median age was 70.2 years (25th-75th percentile 62.0-76.0 years). In total, 10,469 (73.2%) of the study population underwent aortic valve surgery, 3,497 (24.5%) underwent mitral valve surgery, while 339 (2.4%) underwent surgery on both valves. The cumulative incidence of bacteremia at six months of follow-up was 2.4% (95% CI 2.2-2.7%), Figure 1. For the overall study population, the most frequently occurring bacteremia was with Coagulase-negative Staphylococci (28%) and Staphylococcus aureus (14%). Within 30 days 0.35% of the patients had bacteremia with coagulase-negative staphylococci while this was 0.68% at six months of follow-up. For Staphylococcus aureus this was 0.19% and 0.34%, respectively. The cumulative incidence of infective endocarditis at six months of follow up was 1.0% (95% CI 0.8-1.2%). The majority of the infective endocarditis incidents were blood culture negative (27%) or caused by Enterococci (19%), Streptococci (17%) or Coagulase-negative Staphylococci (17%) while Staphylococcus aureus accounted for 14%. In crude analysis, simultaneous surgery on the mitral and aortic valve was associated with a statistically significant higher rate of bacteremia (P=0.004). Similarly, higher age was associated with a statistically significant higher rate of bacteremia (P<0.001). On the contrary, in crude analysis, no difference in the risk of bacteremia was found between sexes (P=0.9). Conclusions Bacteremia following left-sided heart valve surgery occurred in little over 2%. The majority was with Staphylococci, and half of these occurred within 30 days of the surgery. There is a continued need to optimize prophylactic strategies.

Long-term risk of heart failure and postoperative atrial fibrillation following noncardiac surgery: not so different from non-surgical atrial fibrillation

Abstract Background Atrial fibrillation (AF) is associated with the development of heart failure (HF). However, it is unclear if postoperative AF (POAF) after noncardiac surgery differs from non-surgical AF in terms of the risk of HF. Objectives To investigate the long-term rate of incident HF in patients developing new-onset POAF after noncardiac surgery relative to patients with non-surgical nonvalvular AF (NVAF). Methods Using Danish nationwide registries, all patients aged ≥30 years who developed POAF following noncardiac, nonobstetric surgery from 1996 to 2020 were identified. These patients were matched in a 1:3 ratio by age, sex, selected comorbidities, and year of inclusion with patients with non-surgical NVAF. The primary outcome was incident HF. Secondary outcomes were HF hospitalization and all-cause mortality. Results A total of 1,846 patients with POAF were matched with 5,538 patients with non-surgical NVAF (median age: 76 years [25th-75th percentile: 67-83 years]; 53.1% females). The median follow-up was 7.6 years. Compared with patients with non-surgical NVAF, patients with POAF did not have a significantly different rate of incident HF (2.7 versus 3.0 events per 100 person-years; HR 0.89 [95% CI, 0.78-1.03]) or HF hospitalization (2.2 versus 2.4 per 100 person-years; HR 0.88 [95% CI, 0.76-1.03]), but they had a higher rate of all-cause mortality (10.0 versus 8.7 per 100 person-years; HR 1.27 [95% CI, 1.18-1.37]) (Figure 1). Conclusions Patients with new-onset postoperative atrial fibrillation did not have a significantly different rate of incident heart failure or heart failure hospitalization, but they had a higher associated rate of all-cause mortality compared to patients with non-surgical atrial fibrillation. This finding suggests that postoperative atrial fibrillation may be regarded as non-surgical atrial fibrillation in terms of the long-term risk of heart failure. This highlights the importance of increased awareness among physicians of the risk of adverse outcomes, including heart failure, in patients with postoperative atrial fibrillation after noncardiac surgery. Closer postoperative follow-up and monitoring, as well as aggressive treatment of cardiovascular risk factors, may be warranted to reduce the risk of adverse outcomes in these patients.

Anthropometric measures and long-term mortality in heart failure with reduced ejection: debunking the obesity paradox

Abstract Background In patients with heart failure (HF), an "obesity-survival paradox" has been reported. Although body mass index (BMI) is the most commonly used anthropometric measure to assess adiposity, alternative indices such as the waist-to-height ratio may better reflect the location and amount of ectopic fat as well as the weight of the skeleton. Purpose To examine and compare the prognostic value of several alternative anthropometric measures with that of BMI in patients with non-ischemic HF with reduced ejection fraction (HFrEF) enrolled in the DANISH trial. Patients were eligible if they had non-ischemic HFEF, a left ventricular ejection fraction of <35%, New York Heart Association functional class II-III (IV if cardiac resynchronization therapy was planned), and elevated natriuretic peptides. The outcomes of interest were all-cause mortality and cardiovascular death. The association between anthropometric measures and all-cause death was examined with Cox regression models, adjusted for prognostic variables, including natriuretic peptides. Results Among 1,116 patients with non-ischemic HFrEF, there was no evidence for a BMI-related "obesity-survival paradox" during a median follow-up of 9.5 years (25th-75th percentile, 7.9-10.9 years). Indeed, compared to patients with a BMI 18.5-24.9 kg/m2 (N=363), those with a BMI >35 kg/m2 (N=91) had a significantly higher risk of all-cause death (HR 1.78 [95% CI 1.28-2.48]). Greater waist-to-height ratio (as an exemplar of indices not incorporating weight) was also associated with a higher risk of all-cause death, with a HR of 2.11 (95% CI, 1.53-2.92) for the highest quintile (N=205) compared with the lowest quintile (N=196). In the minimally adjusted restricted cubic spline models, the association between adiposity and all-cause death was more apparent for waist-to-height ratio than for BMI. A similar pattern was seen for cardiovascular death (Figure). Conclusion In patients with HFrEF, there was no evidence for an "obesity-survival paradox". Indeed, there was a clear association between adiposity and higher long-term mortality, which appeared to be stronger for waist-to-height ratio than for BMI. There is a need to test the potential benefits of intentional weight loss in patients with HFrEF and obesity.

Postoperative atrial fibrillation following noncardiac surgery is associated with long-term heart failure: insights from a nationwide cohort

Abstract Background Atrial fibrillation (AF) is associated with the development of heart failure (HF). Whether postoperative AF (POAF) also confers a greater risk of HF is unclear. Purpose To investigate the long-term rate of incident HF in patients developing new-onset POAF after noncardiac surgery relative to patients who did not develop POAF after noncardiac surgery. Methods In this cohort study, the Danish nationwide registries were used to identify all patients aged ≥30 years who developed POAF following noncardiac, nonobstetric surgery from 1996 to 2020. These patients were matched in a 1:3 ratio by age, sex, type of surgery, selected comorbidities, and year of inclusion with patients without POAF after noncardiac surgery. The primary outcome was incident HF. Secondary outcomes were HF hospitalization and all-cause mortality. Results A total of 2,270 patients with POAF were matched with 6,810 patients without POAF (median age: 75 years [25th-75th percentile: 67-82 years]; 53.5% females). The median follow-up was 7.2 years. Compared with patients without POAF, those with POAF had a higher associated long-term rate of incident HF (2.6 versus 1.2 events per 100 person-years; HR 2.39 [95% CI 2.06-2.78]]), HF hospitalization (2.2 versus 1.0 events per 100 person-years; HR 2.33 [95% CI 1.97-2.74]), and all-cause mortality (9.8 versus 7.4 events per 100-person-years; HR 1.55 [95% CI 1.45-1.66]) (Figure 1). Conclusions Patients with new-onset postoperative atrial fibrillation following noncardiac surgery had a higher associated long-term rate of incident heart failure compared to those without postoperative atrial fibrillation following noncardiac surgery. These findings highlight the importance of increased awareness among physicians of the risk of adverse outcomes, including heart failure, in patients with postoperative atrial fibrillation after noncardiac surgery. Closer postoperative follow-up and monitoring, as well as aggressive treatment of cardiovascular risk factors, may be warranted to reduce the risk of adverse outcomes in these patients.

Left Ventricular Ejection Fraction Change Following Percutaneous Coronary Intervention: Correlates and Association With Prognosis.

The association between left ventricular ejection fraction (LVEF) change (ΔLVEF) following percutaneous coronary intervention (PCI) and the long-term mortality rate in patients with coronary artery disease is incompletely investigated. We aimed to assess the impact of PCI on LVEF and the association of ΔLVEF after PCI with the long-term mortality rate. This observational study included 8181 patients with paired angiographic LVEF measurements performed at baseline and 6 to 8 months following the index PCI. ΔLVEF was defined as LVEF measured on the 6- to 8-month angiography minus LVEF measured on the baseline angiography. LVEF change was classified according to the following categories: reduced (ΔLVEF <0), mildly improved (ΔLVEF >0% to <10%) and largely improved (ΔLVEF ≥10%). The primary outcome was the 5-year mortality rate. In patients with baseline LVEF <40%, 40% to <50% and ≥50%, ΔLVEF (median [25th-75th percentiles]) was 6.0% [0.0% to 14.0%], 4.0% [-1.0% to 11.0%] and 0.0% [-4.0% to 3.0%], respectively (P<0.001). In patients with reduced, mildly improved, and largely improved ΔLVEF, the 5-year mortality rate (n=712) was 29.1%, 23.1%, and 16.5%, respectively, in patients with baseline LVEF <40%; 17.0%, 12.2% and 9.8%, respectively, in patients with baseline LVEF 40% to <50%; and 7.8%, 7.1%, and 5.6%, respectively, in patients with baseline LVEF ≥50% (adjusted hazard ratio [HR], 0.91 [95% CI, 0.86-0.96]; P<0.001) for all-cause death and adjusted (HR, 0.86 [95% CI, 0.81-0.92]; P<0.001) for cardiac death, calculated for 5% higher ΔLVEF. In patients with coronary artery disease undergoing PCI, improvement of LVEF following PCI was associated with a reduced long-term mortality rate in patients with reduced LVEF but not in patients with preserved LVEF before intervention.

Anti-HBs Seroprevalence in Blood Donors from Tyrol, Austria.

Background/Objectives: Antibodies against the hepatitis B surface antigen (anti-HBs) are a marker of immunity against hepatitis B virus (HBV) infections. There is uncertainty about the anti-HBs seroprevalence in the general population of Austria. Methods: We conducted a cross-sectional analysis in blood donors from the Federal State of Tyrol in Austria (August-September 2023) to estimate anti-HBs seroprevalence and median antibody levels. Results: We enrolled 3935 blood donors (median age 47.6 years [25th-75th percentile: 33.3-56.6]; 40.7% female), who were hepatitis B surface antigen negative and had no detectable HBV-DNA. Overall seroprevalence was 51.4% (95% CI: 49.8-52.9%). Anti-HBs seropositivity decreased with higher age (p < 0.001), with 70.3% (66.1-74.3%) being seropositive among participants < 25 years of age and 30.2% (24.2-36.9%) in those aged ≥ 65 years. More females than males were seropositive (54.3% [51.8-56.7%] vs. 49.4% [47.4-51.4%]; p = 0.003). Seroprevalence was significantly higher in urban than in rural areas in participants aged 40 to <55 (p = 0.045) and ≥55 years (p = 0.001). Among 2022 seropositive participants, the overall median anti-HBs antibody level was 539.3 IU/L (25th-75th percentile: 116.3-5417.0). Furthermore, 5% of the participants had an anti-HBs antibody level between 10 and <20 IU/L, 18% between 20 and <100 IU/L, and 77% ≥100 IU/L. Conclusions: Anti-HBs seroprevalence in blood donors from Tyrol, Austria, was 51.4% between August and September 2023 and differed across age, sex, and residence area. Catch-up vaccination programs, especially targeting the elderly living in rural areas, are needed to close HBV immunity gaps.

A new frontier in biostatistics: evaluating the accuracy of ChatGPT-4 vs. R in analysing liver resection data

Background The rise of ChatGPT-4’s Data Analyst tool presents a new frontier for biostatistical computations. This study evaluates the reliability and improvements of ChatGPT-4 Data Analyst tool by comparing it to R package in performing biostatistical analysis on liver surgery patients. Methods Utilizing data from LiverGroup.org, we conducted our comparative study between October 2023 and March 2024. The variables analyzed by the R package and ChatGPT-4 Data Analyst included age, sex, hospital stay duration, income group, and mortality. Analysis on ChatGPT-4 were performed using two methods: a holistic prompt which included all-at-once analysis were requested and segmented prompts, one-by-one test request for analysis. After the analysis figures were requested from ChatGPT-4, comparison with R package figures was done. Results Descriptive analysis including N (%), Standard Deviation, and (25th–75th Percentile) were consistent between ChatGPT-4 March version and R with a minor variation in the holistic approach on the analysis performed in October. The inferential statistical results of ChatGPT-4 showed inconsistencies in October 2023 while March 2024 revealed accurate results with Crosstabulations, Kruskal Wallis, Wilcoxon Rank Sum, T-test, Pearson’s Chi-squared, and Fisher’s Exact test p-value. ChatGPT-4 March 2024 version was able to inform the user with possible inaccuracies in certain tests (Mann-Whitney U Test: Hospital stay vs mortality p value, Levene’s Test p-value: Age vs mortality, and Fisher’s Exact Test: Odds ratio gender vs. mortality 95% CI). The survival curve and box-and-whisker plot generated by ChatGPT-4 in March 2024 matched those generated by R package except for the CI of survival curve. Conclusions The high accuracy of ChatGPT-4 in certain biostatistical analysis has reached the point where it can replace established statistical software like R for some purposes. Artificial intelligence tools show significant promise but should still be used in conjunction with traditional methods to ensure precision in complex analysis. Consensus on the use of these tools is needed by the scientific community.

12566 Adult Growth Hormone Deficiency, Replacement Therapy Use, and IGF1 Levels in Association with Physical, Psychosocial, and Neurocognitive Outcomes Among Childhood Cancer Survivors

Abstract Disclosure: T. Yoshida: None. J.L. Baedke: None. H. Wang: None. C.H. Yu: None. C.L. Wilson: None. D.A. Mulrooney: None. S.B. Dixon: None. I. Huang: None. T.M. Brinkman: None. K.R. Krull: None. S. Mostoufi-Moab: None. J. Miguel Martínez: None. K.K. Ness: None. M.M. Hudson: None. Y. Yasui: None. A. Delaney: None. Background: Adult growth hormone deficiency (aGHD) is a common and often untreated late effect among childhood cancer survivors. Untreated aGHD likely adds to the burden of health outcomes in survivors already experiencing cancer treatment related late toxicities. As comprehensive data on the consequences of untreated aGHD in survivors are scarce, we assessed the clinical impact of untreated aGHD among survivors, together with socioeconomic factors as potential contributing factors, utilizing a large, clinically characterized cohort of childhood cancer survivors. Methods: 3902 five-year survivors ≥ 18 years old [median (25th-75th percentile) age, 31.7y (25.2-40.0); age at cancer diagnosis 8.1y (3.5-13.6); 47.5% female] were examined. We assessed the: 1) proportion of survivors with aGHD on GH therapy (GHT); 2) association between GHT and socioeconomic factors (e.g., household income, area deprivation index) by multivariable logistic regression; and 3) associations between age- and sex-adjusted insulin-like growth factor 1 (IGF1) z-score and prevalence of clinically-assessed (i.e., body composition, metabolic/cardiovascular factors, neurocognitive function) and self-reported [i.e., quality of life (QoL), emotional symptom] outcomes by multivariable logistic regression with trend test, adjusting for potential confounders (e.g., radiation to the hypothalamic-pituitary region). Results: aGHD was observed in 9.1% (354/3902) of survivors; among them, 9.0% (32/354) were on GHT. Survivors on GHT were more likely to have higher household income, hold health insurance, and reside in less socioeconomically disadvantaged neighborhoods, compared to survivors with untreated aGHD. Socioeconomic factors had significant independent associations with GHT use in multivariable analysis [e.g., annual household income &amp;lt;$40,000 vs. ≥$80,000, adjusted odds ratio (aOR) of GHT use, 0.28; 95% confidence interval (CI), 0.08-0.86]. Lower IGF1 z-score (IGF1 z-score ≤ -2, vs. IGF1 z-score &amp;gt;0) was associated with a higher prevalence of various outcomes (aOR, 95% CI), such as abdominal obesity (2.56, 1.98-5.26), weak handgrip strength (2.49, 1.65-3.73), hypertension (1.47, 1.06-2.04), abnormal glucose metabolism (2.07, 1.49-2.86), impaired health-related QoL (e.g., physical functioning, 1.97, 1.35-2.86), depression (1.58, 1.06-2.33), and impairment in multiple neurocognitive functions (e.g., verbal reasoning, a global measure of intelligence, 2.22, 1.49-3.30) with a dose-response relationship. Conclusions: Our data support a negative impact of untreated aGHD on physical, psychosocial, and neurocognitive outcomes among survivors and suggest the potential of GHT to improve QoL of survivors with aGHD. As lower socioeconomic status may affect survivors’ access to GHT, this disparity should be considered in interventions evaluating GHT for survivors with aGHD. Presentation: 6/3/2024

Unequal smiles: consequences of untreated dental caries in citizens living in vulnerable circumstances in the Netherlands: an exploratory pilot study.

The often poor oral health status of socioeconomically vulnerable adults is widely recognised. Nevertheless, research on it is scarce. To address this gap, this exploratory pilot study aimed to report on the prevalence of untreated caries and its clinical odontogenic consequences, as well as the associated Oral Health Related Quality of Life (OHRQoL) in a marginalised adult Dutch population. The Dutch department of Médecins du Monde (Doctors of the World) included socioeconomically vulnerable (low socioeconomic position [SEP]) adults in the Netherlands through community organisations. The validated Deprivation in Primary Care Questionnaire (DiPCare-Q) was translated in Dutch and used to characterise the SEP of the population. To document untreated caries and severe odontogenic consequences, the DMFT (Decayed, Missing, Filled Permanent Teeth) and PUFA (Pulpal, Fistula, Ulceration, Abscess) index were used. The validated Dutch Oral Health Impact Profile questionnaire (OHIP-14) was used to document the impact of these issues on OHRQoL. Data analysis was conducted in SPSS® (Statistical Package for the Social Sciences) statistics (Kruskal-Wallis, Mann-Whitney-U-test) and STATA software. Data from 59 adult participants were analysed. The prevalence of untreated caries (DT ≥ 1) was 65.5%, 57.9% of which experienced severe odontogenic consequences (DT+PUFA). The prevalence of severe odontogenic consequences (PUFA ≥ 1) was 45.5%. The mean OHIP-14 score of 17.7 ± 13.4 (25th-75th percentile: 6-26) illustrated that untreated caries may have impact on OHRQoL. Individuals who experienced any severe odontogenic consequences from untreated caries reported significantly higher OHIP-14 scores (mean ± s.d.: 21.8 ± 14.8 vs.11.1 ± 7.2). The untreated caries and severe odontogenic consequences seen in a large number of the socioeconomically vulnerable adult participants seemed to have an impact on OHRQoL. These findings emphasise the urgency of including these adults in the professional oral health system for treatment and prevention, and may emphasise the necessity of improving the socioeconomic circumstances of this population. Further exploration of the exact barriers and facilitators to oral healthcare access for socioeconomically vulnerable adults is necessary.

A-023 Early Concentrations of Long Cardiac Troponin T Forms in Myocardial Infarction Patients

Abstract Background Long forms of cardiac troponin T (cTnT) represent a new promising biomarker for more specific diagnostics of myocardial infarction (MI). We studied for the first time the concentrations of long cTnT forms in a panel including very early samples of type 1 MI patients. Methods Heparin plasma samples were drawn from 94 type 1 MI patients 0.4-24 h after the symptom onset and analyzed with Roche hs-cTnT assay and with our novel highly sensitive upconversion luminescence-based long cTnT immunoassay. The long cTnT assay detects all cTnT forms not cleaved at the major C-terminal cleavage site at cTnT amino acid residues 189-220 while the Roche hs-cTnT assay detects all short and long cTnT forms containing the stable central part of cTnT. Troponin ratio, reflecting the fraction of the long cTnT forms, was calculated by dividing the long cTnT result by the Roche hs-cTnT result. Results The long cTnT and Roche hs-cTnT concentrations varied highly (median 107 [25th-75th percentile 20-1195] ng/L and 277 [62-1422] ng/L, respectively) and correlated significantly with each other (r=0.881, p&amp;lt;0.001). Neither had a significant correlation with time from symptom onset. Troponin ratio was highly variable especially at the first hours, but there was a clear decreasing trend in variability later (Figure). Troponin ratio showed significant negative correlation with time (r=-0.284, p=0.005) and the correlation became stronger with longer delays between symptom onset and sampling (6-24 h, r=-0.422, p&amp;lt;0.001). Conclusions A significant portion of circulating cTnT is in long forms in type 1 acute MI patients at early stage. The fraction of long cTnT forms is highly variable in the very early hours after MI, but shows a clear decreasing trend after 6 hours from the pain onset.

Lipomatous Metaplasia Facilitates Ventricular Tachycardia in Patients WithNonischemic Cardiomyopathy.

Ventricular tachycardia (VT) substrate in patients with nonischemic cardiomyopathy (NICM) is complex in distribution and intramural location. This study sought to test the hypothesis that myocardial lipomatous metaplasia (LM) is a vital anatomic substrate for VT corridors in patients with NICM and VT, and that LM stabilizes current propagation in VT corridors. Among 49 patients with NICM in the 2-center INFINITY (Prospective Intra-Myocardial Fat Deposition and Ventricular Tachycardia in Cardiomyopathy) Study, potential VT viable corridors within the myocardial scar and/or LM were computed from late gadolinium enhancement cardiac magnetic resonance images and were registered with electroanatomical maps. Corridors passing through VT entrance, isthmus, and/or exit sites, estimated by entrainment or pace mapping, were defined as VT corridors. LM was separately distinguished from scar using computed tomography. The SD of current amplitude along each corridor was measured. Compared with 151 non-VT corridors, 35 VT corridors traversed a substantially higher volume of LM, with a median 236.6mg (IQR: 13.5-903.4mg) vs 5.8mg (IQR: 0.0-57.9mg) (P< 0.001). Among corridors with computable current amplitude, 28 VT corridors exhibited substantially lower current variation along the corridors, with SD 8.0 μA (25th-75th percentile: 6.1-10.3 μA) vs 14.9 μA (25th-75th percentile: 8.5-23.7 μA) among 71 non-VT corridors (P<0.001). Individual VT circuit sites (95 out 118) were highly colocalized with LM. VT circuitry corridors in NICM are more likely to traverse LM and exhibit reduced current amplitude variation compared with bystander corridors.

NT-proBNP and Cardiac Troponin I, but Not Cardiac Troponin T, Are Associated With 7-Year Changes in Cardiac Structure and Function in Older Adults: The ARIC Study.

Higher circulating concentrations of NT-proBNP (N-terminal pro-B-type natriuretic peptide) and high-sensitivity cardiac troponin T (hs-cTnT) and I (hs-cTnI) are associated with left ventricular remodeling and with incident heart failure. The associations of these cardiac biomarkers with changes in cardiac structure and function over time are uncharacterized. Among 2006 participants in the ARIC prospective cohort study (Atherosclerosis Risk in Communities) who were free of overt cardiovascular disease and underwent echocardiography at study visits 5 (2011- 2013) and 7 (2018-2019), we assessed the associations of NT-proBNP, hs-cTnT, and hs-cTnI concentrations at visit 5 with changes in left ventricular structure and function between visits 5 and 7 (≈7-year change) using multivariable linear regression with the biomarkers modeled as restricted cubic splines. Models were adjusted for age, sex, race, body mass index, smoking, diabetes, hypertension, and renal function at visit 5; blood pressure and heart rate at both visits; and the baseline value of the echocardiographic parameter of interest. Mean±SD age was 74±4 years at visit 5; 61% were women; and 23% were Black adults. Median (25th-75th percentile) concentrations at visit 5 of NT-proBNP, hs-cTnT, and hs-cTnI were 87 ng/L (50-157 ng/L), 9 ng/L (6-12 ng/L), and 2.6 ng/L (1.9-3.9 ng/L). In adjusted models, elevated baseline concentrations of NT-proBNP and hs-cTnI were significantly associated with 7-year decline in left ventricular systolic function (ejection fraction, longitudinal and circumferential strain) and worsening diastolic indices. In contrast, elevated baseline concentrations of hs-cTnT were not significantly associated with 7-year changes in cardiac structure, systolic function, or diastolic function (all P>0.05). Higher concentrations of NT-proBNP and hs-cTnI, but not hs-cTnT, were associated with greater declines in left ventricular function over ≈7 years in late life independently of traditional cardiovascular risk factors.AQ.

Association of Disease-Modifying Treatment With Outcome in Patients With Relapsing Multiple Sclerosis and Isolated MRI Activity.

Isolated value of MRI metrics in relapsing multiple sclerosis (RMS) as a surrogate marker of response to disease-modifying treatment (DMT) and, thus, as decision criteria for DMT escalation in the absence of clinical signs of disease activity is still a matter of debate. The aim of this study was to investigate whether DMT escalation based on isolated MRI activity affects clinical outcome. Combining data from 5 MS centers in Austria and Switzerland, we included patients with RMS aged at least 18 years who (1) had initiated first-line, low-to-moderate-efficacy DMT (interferon β, glatiramer acetate, teriflunomide, or dimethyl fumarate) continued for ≥12 months, (2) were clinically stable (no relapses or disability progression) on DMT for 12 months, (3) had MRI at baseline and after 12 months on DMT, and (4) had available clinical follow-up for ≥2 years after the second MRI. The primary endpoint was occurrence of relapse during follow-up. The number of new T2 lesions (T2L) and DMT strategy (continuing low-/moderate-efficacy DMT vs escalating DMT) were used as covariates in regression analyses. A total of 131 patients with RMS, median age of 36 (25th-75th percentiles: 29-43) years, 73% women, were included and observed over a median period of 6 (5-9) years after second MRI. Sixty-two (47%) patients had relapse. Patients who continued first-line DMT had a 3-fold increased risk of relapse given 2 new T2L (hazard ratio [HR] 3.2, lower limit [LL] of 95% CI: 1.5) and a 4-fold increased risk given ≥3 new T2L (HR 4.0, LL-CI: 2.1). Escalation of DMT lowered the risk of relapse in patients with 2 new T2L by approximately 80% (HR 0.2, upper limit [UL] of 95% CI: 1.3) and with ≥3 new T2L by 70% (HR 0.3, UL-CI: 0.8). In case of only 1 new T2L, the increased risk of relapse and the treatment effect did not reach statistical significance of 5%. In our real-world cohort of patients clinically stable under low-to-moderate-efficacy DMT, escalation of DMT based on isolated MRI activity decreased risk of further relapse when at least 2 new T2L had occurred. This study provides Class III evidence that clinically stable patients with MS on low-/moderate-efficacy DMT with ≥3 new T2L on MRI who escalate DMT have a reduced risk of relapse and Expanded Disability Status Scale progression.