Risk Cohort Research Articles

Evaluation of a Machine Learning-Guided Strategy for Elevated Lipoprotein(a) Screening in Health Systems.

While universal screening for Lp(a; lipoprotein[a]) is increasingly recommended, <0.5% of patients undergo Lp(a) testing. Here, we assessed the feasibility of deploying Algorithmic Risk Inspection for Screening Elevated Lp(a; ARISE), a validated machine learning tool, to health system electronic health records to increase the yield of Lp(a) testing. We randomly sampled 100 000 patients from the Yale-New Haven Health System to evaluate the feasibility of ARISE deployment. We also evaluated Lp(a)-tested populations in the Yale-New Haven Health System (n=7981) and the Vanderbilt University Medical Center (n=10 635) to assess the association of ARISE scores with elevated Lp(a). To compare the representativeness of the Lp(a)-tested population, we included 456 815 participants from the UK Biobank and 23 280 from 3 US-based cohorts of Atherosclerosis Risk in Communities, Coronary Artery Risk Development in Young Adults, and Multi-Ethnic Study of Atherosclerosis. Among 100 000 randomly selected Yale-New Haven Health System patients, 413 (0.4%) had undergone Lp(a) measurement. ARISE scores could be computed for 31 586 patients based on existing data, identifying 2376 (7.5%) patients with a high probability of elevated Lp(a). A positive ARISE score was associated with significantly higher odds of elevated Lp(a) in the Yale-New Haven Health System (odds ratio, 1.87 [95% CI, 1.65-2.12]) and the Vanderbilt University Medical Center (odds ratio, 1.41 [95% CI, 1.24-1.60]). The Lp(a)-tested population significantly differed from other study cohorts in terms of ARISE features. We demonstrate the feasibility of deployment of ARISE in US health systems to define the risk of elevated Lp(a), enabling a high-yield testing strategy. We also confirm the low adoption of Lp(a) testing, which is also being restricted to a highly selected population.

Caregiver report of infant behavior associated with autism likelihood in first year of life.

Identification of prodromal indicators of autism in infancy has the potential to identify behaviors relevant to early autism screening. We report on data from a prospective general population birth cohort with maternal reported measures at 9 and 12 months: the Survey of Well-Being of Young Children (SWYC; general developmental surveillance) and the First Year Inventory-Lite v3.1b (FYI-Lite; autism specific parent report research tool). Mothers completed the surveys and the Broad Autism Phenotype Questionnaire (BAPQ), a self-report measure of subclinical features of autism. In this sample of 332 infants (168 males), maternal-reported infant developmental milestones and behavioral indicators of difficult temperament, poor adaptability, and sleep problems at 9 months (SWYC) and maternal self-reported subclinical autism characteristics (BAPQ) were correlated with maternal-reported autism-related behaviors on the FYI-Lite at 12 months. Regression models revealed significant unique associations between infant temperament, developmental milestones, and FYI-Lite scores while controlling for significant effects of maternal BAPQ scores and education. Maternal report of infant temperament and developmental milestones at 9 months were associated with maternal-report early indicators of autism likelihood at 12 months in a general birth cohort. Follow up of this cohort is needed to determine associations with formal diagnostic outcomes. Identifying scalable measures of infant behaviors in general and specific to autism may help identify targets of intervention for infants in the first year of life. This study aims to contribute to improved first-year surveillance by assessing potential early autism indicators in a prospective general birth cohort, whereas other observational studies utilize enriched risk cohorts (e.g., infant siblings of autistic children). Preliminary findings of this cohort revealed that a maternal report of 9-month temperament significantly predicted higher scores on a maternal report 12-month autism screener and indicated the importance of considering maternal self-reported subclinical autism characteristics when interpreting parent report screeners.

Acute Myeloid Leukemia with Normal Cytogenetics and NPM1-Mutation: Impact of Mutation Topography on Outcomes.

Background: About half of adults with acute myeloid leukemia with normal cytogenetics (CN-AML) have NPM1 mutations. There is controversy regarding their prognosis and best therapy. Methods: We studied 150 subjects with these features using targeted regional sequencing. Prognostic stratification was carried out based on risk factors, and we assessed the effects of two post-remission strategies with and without transplant across risk cohorts. Results: In multi-variable analyses, a positive MRD test after the second consolidation cycle (HR = 6.00; 95% CI [3.31, 10.85]; p < 0.001), DNMT3A mutations (HR = 3.01 [1.57, 5.78]; p < 0.001), FLT3-ITD mutation with high variant allele frequency (HR = 4.40 [1.89, 10.24]; p < 0.001) and DDX11 mutations (HR = 4.38 [2.38, 8.04]; p < 0.001) were independently correlated with higher cumulative incidence of relapse (CIR) and worse leukemia-free survival (LFS) (HR = 5.49 [3.01, 10.04]; p < 0.001; HR = 2.99 [1.60, 5.62]; p < 0.001; HR = 4.20 [1.87, 9.40]; p < 0.001; and HR = 4.22, 95% CI [1.99, 8.95], p < 0.001). Subjects with ≥1 high-risk co-variate who received a transplant had a lower CIR and better LFS, whereas others did not. Conclusions: We identified co-variates associated with CIR and LFS in subjects of NPM1-mutated CN-AML.

Follow up of clinical outcomes in type 1 diabetic patients according to the results of dynamic examination in the mobile center "Diamobil"

Background. Type 1 diabetes mellitus (T1DM) is a severe disease associated with reduced life expectancy. Understanding the causes and methods of reducing risks for this cohort is highly relevant for developing measures to reduce the number of years lost. Aim. To assess clinical outcomes: the frequency of diabetic complications, structure of mortality among T1DM patients who were examined at dynamic examination in the mobile center "Diamobil" in the Arkhangelsk region in 2005 and 2023. Materials and methods. The study was conducted on a cohort of patients with T1DM, examined at "Diamobil" in Arkhangelsk region in 2005 (n=319), with dynamic follow up of vital and clinical status, clinical parameters and frequency of complications over an 18-year period. At 2023, out of 319 people in the primary cohort – 61 patients died, 206 were in "alive" status and 52 were removed from analysis. Statistical analysis is performed with the help of Statistics v.13.3. Results. In the dynamic cohort (n=206) at 2023 median age of patients was 40 years [34; 55], duration of DM – 28 years [24; 33], percentage of women – 55%. Compared to 2005, glycated hemoglobin was comparable, there were an increase in body mass index (21.9 kg/m2 vs 25.1 kg/m2) and obesity rate from 3.1 to 11.2% (p=0.006), a decrease in estimated glomerular filtration rate (103.1 ml/min/1.73 mm2 vs 86.4 ml/min/1.73 mm2; p0.001) and increased frequency of diabetic complications: chronic kidney disease (CKD) any stage from 24.9 to 69.4%, Stage 3a CKD from 0.5 to 7.4% (p=0.003), diabetic retinopathy from 26.4 to 74.6%, diabetic neuropathy from 25.9 to 78.2% (p0.001), which reflects the long-term effect of the hyperglycemia factor. Based on the results of the analysis of mortality structure by proximal cause, it was established that the most frequent causes of death were cardiovascular disease – myocardial infarction, acute cerebral circulation disorder, heart failure and other cardiovascular diseases – 42.6%; death due to hypoglycemic and ketoacidotic coma – 3.2%, terminal cardiovascular disease – 14.8%. Deceased patients were characterized by a longer duration of DM (13 years vs 8 years), higher glycated hemoglobin (9.4% vs 8.4%), lipid profile (total cholesterol 4.77 mmol/l vs 4.41 mmol/l; TG 1.31 mmol/l vs 0.98 mmol/l) and albuminuria (70 mg/mmol vs 6 mg/mmol; p0.001). Conclusion. "Diamobil" control epidemiological studies can be positioned as the optimal method of risk cohort survey coverage for the assessment of dynamic indicators in real clinical practice.

Social connection and its prospective association with adolescent internalising and externalising symptoms: an exploratory cross-country study using retrospective harmonisation.

Social connection factors play a key role for young people's mental health. It is important to understand how their influence may vary across contexts. We investigated structural (e.g. household size), functional (e.g. social support) and quality (e.g. feeling close) social connection factors in relation to adolescent internalising and externalising symptoms, comparing two countries Brazil and the United Kingdom (UK). We pooled data from the UK Millennium Cohort Study (MCS) and the Brazilian High Risk Cohort Study (BHRCS). We included 12 social connection variables, identified through retrospective harmonisation and lived experience expert involvement. We tested measurement invariance and conducted multiple regressions to analyse associations between the social connection factors (age 14) and later internalising and externalising difficulties (age 17.5) in both cohorts. We investigated country-level interactions and used weights to account for attrition, survey design, population representativeness and sample size. We found pooled main associations with later internalising symptoms for 'living with half-siblings' (p < .001), 'moving address' (p = .001), 'mother marital status' (p < .001-.003), 'bullying' (p = .001), 'being bullied' (p < .001) and 'difficulties keeping friends' (p < .001). For externalising, we found main associations with 'household size' (p = .041), 'moving address' (p = .041), 'mother's marital status' (p = .001-.013), 'bullying others' (p < .001) and 'being bullied' (p < .001). Country-level interactions suggested higher internalising symptoms were associated with 'household size' (p = .001) in Brazil and 'being bullied' (p < .001) in MCS. Additionally, 'half-siblings in household' (p = .003), 'poor mother-child relationship' (p = .018), 'single mother' (p = .035), 'bullying' (p < .001) and 'being bullied' (p < .001) were more strongly linked to externalising difficulties in MCS. Social connection factors, mostly structural, contributed to adolescent internalising and externalising difficulties in both countries. Factors relating to bullying and family composition seem to play a stronger role in each country. Cultural and socioeconomic factors might explain these differences. Future research should investigate cross-regional differences to meaningfully inform global mental health efforts.

The POINTER Imaging baseline cohort: Associations between multimodal neuroimaging biomarkers, cardiovascular health, and cognition.

The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) is evaluating lifestyle interventions in older adults at risk for cognitive decline and dementia. Here we characterize the baseline data set of the POINTER Imaging ancillary study. Participants underwent health and cognitive assessments and neuroimaging with multimodal positron emission tomography (PET) (beta-amyloid [Aβ] and tau) and magnetic resonance imaging (MRI). Framingham risk score (FRS) was used to quantify cardiovascular disease (CVD) risk. A total of 1052 participants (31% from underrepresented ethnoracial groups) were enrolled. Compared to Aβ-, Aβ+ (29%) participants were older, had higher apolipoprotein E (APOE) ε4 carriage rate and white matter hyperintensity volume, and greater temporal tau. FRS was related to MRI measures, but not AD biomarkers. FRS and tau had independent effects on cognition. In this heterogenous, at-risk cohort, CVD risk was related to more abnormal brain structure and poorer cognition, representing a putative non-AD (Alzheimer's disease) pathway to brain injury and cognitive decline. ·The U.S. Study to Protect Brain Health Through Lifestyle Intervention to Reduce Risk (U.S. POINTER) cohort is enriched for cardiovascular disease (CVD) and poor lifestyle ·POINTER Imaging collected multimodal neuroimaging data in this unique, at-risk cohort ·Amyloid burden was related to age, apolipoprotein E (APOE) ε4 carriage, and measures of disease progression ·Associations between amyloid and tau, and tau and cognition, were relatively weak ·CVD risk and tau pathology were independently related to memory.

Enhanced neurobiological biomarker differentiation for attention-deficit/hyperactivity disorder through a risk-informed design.

Translation of biomarkers to clinical practice is hindered by the significant overlap in neurobiological measures between ADHD cases and controls. A risk-informed design can enhance the utility and validation of ADHD biomarkers by highlighting differences between individuals with ADHD and those without at differential risk. Participants were 2511 children and adolescents (aged 6 to 14 years) from the Brazilian High Risk Cohort for Mental Conditions. We calculated risk for ADHD among unaffected individuals using a multivariable clinical and sociodemographic risk model. We compared measures of three proposed ADHD biomarkers (polygenic scores, subcortical volumes, and executive function) between participants with vs. without ADHD, and ADHD vs. without ADHD with a high- vs. low-risk loading for ADHD. Compared to the unaffected group, children and adolescents with ADHD had higher ADHD polygenic scores (cohen's d = 0.17), smaller subcortical volumes (d = - 0.25), and poorer executive function (d = - 0.22). Separating the unaffected group into low- and high-risk subgroups revealed more pronounced differences (Cohen's d = 0.20 to 0.60) and nearly doubled the overlap-free area for these three neurobiological measures between the low-risk group and the other two groups. Upon adjustment for the number of ADHD symptoms, simple ADHD vs. without ADHD differences vanished, while the risk-informed analyses remained significant. Here, we demonstrate that a risk-based design increases effect sizes when comparing candidate biomarkers for ADHD. Our study provides a model that may hold promise for evaluating similar contrasts in other mental disorders and samples.

Performance of clinical decision aids (CDA) for the care of young febrile infants: a multicentre prospective cohort study conducted in the UK and Ireland

Between 1% and 4% of febrile infants, aged from birth to 90 days of age, presenting to hospital will be diagnosed with an invasive bacterial infection (IBI). Traditional teaching has advocated a treat all approach but more recently a number of clinical decision aids (CDA) have been developed to classify febrile infants into lower and higher risk cohorts, with lower risk infants suitable for management without immediate parenteral antibiotics and lumbar puncture. The aim of this study was to apply these CDA to a UK and Irish cohort. This was a prospective multicentre cohort study of febrile infants presenting to 35 Paediatric Emergency Research in the UK and Ireland (PERUKI) sites between the 6th July 2022 and the 31st August 2023. All infants received standard care as per local policy. IBI was defined as growth of bacterial pathogen in blood or cerebrospinal fluid. The performance of the following CDAs were assessed, National Institute for Health and Care Excellence (NICE) guidelines NG143 (Fever under 5 years), British Society Antimicrobial Chemotherapy (BSAC), Aronson rule and American Academy of Pediatrics (AAP) CDA. A cost comparison of each CDA against a treat all approach was conducted. Trial registration: NCT05259683. 1821 were included in the final analysis. The median age was 46 days (IQR: 30-64 days), with 1108 (61%) being male. Of the 1821 infants, 67 (3.7%) had IBI. The AAP and BSAC CDAs were the most sensitive at 0.99 (95% CI 0.92-1.0) for both with specificities of 0.23 (95% CI 0.21-0.25) and 0.20 (95% CI 0.18-0.22) respectively. The NICE NG143 and Aronson CDA were the most specific CDAs with values of 0.27 (95% CI 0.25-0.30) and 0.30 (95% CI 0.28-0.32) respectively, but their sensitivity was lower. The AAP CDA performed equally well with either procalcitonin (PCT) or C-reactive protein (CRP) as the biomarker of choice. Of the 1821 infants, 77% were admitted, 14% were discharged and 9% were ambulated. All CDAs were cost saving for hospital services when compared to a treat all approach, with the lowest mean cost per patient estimated for Aronson (£1171; bootstrap 95% CI £1129-£1214) and NICE NG143 CDA (£1218; bootstrap 95% CI £1174-£1263). The AAP and BSAC CDAs are highly sensitive at excluding IBI, with a cost saving to hospital services when compared to a treat all approach. The substitution of CRP for PCT made no difference to the performance of the AAP CDA in this cohort and was more costly. The Febrile Infant Diagnostic Assessment and Outcome (FIDO) study is funded by Royal College of Emergency Medicine Doctoral Fellowship (RCEM 02/03/2021). Procalcitonin analysis was supported by the Public Health Agency Northen Ireland Grant (HSC R&D-COM/5745/22). The funders played no part in the conception or design of this study.

Longitudinal history of mammographic breast density and breast cancer risk by familial risk, menopausal status, and initial mammographic density level in a high risk cohort: a nested case–control study

BackgroundElevated mammographic density is associated with increased breast cancer risk. However, the contribution of longitudinal changes in mammographic density to breast cancer risk beyond initial mammographic density levels, considering familial breast cancer risk and menopausal status, remains uncertain but holds important clinical implications.MethodsIn a nested case–control study within the Sister Study (323 cases, 899 controls; 12,095 mammograms), a cohort enriched for family history of breast cancer, we examined case–control status in relation to the largest annual change in percent density and dense area using mammograms available spanning 5.4 years, on average, using multivariable logistic regression and to the rate of mammographic density change using linear mixed-effects models. We considered effect modification by: mammographic density level of the earlier mammogram, the extent of family history, Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation (BOADICEA) risk strata, and menopausal status.ResultsCases (diagnosed < 60 years) had greater initial percent density and dense area levels and a slower rate of decline in dense area than controls. Women with stable mammographic density (≤ 10% annual change) had an increased breast cancer risk as compared with women whose largest mammographic density change was > 10% annual decline (e.g., Odds Ratio (OR) 2.34, 95% Confidence Interval (CI) 1.63–3.37 for dense area). Increasing vs. decreasing dense area was also associated with elevated risk, especially in women with the highest dense area levels at the earlier mammogram (OR: 2.56, 95%CI 1.50–4.36). Although generally similar across menopausal and familial risk categories, the associations of MD change with risk appeared stronger in pre-menopausal and lower-risk women.ConclusionsWomen who maintain higher levels of mammographic density (i.e. do not decrease over time) or have increasing mammographic density over time have a higher risk of subsequent breast cancer than women with high mammographic density that decreases over time. These findings suggest potential for incorporating mammographic density trajectories in clinical risk assessment, and the importance of additional breast cancer monitoring in women not experiencing declines in mammographic density over time.

Utilization of preoperative EOS imaging to prevent adverse events following total hip arthroplasty

ABSTRACT Introduction Previous studies have demonstrated the use of technology in total hip arthroplasty (THA) provided favorable outcomes. This study sought to describe the effect preoperative two-dimensional low-dose (2DLD) full-body radiographs had on the prevention of adverse outcomes following THA. Methods We reviewed 11,814 cases of patients who underwent primary, elective THA from 2016 to 2021. Patient demographics and clinical data were compared between patients who did or did not have preoperative standing and sitting 2DLD images (29.5% vs. 70.5%, respectively) using Chi-squared test and multivariate logistic regressions. Results The rate of patients with preexisting spinal fusion was higher in the 2DLD cohort (2.2 vs. 0.6%, respectively, p < 0.001). Preoperative 2DLD images were favored in outcomes including length of stay (40.15 vs. 67.16 hours; p < 0.001), rate of discharge to home (94.1 vs. 80.0%; p < 0.001), and 90-day readmission rate (3.5 vs. 6.0%; p < 0.001). Multivariate analysis demonstrated preoperative 2DLD images to be significantly associated with lower odds of dislocation, independent from surgical approach, coexisting spinal fusion, and utilization of dual-mobility implants. Conclusion Preoperative 2DLD images were independently associated with decreased risk for dislocations. Even in a higher risk cohort with spinal fusion, the rate of dislocation in the 2DLD cohort was significantly lower.

EPCO-53. CHARACTERIZING THE FUNCTIONAL IMPACT OF GERMLINE-INHERITED RISK ALLELES IN GLIOMA EVOLUTION

Abstract Efforts to understand etiology of glioma led researchers to investigate associated genetic factors. Genome Wide Association Studies (GWAS) conducted to that end, uncovered an association of various single nucleotide polymorphisms (SNP) among hallmark oncogenes and tumor suppressors as risk variants in glioma incidence. Here, we perform in vitro modeling of four risk alleles/SNPs((rs723527 (EGFR), rs55705857 (MYC), rs7572263 (IDH1), rs78378222 (TP53)) mapped to non-coding regulatory regions of the genome, to assess their causal contribution to glioma evolution. To model the aforementioned risk alleles in an in-vitro system, we used a CRISPR-knock in strategy in human induced pluripotent stem cells (hiPSCs) and verified by Sanger sequencing. To study the effects of the risk alleles on brain cell types, we generated a cerebral organoid model from the edited and control lines and subjected them to downstream morphological and transcriptomic analyses. While we did not see morphological changes in the histological sections relative to controls at the early 14-day timepoint, we observed increased differentiation in both control and risk cohorts, along with an absence of neural rosettes, at the late 90-day timepoint. Bulk RNA-seq of the organoids at 14-days resulted in positive enrichment of oncogenic signaling pathways and negative enrichment of DNA repair pathways in the risk allele cohorts. Furthermore, single cell RNA seq of 14 and 90-day samples revealed a sharp decrease in neural stem cell clusters in both IDH and TP53 cohorts, while control organoids demonstrated robust production of immature neurons at 90 days. Overall, we observed a significant increase in differentiation into mature cell clusters in the control, relative to the risk allele organoids. Ongoing efforts are aimed at understanding this apparent differentiation block in the IDH and TP53 compartments, relative to control. Further analysis will lead to addressing key understudied areas of glioma etiology and associated mechanisms of risk incidence.

Risk stratification in the clinical application of minimal residual disease assessment in acute myeloid leukemia.

In acute myeloid leukemia (AML), further investigation is warranted to integrate measurable residual disease (MRD) with genetic characteristics for formulating a dynamic prognostic system for predicting response and selecting appropriate postremission therapeutic strategies. The authors incorporated MRD with genetic risk classification and assessed its impact on transplantation decision making within different risk cohorts, comprising 769 patients with newly diagnosed AML across three clinical trials. Only patients who achieved complete remission (CR) within two courses of chemotherapy were selected. In the favorable-risk and intermediate-risk groups, patients who underwent transplantation according to the protocol experienced significant 3-year overall survival (OS) benefits compared with those who did not (favorable-risk group: hazard ratio [HR], 0.38; 95% confidence interval [CI], 0.20-0.73l p=.004; intermediate-risk group: HR, 0.53; 95% CI, 0.33-0.85; p=.008). In the intermediate-risk group, early detection of MRD positivity, even after the initial course of chemotherapy, was associated with a significantly elevated cumulative incidence of relapse (47.2% vs. 36.0%; p=.009) and a notable extension of OS with allogeneic hematopoietic stem cell transplantation (HR, 0.47; 95% CI, 0.28-0.79; p=.004). Conversely, patients who achieved MRD negativity at either of the two time points had comparable OS in the favorable-risk and intermediate-risk groups, regardless of whether they underwent transplant or not. In the adverse-risk group, allogeneic hematopoietic stem cell transplantation led to improvements in OS irrespective of MRD status (HR, 0.51; 95% CI, 0.38-0.69; p<.001). Early clearance of MRD demonstrated significant prognostic value, particularly for patients in the favorable-risk and intermediate-risk groups. Positive MRD status after two courses of intensive chemotherapy were associated with a higher relapse rate and inferior OS, necessitating allogeneic hematopoietic stem cell transplantation.

CMR phenotypes and clinical outcomes in NYHA class I versus II-IV hypertrophic cardiomyopathy: identifying high-risk asymptomatic patients

Abstract Background Cardiac myosin inhibition therapy can deliver symptomatic benefit for NYHA class≥II patients with obstructive hypertrophic cardiomyopathy (HCM) and is being actively explored for non-obstructive phenotypes. However, expanding interest in clinical outcome reduction supports growing need to identify high risk cohorts across both symptomatic and asymptomatic cohorts. We aimed to examine phenotypic characteristics of NYHA-I versus NYHA≥II patients with HCM and their association with future outcomes. Methods 727 patients with HCM from the CIROC Registry who completed simultaneous CMR and patient health assessments, inclusive of NYHA evaluation and quality of life surveys, were studied. Baseline clinical and CMR characteristics were compared between NYHA-I and NYHA≥II cohorts, followed by risk modelling for the prediction of major adverse cardiovascular events (MACE), defined as: all-cause mortality, heart failure hospitalization, ventricular arrhythmia, new onset atrial fibrillation, or stroke. Cox models were constructed to identify independent predictors of MACE. Results Of the 727 patients, 546 (75%) reported NYHA-I and 181 (25%) NYHA≥II symptoms. Baseline characteristics are shown in Table 1. Compared to NYHA≥II, NYHA-I patients were younger, more likely male, and had a lower prevalence of diabetes and hypertension. No meaningful differences in CMR chamber volumes, function, left ventricular (LV) mass, or fibrosis burden were observed. Over a median follow up of 3.7 years, 109 patients (15%) experienced MACE: 12% in NYHA-I and 23% in NYHA≥II sub-groups (p&amp;lt;0.001). Baseline LV mass z-scores (determined from sex-matched, BSA-indexed SCMR healthy reference values) were independently associated with MACE by multivariable Cox modelling. An optimal LV mass z-score threshold of 3.9 for prediction of MACE was identified and combined with NYHA status to stratify patients into 4 categories. Kaplan-Meier curves showed patients with LV Mass z-scores &amp;gt;3.9 experienced worse event-free survival in both NYHA sub-groups (Figure 1a). Cox modelling in the overall cohort (Figure 1b) showed NYHA-I patients with LV Mass z-scores &amp;gt;3.9 experienced a 2.2-fold increased risk (p=0.007) of MACE, this exceeding the risk of NYHA ≥II patients below this threshold. Separate NYHA I and ≥II sub-group multivariable models showed LV Mass z-score &amp;gt;3.9 to remain a strong and independent predictor of MACE, providing respective hazards of 2.6 and 4.7 (p=0.001 and &amp;lt;0.001). Conclusions NYHA-I patients with HCM experience significantly lower rates of MACE versus NYHA≥II. However, LV mass z-scoring permits powerful sub-stratification of these sub-groups, identifying NYHA-I patients with higher LV mass who will experience worse outcomes versus NYHA≥II patients with lower LV mass. This simple yet powerful stratification offers unique potential to identify asymptomatic patients with HCM who may benefit from targeted therapeutics to reduce future MACE.

Prognostic significance of coexistent coronary artery disease in patients undergoing transcatheter aortic valve implantation for aortic stenosis

Abstract Background The optimal management of coronary artery disease (CAD) in patients undergoing transcatheter aortic valve implantation (TAVI) for aortic stenosis (AS) is uncertain. As TAVI expands into lower risk cohorts with longer life expectancies there is increasing need to determine the prognostic significance of coexistent CAD and identify which lesions may benefit from revascularisation. Purpose To evaluate the prognostic significance of coexistent CAD in patients with AS undergoing TAVI stratified according to myocardial territories at risk. Methods Using a retrospective, single-centre, observational registry, patients undergoing TAVI for severe AS between 2015 and 2020 were included. CAD was angiographically determined using computed tomography or invasive coronary angiography. CAD was stratified into 1) low-risk: &amp;lt;70% stenosis in all major epicardial coronary arteries or &amp;lt;50% in the left main (LM); 2) intermediate-risk: ≥70% stenosis in one or two arteries, except the proximal left anterior descending (LAD) and LM; 3) high-risk: ≥70% stenosis in the proximal LAD, ≥70% stenosis in 3 arteries or LM stenosis ≥50%. Patients with previous CABG were categorised as high-risk if: ≥70% stenosis of 3 coronary grafts or graft supplying a proximally stenosed LAD; and intermediate-risk if: ≥70% stenosis of 1 or 2 non-LAD grafts. Baseline characteristics and procedural outcomes were compared between the 3 cohorts, with the impact of CAD on outcomes evaluated after adjustment for demographics and comorbidities. Results 1805 patients were included; median age 84 (79-88), 51% male sex, median logistic Euroscore 13 (8-21). 1281 (71%), 384 (21%) and 140 (8%) patients were characterised as low-, intermediate- and high-risk coronary anatomy respectively. High risk patients were older than the other groups, however, did not have the highest prevalence of comorbidities (Table 1). Other than pacemaker implantation (9% vs 12% vs 6%, p=0.04), there were no differences in procedural complications or in-hospital mortality between groups (Table 1). At a median follow-up of 3.5 (2.3-4.8) years, 920 patients (51%) died, 292 (16%) had hospitalisation for heart failure (HHF) and 565 patients (31%) had a major adverse coronary event (MACE); defined as either myocardial infarction, HHF or cardiovascular death. Coronary anatomical stratification was associated with MACE (Log rank p&amp;lt;0.001) (Figure 1). After multivariate adjustment, high-risk anatomy was associated with all-cause mortality (hazard ratio (HR): 1.34, 95% confidence interval (CI): 1.06-1.68, p=0.013), HHF (HR: 1.49, 95% CI: 1.01-2.21, p=0.046) and MACE (HR: 1.68, 95% CI: 1.27-2.21, p&amp;lt;0.001). Conclusions Whilst the presence of CAD does not impact TAVI procedural safety, untreated high-risk coronary anatomy is associated with future adverse events and may warrant intensive medical therapy and/or revascularisation.

Prediction of cardiovascular risk in patients type 2 diabetes using the SCORE2-Diabetes risk score

Abstract Background/Introduction The SCORE2-Diabetes risk score was developed to predict the risk of cardiovascular events (CV-death, non-fatal MI and non-fatal stroke) in patients with T2DM without known cardiovascular disease. Current ESC guidelines recommend the use of this risk score to tailor treatment strategies in this population. Purpose We sought to determine whether the SCORE2-Diabetes risk score was able to appropriately stratify an international cohort of patients from recent cardiovascular clinical outcomes trials. Furthermore, we sought to determine the accuracy and precision of the model including in patients with and without known cardiovascular disease. Methods Patients from 4 randomized cardiovascular outcome trials (DEVOTE, LEADER, PIONEER-6, SUSTAIN-6) were included (n=23,464). Mean follow-up was 2.6 years and outcomes were adjudicated. The SCORE2-Diabetes risk score was calculated using the uncalibrated version which does not account for risk-region. Patients were stratified into low (&amp;lt;5%), moderate (5-&amp;lt;10%), high (10-&amp;lt;20%), and very high risk (≥20%) groups. The SCORE2-Diabetes risk predication model was designed to predict 10-year risk; however, given the mean follow-up from the cohort, outcomes were reported at 36 months. The Brier score, which evaluates estimated risk, and c-index, which evaluates the ability to discriminate between participants, were used to evaluate the precision of the risk score. We further compared the risk score with an estimated risk of MACE calculated using a cause specific Cox model that accounts for competing risk. Results Most patients in the cohort did not have prior myocardial infarction or stroke (57.4%, n=13,467). The SCORE2-Diabetes risk score was able to stratify patients into low, moderate, high, and very high risk cohorts (Figure 1). Observed cardiovascular events at 36 months were higher than the SCORE2-Diabetes risk score predicted (Table 1). The risk score, when included in a regression model, independently predicted cardiovascular death, myocardial infarction, or stroke (HRadj 1.03, p&amp;lt;0.001) and non-cardiovascular death (HRadj 1.05, p&amp;lt;0.001). Including the score in models with only age and sex improved the discrimination and performance of the model. The c-index for the risk score in the overall cohort was 0.62 and was 0.66 in the cohort without known cardiovascular disease. When using the Brier score to evaluate the utility of the model, the Brier score of the SCORE2-D model was 0.08 which is no different than a null model which assumes a baseline risk of 10% in all patients. Conclusion In a cohort of patients that was older, more geographically diverse, and at higher risk of cardiovascular events, the SCORE2-D risk score appropriately stratified patients into categories of risk. However, the overall risk prediction underestimated the risk of cardiovascular events and the discrimination of the risk score was modest.Figure:CV events over timeTable:CV events by risk group

Machine learning identifies individuals at higher risk of incident cardio-renal-metabolic diseases and cardiovascular death who have unrealised opportunities to reduce future cardiovascular risk

Abstract Background Machine learning may be able to identify individuals at risk of cardio-renal-metabolic events using routinely-collected data, and these individuals may be suitable for targeted preventative strategies.(1, 2) Purpose To train and test a machine learning algorithm to identify individuals at higher risk of incident cardio-renal-metabolic diseases and cardiovascular death, and then establish if there are opportunities to reduce their future cardiovascular risk. Methods We trained a random classifier (OPTIMISE) in UK primary care EHR data from 2 081 139 individuals aged ≥30 years (Jan 2, 1998, Nov 30, 2018), randomly divided into training (80%) and testing (20%) datasets. We calculated the cumulative incidence rate for ten cardio-renal-metabolic diseases and death. Fine and Gray’s models with competing risk of death were fit for each outcome between higher and lower predicted risk. In a multi-centre pilot interventional single arm study consenting individuals aged ≥30 years at higher predicted risk received cardio-renal-metabolic phenotyping and assessment for guideline target attainment. Results In the testing dataset (n = 416 228), individuals at higher predicted risk had higher long-term risk of heart failure (HR 12.54), aortic stenosis (HR 9.98), AF (HR 8·75), stroke/TIA (HR 8.07), CKD (HR 6.85), PVD (HR 6.62), valvular heart disease (HR 6.49), MI (HR 5.02), diabetes (HR 2.05) and COPD (HR 2.02) (Figure 1). This cohort were also at higher risk of death (HR 10.45), accounting for 74% of cardiovascular deaths (8 582 of 11 676) during 10-year follow up. Of 82 higher risk patients in the pilot study (mean age 71.6 years (SD 7.5), 50% women), the prevalence of cardio-renal-metabolic disease was high (Table 1), and there were opportunities to reduce future cardiovascular risk. Of higher risk patients with hypertension, 58.5% (31/53) of those aged &amp;lt;80 years had a systolic blood pressure (SBP)&amp;gt;140mmHg, and 54.5% (6/11) of those aged ≥80 years had a SBP &amp;gt;150mmHg. Of those with type 2 diabetes and co-existent ASCVD, only 23.1% (3/13) were on SGLT2 inhibitor therapy. Of higher risk patients on statin therapy, 37.0% (20/54) had LDL-cholesterol &amp;gt;1.8 mmol/L, and 52.0% (12/25) of patients with previous ASCVD had an LDL-cholesterol &amp;gt;1.4mmol/L. Furthermore, 19.5% (16/82) of the higher risk cohort had undiagnosed moderate or high risk CKD; who were infrequently prescribed a statin (41.7%; 5/12), ACE-i/ARB therapy with co-existent hypertension (61.5%. 8/13), or SGLT2 inhibitor with co-existent diabetes (83.3% (5/6)). Obesity was present in 49%, and 17% (14/82) were eligible for GLP-1 RA therapy. Conclusions The machine learning OPTIMISE algorithm can identify people at higher risk of cardio-renal-metabolic diseases and death using routinely collected data. On prospective evaluation higher risk individuals have unrecorded and undertreated cardio-renal-metabolic diseases, which are actionable targets for preventative care.Figure 1

Prediction of cardiovascular outcomes by subtle changes in the peripheral immune cell landscape - insights from the LURIC single cell RNA-sequencing study (LuRNA)

Abstract Background and Aims Atherosclerosis and its clinical sequelae, myocardial infarction and stroke, represent the main causes of death worldwide. Although preclinical evidence has suggested the existence of an inflammatory response driving disease, the extend of cellular alterations in human atherosclerosis remains enigmatic. Here, we employ single cell RNA-sequencing (scRNA-seq) on peripheral blood mononucleated cells (PBMCs) in a well-defined cardiovascular risk cohort from the "Ludwigshafen Risk and Cardiovascular Health (LURIC) trial" to define changes in the immune cell landscape in atherosclerotic patients. Methods and Results Of 3317 patients enrolled in the LURIC trial between 1997 and 2000, we selected individuals with stable coronary-artery disease (CAD) (n=31) and healthy patients (no CAD) (n=16) by propensity score matching, adjusted for CRP, NTproBNP, Troponin T, LDL-C, and Cystatin-C, in a case-control design. scRNA-seq was performed by droplet sequencing on PBMCs stored in liquid nitrogen. Individual data sets were integrated and changes between healthy individuals and patients with CAD were evaluated on numeric and transcriptional level. Single cell transcriptomes were annotated using an established CITE-seq reference atlas. While bulk RNA-sequencing of PBMC preparations revealed only minor changes between both conditions, we identified several leukocyte populations on a single cell level with specific transcriptomes that were differentially regulated between both conditions. Interestingly, we found that several subsets of Natural Killer (NK) cells, T cells with an enrichment of proliferation-associated pathways, and a population resembling hematopoietic stem cells were more frequent in patients with CAD, while naïve phenotypes of B and T cells were overrepresented in the absence of CAD. Consistently, most T and B cell populations in patients with CAD were enriched in pathways associated with cell activation, immune receptor signalling, and differentiation. In addition, we detected restricted repertoires of T cell receptor sequences in several adaptive immune cell subtypes from patients with CAD, suggestive of increased cellular clonality and antigen-specificity. Finally, in a comparison of cellular frequencies with cardiovascular outcomes over more than 15 years, several immune cell subsets and cell-type specific transcriptional programs predicted cardiovascular death in this case-control scenario in multi-variate adjusted regression analysis. Notably, addition of scRNA-seq derived parameters was superior to traditional risk prediction with clinical characteristics and soluble biomarkers alone. Conclusion Employing scRNAseq, we demonstrate that atherosclerosis is associated with a profound change in the circulating immune cell landscape even in the absence of measurable differences in inflammatory biomarkers. These findings propose the usage of scRNAseq for the discovery of outcome-relevant cellular biomarkers in the future.

Kidney function, uric acid, and risk of atrial fibrillation: experience from the AMORIS cohort

BackgroundUric acid closely relates to both kidney disease and atrial fibrillation (AF), yet the extent to which it influences the kidney-AF association remains uncertain. We examined the relationship between kidney function and risk of AF, accounting for uric acid levels.MethodsA total of 308,509 individuals in the Swedish Apolipoprotein-Related Mortality Risk (AMORIS) cohort were included and their serum creatinine and uric acid were measured during 1985–1996. Ten-year incident AF was identified via linkage with the national registers. Glomerular filtration rate (eGFR) (ml/min/1.73 m2) was calculated with the 2009 Chronic Kidney Disease Epidemiology Collaboration equation. Hyperuricemia was defined as > 420 µmol/L for men and > 360 µmol/L for women.ResultsOver a mean follow-up of 9.4 years, 10,007 (3.2%) incident AF cases occurred. After adjusting for age, sex, cardiovascular diseases, total cholesterol, triglycerides, and glucose, individuals with low eGFR (< 30 and 30–59 ml/min/1.73 m2 ) had a higher risk of AF compared to those with normal eGFR (60–89) (hazard ratio (HR) = 1.72, 95% confidence interval (CI):1.29–2.30; HR = 1.10, 95% CI: 1.03–1.18, respectively). After further adjusting for uric acid levels, the association disappeared (HR = 0.97, 95% CI: 0.72–1.30; HR = 0.93, 95% CI: 0.86-1.00, respectively). When stratifying by hyperuricemia yes/no, eGFR < 30 ml/min/1.73 m2 was associated with higher AF risk in a small group of individuals without hyperuricemia (HR = 2.58, 95% CI: 1.64–4.07).ConclusionUric acid largely accounted for the relationship between eGFR and AF in this study. However, in individuals without hyperuricemia, eGFR in the lowest range (< 30 ml/min/1.73 m2) was still associated with increased risk of AF.

Misfolded alpha synuclein co-occurrence with Alzheimer's disease proteinopathy.

Multi-etiology dementia necessitates in-vivo markers of copathologies including misfolded α -synuclein (syn). We measured misfolded syn aggregates (syn-seeds) via qualitative seed amplifcation assays (synSAA) and examined relationships with markers of Alzheimer's disease (AD). Cerebrospinal fluid (CSF) was obtained from 420 participants in two Wisconsin AD risk cohorts (35% male; 91% cognitively unimpaired; mean (SD) age, 65.42 (7.78) years; education, 16.17 (2.23) years). synSAA results were compared to phosphorylated tau (T), beta amyloid (A), and clinical outcomes. Longitudinal cognition was modeled with mixed effects. Syn positivity (synSAA+) co-occurred with T (in synSAA+ vs synSAA-, 36% vs 20% T+; p=0.011) and with cognitive impairment (10% vs 7% MCI; 10% vs 0% dementia; p=0.00050). synSAA+ participants' cognitive performance declined ∼40% faster than synSAA-for Digit Symbol, but not other tests. Findings support prevalent syn copathology in a mostly-unimpaired AD risk cohort. Future work will explore relationships with disease progression.

Prognostic Significance and Immune Landscape of an Efferocytosis-Related Gene Signature in Bladder Cancer.

Bladder cancer poses a significant global health challenge, underscoring the imperative for precise prognostic instruments to advance patient care. Against the backdrop of efferocytosis's increasingly recognized role in cancer, this research endeavors to develop and authenticate a prognostic signature intricately linked to efferocytosis in bladder cancer. LASSO-COX regression analysis crafted an efferocytosis-related genes risk prognostic model, followed by the construction of a column chart. External validation sets confirmed the predictive accuracy of both the model and chart. Clinical, tumor microenvironment, drug sensitivity, and immunotherapy analyses were employed to comprehensively assess efferocytosis-related scores. The expression of TGFB3 key genes was validated via RT-PCR and western blotting. Further validation included Transwell, Wound healing, Colony formation, and EDU assays. We formulated and validated an efferocytosis-related genes risk model in bladder cancer, comprising 13 core genes. The risk model demonstrated autonomous prognostic significance in both univariate and multivariate Cox analyses. Following the multivariate analysis, we devised a nomogram. Moreover, by utilizing individual risk scores derived from this risk model, we successfully stratified patients into two discernible risk cohorts, unveiling noteworthy variances in immune infiltration profiles and responsiveness to immunotherapy. Notably, the model's key gene TGFB3 was validated through comprehensive experimental investigations, including Transwell assays for migration and invasion and Wound healing assays for motility on the T24 and BIU cell lines. This study has furnished innovative perspectives on an efferocytosis-related prognostic signature, elucidating the prognosis and immune milieu intricacies in patients with bladder cancer.