Missouri Heart Center

Background: Given the importance of understanding the impact of treatment on patients’ symptoms, function, and quality of life, the Kansas City Cardiomyopathy Questionnaire (KCCQ) has been used as an endpoint for trials in Hypertrophic cardiomyopathy (HCM). The KCCQ has been studied in heart diseases, but it has not been extensively psychometrically assessed in HCM. How well the KCCQ captures patients’ lived experiences and how they feel about the tool are incompletely understood. Thus, understanding how the KCCQ functions in those with HCM is critically needed. Methods: Focus groups of individuals with HCM, both with and without obstruction and irrespective of genotype, were conducted using a standardized interview guide developed from a multidisciplinary team that elicited patients’ perspectives of their symptoms, limitations, and determinants of quality of life associated with HCM. The guide also included the KCCQ-23 item in order to perform cognitive debriefing to understand how patients felt about the tool. Transcripts were reviewed and coded by 3 separate scientists to identify key themes, achieve consensus on key concepts, and to assure saturation. Results: Over 4 groups of 4-9 participants each, many reported concerns that were not captured by the KCCQ, but content saturation was achieved with no new concepts in the final focus group. Additional symptoms of importance not included in the KCCQ were chest pain, dizziness, lightheadedness, palpitations, and pre-syncope, with provoking factors being bending over, meals, and dehydration. Quality of life was impacted by participants’ fear of symptoms and clinical events. The KCCQ, while relevant and understandable to participants, seemed to incompletely reflect participants’ experiences - particularly when considering symptoms other than fatigue and shortness of breath. Some felt swelling and orthopnea were less relevant, but without a clear consensus. “Heart failure” was felt by some to be confusing or upsetting. Lastly, questions regarding the recall period were raised given variability in symptoms. Conclusions: Considerations to supplement the KCCQ with additional to modify the introduction, include other symptoms, variability items, and omitting the term ‘heart failure’ may improve its content validity for patients with HCM. Further work is planned to quantify these concerns are underway prior to developing a supplement.

Background: Intensive blood pressure (BP) control reduces the risk of cardiovascular (CV) events, yet we recently reported a U-shaped association between BP and limb events in peripheral artery disease (PAD). Whether the involvement of pedal arteries or small vessel disease (SVD), which further compromises lower extremity perfusion, modifies this association is unknown. Methods: We analyzed the Peripheral Artery Long-term Survival (PEARLS) cohort, a longitudinal registry of ~100,000 US Veterans with incident PAD between 2015-2020. We defined SVD as a low toe-brachial index (TBI≤0.7) with a normal ankle brachial index (ABI > 0.9) in any limb, suggesting involvement of distal pedal arteries. Cox regression models, with death as a competing risk, were used to evaluate the association between BP as a time-varying exposure and risk of CV (myocardial infarction, stroke) and limb (chronic limb-threatening ischemia, major amputation) events, adjusted for patient demographics, comorbidities, risk factors, and severity of PAD. Analyses were performed separately in patients with and without SVD, and interaction testing was also performed. Results: Among 92,909 patients (mean age 70.5 ± 9.3 years; 97% men; 18.5% Black), 35,496 [38.2%] had SVD. Compared to those without, those with SVD only were older, less likely to be Black or current smokers, but had a higher burden of diabetes and chronic kidney disease (Table 1). Baseline BP differences between groups were small. Over a median follow-up of 3.9 years, SVD was associated with a lower crude incidence rate (per-100 patient years) of CV events (4.1 vs. 5.0) and limb events (4.4 vs. 5.6), compared to patients without SVD. In both strata, there was a graded positive association between increasing systolic BP risk of CV events (P for interaction=0.54; Figure 1). Conversely, systolic BP displayed a U-shaped association with limb events, with increased hazard in both low and high BP. This pattern was more pronounced in patients with SVD (P for interaction <0.01; Figure 1). Findings for diastolic blood pressure were similar (Figure 2). Conclusion: In PAD, higher BP is associated with a higher risk of CV events, whereas the association with limb events was U-shaped. The increased hazard of limb events at both low and high BP is accentuated in patients with SVD. These findings highlight the need for individualized BP targets in PAD, particularly when SVD is present.

Abstract In this report, we summarize and analyze the 2024 Adaptyv protein design competition. Participants used computational and Machine Learning (ML) methods of their choice to design proteins that bind the Epidermal Growth Factor Receptor (EGFR), a key drug target involved in cell growth, differentiation, and cancer development. Over 1,800 designs were submitted across two rounds. Of these, 601 proteins were selected and characterized for expression and binding affinity to EGFR, with competitors both optimizing existing binders ( K D = 1.21 nM) and creating de novo binders ( K D = 82 nM). All selected designs were experimentally validated using Adaptyv’s automated Bio-Layer Interferometry (BLI) pipeline. This competition illustrates the potential of crowdsourcing to drive creativity and innovation in protein design. However, it also exposed key challenges, such as the lack of standardized benchmarks, experimental design targets, and robust computational metrics for method comparison. We anticipate that future competitions will address these gaps and further motivate progress in computational protein design.

Introduction: Anticoagulation therapy plays a pivotal role in stroke prevention for people with atrial fibrillation. Despite its efficacy, some patients still have an ischemic stroke while on therapy. Since it remains unclear how best to modify risk in these cases and guidance for clinical decision-making is limited, understanding real-world patterns is crucial for improving outcomes. Methods: Using data from the Get With The Guidelines-Stroke Registry between 2016 and 2023, we assessed the real-world strategies clinicians use for ischemic stroke patients with atrial fibrillation who experience stroke despite being on anticoagulation therapy. Multivariate logistic regression models with generalized estimating equations were used to identify factors associated with changes in oral anticoagulants (OAC). Results: Of 60,334 ischemic stroke patients with atrial fibrillation who were taking OAC but were not on antiplatelet prior to stroke, 14.4% were taking warfarin with subtherapeutic INR, 8.9% therapeutic warfarin, and 76.7% direct oral anticoagulant (DOAC) prior to stroke (4.7% dabigatran, 20.4% rivaroxaban, and 51.6% apixaban). The distribution of discharge antithrombotics is shown in the Figure . Among patients taking DOAC prior to stroke, 83.3% remained on the same DOAC at discharge, of whom 45.5% added an antiplatelet agent. Among patients on warfarin, 37.0% switched to DOAC at discharge. For those who remained on warfarin, 47.8% added an antiplatelet agent. Patients on warfarin with subtherapeutic INR (aOR 1.86), dabigatran (aOR 1.58), or rivaroxaban (aOR 1.09) were more likely to switch OACs, while those on apixaban (aOR 0.27) were less likely to switch as compared with those on warfarin with therapeutic INR prior to stroke. Conclusion: Among people with AF who were anticoagulated prior to hospitalization for ischemic stroke, switching OACs or adding an antiplatelet agent is common. Understanding the factors influencing treatment selection after stroke underscores the need for a prospective study of treatment strategies and could support the development of personalized antithrombotic strategies to reduce recurrent stroke risk.

The prevalence of microplastics (MPs) in the environment is an escalating global concern, driven by their increasing abundance and potential adverse effects. Their detrimental environmental consequences and risks to public health necessitate urgent action to mitigate their impacts. To better understand MP accumulation within the environment, estimate their impacts, and develop effective mitigation strategies, it is imperative to advance our knowledge of MPs’ environmental fate and how this fate is linked with plastics’ intrinsic properties. We highlight the current research on MPs’ accumulation within different environmental sinks and identify the critical knowledge gaps in understanding the flux of MPs between these sinks. We also discuss how the intrinsic properties of MPs, including polymeric backbone, structure, chemical additives, crystallinity, molecular weight, and hydrophilicity, influence their environmental behavior and degradation pathways. Among these properties, the polymeric backbone and functional groups serve as primary drivers of MP stability when exposed to external physical and chemical factors, thereby influencing the pathway and rate of MP degradation. Other intrinsic properties and environmental conditions mostly impact the rate of MP degradation. As MPs undergo environmental degradation, changes in their intrinsic characteristics can lead to further fragmentation. This process potentially enhances environmental harm due to the resulting particles’ increased surface area, greater environmental mobility, and higher potential for contaminant transport. These factors collectively contribute to the complex dynamics of MPs’ fate and impact on the environment.

We present a combination of laboratory experiments and computational fluid dynamics (CFD) simulations to understand the wind-induced drag force and drag coefficient for Saccharum contortum seeds. Seed drop experiments indicate that the settling fall velocities of hair-equipped seeds are within 1–2 m/s, compared to 2.34 times higher settling fall velocity of the seed without hairs. The experimental data illustrate a power-law relationship between drag coefficient (Cd) and Reynolds number (Re) under the free fall condition: Cd∼Re−1.1. CFD simulations show that both viscous and pressure drag force components are important in contributing to wind drag. The presence of hairs substantially increases pressure drag, and its relative importance depends on hair number and orientation. Seed morphology including hair number and orientation influences the drag coefficient under different flow directions relatively to the seed body. The lower drag coefficient observed with crossflow wind compared to free fall suggests that seeds encounter less air resistance while drifting horizontally in the wind, favoring extended flying time and distance. Based on the varying drag coefficients under different conditions, we propose the incorporation of varying drag coefficients in future wind-driven seed dispersal models.

Abstract Enzymes, nature’s catalysts, possess remarkable properties such as high stereo-, regio-, and chemo-specificity. These properties allow enzymes to greatly simplify complex synthetic processes, resulting in improved yields and reduced manufacturing costs compared to traditional chemical methods. However, the lack of experimental characterization of enzyme substrates, with only a few thousand out of tens of millions of known enzymes in Uniprot having annotated substrates, severely limits the ability of chemists to repurpose enzymes for industrial applications. Previous machine learning models aimed at predicting enzyme substrates have been hampered by poor generalization to new substrates. Here, we introduce VIPER (Virtual Interaction Predictor for Enzyme Reactivity), a model that achieves an average 34% improvement over the previous state-of-the-art model (ProSmith) in reaction prediction for unseen substrates. Furthermore, we present a novel benchmarking methodology for assessing the out-of-distribution generalization capabilities of enzyme-substrate prediction models. VIPER represents a significant advance towards the in silico prediction of enzyme-substrate compatibility, paving the way for the discovery of novel biocatalytic routes for the sustainable synthesis of high-value chemicals.

Atrial fibrillation (AF) significantly reduces health-related quality of life (HRQoL), previously measured in clinical trials using patient-reported outcomes (PROs). We examined AF PROs in clinical practice and their association with subsequent clinical management. The Utah My Evaluation (mEVAL) program collects the Toronto AF Symptom Severity Scale (AFSS) in AF outpatients at the University of Utah. Baseline factors associated with worse AF symptom score (range 0-35, higher is worse) were identified in univariate and multivariable analyses. Secondary outcomes included AF burden and AF healthcare utilization. We also compared subsequent clinical management at 6 months between patients with better versus worse AF HRQoL. Overall, 1338 patients completed the AFSS symptom score, which varied by sex (mean 7.26 for males vs. 10.27 for females; p < .001), age (<65, 9.73; 65-74, 7.66;≥75, 7.58; p < .001), heart failure (9.39 with HF vs. 7.67 without; p < .001), and prior ablation (7.28 with prior ablation vs. 8.84; p < .001). In multivariable analysis, younger age (mean difference 2.92 for<65 vs.≥75; p < .001), female sex (mean difference 2.57; p < .001), pulmonary disease (mean difference 1.88;p < .001), and depression (mean difference 2.46; p < .001) were associated with higher scores. At 6-months, worse baseline symptom score was associated with the use of rhythm control (37.1% vs. 24.5%; p < .001). Similar cofactors and results were associated with increased AF burden and health care utilization scores. AF PROs in clinical practice identify highly-symptomatic patients, corroborating findings in more controlled, clinical trials. Increased AFSS score correlates with more aggressive clinical management, supporting the utility of disease-specific PROs guiding clinical practice.