Parasitic Contamination of Soil in the Southern United States.

Parasites are generally associated with lower income countries in tropical and subtropical areas. Still, they are also prevalent in low-income communities in the southern United States. Studies characterizing the epidemiology of parasites in the United States are limited, resulting in little comprehensive understanding of the problem. This study investigated the environmental contamination of parasites in the southern United States by determining each parasite's contamination rate and burden in five low-income communities. A total of 499 soil samples of approximately 50 g were collected from public parks and private residences in Alabama, Louisiana, Mississippi, South Carolina, and Texas. A technique using parasite floatation, filtration, and bead-beating was applied to dirt samples to concentrate and extract parasite DNA from samples and detected via multiparallel quantitative polymerase chain reaction (qPCR). qPCR detected total sample contamination of Blastocystis spp. (19.03%), Toxocara cati (6.01%), Toxocara canis (3.61%), Strongyloides stercoralis (2.00%), Trichuris trichiura (1.80%), Ancylostoma duodenale (1.42%), Giardia intestinalis (1.40%), Cryptosporidium spp. (1.01%), Entamoeba histolytica (0.20%), and Necator americanus (0.20%). The remaining samples had no parasitic contamination. Overall parasite contamination rates varied significantly between communities: western Mississippi (46.88%), southwestern Alabama (39.62%), northeastern Louisiana (27.93%), southwestern South Carolina (27.93%), and south Texas (6.93%) (P <0.0001). T. cati DNA burdens were more significant in communities with higher poverty rates, including northeastern Louisiana (50.57%) and western Mississippi (49.60%) compared with southwestern Alabama (30.05%) and southwestern South Carolina (25.01%) (P = 0.0011). This study demonstrates the environmental contamination of parasites and their relationship with high poverty rates in communities in the southern United States.

RAndomized Cluster Evaluation of Cardiac ARrest Systems (RACE-CARS) trial: Study Rationale and Design.

Out-of-hospital cardiac arrest (OHCA) occurs in nearly 350,000 people each year in the United States (US). Despite advances in pre- and in-hospital care, OHCA survival remains low and is highly variable across systems and regions. The critical barrier to improving cardiac arrest outcomes is not a lack of knowledge about effective interventions, but rather the widespread lack of systems of care to deliver interventions known to be successful. The RAndomized Cluster Evaluation of Cardiac ARrest Systems (RACE-CARS) trial is a 7-year pragmatic, cluster-randomized trial of 60 counties (57 clusters) in North Carolina using an established registry and is testing whether implementation of a customized set of strategically targeted community-based interventions improves survival to hospital discharge with good neurologic function in OHCA relative to control/standard care. The multi-faceted intervention comprises rapid cardiac arrest recognition and systematic bystander CPR instructions by 9-1-1 telecommunicators, comprehensive community CPR training and enhanced early automated external defibrillator (AED) use prior to emergency medical systems (EMS) arrival. Approximately 20,000 patients are expected to be enrolled in the RACE CARS Trial over 4 years of the assessment period. The primary endpoint is survival to hospital discharge with good neurologic outcome defined as a cerebral performance category (CPC) of 1 or 2. Secondary outcomes include the rate of bystander CPR, defibrillation prior to arrival of EMS, and quality of life. We aim to identify successful community- and systems-based strategies to improve outcomes of OHCA using a cluster randomized-controlled trial design that aims to provide a high level of evidence for future application.

Murine models of erythroid 5ALA synthesis disorders and their conditional synthetic lethal dependency on pyridoxine.

X-linked sideroblastic anemia (XLSA) and X-linked protoporphyria (XLPP) are uncommon diseases caused by loss-of-function and gain-of-function mutations, respectively, in the erythroid form of 5-aminolevulinic acid synthetase, ALAS2, which encodes the first enzyme in heme biosynthesis. A related sideroblastic anemia is due to mutations in SLC25A38, which supplies mitochondrial glycine for ALAS2 (SLC25A38-CSA). The lack of viable animal models has limited studies on the pathophysiology and development of therapies for these conditions. Here, using CRISPR-CAS9 gene editing technology, we have generated knock-in mouse models that recapitulate the main features of XLSA and XLPP, and, using conventional conditional gene targeting in embryonic stem cells, we also developed a faithful model of the SLC25A38-CSA. In addition to examining the phenotypes and natural history of each disease, we determine the effect of restriction or supplementation of dietary pyridoxine (vitamin B6), the essential cofactor of ALAS2, on the anemia and porphyria. In addition to the well-documented response of XLSA mutations to pyridoxine supplementation, we also demonstrate the relative insensitivity of the XLPP porphyria, severe sensitivity of the XLSA models, and an extreme hypersensitivity of the SLC25A38-CSA model to pyridoxine deficiency, a phenotype that is not shared with another mouse hereditary anemia model, Hbbth3/+ -thalassemia intermedia. Thus, in addition to generating animal models useful for examining the pathophysiology and treatment of these diseases, we have uncovered an unsuspected conditional synthetic lethality between the heme synthesis-related CSAs and pyridoxine deficiency. These findings have the potential to inform novel therapeutic paradigms for the treatment of these diseases.

Forecasting the Economic Burden of Cardiovascular Disease and Stroke in the United States Through 2050: A Presidential Advisory From the American Heart Association.

BACKGROUND: Quantifying the economic burden of cardiovascular disease and stroke over the coming decades may inform policy, health system, and community-level interventions for prevention and treatment. METHODS: We used nationally representative health, economic, and demographic data to project health care costs attributable to key cardiovascular risk factors (hypertension, diabetes, hypercholesterolemia) and conditions (coronary heart disease, stroke, heart failure, atrial fibrillation) through 2050. The human capital approach was used to estimate productivity losses from morbidity and premature mortality due to cardiovascular conditions. RESULTS: One in 3 US adults received care for a cardiovascular risk factor or condition in 2020. Annual inflation-adjusted (2022 US dollars) health care costs of cardiovascular risk factors are projected to triple between 2020 and 2050, from $400 billion to $1344 billion. For cardiovascular conditions, annual health care costs are projected to almost quadruple, from $393 billion to $1490 billion, and productivity losses are projected to increase by 54%, from $234 billion to $361 billion. Stroke is projected to account for the largest absolute increase in costs. Large relative increases among the Asian American population (497%) and Hispanic American population (489%) reflect the projected increases in the size of these populations. CONCLUSIONS: The economic burden of cardiovascular risk factors and overt cardiovascular disease in the United States is projected to increase substantially in the coming decades. Development and deployment of cost-effective programs and policies to promote cardiovascular health are urgently needed to rein in costs and to equitably enhance population health.

Baseline characteristics including blood and urine metal levels in the Trial to Assess Chelation Therapy 2 (TACT2).

BACKGROUND: The reduction in cardiovascular disease (CVD) events with edetate disodium (EDTA) in the Trial to Assess Chelation Therapy (TACT) suggested that chelation of toxic metals might provide novel opportunities to reduce CVD in patients with diabetes. Lead and cadmium are vasculotoxic metals chelated by EDTA. We present baseline characteristics for participants in TACT2, a randomized, double-masked, placebo-controlled trial designed as a replication of the TACT trial limited to patients with diabetes. METHODS: TACT2 enrolled 1,000 participants with diabetes and prior myocardial infarction, age 50 years or older between September 2016 and December 2020. Among 959 participants with at least one infusion, 933 had blood and/or urine metals measured at the Centers for Diseases Control and Prevention using the same methodology as in the National Health and Nutrition Examination Survey (NHANES). We compared metal levels in TACT2 to a contemporaneous subset of NHANES participants with CVD, diabetes and other inclusion criteria similar to TACT2's participants. RESULTS: At baseline, the median (interquartile range, IQR) age was 67 (60, 72) years, 27% were women, 78% reported white race, mean (SD) BMI was 32.7 (6.6) kg/m2, 4% reported type 1 diabetes, 46.8% were treated with insulin, 22.3% with GLP1-receptor agonists or SGLT-2 inhibitors, 90.2% with aspirin, warfarin or P2Y12 inhibitors, and 86.5% with statins. Blood lead was detectable in all participants; median (IQR) was 9.19 (6.30, 13.9) µg/L. Blood and urine cadmium were detectable in 97% and median (IQR) levels were 0.28 (0.18, 0.43) µg/L and 0.30 (0.18, 0.51) µg/g creatinine, respectively. Metal levels were largely similar to those in the contemporaneous NHANES subset. CONCLUSIONS: TACT2 participants were characterized by high use of medication to treat CVD and diabetes and similar baseline metal levels as in the general US population. TACT2 will determine whether chelation therapy reduces the occurrence of subsequent CVD events in this high-risk population. CLINICAL TRIALS REGISTRATION: ClinicalTrials.gov. Identifier: NCT02733185. https://clinicaltrials.gov/study/NCT02733185.

Prognostic Impact of Sinus Rhythm in Atrial Fibrillation Patients: Separating Rhythm Outcomes From Randomized Strategy Findings From the CABANA Trial.

BACKGROUND: Clinically detected atrial fibrillation (AF) is associated with a significant increase in mortality and other adverse cardiovascular events. Since the advent of effective methods for AF rhythm control, investigators have attempted to determine how much these adverse prognostic AF effects could be mitigated by the restoration of sinus rhythm (SR) and whether the method used mattered. METHODS: The CABANA trial (Catheter Ablation versus Antiarrhythmic Drug Therapy for Atrial Fibrillation) randomized 2204 AF patients to ablation versus drug therapy, of which 1240 patients were monitored in follow-up using the CABANA ECG rhythm monitoring system. To assess the prognostic benefits of SR, we performed a prespecified analysis using Cox survival modeling with heart rhythm as a time-dependent variable and randomized treatment group as a stratification factor. RESULTS: In the 1240 patient study cohort, 883 (71.2%) had documented AF at some point during their postblanking follow-up. Among the 883 patients, 671 (76.0%) experienced AF within the first year of postblanking follow-up, and 212 (24.0%) experienced their first AF after ≥1 year of postblanking follow-up. The primary CABANA end point (death, disabling stroke, serious bleeding, or cardiac arrest) occurred in 95 (10.8%) of the 883 patients with documented AF and in 29 (8.1%) of the 357 patients with no AF recorded during follow-up. In multivariable time-dependent analysis, the presence of SR (compared with non-SR) was associated with a significantly reduced risk of the primary end point (adjusted hazard ratio, 0.57 [95% CI, 0.38-0.85]; P=0.006; independent of treatment strategy [ablation versus drugs]). Corresponding results for all-cause mortality were adjusted hazard ratio of 0.59 [95% CI, 0.35-1.01]; P=0.053). CONCLUSIONS: In patients in the CABANA trial with detailed long-term rhythm follow-up, increased time in SR was associated with a clinically consequential decrease in mortality and other adverse prognostic events. The predictive value of SR was independent of the therapeutic approach responsible for reducing the burden of detectable AF. REGISTRATION: URL: https://clinicaltrials.gov; Unique Identifier: NCT00911508.

Variation in Health Status With Invasive vs Conservative Management of Chronic Coronary Disease.

BACKGROUND: The ISCHEMIA trial found that patients with chronic coronary disease randomized to invasive strategy had better health status than those randomized to conservative strategy. It is unclear how best to translate these population-level results to individual patients. OBJECTIVES: The authors sought to identify patient characteristics associated with health status from invasive and conservative strategies, and develop a prediction algorithm for shared decision-making. METHODS: One-year disease-specific health status was assessed in ISCHEMIA with the Seattle Angina Questionnaire (SAQ) Summary Score (SAQ SS) and Angina Frequency, Physical Limitations (PL), and Quality of Life (QL) domains (range 0-100, higher = less angina/better health status). RESULTS: Among 4,617 patients from 320 sites in 37 countries, mean SAQ SS was 74.1 ± 18.9 at baseline and 85.7 ± 15.6 at 1 year. Lower baseline SAQ SS and younger age were associated with better 1-year health status with invasive strategy (P interaction = 0.009 and P interaction = 0.004, respectively). For the individual domains, there were significant treatment interactions for baseline SAQ score (Angina Frequency, PL), age (PL, QL), anterior ischemia (PL), and number of baseline antianginal medications (QL), with more benefit of invasive in patients with worse baseline health status, younger age, anterior ischemia, and on more antianginal medications. Parsimonious prediction models were developed for 1-year SAQ domains with invasive or conservative strategies to support shared decision-making. CONCLUSIONS: In the management of chronic coronary disease, individual patient characteristics are associated with 1-year health status, with younger age and poorer angina-related health status showing greater benefit from invasive management. This prediction algorithm can support the translation of the ISCHEMIA trial results to individual patients. (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches [ISCHEMIA]; NCT01471522).

A Fingertip-Mimicking 12×16 200µm-Resolution e-skin Taxel Readout Chip with per-Taxel Spiking Readout and Embedded Receptive Field Processing.

This paper presents an electronic skin (e-skin) taxel array readout chip in 0.18µm CMOS technology, achieving the highest reported spatial resolution of 200µm, comparable to human fingertips. A key innovation is the integration on chip of a 12×16 polyvinylidene fluoride (PVDF)-based piezoelectric sensor array with per-taxel signal conditioning frontend and spiking readout combined with local embedded neuromorphic first-order processing through Complex Receptive Fields (CRFs). Experimental results show that Spiking Neural Network (SNN)-based classification of the chip's spatiotemporal spiking output for input tactile stimuli such as texture and flutter frequency achieves excellent accuracies up to 97.1% and 99.2%, respectively. SNN-based classification of the indentation period applied to the on-chip PVDF sensors achieved 95.5% classification accuracy, despite using only a small 256-neuron SNN classifier, a low equivalent spike encoding resolution of 3-5 bits, and a sub-Nyquist 2.2kevent/s population spiking rate, a state-of-the-art power consumption of 12.33nW per-taxel, and 75µW-5mW for the entire chip is obtained. Finally, a comparison of the texture classification accuracies between two on-chip spike encoder outputs shows that the proposed neuromorphic level-crossing sampling (NLCS) architecture with a decaying threshold outperforms the conventional bipolar level-crossing sampling (LCS) architecture with fixed threshold.

Optimizing cultivation strategies and scaling up for fucoxanthin production using Pavlova sp.

The microalgal-based production of fucoxanthin has emerged as an imperative research endeavor due to its antioxidant, and anticancer properties. In this study, three brown marine microalgae, namely Skeletonema costatum, Chaetoceros gracilis, and Pavlova sp., were screened for fucoxanthin production. All strains displayed promising results, with Pavlova sp. exhibiting the highest fucoxanthin content (27.91 mg/g) and productivity (1.16 mg/L·day). Moreover, the influence of various cultivation parameters, such as culture media, salinity, sodium nitrate concentration, inoculum size, light intensity, and iron concentration, were investigated and optimized, resulting in a maximum fucoxanthin productivity of 7.89 mg/L·day. The investigation was further expanded to large-scale outdoor cultivation using 50 L tubular photobioreactors, illustrating the potential of Pavlova sp. and the cultivation process for future commercialization. The biomass and fucoxanthin productivity for the large-scale cultivation were 70.7 mg/L·day and 4.78 mg/L·day, respectively. Overall, the findings demonstrated considerable opportunities for fucoxanthin synthesis via microalgae cultivation and processing.

Benchmarking highly entangled states on a 60-atom analogue quantum simulator.

Quantum systems have entered a competitive regime in which classical computers must make approximations to represent highly entangled quantum states1,2. However, in this beyond-classically-exact regime, fidelity comparisons between quantum and classical systems have so far been limited to digital quantum devices2-5, and it remains unsolved how to estimate the actual entanglement content of experiments6. Here, we perform fidelity benchmarking and mixed-state entanglement estimation with a 60-atom analogue Rydberg quantum simulator, reaching a high-entanglement entropy regime in which exact classical simulation becomes impractical. Our benchmarking protocol involves extrapolation from comparisons against an approximate classical algorithm, introduced here, with varying entanglement limits. We then develop and demonstrate an estimator of the experimental mixed-state entanglement6, finding our experiment is competitive with state-of-the-art digital quantum devices performing random circuit evolution2-5. Finally, we compare the experimental fidelity against that achieved by various approximate classical algorithms, and find that only the algorithm we introduce is able to keep pace with the experiment on the classical hardware we use. Our results enable a new model for evaluating the ability of both analogue and digital quantum devices to generate entanglement in the beyond-classically-exact regime, and highlight the evolving divide between quantum and classical systems.

Incorporation of Drone Technology Into the Chain of Survival for OHCA: Estimation of Time Needed for Bystander Treatment of OHCA and CPR Performance.

BACKGROUND: Drone-delivered automated external defibrillators (AEDs) hold promises in the treatment of out-of-hospital cardiac arrest. Our objective was to estimate the time needed to perform resuscitation with a drone-delivered AED and to measure cardiopulmonary resuscitation (CPR) quality. METHODS: Mock out-of-hospital cardiac arrest simulations that included a 9-1-1 call, CPR, and drone-delivered AED were conducted. Each simulation was timed and video-recorded. CPR performance metrics were recorded by a Laerdal Resusci Anne Quality Feedback System. Multivariable regression modeling examined factors associated with time from 9-1-1 call to AED shock and CPR quality metrics (compression rate, depth, recoil, and chest compression fraction). Comparisons were made among those with recent CPR training (≤2 years) versus no recent (>2 years) or prior CPR training. RESULTS: We recruited 51 research participants between September 2019 and March 2020. The median age was 34 (Q1-Q3, 23-54) years, 56.9% were female, and 41.2% had recent CPR training. The median time from 9-1-1 call to initiation of CPR was 1:19 (Q1-Q3, 1:06-1:26) minutes. A median time of 1:59 (Q1-Q3, 01:50-02:20) minutes was needed to retrieve a drone-delivered AED and deliver a shock. The median CPR compression rate was 115 (Q1-Q3, 109-124) beats per minute, the correct compression depth percentage was 92% (Q1-Q3, 25-98), and the chest compression fraction was 46.7% (Q1-Q3, 39.9%-50.6%). Recent CPR training was not associated with CPR quality or time from 9-1-1 call to AED shock. Younger age (per 10-year increase; ß, 9.97 [95% CI, 4.63-15.31] s; P<0.001) and prior experience with AED (ß, -30.0 [95% CI, -50.1 to -10.0] s; P=0.004) were associated with more rapid time from 9-1-1 call to AED shock. Prior AED use (ß, 6.71 [95% CI, 1.62-11.79]; P=0.011) was associated with improved chest compression fraction percentage. CONCLUSION: Research participants were able to rapidly retrieve an AED from a drone while largely maintaining CPR quality according to American Heart Association guidelines. Chest compression fraction was lower than expected.

Regional differences in outcomes with ablation versus drug therapy for atrial fibrillation: Results from the CABANA trial.

BACKGROUND: The finding of unexpected variations in treatment benefits by geographic region in international clinical trials raises complex questions about the interpretation and generalizability of trial findings. We observed such geographical variations in outcome and in the effectiveness of atrial fibrillation (AF) ablation versus drug therapy in the Catheter Ablation vs Antiarrhythmic Drug Therapy for Atrial Fibrillation (CABANA) trial. This paper describes these differences and investigates potential causes. METHODS: The examination of treatment effects by geographic region was a prespecified analysis. CABANA enrolled patients from 10 countries, with 1,285 patients at 85 North American (NA) sites and 919 at 41 non-NA sites. The primary endpoint was a composite of death, disabling stroke, serious bleeding, or cardiac arrest. Death and first atrial fibrillation recurrence were secondary endpoints. RESULTS: At least 1 primary endpoint event occurred in 157 patients (12.2%) from NA and 33 (3.6%) from non-NA sites over a median 54.9 and 40.5 months of follow-up, respectively (NA/non-NA adjusted hazard ratio (HR) 2.18, 95% confidence interval (CI) 1.48-3.21, P < .001). In NA patients, 78 events occurred in the ablation and 79 in the drug arm, (HR 0.91, 95% CI 0.66, 1.24) while 11 and 22 events occurred in non-NA patients (HR 0.51, 95% CI 0.25,1.05, interaction P = .154). Death occurred in 53 ablation and 51 drug therapy patients in the NA group (HR 0.96, 95% CI 0.65,1.42) and in 5 ablation and 16 drug therapy patients in the non-NA group (HR 0.32, 95% CI 0.12,0.86, interaction P = .044). Adjusting for baseline regional differences or prognostic risk variables did not account for the regional differences in treatment effects. Atrial fibrillation recurrence was reduced by ablation in both regions (NA: HR 0.54, 95% CI 0.46, 0.63; non-NA: HR 0.44, 95% CI 0.30, 0.64, interaction P = .322). CONCLUSIONS: In CABANA, primary outcome events occurred significantly more often in the NA group but assignment to ablation significantly reduced all-cause mortality in the non-NA group only. These differences were not explained by regional variations in procedure effectiveness, safety, or patient characteristics. CLINICAL TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT0091150; https://clinicaltrials.gov/study/NCT00911508.

Severe mucoid degeneration of the anterior cruciate ligament (ACL) treated with conservative arthroscopic debridement and platelet-rich plasma (PRP) injection.

Mucoid degeneration of the anterior cruciate ligament (ACL) can be treated with arthroscopic debridement, however, instability can ensue. Here, we present a fit and active woman in her 60s with severe mucoid degeneration of the ACL who underwent conservative arthroscopic debridement and treatment with intraligamentous administration of platelet-rich plasma (PRP). After 1 month, the patient demonstrated significant improvements in range of motion and pain symptoms, with nil resultant laxity. The patient was able to return to all recreational sporting activities and professional duties. Quantitative MRI conducted 6 months postoperatively revealed improved fibre orientation and formation of new parallel fibres. Compared with the preoperative scan, the mean grey value demonstrated darker pixel intensity with a smaller standard deviation (SD), potentially indicating a more uniform and less variable formation of ligamentous tissue. Therefore, PRP did not cause harm and was associated with benefit in combination with arthroscopic debridement.

Prognostic Impact of Repeated NT-proBNP Measurements in Patients With Heart Failure With Reduced Ejection Fraction.

BACKGROUND: Although clinical studies have demonstrated the association between a single N-terminal pro-B-type natriuretic peptide (NT-proBNP) measurement and clinical outcomes in chronic heart failure, the biomarker is frequently measured serially in clinical practice. OBJECTIVES: The aim of this study was to determine the added prognostic value of repeated NT-proBNP measurements compared with single measurements alone for chronic heart failure patients. METHODS: In the GUIDE-IT (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure) study, 894 study participants with chronic heart failure with reduced ejection fraction were enrolled at 45 outpatient sites in the United States and Canada. Repeated NT-proBNP levels were measured over a 2-year study period. Associations between repeated NT-proBNP measurements and trial endpoints were assessed using a joint longitudinal and survival model. RESULTS: After adjustment for baseline covariates, each doubling of the baseline NT-proBNP level was associated with a HR of 1.17 (95% CI: 1.08-1.28; P = 0.0003) for the primary trial endpoint of cardiovascular death or heart failure hospitalization. Serial measurements increased the adjusted HR for the primary trial endpoint to 1.66 (95% CI: 1.50-1.84; P < 0.0001), and a similar increased risk was observed across secondary trial endpoints. In joint modeling, an increase in NT-proBNP occurred weeks before the onset of adjudicated events. CONCLUSIONS: Repeated NT-proBNP measurements are a strong predictor of outcomes in heart failure with reduced ejection fraction with an increase in concentration occurring well before event onset. These results may support routine NT-proBNP monitoring to assist in clinical decision making. (Guiding Evidence Based Therapy Using Biomarker Intensified Treatment in Heart Failure [GUIDE-IT]; NCT01685840).

Cost-Effectiveness of Vericiguat in Patients With Heart Failure With Reduced Ejection Fraction: The VICTORIA Randomized Clinical Trial.

BACKGROUND: The VICTORIA trial (Vericiguat Global Study in Subjects With Heart Failure With Reduced Ejection Fraction) demonstrated that, in patients with high-risk heart failure, vericiguat reduced the primary composite outcome of cardiovascular death or heart failure hospitalization relative to placebo. The hazard ratio for all-cause mortality was 0.95 (95% CI, 0.84-1.07). In a prespecified analysis, treatment effects varied substantially as a function of baseline NT-proBNP (N-terminal pro-B-type natriuretic peptide) levels, with survival benefit for vericiguat in the lower NT-proBNP quartiles (hazard ratio, 0.82 [95% CI, 0.69-0.97]) and no benefit in the highest NT-proBNP quartile (hazard ratio, 1.14 [95% CI, 0.95-1.38]). An economic analysis was a major secondary objective of the VICTORIA research program. METHODS: Medical resource use data were collected for all VICTORIA patients (N=5050). Costs were estimated by applying externally derived US cost weights to resource use counts. Life expectancy was projected from patient-level empirical trial survival results with the use of age-based survival modeling methods. Quality-of-life adjustments were based on prospectively collected EQ-5D-based utilities. The primary outcome was the incremental cost-effectiveness ratio, comparing vericiguat with placebo, assessed from the US health care sector perspective over a lifetime horizon. Cost-effectiveness was estimated using the total VICTORIA cohort, both with and without interaction between treatment and baseline NT-proBNP. RESULTS: Life expectancy modeling results varied according to whether the observed heterogeneity of treatment effect by baseline NT-proBNP values was incorporated into the modeling. Including the interaction term, the vericiguat arm had an estimated quality-adjusted life expectancy of 4.56 quality-adjusted life-years (QALYs) compared with 4.13 QALYs for placebo (incremental discounted QALY, 0.43). Without the treatment heterogeneity/interaction term, vericiguat had 4.50 QALYs compared with 4.33 QALYs for placebo (incremental discounted QALY, 0.17). Incremental discounted costs (vericiguat minus placebo) were $28 546 with the treatment interaction and $20 948 without it. Corresponding incremental cost-effectiveness ratios were $66 509 per QALY allowing for treatment heterogeneity and $124 512 without heterogeneity. CONCLUSIONS: Vericiguat use in the VICTORIA trial met criteria for intermediate value, but the incremental cost-effectiveness ratio estimates were sensitive to whether the analysis accounted for observed NT-proBNP treatment effect heterogeneity. The cost-effectiveness of vericiguat was driven by the projected incremental life expectancy among patients in the lowest 3 quartiles of NT-proBNP. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02861534.

Benchmarking Quantum Simulators Using Ergodic Quantum Dynamics.

We propose and analyze a sample-efficient protocol to estimate the fidelity between an experimentally prepared state and an ideal target state, applicable to a wide class of analog quantum simulators without advanced spatiotemporal control. Our protocol relies on universal fluctuations emerging from generic Hamiltonian dynamics, which we discover in the present work. It does not require fine-tuned control over state preparation, quantum evolution, or readout capability, while achieving near optimal sample complexity: a percent-level precision is obtained with ∼10^{3} measurements, independent of system size. Furthermore, the accuracy of our fidelity estimation improves exponentially with increasing system size. We numerically demonstrate our protocol in a variety of quantum simulator platforms, including quantum gas microscopes, trapped ions, and Rydberg atom arrays. We discuss applications of our method for tasks such as multiparameter estimation of quantum states and processes.

Comparison of an Initial Risk-Based Testing Strategy vs Usual Testing in Stable Symptomatic Patients With Suspected Coronary Artery Disease: The PRECISE Randomized Clinical Trial.

Importance: Trials showing equivalent or better outcomes with initial evaluation using coronary computed tomography angiography (cCTA) compared with stress testing in patients with stable chest pain have informed guidelines but raise questions about overtesting and excess catheterization. Objective: To test a modified initial cCTA strategy designed to improve clinical efficiency vs usual testing (UT). Design, Setting, and Participants: This was a pragmatic randomized clinical trial enrolling participants from December 3, 2018, to May 18, 2021, with a median of 11.8 months of follow-up. Patients from 65 North American and European sites with stable symptoms of suspected coronary artery disease (CAD) and no prior testing were randomly assigned 1:1 to precision strategy (PS) or UT. Interventions: PS incorporated the Prospective Multicenter Imaging Study for the Evaluation of Chest Pain (PROMISE) minimal risk score to quantitatively select minimal-risk participants for deferred testing, assigning all others to cCTA with selective CT-derived fractional flow reserve (FFR-CT). UT included site-selected stress testing or catheterization. Site clinicians determined subsequent care. Main Outcomes and Measures: Outcomes were clinical efficiency (invasive catheterization without obstructive CAD) and safety (death or nonfatal myocardial infarction [MI]) combined into a composite primary end point. Secondary end points included safety components of the primary outcome and medication use. Results: A total of 2103 participants (mean [SD] age, 58.4 [11.5] years; 1056 male [50.2%]) were included in the study, and 422 [20.1%] were classified as minimal risk. The primary end point occurred in 44 of 1057 participants (4.2%) in the PS group and in 118 of 1046 participants (11.3%) in the UT group (hazard ratio [HR], 0.35; 95% CI, 0.25-0.50). Clinical efficiency was higher with PS, with lower rates of catheterization without obstructive disease (27 [2.6%]) vs UT participants (107 [10.2%]; HR, 0.24; 95% CI, 0.16-0.36). The safety composite of death/MI was similar (HR, 1.52; 95% CI, 0.73-3.15). Death occurred in 5 individuals (0.5%) in the PS group vs 7 (0.7%) in the UT group (HR, 0.71; 95% CI, 0.23-2.23), and nonfatal MI occurred in 13 individuals (1.2%) in the PS group vs 5 (0.5%) in the UT group (HR, 2.65; 95% CI, 0.96-7.36). Use of lipid-lowering (450 of 900 [50.0%] vs 365 of 873 [41.8%]) and antiplatelet (321 of 900 [35.7%] vs 237 of 873 [27.1%]) medications at 1 year was higher in the PS group compared with the UT group (both P < .001). Conclusions and Relevance: An initial diagnostic approach to stable chest pain starting with quantitative risk stratification and deferred testing for minimal-risk patients and cCTA with selective FFR-CT in all others increased clinical efficiency relative to UT at 1 year. Additional randomized clinical trials are needed to verify these findings, including safety. Trial Registration: ClinicalTrials.gov Identifier: NCT03702244.

Deferred Testing in Stable Outpatients With Suspected Coronary Artery Disease: A Prespecified Secondary Analysis of the PRECISE Randomized Clinical Trial.

Importance: Guidelines recommend deferral of testing for symptomatic people with suspected coronary artery disease (CAD) and low pretest probability. To our knowledge, no randomized trial has prospectively evaluated such a strategy. Objective: To assess process of care and health outcomes in people identified as minimal risk for CAD when testing is deferred. Design, Setting, and Participants: This randomized, pragmatic effectiveness trial included prespecified subgroup analysis of the PRECISE trial at 65 North American and European sites. Participants identified as minimal risk by the validated PROMISE minimal risk score (PMRS) were included. Intervention: Randomization to a precision strategy using the PMRS to assign those with minimal risk to deferred testing and others to coronary computed tomography angiography with selective computed tomography-derived fractional flow reserve, or to usual testing (stress testing or catheterization with PMRS masked). Randomization was stratified by PMRS risk. Main Outcome: Composite of all-cause death, nonfatal myocardial infarction (MI), or catheterization without obstructive CAD through 12 months. Results: Among 2103 participants, 422 were identified as minimal risk (20%) and randomized to deferred testing (n = 214) or usual testing (n = 208). Mean age (SD) was 46 (8.6) years; 304 were women (72%). During follow-up, 138 of those randomized to deferred testing never had testing (64%), whereas 76 had a downstream test (36%) (at median [IQR] 48 [15-78] days) for worsening (30%), uncontrolled (10%), or new symptoms (6%), or changing clinician preference (19%) or participant preference (10%). Results were normal for 96% of these tests. The primary end point occurred in 2 deferred testing (0.9%) and 13 usual testing participants (6.3%) (hazard ratio, 0.15; 95% CI, 0.03-0.66; P = .01). No death or MI was observed in the deferred testing participants, while 1 noncardiovascular death and 1 MI occurred in the usual testing group. Two participants (0.9%) had catheterizations without obstructive CAD in the deferred testing group and 12 (5.8%) with usual testing (P = .02). At baseline, 70% of participants had frequent angina and there was similar reduction of frequent angina to less than 20% at 12 months in both groups. Conclusion and Relevance: In symptomatic participants with suspected CAD, identification of minimal risk by the PMRS guided a strategy of initially deferred testing. The strategy was safe with no observed adverse outcome events, fewer catheterizations without obstructive CAD, and similar symptom relief compared with usual testing. Trial Registration: ClinicalTrials.gov Identifier: NCT03702244.

Surgical or Percutaneous Repair of Sinus of Valsalva Rupture: Case Series and Literature Review.

The rupture of the sinus of the Valsalva aneurysm is a rare but very serious condition. Rapid and accurate diagnosis and prompt treatment are critical for these cases. We present two cases of sinus of Valsalva ruptures. One case was managed with open surgical repair and the second case was treated percutaneously. We have discussed these two therapeutic approaches available to treat sinus of Valsalva rupture.