Researching COVID to enhance recovery (RECOVER) pediatric study protocol: Rationale, objectives and design.

IMPORTANCE: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. OBSERVATIONS: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's REsearching COVID to Enhance Recovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of four cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study (n = 10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n = 6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n = 6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n = 600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. CONCLUSIONS AND RELEVANCE: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. CLINICAL TRIALS.GOV IDENTIFIER: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

Development and external validation of a dynamic risk score for early prediction of cardiogenic shock in cardiac intensive care units using machine learning.

BACKGROUND: Myocardial infarction and heart failure are major cardiovascular diseases that affect millions of people in the US with the morbidity and mortality being highest among patients who develop cardiogenic shock. Early recognition of cardiogenic shock allows prompt implementation of treatment measures. Our objective is to develop a new dynamic risk score, called CShock, to improve early detection of cardiogenic shock in cardiac intensive care unit (ICU). METHODS: We developed and externally validated a deep learning-based risk stratification tool, called CShock, for patients admitted into the cardiac ICU with acute decompensated heart failure and/or myocardial infarction to predict onset of cardiogenic shock. We prepared a cardiac ICU dataset using MIMIC-III database by annotating with physician adjudicated outcomes. This dataset that consisted of 1500 patients with 204 having cardiogenic/mixed shock was then used to train CShock. The features used to train the model for CShock included patient demographics, cardiac ICU admission diagnoses, routinely measured laboratory values and vital signs, and relevant features manually extracted from echocardiogram and left heart catheterization reports. We externally validated the risk model on the New York University (NYU) Langone Health cardiac ICU database that was also annotated with physician adjudicated outcomes. The external validation cohort consisted of 131 patients with 25 patients experiencing cardiogenic/mixed shock. RESULTS: CShock achieved an area under the receiver operator characteristic curve (AUROC) of 0.821 (95% CI 0.792-0.850). CShock was externally validated in the more contemporary NYU cohort and achieved an AUROC of 0.800 (95% CI 0.717-0.884), demonstrating its generalizability in other cardiac ICUs. Having an elevated heart rate is most predictive of cardiogenic shock development based on Shapley values. The other top ten predictors are having an admission diagnosis of myocardial infarction with ST-segment elevation, having an admission diagnosis of acute decompensated heart failure, Braden Scale, Glasgow Coma Scale, Blood urea nitrogen, Systolic blood pressure, Serum chloride, Serum sodium, and Arterial blood pH. CONCLUSIONS: The novel CShock score has the potential to provide automated detection and early warning for cardiogenic shock and improve the outcomes for the millions of patients who suffer from myocardial infarction and heart failure.

Association of hepatokines with markers of endothelial dysfunction and vascular reactivity in obese adolescents.

OBJECTIVES: Obesity-induced insulin resistance (IR) is known to influence hepatic cytokines (hepatokines), including fibroblast growth factor (FGF-21), fetuin-A, and chemerin. This study aimed to investigate the association between hepatokines and markers of endothelial dysfunction and vascular reactivity in obese adolescents. METHODS: A total of 45 obese adolescents were categorized into three groups based on glucose tolerance: normal glucose tolerance (NGT), prediabetes (PD), and type 2 diabetes (T2D). We examined the relationships between FGF-21, fetuin-A, and chemerin with endothelial markers (plasminogen activator inhibitor-1 [PAI-1], intercellular adhesion molecule-1 [ICAM-1], and vascular cell adhesion marker-1 [VCAM-1]) and vascular surrogates (brachial artery reactivity testing [BART] and peak reactive hyperemia [PRH]). RESULTS: Obese adolescents (age 16.2±1.2 years; 62 % female, 65 % Hispanic) with NGT (n=20), PD (n=14), and T2D (n=11) had significant differences between groups in BMI; waist-hip ratio (p=0.05), systolic BP (p=0.008), LDL-C (p=0.02), PAI-1 (p<0.001). FGF-21 pg/mL (mean±SD: NGT vs. PD vs. T2D 54±42; 266±286; 160±126 p=0.006) and fetuin-A ng/mL (266±80; 253±66; 313±50 p=0.018), were significantly different while chemerin ng/mL (26±5; 31±10; 28±2) did not significantly differ between the groups. Positive correlations were found between chemerin and both PAI-1 (r=0.6; p=0.05) and ICAM-1 (r=0.6; p=0.05), FGF-21 and PAI-1 (r=0.6; p<0.001), and fetuin-A with TNFα (r=-0.4; p=0.05). Negative correlations were found between chemerin and PRH (r= -0.5; p=0.017) and fetuin-A and PRH (r=-0.4; p=0.05). CONCLUSIONS: In our cohort, IR predicted higher FGF-21 levels suggesting a linear relationship may exist between the two parameters. Hepatokines can augment alterations in the microvascular milieu in obese adolescents as demonstrated by their associations with the markers PAI-1, ICAM-1, and PRH.

Researching COVID to enhance recovery (RECOVER) tissue pathology study protocol: Rationale, objectives, and design.

IMPORTANCE: SARS-CoV-2 infection can result in ongoing, relapsing, or new symptoms or organ dysfunction after the acute phase of infection, termed Post-Acute Sequelae of SARS-CoV-2 (PASC), or long COVID. The characteristics, prevalence, trajectory and mechanisms of PASC are poorly understood. The objectives of the Researching COVID to Enhance Recovery (RECOVER) tissue pathology study (RECOVER-Pathology) are to: (1) characterize prevalence and types of organ injury/disease and pathology occurring with PASC; (2) characterize the association of pathologic findings with clinical and other characteristics; (3) define the pathophysiology and mechanisms of PASC, and possible mediation via viral persistence; and (4) establish a post-mortem tissue biobank and post-mortem brain imaging biorepository. METHODS: RECOVER-Pathology is a cross-sectional study of decedents dying at least 15 days following initial SARS-CoV-2 infection. Eligible decedents must meet WHO criteria for suspected, probable, or confirmed infection and must be aged 18 years or more at the time of death. Enrollment occurs at 7 sites in four U.S. states and Washington, DC. Comprehensive autopsies are conducted according to a standardized protocol within 24 hours of death; tissue samples are sent to the PASC Biorepository for later analyses. Data on clinical history are collected from the medical records and/or next of kin. The primary study outcomes include an array of pathologic features organized by organ system. Causal inference methods will be employed to investigate associations between risk factors and pathologic outcomes. DISCUSSION: RECOVER-Pathology is the largest autopsy study addressing PASC among US adults. Results of this study are intended to elucidate mechanisms of organ injury and disease and enhance our understanding of the pathophysiology of PASC.

Implementing a Clinical Decision Support Tool to Improve Physical Activity.

BACKGROUND: Currently, only about half of U.S. adults achieve current physical activity guidelines. Routine physical activity is not regularly assessed, nor are patients routinely counseled by their healthcare provider on achieving recommended levels. The three-question physical activity vital sign (PAVS) was developed to assess physical activity duration and intensity and identify adults not meeting physical activity guidelines. Clinical decision support provided via a best practice advisory in an electronic health record (EHR) system can be triggered as a prompt, reminding healthcare providers to implement the best practice intervention when appropriate. Remote patient monitoring of physical activity can provide objective data in the EHR. OBJECTIVES: This study aimed to evaluate the feasibility and clinical utility of embedding the PAVS and a triggered best practice advisor into the EHR in an ambulatory preventive cardiology practice setting to alert providers to patients reporting low physical activity and prompt healthcare providers to counsel these patients as needed. METHODS: Three components based in the EHR were integrated for the purpose of this study: Patients completed the PAVS through their electronic patient portal prior to an office visit, a best practice advisory was created to prompt providers to counsel patients who reported low levels of physical activity, and remote patient monitoring via Fitbit synced to the EHR provided objective physical activity data. The intervention was pilot-tested in the Epic EHR for 1 year (July 1, 2021 to June 30, 2022). Qualitative feedback on the intervention from both providers and patients was obtained at the completion of the study. RESULTS: Monthly assessments of the use of the PAVS and best practice advisory and remote patient monitoring were completed. Patients' completion of the PAVS varied from 35% to 48% per month. The best practice advisory was signed by providers between 2% and 65% and was acknowledged by 2%-22% per month. The majority (58%) of patients were able to sync a Fitbit device to their EHR for remote monitoring. DISCUSSION: Although uptake of each component needs improvement, this pilot demonstrated the feasibility of incorporating a physical activity promotion intervention into the EHR. Qualitative feedback provided guidance for future implementation.

Impact of Visit Volume on the Effectiveness of Electronic Tools to Improve Heart Failure Care.

BACKGROUND: Electronic health record (EHR) tools can improve prescribing of guideline-recommended therapies for heart failure with reduced ejection fraction (HFrEF), but their effectiveness may vary by physician workload. OBJECTIVES: This paper aims to assess whether physician workload modifies the effectiveness of EHR tools for HFrEF. METHODS: This was a prespecified subgroup analysis of the BETTER CARE-HF (Building Electronic Tools to Enhance and Reinforce Cardiovascular Recommendations for Heart Failure) cluster-randomized trial, which compared effectiveness of an alert vs message vs usual care on prescribing of mineralocorticoid antagonists (MRAs). The trial included adults with HFrEF seen in cardiology offices who were eligible for and not prescribed MRAs. Visit volume was defined at the cardiologist-level as number of visits per 6-month study period (high = upper tertile vs non-high = remaining). Analysis at the patient-level used likelihood ratio test for interaction with log-binomial models. RESULTS: Among 2,211 patients seen by 174 cardiologists, 932 (42.2%) were seen by high-volume cardiologists (median: 1,853; Q1-Q3: 1,637-2,225 visits/6 mo; and median: 10; Q1-Q3: 9-12 visits/half-day). MRA was prescribed to 5.5% in the high-volume vs 14.8% in the non-high-volume groups in the usual care arm, 10.3% vs 19.6% in the message arm, and 31.2% vs 28.2% in the alert arm, respectively. Visit volume modified treatment effect (P for interaction = 0.02) such that the alert was more effective in the high-volume group (relative risk: 5.16; 95% CI: 2.57-10.4) than the non-high-volume group (relative risk: 1.93; 95% CI: 1.29-2.90). CONCLUSIONS: An EHR-embedded alert increased prescribing by >5-fold among patients seen by high-volume cardiologists. Our findings support use of EHR alerts, especially in busy practice settings. (Building Electronic Tools to Enhance and Reinforce Cardiovascular Recommendations for Heart Failure [BETTER CARE-HF]; NCT05275920).

Researching COVID to enhance recovery (RECOVER) pregnancy study: Rationale, objectives and design.

IMPORTANCE: Pregnancy induces unique physiologic changes to the immune response and hormonal changes leading to plausible differences in the risk of developing post-acute sequelae of SARS-CoV-2 (PASC), or Long COVID. Exposure to SARS-CoV-2 during pregnancy may also have long-term ramifications for exposed offspring, and it is critical to evaluate the health outcomes of exposed children. The National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC aims to evaluate the long-term sequelae of SARS-CoV-2 infection in various populations. RECOVER-Pregnancy was designed specifically to address long-term outcomes in maternal-child dyads. METHODS: RECOVER-Pregnancy cohort is a combined prospective and retrospective cohort that proposes to enroll 2,300 individuals with a pregnancy during the COVID-19 pandemic and their offspring exposed and unexposed in utero, including single and multiple gestations. Enrollment will occur both in person at 27 sites through the Eunice Kennedy Shriver National Institutes of Health Maternal-Fetal Medicine Units Network and remotely through national recruitment by the study team at the University of California San Francisco (UCSF). Adults with and without SARS-CoV-2 infection during pregnancy are eligible for enrollment in the pregnancy cohort and will follow the protocol for RECOVER-Adult including validated screening tools, laboratory analyses and symptom questionnaires followed by more in-depth phenotyping of PASC on a subset of the overall cohort. Offspring exposed and unexposed in utero to SARS-CoV-2 maternal infection will undergo screening tests for neurodevelopment and other health outcomes at 12, 18, 24, 36 and 48 months of age. Blood specimens will be collected at 24 months of age for SARS-CoV-2 antibody testing, storage and anticipated later analyses proposed by RECOVER and other investigators. DISCUSSION: RECOVER-Pregnancy will address whether having SARS-CoV-2 during pregnancy modifies the risk factors, prevalence, and phenotype of PASC. The pregnancy cohort will also establish whether there are increased risks of adverse long-term outcomes among children exposed in utero. CLINICAL TRIALS.GOV IDENTIFIER: Clinical Trial Registration: http://www.clinicaltrials.gov. Unique identifier: NCT05172011.

DIAPH1-MFN2 interaction regulates mitochondria-SR/ER contact and modulates ischemic/hypoxic stress.

Inter-organelle contact and communication between mitochondria and sarco/endoplasmic reticulum (SR/ER) maintain cellular homeostasis and are profoundly disturbed during tissue ischemia. We tested the hypothesis that the formin Diaphanous-1 (DIAPH1), which regulates actin dynamics, signal transduction and metabolic functions, contributes to these processes. We demonstrate that DIAPH1 interacts directly with Mitofusin-2 (MFN2) to shorten mitochondria-SR/ER distance, thereby enhancing mitochondria-ER contact in cells including cardiomyocytes, endothelial cells and macrophages. Solution structure studies affirm the interaction between the Diaphanous Inhibitory Domain and the cytosolic GTPase domain of MFN2. In male rodent and human cardiomyocytes, DIAPH1-MFN2 interaction regulates mitochondrial turnover, mitophagy, and oxidative stress. Introduction of synthetic linker construct, which shorten the mitochondria-SR/ER distance, mitigated the molecular and functional benefits of DIAPH1 silencing in ischemia. This work establishes fundamental roles for DIAPH1-MFN2 interaction in the regulation of mitochondria-SR/ER contact networks. We propose that targeting pathways that regulate DIAPH1-MFN2 interactions may facilitate recovery from tissue ischemia.

Genetic Architecture of Dilated Cardiomyopathy in Individuals of African and European Ancestry.

Importance: Black patients with dilated cardiomyopathy (DCM) have increased familial risk and worse outcomes than White patients, but most DCM genetic data are from White patients. Objective: To compare the rare variant genetic architecture of DCM by genomic ancestry within a diverse population of patients with DCM. Design: Cross-sectional study enrolling patients with DCM who self-identified as non-Hispanic Black, Hispanic, or non-Hispanic White from June 7, 2016, to March 15, 2020, at 25 US advanced heart failure programs. Variants in 36 DCM genes were adjudicated as pathogenic, likely pathogenic, or of uncertain significance. Exposure: Presence of DCM. Main Outcomes and Measures: Variants in DCM genes classified as pathogenic/likely pathogenic/uncertain significance and clinically actionable (pathogenic/likely pathogenic). Results: A total of 505, 667, and 26 patients with DCM of predominantly African, European, or Native American genomic ancestry, respectively, were included. Compared with patients of European ancestry, a lower percentage of patients of African ancestry had clinically actionable variants (8.2% [95% CI, 5.2%-11.1%] vs 25.5% [95% CI, 21.3%-29.6%]), reflecting the lower odds of a clinically actionable variant for those with any pathogenic variant/likely pathogenic variant/variant of uncertain significance (odds ratio, 0.25 [95% CI, 0.17-0.37]). On average, patients of African ancestry had fewer clinically actionable variants in TTN (difference, -0.09 [95% CI, -0.14 to -0.05]) and other genes with predicted loss of function as a disease-causing mechanism (difference, -0.06 [95% CI, -0.11 to -0.02]). However, the number of pathogenic variants/likely pathogenic variants/variants of uncertain significance was more comparable between ancestry groups (difference, -0.07 [95% CI, -0.22 to 0.09]) due to a larger number of non-TTN non-predicted loss of function variants of uncertain significance, mostly missense, in patients of African ancestry (difference, 0.15 [95% CI, 0.00-0.30]). Published clinical case-based evidence supporting pathogenicity was less available for variants found only in patients of African ancestry (P < .001). Conclusion and Relevance: Patients of African ancestry with DCM were less likely to have clinically actionable variants in DCM genes than those of European ancestry due to differences in genetic architecture and a lack of representation of African ancestry in clinical data sets.

Major Adverse Cardiovascular Events After Colchicine Administration Before Percutaneous Coronary Intervention: Follow-Up of the Colchicine-PCI Trial.

Periprocedural inflammation is associated with major adverse cardiovascular events in patients who undergo percutaneous coronary intervention (PCI). In the contemporary era, 5% to 10% of patients develop restenosis, and in the acute coronary syndrome cohort, there remains a 20% major adverse cardiovascular events rate at 3 years, half of which are culprit-lesion related. In patients at risk of restenosis, colchicine has been shown to reduce restenosis when started within 24 hours of PCI and continued for 6 months thereafter, compared with placebo. The Colchicine-PCI trial, which randomized patients to a 1-time loading dose of colchicine or placebo 1 to 2 hours before PCI, showed a dampening of the inflammatory response to PCI but no difference in postprocedural myocardial injury. On mean follow-up of 3.3 years, the incidence of major adverse cardiovascular events did not differ between colchicine and placebo groups (32.5% vs 34.9%; hazard ratio 0.95 [0.68 to 1.34]).

Rare Variant Genetics and Dilated Cardiomyopathy Severity: The DCM Precision Medicine Study.

BACKGROUND: Dilated cardiomyopathy (DCM) can lead to advanced disease, defined herein as necessitating a durable left ventricular assist device or a heart transplant (LVAD/HT). DCM is known to have a genetic basis, but the association of rare variant genetics with advanced DCM has not been studied. METHODS: We analyzed clinical and genetic sequence data from patients enrolled between 2016 and 2021 in the US multisite DCM Precision Medicine Study, which was a geographically diverse, multiracial, multiethnic cohort. Clinical evaluation included standardized patient interview and medical record query forms. DCM severity was classified into 3 groups: patients with advanced disease with LVAD/HT; patients with an implantable cardioverter defibrillator (ICD) only; or patients with no ICD or LVAD/HT. Rare variants in 36 DCM genes were classified as pathogenic or likely pathogenic or variants of uncertain significance. Confounding factors we considered included demographic characteristics, lifestyle factors, access to care, DCM duration, and comorbidities. Crude and adjusted associations between DCM severity and rare variant genetic findings were assessed using multinomial models with generalized logit link. RESULTS: Patients' mean (SD) age was 51.9 (13.6) years; 42% were of African ancestry, 56% were of European ancestry, and 44% were female. Of 1198 patients, 347 had LVAD/HT, 511 had an ICD, and 340 had no LVAD/HT or ICD. The percentage of patients with pathogenic or likely pathogenic variants was 26.2%, 15.9%, and 15.0% for those with LVAD/HT, ICD only, or neither, respectively. After controlling for sociodemographic characteristics and comorbidities, patients with DCM with LVAD/HT were more likely than those without LVAD/HT or ICD to have DCM-related pathogenic or likely pathogenic rare variants (odds ratio, 2.3 [95% CI, 1.5-3.6]). The association did not differ by ancestry. Rare variant genetic findings were similar between patients with DCM with an ICD and those without LVAD/HT or ICD. CONCLUSIONS: Advanced DCM was associated with higher odds of rare variants in DCM genes adjudicated as pathogenic or likely pathogenic, compared with individuals with less severe DCM. This finding may help assess the risk of outcomes in management of patients with DCM and their at-risk family members. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03037632.

The Impact of an Electronic Best Practice Advisory on Patients' Physical Activity and Cardiovascular Risk Profile.

BACKGROUND: Regular physical activity (PA) is a component of cardiovascular health and is associated with a lower risk of cardiovascular disease (CVD). However, only about half of US adults achieved the current PA recommendations. OBJECTIVE: The study purpose was to implement PA counseling using a clinical decision support tool in a preventive cardiology clinic and to assess changes in CVD risk factors in a sample of patients enrolled over 12 weeks of PA monitoring. METHODS: This intervention, piloted for 1 year, had 3 components embedded in the electronic health record: assessment of patients' PA, an electronic prompt for providers to counsel patients reporting low PA, and patient monitoring using a Fitbit. Cardiovascular disease risk factors included PA (self-report and Fitbit), body mass index, blood pressure, lipids, and cardiorespiratory fitness assessed with the 6-minute walk test. Depression and quality of life were also assessed. Paired t tests assessed changes in CVD risk. RESULTS: The sample who enrolled in the remote patient monitoring (n = 59) were primarily female (51%), White adults (76%) with a mean age of 61.13 ± 11.6 years. Self-reported PA significantly improved over 12 weeks (P = .005), but not Fitbit steps (P = .07). There was a significant improvement in cardiorespiratory fitness (469 ± 108 vs 494 ± 132 m, P = .0034), and 23 participants (42%) improved at least 25 m, signifying a clinically meaningful improvement. Only 4 participants were lost to follow-up over 12 weeks of monitoring. CONCLUSIONS: Patients may need more frequent reminders to be active after an initial counseling session, perhaps getting automated messages based on their step counts syncing to their electronic health record.

Risk of post-acute sequelae of SARS-CoV-2 infection associated with pre-coronavirus disease obstructive sleep apnea diagnoses: an electronic health record-based analysis from the RECOVER initiative.

STUDY OBJECTIVES: Obstructive sleep apnea (OSA) has been associated with more severe acute coronavirus disease-2019 (COVID-19) outcomes. We assessed OSA as a potential risk factor for Post-Acute Sequelae of SARS-CoV-2 (PASC). METHODS: We assessed the impact of preexisting OSA on the risk for probable PASC in adults and children using electronic health record data from multiple research networks. Three research networks within the REsearching COVID to Enhance Recovery initiative (PCORnet Adult, PCORnet Pediatric, and the National COVID Cohort Collaborative [N3C]) employed a harmonized analytic approach to examine the risk of probable PASC in COVID-19-positive patients with and without a diagnosis of OSA prior to pandemic onset. Unadjusted odds ratios (ORs) were calculated as well as ORs adjusted for age group, sex, race/ethnicity, hospitalization status, obesity, and preexisting comorbidities. RESULTS: Across networks, the unadjusted OR for probable PASC associated with a preexisting OSA diagnosis in adults and children ranged from 1.41 to 3.93. Adjusted analyses found an attenuated association that remained significant among adults only. Multiple sensitivity analyses with expanded inclusion criteria and covariates yielded results consistent with the primary analysis. CONCLUSIONS: Adults with preexisting OSA were found to have significantly elevated odds of probable PASC. This finding was consistent across data sources, approaches for identifying COVID-19-positive patients, and definitions of PASC. Patients with OSA may be at elevated risk for PASC after SARS-CoV-2 infection and should be monitored for post-acute sequelae.

Researching COVID to enhance recovery (RECOVER) pregnancy study: Rationale, objectives and design.

Importance: Pregnancy induces unique physiologic changes to the immune response and hormonal changes leading to plausible differences in the risk of developing post-acute sequelae of SARS-CoV-2 (PASC), or Long COVID. Exposure to SARS-CoV-2 during pregnancy may also have long-term ramifications for exposed offspring, and it is critical to evaluate the health outcomes of exposed children. The National Institutes of Health (NIH) Researching COVID to Enhance Recovery (RECOVER) Multi-site Observational Study of PASC aims to evaluate the long-term sequelae of SARS-CoV-2 infection in various populations. RECOVER- Pregnancy was designed specifically to address long-term outcomes in maternal-child dyads. Methods: RECOVER-Pregnancy cohort is a combined prospective and retrospective cohort that proposes to enroll 2,300 individuals with a pregnancy during the COVID-19 pandemic and their offspring exposed and unexposed in utero, including single and multiple gestations. Enrollment will occur both in person at 27 sites through the Eunice Kennedy Shriver National Institutes of Health Maternal-Fetal Medicine Units Network and remotely through national recruitment by the study team at the University of California San Francisco (UCSF). Adults with and without SARS-CoV-2 infection during pregnancy are eligible for enrollment in the pregnancy cohort and will follow the protocol for RECOVER-Adult including validated screening tools, laboratory analyses and symptom questionnaires followed by more in-depth phenotyping of PASC on a subset of the overall cohort. Offspring exposed and unexposed in utero to SARS-CoV-2 maternal infection will undergo screening tests for neurodevelopment and other health outcomes at 12, 18, 24, 36 and 48 months of age. Blood specimens will be collected at 24 months of age for SARS-CoV-2 antibody testing, storage and anticipated later analyses proposed by RECOVER and other investigators. Discussion: RECOVER-Pregnancy will address whether having SARS-CoV-2 during pregnancy modifies the risk factors, prevalence, and phenotype of PASC. The pregnancy cohort will also establish whether there are increased risks of adverse long-term outcomes among children exposed in utero. Registration: NCT05172024.

Researching COVID to enhance recovery (RECOVER) pediatric study protocol: Rationale, objectives and design.

Importance: The prevalence, pathophysiology, and long-term outcomes of COVID-19 (post-acute sequelae of SARS-CoV-2 [PASC] or "Long COVID") in children and young adults remain unknown. Studies must address the urgent need to define PASC, its mechanisms, and potential treatment targets in children and young adults. Observations: We describe the protocol for the Pediatric Observational Cohort Study of the NIH's RE searching COV ID to E nhance R ecovery (RECOVER) Initiative. RECOVER-Pediatrics is an observational meta-cohort study of caregiver-child pairs (birth through 17 years) and young adults (18 through 25 years), recruited from more than 100 sites across the US. This report focuses on two of five cohorts that comprise RECOVER-Pediatrics: 1) a de novo RECOVER prospective cohort of children and young adults with and without previous or current infection; and 2) an extant cohort derived from the Adolescent Brain Cognitive Development (ABCD) study ( n =10,000). The de novo cohort incorporates three tiers of data collection: 1) remote baseline assessments (Tier 1, n=6000); 2) longitudinal follow-up for up to 4 years (Tier 2, n=6000); and 3) a subset of participants, primarily the most severely affected by PASC, who will undergo deep phenotyping to explore PASC pathophysiology (Tier 3, n=600). Youth enrolled in the ABCD study participate in Tier 1. The pediatric protocol was developed as a collaborative partnership of investigators, patients, researchers, clinicians, community partners, and federal partners, intentionally promoting inclusivity and diversity. The protocol is adaptive to facilitate responses to emerging science. Conclusions and Relevance: RECOVER-Pediatrics seeks to characterize the clinical course, underlying mechanisms, and long-term effects of PASC from birth through 25 years old. RECOVER-Pediatrics is designed to elucidate the epidemiology, four-year clinical course, and sociodemographic correlates of pediatric PASC. The data and biosamples will allow examination of mechanistic hypotheses and biomarkers, thus providing insights into potential therapeutic interventions. Clinical Trialsgov Identifier: Clinical Trial Registration: http://www.clinicaltrials.gov . Unique identifier: NCT05172011.

Screening for Dilated Cardiomyopathy in At-Risk First-Degree Relatives.

BACKGROUND: Cardiovascular screening is recommended for first-degree relatives (FDRs) of patients with dilated cardiomyopathy (DCM), but the yield of FDR screening is uncertain for DCM patients without known familial DCM, for non-White FDRs, or for DCM partial phenotypes of left ventricular enlargement (LVE) or left ventricular systolic dysfunction (LVSD). OBJECTIVES: This study examined the yield of clinical screening among reportedly unaffected FDRs of DCM patients. METHODS: Adult FDRs of DCM patients at 25 sites completed screening echocardiograms and ECGs. Mixed models accounting for site heterogeneity and intrafamilial correlation were used to compare screen-based percentages of DCM, LVSD, or LVE by FDR demographics, cardiovascular risk factors, and proband genetics results. RESULTS: A total of 1,365 FDRs were included, with a mean age of 44.8 ± 16.9 years, 27.5% non-Hispanic Black, 9.8% Hispanic, and 61.7% women. Among screened FDRs, 14.1% had new diagnoses of DCM (2.1%), LVSD (3.6%), or LVE (8.4%). The percentage of FDRs with new diagnoses was higher for those aged 45 to 64 years than 18 to 44 years. The age-adjusted percentage of any finding was higher among FDRs with hypertension and obesity but did not differ statistically by race and ethnicity (16.2% for Hispanic, 15.2% for non-Hispanic Black, and 13.1% for non-Hispanic White) or sex (14.6% for women and 12.8% for men). FDRs whose probands carried clinically reportable variants were more likely to be identified with DCM. CONCLUSIONS: Cardiovascular screening identified new DCM-related findings among 1 in 7 reportedly unaffected FDRs regardless of race and ethnicity, underscoring the value of clinical screening in all FDRs.

Cluster-Randomized Trial Comparing Ambulatory Decision Support Tools to Improve Heart Failure Care.

BACKGROUND: Mineralocorticoid receptor antagonists (MRAs) are underprescribed for patients with heart failure with reduced ejection fraction (HFrEF). OBJECTIVES: This study sought to compare effectiveness of 2 automated, electronic health record-embedded tools vs usual care on MRA prescribing in eligible patients with HFrEF. METHODS: BETTER CARE-HF (Building Electronic Tools to Enhance and Reinforce Cardiovascular Recommendations for Heart Failure) was a 3-arm, pragmatic, cluster-randomized trial comparing the effectiveness of an alert during individual patient encounters vs a message about multiple patients between encounters vs usual care on MRA prescribing. This study included adult patients with HFrEF, no active MRA prescription, no contraindication to MRAs, and an outpatient cardiologist in a large health system. Patients were cluster-randomized by cardiologist (60 per arm). RESULTS: The study included 2,211 patients (alert: 755, message: 812, usual care [control]: 644), with average age 72.2 years, average ejection fraction 33%, who were predominantly male (71.4%) and White (68.9%). New MRA prescribing occurred in 29.6% of patients in the alert arm, 15.6% in the message arm, and 11.7% in the control arm. The alert more than doubled MRA prescribing compared to usual care (relative risk: 2.53; 95% CI: 1.77-3.62; P < 0.0001) and improved MRA prescribing compared to the message (relative risk: 1.67; 95% CI: 1.21-2.29; P = 0.002). The number of patients with alert needed to result in an additional MRA prescription was 5.6. CONCLUSIONS: An automated, patient-specific, electronic health record-embedded alert increased MRA prescribing compared to both a message and usual care. These findings highlight the potential for electronic health record-embedded tools to substantially increase prescription of life-saving therapies for HFrEF. (Building Electronic Tools to Enhance and Reinforce Cardiovascular Recommendations-Heart Failure [BETTER CARE-HF]; NCT05275920).

Effectiveness of the Family Heart Talk Communication Tool in Improving Family Member Screening for Dilated Cardiomyopathy: Results of a Randomized Trial.

BACKGROUND: Managing disease risk among first-degree relatives of probands diagnosed with a heritable disease is central to precision medicine. A critical component is often clinical screening, which is particularly important for conditions like dilated cardiomyopathy (DCM) that remain asymptomatic until severe disease develops. Nonetheless, probands are frequently ill-equipped to disseminate genetic risk information that motivates at-risk relatives to complete recommended clinical screening. An easily implemented remedy for this key issue has been elusive. METHODS: The DCM Precision Medicine Study developed Family Heart Talk, a booklet designed to help probands with DCM communicate genetic risk and the need for cardiovascular screening to their relatives. The effectiveness of the Family Heart Talk booklet in increasing cardiovascular clinical screening uptake among first-degree relatives was assessed in a multicenter, open-label, cluster-randomized, controlled trial. The primary outcome measured in eligible first-degree relatives was completion of screening initiated within 12 months after proband enrollment. Because probands randomized to the intervention received the booklet at the enrollment visit, eligible first-degree relatives were limited to those who were alive the day after proband enrollment and not enrolled on the same day as the proband. RESULTS: Between June 2016 and March 2020, 1241 probands were randomized (1:1) to receive Family Heart Talk (n=621) or not (n=620) within strata defined by site and self-identified race/ethnicity (non-Hispanic Black, non-Hispanic White, or Hispanic). Final analyses included 550 families (n=2230 eligible first-degree relatives) in the Family Heart Talk arm and 561 (n=2416) in the control arm. A higher percentage of eligible first-degree relatives completed screening in the Family Heart Talk arm (19.5% versus 16.0%), and the odds of screening completion among these first-degree relatives were higher in the Family Heart Talk arm after adjustment for proband randomization stratum, sex, and age quartile (odds ratio, 1.30 [1-sided 95% CI, 1.08-∞]). A prespecified subgroup analysis did not find evidence of heterogeneity in the adjusted intervention odds ratio across race/ethnicity strata (P=0.90). CONCLUSIONS: Family Heart Talk, a booklet that can be provided to patients with DCM by clinicians with minimal additional time investment, was effective in increasing cardiovascular clinical screening among first-degree relatives of these patients. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03037632.

Physician preferences for revascularization in patients with ischemic cardiomyopathy: Defining equipoise from web-based surveys.

Background: The optimal revascularization approach in patients with heart failure with reduced ejection fraction (HFrEF) and ischemic heart disease ("ischemic cardiomyopathy") is unknown. Physician preferences regarding clinical equipoise for mode of revascularization and their willingness to consider offering enrollment in a randomized trial to patients with ischemic cardiomyopathy have not been characterized. Methods: We conducted two anonymous online surveys: 1) a clinical case scenario-based survey to assess willingness to offer clinical trial enrollment for a patient with ischemic cardiomyopathy (overall response rate to email invitation 0.45 %), and 2) a Delphi consensus-building survey to identify specific areas of clinical equipoise (overall response rate to email invitation 37 %). Results: Among 304 physicians responding to the clinical case scenario-based survey, the majority were willing to offer the opportunity for clinical trial enrollment to a prototypical patient with ischemic cardiomyopathy (92 %), and felt that a finding of non-inferiority for PCI vs. CABG would influence their clinical practice (78 %). Among 53 physicians responding to the Delphi consensus-building survey, the median appropriateness rating for CABG was significantly higher than that of PCI (p < 0.0001). In 17 scenarios (11.8 %), there was no difference in CABG or PCI appropriateness ratings, suggesting clinical equipoise in these settings. Conclusions: Our findings demonstrate willingness to consider offering enrollment in a randomized clinical trial and areas of clinical equipoise, two factors that support the feasibility of a randomized trial to compare clinical outcomes after revascularization with CABG vs. PCI in selected patients with ischemic cardiomyopathy, suitable coronary anatomy and co-morbidity profile.