Mitochondria regulate proliferation in adult cardiac myocytes.

Newborn mammalian cardiomyocytes quickly transition from a fetal to an adult phenotype that utilizes mitochondrial oxidative phosphorylation but loses mitotic capacity. We tested whether forced reversal of adult cardiomyocytes back to a fetal glycolytic phenotype would restore proliferative capacity. We deleted Uqcrfs1 (mitochondrial Rieske Iron-Sulfur protein, RISP) in hearts of adult mice. As RISP protein decreased, heart mitochondrial function declined, and glucose utilization increased. Simultaneously, they underwent hyperplastic remodeling during which cardiomyocyte number doubled without cellular hypertrophy. Cellular energy supply was preserved, AMPK activation was absent, and mTOR activation was evident. In ischemic hearts with RISP deletion, new cardiomyocytes migrated into the infarcted region, suggesting the potential for therapeutic cardiac regeneration. RNA-seq revealed upregulation of genes associated with cardiac development and proliferation. Metabolomic analysis revealed a decrease in alpha-ketoglutarate (required for TET-mediated demethylation) and an increase in S-adenosylmethionine (required for methyltransferase activity). Analysis revealed an increase in methylated CpGs near gene transcriptional start sites. Genes that were both differentially expressed and differentially methylated were linked to upregulated cardiac developmental pathways. We conclude that decreased mitochondrial function and increased glucose utilization can restore mitotic capacity in adult cardiomyocytes resulting in the generation of new heart cells, potentially through the modification of substrates that regulate epigenetic modification of genes required for proliferation.

Normative Values of Echocardiographic Chamber Size and Function in Older Healthy Adults: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Echocardiographic (2-dimensional echocardiography) thresholds indicating disease or impaired functional status compared with normal physiological aging in individuals aged ≥65 years are not clearly defined. In the present study, we sought to establish standard values for 2-dimensional echocardiography parameters related to chamber size and function in older adults without cardiopulmonary or cardiometabolic conditions. METHODS: In this cross-sectional study of 3032 individuals who underwent 2-dimensional echocardiography at exam 6 in the MESA (Multi-Ethnic Study of Atherosclerosis), 608 participants fulfilled our inclusion criteria of healthy aging, with normative values defined as the mean ± 1.96 standard deviation and compared across sex and race and ethnicity. Functional status measures included NT-proBNP (N-terminal pro-B-type natriuretic peptide), 6-minute walk distance, and Kansas City Cardiomyopathy Questionnaire. Prognostic performance using MESA cutoffs was compared with established guideline cutoffs using time-to-event analysis. RESULTS: The normative aging cohort (69.5±7.0 years, 46.2% male, 47.5% White) had lower NT-proBNP, higher 6-minute walk distance, and higher (better) Kansas City Cardiomyopathy Questionnaire summary values. Women had significantly smaller chamber sizes and better biventricular systolic function. White participants had the largest chamber dimensions, whereas Chinese participants had the smallest, even after adjustment for body size. Current guidelines identified 81.6% of healthy older adults in MESA as having cardiac abnormalities. CONCLUSIONS: Among a large, diverse group of healthy older adults, we found significant differences in cardiac structure and function by sex and race/ethnicity, which may signal sex-specific cardiac remodeling with advancing age. It is crucial for existing guidelines to consider the observed and clinically significant differences in cardiac structure and function associated with healthy aging. Our study highlights that existing guidelines, which grade abnormalities in echocardiographic cardiac chamber size and function based on younger individuals, may not adequately address the anticipated changes associated with normal aging.

Reference Values for Indexed Echocardiographic Chamber Sizes in Older Adults: The Multi-Ethnic Study of Atherosclerosis.

BACKGROUND: Normalization of echocardiographic chamber measurements for body surface area may result in misclassification of individuals with obesity or sarcopenia. Normalization for alternative measures of body size may be preferable, but there remains a dearth of information on their normative values and association with cardiovascular function metrics. METHODS AND RESULTS: A total of 3032 individuals underwent comprehensive 2-dimensional echocardiography at Exam 6 in MESA (Multi-Ethnic Study of Atherosclerosis). In the subgroup of 608 individuals free of cardiopulmonary disease (69.5±7.0 years, 46% male, 48% White, 17% Chinese, 15% Black, 21% Hispanic), normative values were derived for left and right cardiac chamber measurements across a variety of ratiometric (body surface area, body mass index, height) and allometric (height1.6, height2.7) scaling parameters. Normative upper and lower reference values were provided for each scaling parameter stratified across age groups, sex, and race or ethnicity. Among scaling parameters, body surface area and height were associated with the least variability across race and ethnicity categories and height2.7 was associated with the least variability across sex categories. CONCLUSIONS: In this diverse cohort of community-dwelling older adults, we provide normative values for common echocardiographic parameters across a variety of indexation methods.

Optimal Method for Assessing Right Ventricular to Pulmonary Arterial Coupling in Older Healthy Adults: The Multi-Ethnic Study of Atherosclerosis.

Right ventricular (RV) to pulmonary arterial (PA) coupling describes the ability of the RV to augment contractility in response to increased afterload. Several echocardiographic indexes of RV-PA coupling have been defined; however, the optimal numerator in the coupling ratio is unclear. We sought to establish which of these ratios is best for assessing RV-PA coupling based on their relations with 6-minute walk distance (6MWD), N-terminal pro-B-type natriuretic peptide (NT-proBNP), and the Kansas City Cardiomyopathy Questionnaire (KCCQ) in aging adults. In this study of 1,611 Multi-Ethnic Study of Atherosclerosis participants who underwent echocardiography at Exam 6, we evaluated the association between different numerators, including tricuspid annular planar systolic excursion (TAPSE), fractional area change (FAC), RV free wall strain, and tissue Doppler imaging S' velocity to pulmonary artery systolic pressure (PASP) with 6MWD, NT-proBNP, and KCCQ score, adjusted for socioeconomic and cardiovascular disease risk factors. Our cohort had a mean age of 73 ± 8 years, 54% female, 17% Chinese American, 22% African American, 22% Hispanic, and 39% White participants. The mean ( ± SD) TAPSE/PASP, FAC/PASP, tissue Doppler imaging S' velocity/PASP, and RV free wall strain:PASP ratios were 0.7 ± 0.2, 1.3 ± 0.3, 0.5 ± 0.1, and 0.8 ± 0.2, respectively. All RV-PA coupling indices decreased with age (p <0.0001 for all). TAPSE:PASP ratio was lower in older (³85 years) female (0.59 ± 0.14) versus male (0.65 ± 0.17) participants (p = 0.01), whereas FAC/PASP ratio was higher in the same female versus male participants (p <0.01). TAPSE/PASP and FAC/PASP ratios were significantly and strongly associated with all NT-proBNP, 6MWD, and KCCQ scores in fully adjusted and receiver operating characteristic analysis. In older community-dwelling adults free of heart failure and pulmonary hypertension, both FAC/PASP and TAPSE:PASP ratios are optimal for assessment of RV-PA coupling based on its association with 6MWD, NT-proBNP, and KCCQ score. FAC/PASP ratio has the additional benefit of reflecting age and gender-related geometric and functional changes.

Multi-Ethnic Study of Atherosclerosis Early Heart Failure Study: Rationale, Design, and Baseline Characteristics.

BACKGROUND: Current prevalence estimates of heart failure (HF) are primarily based on self-report or HF hospitalizations. There is an unmet need to define the prevalence and pathogenesis of early symptomatic HF, which may be undiagnosed and precedes HF hospitalization. METHODS: The MESA (Multi-Ethnic Study of Atherosclerosis) Early HF study was conducted during MESA exam 6 to determine the prevalence of early HF and investigate the transition from risk factors to early HF in a diverse population-based cohort of older adults. Between 2016 and 2018, 3285 MESA participants from 6 field centers underwent comprehensive speckle-tracking echocardiography with passive leg raise maneuver, Kansas City Cardiomyopathy Questionnaire, 6-minute walk test, arterial stiffness assessment, and proteomics (including NT-proBNP [N-terminal pro-B-type natriuretic peptide]). RESULTS: Median age was 73 (25th-75th percentile 67-81) years, 53.2% were female, 25.6% were Black, 12.8% were Chinese, and 40.0% were White. The prevalence of HF risk factors was high: hypertension, 61.9%; former or current smoking, 53.7%; obesity 34.8%; diabetes; 24.7%; and chronic kidney disease; 22%. Overt cardiovascular disease, which ranged from 2.1% (HF) to 13.6% (atrial fibrillation), was less common. Of the 3285 participants, 96% underwent proteomics, 94% Kansas City Cardiomyopathy Questionnaire, 93% speckle-tracking echocardiography with passive leg raise, 82% arterial stiffness exam, and 77% 6-minute walk test. Feasibility of resting speckle-tracking echocardiography (87%-99% across cardiac chambers) and passive leg raise Doppler/speckle-tracking echocardiography (>84%) measurements was high. A total of 120 unique echocardiographic indices were measured. CONCLUSIONS: The MESA Early HF study is a key resource for cardiovascular researchers who are interested in improving the epidemiological and phenotypic characterization of early HF. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT00005487.

External validation of a deep learning algorithm for automated echocardiographic strain measurements.

Aims: Echocardiographic strain imaging reflects myocardial deformation and is a sensitive measure of cardiac function and wall-motion abnormalities. Deep learning (DL) algorithms could automate the interpretation of echocardiographic strain imaging. Methods and results: We developed and trained an automated DL-based algorithm for left ventricular (LV) strain measurements in an internal dataset. Global longitudinal strain (GLS) was validated externally in (i) a real-world Taiwanese cohort of participants with and without heart failure (HF), (ii) a core-lab measured dataset from the multinational prevalence of microvascular dysfunction-HF and preserved ejection fraction (PROMIS-HFpEF) study, and regional strain in (iii) the HMC-QU-MI study of patients with suspected myocardial infarction. Outcomes included measures of agreement [bias, mean absolute difference (MAD), root-mean-squared-error (RMSE), and Pearson's correlation (R)] and area under the curve (AUC) to identify HF and regional wall-motion abnormalities. The DL workflow successfully analysed 3741 (89%) studies in the Taiwanese cohort, 176 (96%) in PROMIS-HFpEF, and 158 (98%) in HMC-QU-MI. Automated GLS showed good agreement with manual measurements (mean ± SD): -18.9 ± 4.5% vs. -18.2 ± 4.4%, respectively, bias 0.68 ± 2.52%, MAD 2.0 ± 1.67, RMSE = 2.61, R = 0.84 in the Taiwanese cohort; and -15.4 ± 4.1% vs. -15.9 ± 3.6%, respectively, bias -0.65 ± 2.71%, MAD 2.19 ± 1.71, RMSE = 2.78, R = 0.76 in PROMIS-HFpEF. In the Taiwanese cohort, automated GLS accurately identified patients with HF (AUC = 0.89 for total HF and AUC = 0.98 for HF with reduced ejection fraction). In HMC-QU-MI, automated regional strain identified regional wall-motion abnormalities with an average AUC = 0.80. Conclusion: DL algorithms can interpret echocardiographic strain images with similar accuracy as conventional measurements. These results highlight the potential of DL algorithms to democratize the use of cardiac strain measurements and reduce time-spent and costs for echo labs globally.

Psychometric Analysis of the Patient-Reported Hypoparathyroidism Symptom Diary Symptom Subscale Using Data from Two Clinical Trials.

Purpose: The hypoparathyroidism symptom diary (HypoPT-SD) is a disease-specific patient-reported outcome (PRO) tool comprising a 7-item symptom subscale, a 4-item impact subscale and 1-item anxiety, and sadness or depression components. This analysis assessed the psychometric properties of the HypoPT-SD symptom subscale scores using data from two open-label, single arm, Phase 4 studies (Study 402 and Study 404). Patients and Methods: Eligible patients were aged 18 years or older with a confirmed diagnosis of hypoparathyroidism. All patients received recombinant human parathyroid hormone (1-84) during the analysis period. Scores were recorded at baseline, and at months 6, 30 and 36 (end of treatment [EOT]) in Study 402, and at baseline and week 52 (EOT) in Study 404. The structure of the HypoPT-SD Symptom subscale was analyzed by measuring correlations between pairs of item scores; internal consistency and reliability were evaluated using Cronbach's coefficient α; test-retest reliability was assessed using intraclass correlation; and construct validity was determined by performing correlational analyses between scores recorded using the HypoPT-SD and those for other conceptually similar PRO tools. Results: A total of 60 patients were included in the analysis. Inter-item pairwise correlations were strong for all but 5 of the item pairs analysed. Cronbach's α values for the HypoPT-SD Symptom subscale were 0.88 using data from Study 402 and 0.92 using data from Study 404. In general, the HypoPT-SD Symptom subscale scores had moderate or strong correlations with scores recorded using PRO tools. Intraclass correlation coefficients exceeded 0.70 using test-retest data from all patients in Study 402 and from a subgroup of patients with stable disease from Study 404. Conclusion: This analysis demonstrated the test-retest reliability, internal consistency and construct validity of the HypoPT-SD using data from longitudinal prospective studies and supports the use of the HypoPT-SD in future clinical studies.

Normative Values of Echocardiographic Chamber Size and Function in Older Healthy Adults: The Multi-Ethnic Study of Atherosclerosis.

Background: Echocardiographic (2DE) thresholds indicating disease or impaired functional status compared to normal physiologic aging in individuals ≥ 65 years are not clearly defined. In the present study, we sought to establish standard values for 2DE parameters related to chamber size and function in older adults without cardiopulmonary or cardiometabolic conditions. Methods: In this cross-sectional study of 3032 individuals who underwent 2DE at Exam 6 in the Multi-Ethnic Study of Atherosclerosis (MESA), 608 participants fulfilled our inclusion criteria, with normative values defined as the mean value ± 1.96 standard deviations and compared across sex and race/ethnicity. Functional status measures included NT-proBNP, 6-minute walk distance [6MWD], and Kansas City Cardiomyopathy Questionnaire [KCCQ]. Prognostic performance using MESA cutoffs was compared to established guideline cutoffs using time-to-event analysis. Results: Participants meeting our inclusion criteria (69.5 ± 7.0 years, 46.2% male, 47.5% White) had lower NT-proBNP, higher 6MWD, and higher (better) KCCQ summary values. Women had significantly smaller chamber sizes and better biventricular systolic function. White participants had the largest chamber dimensions, while Chinese participants had the smallest, even after adjustment for body size. Current guidelines identified 81.6% of healthy older adults in MESA as having cardiac abnormalities. Conclusions: Among a large, diverse group of healthy older adults, we found significant differences in cardiac structure and function across sexes and races/ethnicities, which may signal sex-specific cardiac remodeling with advancing age. It is crucial for existing guidelines to consider the observed and clinically significant differences in cardiac structure and function associated with healthy aging. Our study highlights that existing guidelines, which grade abnormalities in echocardiographic cardiac chamber size and function based on younger individuals, may not adequately address the anticipated changes associated with normal aging.

Application of a life table approach to assess duration of BNT162b2 vaccine-derived immunity by age using COVID-19 case surveillance data during the Omicron variant period.

BACKGROUND: SARS-CoV-2 Omicron variants have the potential to impact vaccine effectiveness and duration of vaccine-derived immunity. We analyzed U.S. multi-jurisdictional COVID-19 vaccine breakthrough surveillance data to examine potential waning of protection against SARS-CoV-2 infection for the Pfizer-BioNTech (BNT162b) primary vaccination series by age. METHODS: Weekly numbers of SARS-CoV-2 infections during January 16, 2022-May 28, 2022 were analyzed by age group from 22 U.S. jurisdictions that routinely linked COVID-19 case surveillance and immunization data. A life table approach incorporating line-listed and aggregated COVID-19 case datasets with vaccine administration and U.S. Census data was used to estimate hazard rates of SARS-CoV-2 infections, hazard rate ratios (HRR) and percent reductions in hazard rate comparing unvaccinated people to people vaccinated with a Pfizer-BioNTech primary series only, by age group and time since vaccination. RESULTS: The percent reduction in hazard rates for persons 2 weeks after vaccination with a Pfizer-BioNTech primary series compared with unvaccinated persons was lowest among children aged 5-11 years at 35.5% (95% CI: 33.3%, 37.6%) compared to the older age groups, which ranged from 68.7%-89.6%. By 19 weeks after vaccination, all age groups showed decreases in the percent reduction in the hazard rates compared with unvaccinated people; with the largest declines observed among those aged 5-11 and 12-17 years and more modest declines observed among those 18 years and older. CONCLUSIONS: The decline in vaccine protection against SARS-CoV-2 infection observed in this study is consistent with other studies and demonstrates that national case surveillance data were useful for assessing early signals in age-specific waning of vaccine protection during the initial period of SARS-CoV-2 Omicron variant predominance. The potential for waning immunity during the Omicron period emphasizes the importance of continued monitoring and consideration of optimal timing and provision of booster doses in the future.

Differences in Cardiac Mechanics among Genetically At-Risk First-Degree Relatives: The DCM Precision Medicine Study.

Aims: Among genetically at-risk first-degree relatives (FDRs) of probands with dilated cardiomyopathy (DCM), the ability to detect changes in left ventricular (LV) mechanics with normal LV size and ejection fraction (LVEF) remains incompletely explored. We sought to define a pre-DCM phenotype among at-risk FDRs, including those with variants of uncertain significance (VUSs), using echocardiographic measures of cardiac mechanics. Methods and Results: LV structure and function, including speckle-tracking analysis for LV global longitudinal strain (GLS), were evaluated in 124 FDRs (65% female; median age 44.9 [IQR: 30.6-60.3] years) of 66 DCM probands of European ancestry sequenced for rare variants in 35 DCM genes. FDRs had normal LV size and LVEF. Negative FDRs of probands with pathogenic or likely pathogenic (P/LP) variants (n=28) were a reference group to which negative FDRs of probands without P/LP variants (n=30), FDRs with only VUSs (n=27), and FDRs with P/LP variants (n=39) were compared. In an analysis accounting for age-dependent penetrance, FDRs below the median age showed minimal differences in LV GLS across groups while those above it with P/LP variants or VUSs had lower absolute values than the reference group (-3.9 [95% CI: -5.7, -2.1] or -3.1 [-4.8, -1.4] %-units) and negative FDRs of probands without P/LP variants (-2.6 [-4.0, -1.2] or -1.8 [-3.1, -0.6]). Conclusions: Older FDRs with normal LV size and LVEF who harbored P/LP variants or VUSs had lower absolute LV GLS values, indicating that some DCM-related VUSs are clinically relevant. LV GLS may have utility for defining a pre-DCM phenotype. Clinical Trial Registration: clinicaltrials.gov, NCT03037632.

Evaluation of symptoms in respiratory syncytial virus infection in adults: psychometric evaluation of the Respiratory Infection Intensity and Impact Questionnaire™ symptom scores.

BACKGROUND: The Respiratory Infection Intensity and Impact Questionnaire (RiiQ™) is a patient-reported outcome measure designed to assess symptoms and impacts of respiratory syncytial virus (RSV) infection. This study evaluated the construct validity, reliability, and responsiveness of the RiiQ™ Respiratory and Systemic Symptoms Scale scores. METHODS: Prospective data were analyzed from a total of 1795 participants, including from non-hospitalized patients with acute respiratory infection (ARI) and no coinfections enrolled in a Phase 2b RSV vaccine study (RSV-positive: n = 60; RSV-negative: n = 1615), and two observational studies of patients hospitalized with RSV (n = 20; n = 100). Descriptive statistics, confirmatory factor analysis (CFA), test-retest intraclass correlation coefficients (ICCs), construct validity correlations (between a clinician-assessed clinical questionnaire and the RiiQ™ symptoms scale), known-groups validity, and responsiveness (correlations of change scores) were evaluated. RESULTS: Mean patient age ranged from 66.5 to 71.5 years and the majority of patients were female. Initial assessments in the vaccine trial (ARI Day 1) were suggestive of less severe illness than in the observational studies with hospitalized patients. CFA loadings (> 0.40) supported summary scores. ICCs exceeding the recommended threshold of 0.70 supported test-retest reliability for Respiratory and Systemic Symptoms, except in the small observational study. At the scale level, correlations were moderate to strong (|r| ≥ 0.3) and positive between the Respiratory Symptoms Scale and the related clinical questionnaire scores, reflecting measurement of similar symptoms in support of convergent validity. Correlations with change in Patient Global Impression of Severity > 0.30 supported responsiveness. CONCLUSIONS: Psychometric tests applied to the RiiQ™ Symptoms scales provide evidence of its reliability, construct validity, discriminating ability, and responsiveness for use in clinical studies to assess the onset and severity of RSV symptoms.

Characteristics of Right Ventricular to Pulmonary Arterial Coupling and Association With Functional Status Among Older Aged Adults from the Multi-Ethnic Study of Atherosclerosis.

Although the echocardiographic:derived ratio of tricuspid annular plane systolic excursion (TAPSE) to pulmonary arterial systolic pressure (PASP) is an important prognostic tool in heart failure (HF), the relation with 6-minute walk distance (6MWD) and N-terminal pro-B-type natriuretic peptide (NT-proBNP) is less established. We sought to establish the normative values of TAPSE:PASP among older adults without cardiovascular disease (CVD) and evaluate the relation with NT-proBNP and 6MWD. Among 1,542 participants of the Multi-Ethnic Study of Atherosclerosis-HF ancillary study, the cross-sectional association of TAPSE:PASP with the outcomes of 6MWD and NT-proBNP was analyzed using multivariable linear regression, with progressive adjustment for sociodemographic and CVD risk factors. Our cohort had a mean age (SD) of 73 ± 8 years, 55% women, and a mean TAPSE:PASP ratio of 0.68 ± 0.16. In the unadjusted analysis, increasing tertiles of TAPSE:PASP were associated with younger age, less diabetes, higher estimated glomerular filtration rate, and less antihypertensive medication use. The TAPSE:PASP ratio significantly correlated with both 6MWD and NT-proBNP in the fully adjusted models. A 1-unit increment in TAPSE:PASP was associated with an adjusted 9.9% (4.8% to 15.2%) higher 6MWD, whereas a 1-unit increment in TAPSE:PASP was associated with an adjusted 38.0% (16.0% to 54.2%) lower NT-proBNP. There was a significant gender interaction of the association of TAPSE:PASP ratio and 6MWD, with stronger association seen in women. Among multiethnic older adults free of clinical CVD, the TAPSE:PASP ratio decreased with age, especially in women and was associated with decreased 6MWD and increasing NT-proBNP, the markers of subclinical HF.

Differences in Cardiac Mechanics and Exercise Physiology Among Heart Failure With Preserved Ejection Fraction Phenomapping Subgroups.

Unsupervised machine learning (phenomapping) has been used successfully to identify novel subgroups (phenogroups) of heart failure with preserved ejection fraction (HFpEF). However, further investigation of pathophysiological differences between HFpEF phenogroups is necessary to help determine potential treatment options. We performed speckle-tracking echocardiography and cardiopulmonary exercise testing (CPET) in 301 and 150 patients with HFpEF, respectively, as part of a prospective phenomapping study (median age 65 [25th to 75th percentile 56 to 73] years, 39% Black individuals, 65% female). Linear regression was used to compare strain and CPET parameters by phenogroup. All indicies of cardiac mechanics except for left ventricular global circumferential strain worsened in a stepwise fashion from phenogroups 1 to 3 after adjustment for demographic and clinical factors. After further adjustment for conventional echocardiographic parameters, phenogroup 3 had the worst left ventricular global longitudinal, right ventricular free wall, and left atrial booster and reservoir strain. On CPET, phenogroup 2 had the lowest exercise time and absolute peak oxygen consumption (VO2), driven primarily by obesity, whereas phenogroup 3 achieved the lowest workload, relative peak oxygen consumption (VO2), and heart rate reserve on multivariable-adjusted analyses. In conclusion, HFpEF phenogroups identified by unsupervised machine learning analysis differ in the indicies of cardiac mechanics and exercise physiology.

Real-world uptake of COVID-19 vaccination among individuals expressing vaccine hesitancy: A registry-linkage study.

INTRODUCTION: Uptake of COVID-19 vaccination remains suboptimal in the United States and other settings. Though early reports indicated that a strong majority of people were interested in receiving the COVID-19 vaccine, the association between vaccine intention and uptake is not yet fully understood. Ourobjective was todescribe predictors of vaccine uptake, and estimate the sensitivity, specificity, and predictive values of self-reported COVID-19 vaccine status compared to a comprehensive statewide COVID-19 vaccine registry. METHODS: A cohort of California residents that received a molecular test for SARS-CoV-2 infection during 24 February-5 December 2021 were enrolled in a telephone-administered survey. Survey participants were matched with records in a statewide immunization registry. Cox proportional hazards model were used to compare time to vaccination among those unvaccinated at survey enrollment by self-reported COVID-19 vaccination intention. RESULTS: Among 864 participants who were unvaccinated at the time of interview, 272 (31%) had documentation of receipt of COVID-19 vaccination at a later date; including 194/423 (45.9%) who had initially reported being willing to receive vaccination, 41/185 (22.2%) who reported being unsure about vaccination, and 37/278 (13.3%) who reported unwillingness to receive vaccination.Adjusted hazard ratios (aHRs) for registry-confirmed COVID-19 vaccination were 0.49 (95% confidence interval: 0.32-0.76) and 0.21 (0.12-0.36) for participants expressing uncertainty and unwillingness to receive vaccination, respectively, as compared with participants who reported being willing to receive vaccination. Time to vaccination was shorter among participants from higher-income households (aHR = 3.30 [2.02-5.39]) and who reported co-morbidities or immunocompromising conditions (aHR = 1.54 [1.01-2.36]).Sensitivity of self-reported COVID-19 vaccination status was 82% (80-85%) overall, and 98% (97-99%) among those referencing vaccination records; specificity was 87% (86-89%). CONCLUSION: Willingness to receive COVID-19 vaccination was an imperfect predictor of real-world vaccine uptake. Improved messaging about COVID-19 vaccination regardless of previous SARS-CoV-2 infection status may help improve uptake.

Development and evaluation of the Acromegaly Symptom Diary.

BACKGROUND: Patient-reported outcome (PRO) measures are important to consider when evaluating treatments, yet there are no PRO measures for patients with acromegaly that have been developed in accordance with US Food and Drug Administration guidance. Acromegaly is a rare, chronic condition caused by hypersecretion of growth hormone. Disease activity is monitored by measurement in serum of growth hormone and insulin-like growth factor-I. The objectives of this research were to develop the Acromegaly Symptom Diary (ASD), establish a scoring algorithm, and evaluate the psychometric measurement properties of the ASD. METHODS: Semistructured interviews consisting of concept elicitation and cognitive debriefing components were conducted with 16 adult participants with acromegaly. The concept elicitation component identified symptoms important to individuals with acromegaly. The cognitive debriefing component gathered information about the participants' experience with each proposed item of the ASD, their thought process for answering each question, and their interpretation of the items. The psychometric properties of the draft ASD were then evaluated using data from the ACROBAT Evolve (NCT03792555; n = 13) and ACROBAT Edge (NCT03789656; n = 47) clinical trials. RESULTS: The 16 participants from the interviews described ongoing symptoms, with the most frequently reported being joint pain (n = 13) and fatigue (n = 12), followed by swelling (n = 8), headache (n = 7), and mood swings (n = 6), and were able to interpret and understand the ASD items and had no issues with the 24-hour recall period. From data collected in the clinical studies, the psychometric properties of internal consistency (0.91 - 0.80), test-retest reliability with item-level and total ASD scores (> 0.70), baseline construct validity (r ≥ |0.38|) across scales, and responsiveness to change (r = 0.52-0.56) were supported for the ASD. The proposed preliminary threshold range to characterize a meaningful change from the patients' perspective for the ASD total is a 4- to 6-point change for improvement or worsening out of a total score of 70. CONCLUSION: These findings provide qualitative and quantitative evidence to support the ASD as fit for the purpose of evaluating the symptom experience of patients with acromegaly in clinical trials.

Comparison of anchor-based methods for estimating thresholds of meaningful within-patient change using simulated PROMIS PF 20a data under various joint distribution characteristic conditions.

PURPOSE: To compare the performance of anchor-based methods for estimating thresholds of meaningful within-patient change (i.e., individual change) of clinical outcome assessments in conditions reflecting data characteristics of small- to medium-sized clinical trials. METHODS: Datasets were generated from the joint distributions of the PROMIS PF 20a T-score changes and a seven-point global change anchor measure. The 108 simulation conditions (1000 replications per condition) included combinations of three marginal distributions of T-score changes, three improvement percentages in the anchor measure, four levels of responsiveness correlations, and three sample sizes. Threshold estimation methods included mean change, median change, ROC curve, predictive modeling, half SD, and SEM. Relative bias, precision, accuracy, and measurement significance of the estimates were evaluated based on comparison with true thresholds and IRT-based individual reliable changes of PROMIS scores. Quantile regression models were applied to select and interpret effects of simulation conditions on estimation bias. RESULTS: When PROMIS T-score changes were distributed normally, the predictive modeling method performed best with 50% or more responders identified by the anchor; the mean and median methods were preferred with 30% responders. For skewed distributions, the median method and ROC method gained more advantages. Among the evaluated study conditions, the improvement percentage condition had the most obvious effects on estimation bias. CONCLUSION: To establish accurate and precise thresholds, clinical researchers are recommended to prioritize study designs with at least 50% anchor-defined responders and strongly responsive target endpoints with highly reliable scoring calibration and to select optimal anchor-based methods given the data characteristics.

Clinical Phenotypes of Patients With Systemic Sclerosis With Distinct Molecular Signatures in Skin.

OBJECTIVE: Systemic sclerosis (SSc) patients are classified according to degree of skin fibrosis (limited and diffuse cutaneous [lc and dc]) and serum autoantibodies. We undertook the present multicenter study to determine whether intrinsic subset (IS) classification based upon skin gene expression yields additional valuable clinical information. METHODS: SSc patients and healthy participants (HPs) were classified into Normal-like, Limited, Fibroproliferative, and Inflammatory ISs using a previously trained classifier. Clinical data were obtained (serum autoantibodies, pulmonary function testing, modified Rodnan skin thickness scores [mRSS], and high-resolution chest computed tomography [HRCT]). Statistical analyses were performed to compare patients classified by IS, traditional cutaneous classification, and serum autoantibodies. RESULTS: A total of 223 participants (165 SSc [115 dcSSc and 50 lcSSc] and 58 HPs) were classified. Inflammatory IS patients had higher mRSS (22.1 ± 9.9; P < 0.001) than other ISs and dcSSc patients (19.4 ± 9.4; P = 0.05) despite similar disease duration (median [interquartile range] months 14.9 [19.9] vs. 18.4 [31.6]; P = 0.48). In multivariable modeling, no significant association between mRSS and RNA polymerase III (P = 0.07) or anti-topoisomerase I (Scl-70) (P = 0.09) was found. Radiographic interstitial lung disease (ILD) was more prevalent in Fibroproliferative IS compared with other ISs (91%; P = 0.04) with similar prevalence between lcSSc and dcSSc (67% vs. 76%; P = 0.73). Positive Scl-70 antibody was the strongest ILD predictor (P < 0.001). Interestingly, all lcSSc/Fibroproliferative patients demonstrated radiographic ILD. CONCLUSIONS: Classification by IS identifies patients with distinct clinical phenotypes versus traditional cutaneous or autoantibody classification. IS classification identifies subgroups of SSc patients with more radiographic ILD (Fibroproliferative), higher mRSS (Inflammatory), and milder phenotype (Normal-like) and may provide additional clinically useful information to current SSc classification systems.

Association of epicardial adipose tissue with proteomics, coronary flow reserve, cardiac structure and function, and quality of life in heart failure with preserved ejection fraction: insights from the PROMIS-HFpEF study.

AIM: Epicardial adipose tissue (EAT) may play a role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). We investigated associations of EAT with proteomics, coronary flow reserve (CFR), cardiac structure and function, and quality of life (QoL) in the prospective multinational PROMIS-HFpEF cohort. METHODS AND RESULTS: Epicardial adipose tissue was measured by echocardiography in 182 patients and defined as increased if ≥9 mm. Proteins were measured using high-throughput proximity extension assays. Microvascular dysfunction was evaluated with Doppler-based CFR, cardiac structural and functional indices with echocardiography and QoL by Kansas City Cardiomyopathy Questionnaire (KCCQ). Patients with increased EAT (n = 54; 30%) had higher body mass index (32 [28-40] vs. 27 [23-30] kg/m2 ; p < 0.001), lower N-terminal pro-B-type natriuretic peptide (466 [193-1133] vs. 1120 [494-1990] pg/ml; p < 0.001), smaller indexed left ventricular (LV) end-diastolic and left atrial (LA) volumes and tendency to lower KCCQ score. Non-indexed LV/LA volumes did not differ between groups. When adjusted for body mass index, EAT remained associated with LV septal wall thickness (coefficient 1.02, 95% confidence interval [CI] 1.00-1.04; p = 0.018) and mitral E wave deceleration time (coefficient 1.03, 95% CI 1.01-1.05; p = 0.005). Increased EAT was associated with proteomic markers of adipose biology and inflammation, insulin resistance, endothelial dysfunction, and dyslipidaemia but not significantly with CFR. CONCLUSION: Increased EAT was associated with cardiac structural alterations and proteins expressing adiposity, inflammation, lower insulin sensitivity and endothelial dysfunction related to HFpEF pathology, probably driven by general obesity. Potential local mechanical or paracrine effects mediated by EAT remain to be elucidated.