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.

COVID-19 Cases and Hospitalizations by COVID-19 Vaccination Status and Previous COVID-19 Diagnosis - California and New York, May-November 2021.

By November 30, 2021, approximately 130,781 COVID-19-associated deaths, one in six of all U.S. deaths from COVID-19, had occurred in California and New York.* COVID-19 vaccination protects against infection with SARS-CoV-2 (the virus that causes COVID-19), associated severe illness, and death (1,2); among those who survive, previous SARS-CoV-2 infection also confers protection against severe outcomes in the event of reinfection (3,4). The relative magnitude and duration of infection- and vaccine-derived protection, alone and together, can guide public health planning and epidemic forecasting. To examine the impact of primary COVID-19 vaccination and previous SARS-CoV-2 infection on COVID-19 incidence and hospitalization rates, statewide testing, surveillance, and COVID-19 immunization data from California and New York (which account for 18% of the U.S. population) were analyzed. Four cohorts of adults aged ≥18 years were considered: persons who were 1) unvaccinated with no previous laboratory-confirmed COVID-19 diagnosis, 2) vaccinated (14 days after completion of a primary COVID-19 vaccination series) with no previous COVID-19 diagnosis, 3) unvaccinated with a previous COVID-19 diagnosis, and 4) vaccinated with a previous COVID-19 diagnosis. Age-adjusted hazard rates of incident laboratory-confirmed COVID-19 cases in both states were compared among cohorts, and in California, hospitalizations during May 30-November 20, 2021, were also compared. During the study period, COVID-19 incidence in both states was highest among unvaccinated persons without a previous COVID-19 diagnosis compared with that among the other three groups. During the week beginning May 30, 2021, compared with COVID-19 case rates among unvaccinated persons without a previous COVID-19 diagnosis, COVID-19 case rates were 19.9-fold (California) and 18.4-fold (New York) lower among vaccinated persons without a previous diagnosis; 7.2-fold (California) and 9.9-fold lower (New York) among unvaccinated persons with a previous COVID-19 diagnosis; and 9.6-fold (California) and 8.5-fold lower (New York) among vaccinated persons with a previous COVID-19 diagnosis. During the same period, compared with hospitalization rates among unvaccinated persons without a previous COVID-19 diagnosis, hospitalization rates in California followed a similar pattern. These relationships changed after the SARS-CoV-2 Delta variant became predominant (i.e., accounted for >50% of sequenced isolates) in late June and July. By the week beginning October 3, compared with COVID-19 cases rates among unvaccinated persons without a previous COVID-19 diagnosis, case rates among vaccinated persons without a previous COVID-19 diagnosis were 6.2-fold (California) and 4.5-fold (New York) lower; rates were substantially lower among both groups with previous COVID-19 diagnoses, including 29.0-fold (California) and 14.7-fold lower (New York) among unvaccinated persons with a previous diagnosis, and 32.5-fold (California) and 19.8-fold lower (New York) among vaccinated persons with a previous diagnosis of COVID-19. During the same period, compared with hospitalization rates among unvaccinated persons without a previous COVID-19 diagnosis, hospitalization rates in California followed a similar pattern. These results demonstrate that vaccination protects against COVID-19 and related hospitalization, and that surviving a previous infection protects against a reinfection and related hospitalization. Importantly, infection-derived protection was higher after the Delta variant became predominant, a time when vaccine-induced immunity for many persons declined because of immune evasion and immunologic waning (2,5,6). Similar cohort data accounting for booster doses needs to be assessed, as new variants, including Omicron, circulate. Although the epidemiology of COVID-19 might change with the emergence of new variants, vaccination remains the safest strategy to prevent SARS-CoV-2 infections and associated complications; all eligible persons should be up to date with COVID-19 vaccination. Additional recommendations for vaccine doses might be warranted in the future as the virus and immunity levels change.

Proteomic Evaluation of the Comorbidity-Inflammation Paradigm in Heart Failure With Preserved Ejection Fraction: Results From the PROMIS-HFpEF Study.

BACKGROUND: A systemic proinflammatory state has been hypothesized to mediate the association between comorbidities and abnormal cardiac structure/function in heart failure with preserved ejection fraction (HFpEF). We conducted a proteomic analysis to investigate this paradigm. METHODS: In 228 patients with HFpEF from the multicenter PROMIS-HFpEF study (Prevalence of Microvascular Dysfunction in Heart Failure With Preserved Ejection Fraction), 248 unique circulating proteins were quantified by a multiplex immunoassay (Olink) and used to recapitulate systemic inflammation. In a deductive approach, we performed principal component analysis to summarize 47 proteins known a priori to be involved in inflammation. In an inductive approach, we performed unbiased weighted coexpression network analyses of all 248 proteins to identify clusters of proteins that overrepresented inflammatory pathways. We defined comorbidity burden as the sum of 8 common HFpEF comorbidities. We used multivariable linear regression and statistical mediation analyses to determine whether and to what extent inflammation mediates the association of comorbidity burden with abnormal cardiac structure/function in HFpEF. We also externally validated our findings in an independent cohort of 117 HFpEF cases and 30 comorbidity controls without heart failure. RESULTS: Comorbidity burden was associated with abnormal cardiac structure/function and with principal components/clusters of inflammation proteins. Systemic inflammation was also associated with increased mitral E velocity, E/e' ratio, and tricuspid regurgitation velocity; and worse right ventricular function (tricuspid annular plane systolic excursion and right ventricular free wall strain). Inflammation mediated the association between comorbidity burden and mitral E velocity (proportion mediated 19%-35%), E/e' ratio (18%-29%), tricuspid regurgitation velocity (27%-41%), and tricuspid annular plane systolic excursion (13%) (P<0.05 for all), but not right ventricular free wall strain. TNFR1 (tumor necrosis factor receptor 1), UPAR (urokinase plasminogen activator receptor), IGFBP7 (insulin-like growth factor binding protein 7), and GDF-15 (growth differentiation factor-15) were the top individual proteins that mediated the relationship between comorbidity burden and echocardiographic parameters. In the validation cohort, inflammation was upregulated in HFpEF cases versus controls, and the most prominent inflammation protein cluster identified in PROMIS-HFpEF was also present in HFpEF cases (but not controls) in the validation cohort. CONCLUSIONS: Proteins involved in inflammation form a conserved network in HFpEF across 2 independent cohorts and may mediate the association between comorbidity burden and echocardiographic indicators of worse hemodynamics and right ventricular dysfunction. These findings support the comorbidity-inflammation paradigm in HFpEF.

The timing of intermittent hypoxia differentially affects macronutrient intake and energy substrate utilization in mice.

Sleep apnea is a common sleep disorder characterized by periodic breathing cessation and intermittent hypoxia (IH). Although previous studies have demonstrated that IH alone can influence metabolic outcomes such as body weight, it remains unclear how the timing of IH can specifically affect these outcomes. Here, we examine how pairing 10-h periods of IH to either the animals' resting phase (e.g., IH during the day) or active phase (e.g., IH during the night) differentially affects body weight, macronutrient selection, energy expenditure, respiratory exchange rate, and glucose tolerance. We find that in contrast to mice exposed to IH during the night, mice exposed to IH during the day preferentially decrease their carbohydrate intake and switch to fat metabolism. Moreover, when the IH stimulus was removed, mice that had been exposed to day IH continued to eat a minimal amount of carbohydrates and consumed a higher percentage of kilocalorie from fat for at least 5 days. These data demonstrate that food choice and substrate utilization are secondary to the timing of IH but not IH itself. Taken together, these data have key clinical implications for individuals with sleep apnea and particularly those who are also experiencing circadian disruption such as night-shift workers.NEW & NOTEWORTHY Pairing repeated hypoxic episodes to a mouse's resting phase during the day preferentially decreases carbohydrate intake and results in a switch to metabolic fat oxidation. These data indicate that the timing of intermittent hypoxia should be considered when calculating sleep apnea's effects on metabolic outcomes.

Role of t-tubule remodeling on mechanisms of abnormal calcium release during heart failure development in canine ventricle.

The goal of this work was to investigate the role of t-tubule (TT) remodeling in abnormal Ca2+ cycling in ventricular myocytes of failing dog hearts. Heart failure (HF) was induced using rapid right ventricular pacing. Extensive changes in echocardiographic parameters, including left and right ventricular dilation and systolic dysfunction, diastolic dysfunction, elevated left ventricular filling pressures, and abnormal cardiac mechanics, indicated that severe HF developed. TT loss was extensive when measured as the density of total cell volume, derived from three-dimensional confocal image analysis, and significantly increased the distances in the cell interior to closest cell membrane. Changes in Ca2+ transients indicated increases in heterogeneity of Ca2+ release along the cell length. When critical properties of Ca2+ release variability were plotted as a function of TT organization, there was a complex, nonlinear relationship between impaired calcium release and decreasing TT organization below a certain threshold of TT organization leading to increased sensitivity in Ca2+ release below a TT density threshold of 1.5%. The loss of TTs was also associated with a greater incidence of triggered Ca2+ waves during rapid pacing. Finally, virtually all of these observations were replicated by acute detubulation by formamide treatment, indicating an important role of TT remodeling in impaired Ca2+ cycling. We conclude that TT remodeling itself is a major contributor to abnormal Ca2+ cycling in HF, reducing myocardial performance. The loss of TTs is also responsible for a greater incidence of triggered Ca2+ waves that may play a role in ventricular arrhythmias arising in HF.NEW & NOTEWORTHY Three-dimensional analysis of t-tubule density showed t-tubule disruption throughout the whole myocyte in failing dog ventricle. A double-linear relationship between Ca2+ release and t-tubule density displays a steeper slope at t-tubule densities below a threshold value (∼1.5%) above which there is little effect on Ca2+ release (T-tubule reserve). T-tubule loss increases incidence of triggered Ca2+ waves. Chemically induced t-tubule disruption suggests that t-tubule loss alone is a critical component of abnormal Ca2+ cycling in heart failure.

Generalizability of HFA-PEFF and H2FPEF Diagnostic Algorithms and Associations With Heart Failure Indices and Proteomic Biomarkers: Insights From PROMIS-HFpEF.

BACKGROUND: Diagnosing heart failure with preserved ejection fraction (HFpEF) remains challenging. We aimed to evaluate the generalizability of the HFA-PEFF (Heart Failure Association Pre-test assessment, Echocardiography & natriuretic peptide, Functional testing, Final etiology) and weighted H2FPEF (Heavy, 2 or more Hypertensive drugs, atrial Fibrillation, Pulmonary hypertension, Elder age > 60, elevated Filling pressures) diagnostic algorithms and associations with HF severity, coronary microvascular dysfunction and proteomic biomarkers. METHODS AND RESULTS: Diagnostic likelihood of HFpEF was calculated in the prospective, multinational PROMIS-HFpEF (Prevalence of microvascular dysfunction in HFpEF) cohort using current European Society of Cardiology recommendations, HFA-PEFF and H2FPEF algorithms. Associations between the 2 algorithms and left atrial function, Doppler-based coronary flow reserve, 6-minute walk test, quality of life, and proteomic biomarkers were investigated. Of 181 patients with an EF of ≥50%, 129 (71%) and 94 (52%) fulfilled criteria for high likelihood HFpEF as per HFA-PEFF and H2FPEF, and 28% and 46% were classified as intermediate likelihood, requiring additional hemodynamic testing. High likelihood HFpEF patients were older with higher prevalence of atrial fibrillation and lower global longitudinal strain and left atrial reservoir strain (P < .001 for all variables). left atrial reservoir strain and global longitudinal strain were inversely associated with both HFA-PEFF and H2FPEF scores (TauB = -0.35 and -0.46 and -0.21 and -0.31; P < .001 for all). There were no associations between scoring and 6-minute walk test, quality of life, and coronary flow reserve. Both scores were associated with biomarkers related to inflammation, oxidative stress, and fibrosis. CONCLUSIONS: Although the HFA-PEFF and H2FPEF scores were associated with measures of HF severity and biomarkers related to HFpEF, they demonstrated a modest and differential ability to identify HFpEF noninvasively, necessitating additional functional testing to confirm the diagnosis.

Neurosyphilis Surveillance: Exploring the Use of Multiple Data Sources to Better Understand Morbidity in California.

ABSTRACT: Accurate reporting of neurosyphilis diagnoses is important to quantify and monitor severe outcomes associated with infection of Treponemal pallidum. This analysis compared the demographic distribution of neurosyphilis diagnoses in sexually transmitted disease surveillance data with administrative hospital data in the California Project Area from 2016 to 2018. Although neurosyphilis morbidity was similar, significant differences were noted by sex, age group, race/ethnicity, and region. Both sexually transmitted disease surveillance and administrative hospital data may be imperfect systems to understand the true morbidity of neurosyphilis.

Implementation of the QUBE Force Field in SOMD for High-Throughput Alchemical Free-Energy Calculations.

The quantum mechanical bespoke (QUBE) force-field approach has been developed to facilitate the automated derivation of potential energy function parameters for modeling protein-ligand binding. To date, the approach has been validated in the context of Monte Carlo simulations of protein-ligand complexes. We describe here the implementation of the QUBE force field in the alchemical free-energy calculation molecular dynamics simulation package SOMD. The implementation is validated by demonstrating the reproducibility of absolute hydration free energies computed with the QUBE force field across the SOMD and GROMACS software packages. We further demonstrate, by way of a case study involving two series of non-nucleoside inhibitors of HIV-1 reverse transcriptase, that the availability of QUBE in a modern simulation package that makes efficient use of graphics processing unit acceleration will facilitate high-throughput alchemical free-energy calculations.

Operative vs. Nonoperative Treatment of Isolated Humeral Shaft Fractures: A Prospective Cohort Study.

The purpose was to compare plate and screw fixation (open reduction internal fixation [ORIF]) and functional bracing (FB) of isolated humeral shaft fractures with treatment and patient-based outcomes. We performed a prospective trial of ORIF v. FB at 12 centers. Surgeons counseled patients on treatment options and a patient centered decision was made. We enrolled 179 patients, of which 6-month data was analyzed for 102 (39 female; 63 male). Forty-five were treated with ORIF and 57 with FB. We found no difference in the disability of the arm, shoulder and hand (DASH) score, visual analogue score (VAS) or elbow range of motion (ROM) at 6 months. However, 11% of the FB group developed nonunion. Complications in the ORIF group included a 2% infection and nonunion rate and 13% iatrogenic radial nerve dysfunction (RND). ORIF can be expected to result in higher union rates with the inherent risks of infection and RND. Finally, at 6 months, both groups demonstrated higher DASH scores than population norms, indicating a lack of full recovery. (Journal of Surgical Orthopaedic Advances 30(2):067-072, 2021).

Is There a Critical Radiographic Angle That Portends Poor Functional Outcome Scores in Nonoperative Treatment of Isolated Humeral Shaft Fractures?

Our purpose was to evaluate radiographic alignment of nonoperatively treated humerus fractures and determine if there is a critical angle associated with worse outcomes. All patients with humeral shaft fractures that were prospectively followed as part of a larger multicenter trial were reviewed. These patients were selected for nonoperative management based on shared decision making. There were 80 patients that healed with adequate data. The receiver operating characteristic (ROC) had best fit with a sagittal radiographic angle of 10° (AUC: 0.731) and coronal angle of 15° (AUC: 0.580) at 1-year follow-up. We found increased or worse disabilities of the arm, shoulder and hand (DASH) scores with > 10° sagittal alignment or > 15° of coronal alignment. Poor DASH scores were observed at angles lower than previously accepted for nonoperative treatment. These findings are useful in decision making and patient guidance. (Journal of Surgical Orthopaedic Advances 30(2):073-077, 2021).

Improving communication with patients in post-traumatic amnesia: development and impact of a clinical protocol.

OBJECTIVE: To assess the impact of staff training focused on improved treatment and communication with patients in post-traumatic amnesia (PTA) or other disorders of explicit (declarative) memory. A major aim was to minimize questions demanding recall from explicit memory, e.g., orientation quizzing, and personal/medical history questions, which may produce unreliable information and exacerbate patient frustration and anxiety. METHODS: Mixed-methods design. Inpatients with impairments of explicit memory were observed before (n = 4) and after (n = 4) training, with staff interactions recorded verbatim. Records were coded for types of questions and patient responses. Clinicians who worked before and after training were surveyed regarding perceived changes in practice, team functioning, and patient behavior. RESULTS: Explicit memory questions decreased significantly, as did irrelevant or "don't know" responses from patients, with large nonparametric effect sizes noted. The frequency of questions not relying on explicit memory remained stable. Most clinicians reported positive effects on their own and others' practice with memory impaired patients, and one-quarter noted less patient frustration or agitation. CONCLUSIONS: Although questioning patients is a natural part of medical care, targeted staff training can result in positive changes in communication practice and should be considered for facilities treating patients in PTA.

Fully Automated Echocardiogram Interpretation in Clinical Practice.

BACKGROUND: Automated cardiac image interpretation has the potential to transform clinical practice in multiple ways, including enabling serial assessment of cardiac function by nonexperts in primary care and rural settings. We hypothesized that advances in computer vision could enable building a fully automated, scalable analysis pipeline for echocardiogram interpretation, including (1) view identification, (2) image segmentation, (3) quantification of structure and function, and (4) disease detection. METHODS: Using 14 035 echocardiograms spanning a 10-year period, we trained and evaluated convolutional neural network models for multiple tasks, including automated identification of 23 viewpoints and segmentation of cardiac chambers across 5 common views. The segmentation output was used to quantify chamber volumes and left ventricular mass, determine ejection fraction, and facilitate automated determination of longitudinal strain through speckle tracking. Results were evaluated through comparison to manual segmentation and measurements from 8666 echocardiograms obtained during the routine clinical workflow. Finally, we developed models to detect 3 diseases: hypertrophic cardiomyopathy, cardiac amyloid, and pulmonary arterial hypertension. RESULTS: Convolutional neural networks accurately identified views (eg, 96% for parasternal long axis), including flagging partially obscured cardiac chambers, and enabled the segmentation of individual cardiac chambers. The resulting cardiac structure measurements agreed with study report values (eg, median absolute deviations of 15% to 17% of observed values for left ventricular mass, left ventricular diastolic volume, and left atrial volume). In terms of function, we computed automated ejection fraction and longitudinal strain measurements (within 2 cohorts), which agreed with commercial software-derived values (for ejection fraction, median absolute deviation=9.7% of observed, N=6407 studies; for strain, median absolute deviation=7.5%, n=419, and 9.0%, n=110) and demonstrated applicability to serial monitoring of patients with breast cancer for trastuzumab cardiotoxicity. Overall, we found automated measurements to be comparable or superior to manual measurements across 11 internal consistency metrics (eg, the correlation of left atrial and ventricular volumes). Finally, we trained convolutional neural networks to detect hypertrophic cardiomyopathy, cardiac amyloidosis, and pulmonary arterial hypertension with C statistics of 0.93, 0.87, and 0.85, respectively. CONCLUSIONS: Our pipeline lays the groundwork for using automated interpretation to support serial patient tracking and scalable analysis of millions of echocardiograms archived within healthcare systems.

Assessing test-retest reliability of patient-reported outcome measures using intraclass correlation coefficients: recommendations for selecting and documenting the analytical formula.

PURPOSE: The US Food and Drug Administration (FDA) 2009 guidance for industry on patient-reported outcome (PRO) measures describes how the Agency evaluates the psychometric properties of measures intended to support medical product labeling claims. An important psychometric property is test-retest reliability. The guidance lists intraclass correlation coefficients (ICCs) and the assessment time period as key considerations for test-retest reliability evaluations. However, the guidance does not provide recommendations regarding ICC computation, nor is there consensus within the measurement literature regarding the most appropriate ICC formula for test-retest reliability assessment. This absence of consensus emerged as an issue within Critical Path Institute's PRO Consortium. The purpose of this project was to generate thoughtful and informed recommendations regarding the most appropriate ICC formula for assessing a PRO measure's test-retest reliability. METHODS: Literature was reviewed and a preferred ICC formula was proposed. Feedback on the chosen formula was solicited from psychometricians, biostatisticians, regulators, and other scientists who have collaborated on PRO Consortium initiatives. RESULTS AND CONCLUSIONS: Feedback was carefully considered and, after further deliberation, the proposed ICC formula was confirmed. In conclusion, to assess test-retest reliability for PRO measures, the two-way mixed-effect analysis of variance model with interaction for the absolute agreement between single scores is recommended.

Validation of the Atopic Dermatitis Control Tool (ADCT©) using a longitudinal survey of biologic-treated patients with atopic dermatitis.

BACKGROUND: The Atopic Dermatitis Control Tool (ADCT©) is a brief patient self-administered instrument designed and validated to assess atopic dermatitis (AD) control; six AD symptoms and impacts are evaluated over the past week, including overall severity of symptoms, days with intense episodes of itching, intensity of bother, problem with sleep, impact on daily activities, and impact on mood or emotions. This study assessed the reliability, validity, and responsiveness of the ADCT in a longitudinal context, and provided thresholds to identify meaningful within-person change. METHODS: Data were from a prospective, longitudinal patient survey study of real-world effectiveness of dupilumab in patients with AD. Eligible patients completed a baseline survey before starting dupilumab and were followed at Months 1, 2, 3, and 6 post-initiation as they became eligible. RESULTS: Psychometric analyses confirmed internal consistency; Cronbach's α coefficients were consistently above the threshold of 0.70 across each follow-up; item-to-total correlations were above the threshold of r ≥ 0.50. High correlations between the ADCT and the Dermatology Life Quality Index (DLQI) and skin pain supported construct validity, while known-group validity was shown on Patient Global Assessment of Disease (PGAD) overall well-being subgroups with worse AD-related overall well-being having higher mean ADCT total scores at all time points. The ability of the ADCT to detect change was confirmed; the threshold for meaningful within-person change was estimated to be 5 points. Finally, test-retest reliability was confirmed in subgroups of patients with stable PGAD responses. CONCLUSIONS: Our findings confirm that the ADCT is a valid and reliable tool for assessing AD control.

Prevalence and correlates of coronary microvascular dysfunction in heart failure with preserved ejection fraction: PROMIS-HFpEF.

Aims: To date, clinical evidence of microvascular dysfunction in patients with heart failure (HF) with preserved ejection fraction (HFpEF) has been limited. We aimed to investigate the prevalence of coronary microvascular dysfunction (CMD) and its association with systemic endothelial dysfunction, HF severity, and myocardial dysfunction in a well defined, multi-centre HFpEF population. Methods and results: This prospective multinational multi-centre observational study enrolled patients fulfilling strict criteria for HFpEF according to current guidelines. Those with known unrevascularized macrovascular coronary artery disease (CAD) were excluded. Coronary flow reserve (CFR) was measured with adenosine stress transthoracic Doppler echocardiography. Systemic endothelial function [reactive hyperaemia index (RHI)] was measured by peripheral arterial tonometry. Among 202 patients with HFpEF, 151 [75% (95% confidence interval 69-81%)] had CMD (defined as CFR <2.5). Patients with CMD had a higher prevalence of current or prior smoking (70% vs. 43%; P = 0.0006) and atrial fibrillation (58% vs. 25%; P = 0.004) compared with those without CMD. Worse CFR was associated with higher urinary albumin-to-creatinine ratio (UACR) and NTproBNP, and lower RHI, tricuspid annular plane systolic excursion, and right ventricular (RV) free wall strain after adjustment for age, sex, body mass index, atrial fibrillation, diabetes, revascularized CAD, smoking, left ventricular mass, and study site (P < 0.05 for all associations). Conclusions: PROMIS-HFpEF is the first prospective multi-centre, multinational study to demonstrate a high prevalence of CMD in HFpEF in the absence of unrevascularized macrovascular CAD, and to show its association with systemic endothelial dysfunction (RHI, UACR) as well as markers of HF severity (NTproBNP and RV dysfunction). Microvascular dysfunction may be a promising therapeutic target in HFpEF.

Estimating the Proportion of Childhood Cancer Cases and Costs Attributable to the Environment in California.

OBJECTIVES: To estimate the proportion of cases and costs of the most common cancers among children aged 0 to 14 years (leukemia, lymphoma, and brain or central nervous system tumors) that were attributable to preventable environmental pollution in California in 2013. METHODS: We conducted a literature review to identify preventable environmental hazards associated with childhood cancer. We combined risk estimates with California-specific exposure prevalence estimates to calculate hazard-specific environmental attributable fractions (EAFs). We combined hazard-specific EAFs to estimate EAFs for each cancer and calculated an overall EAF. Estimated economic costs included annual (indirect and direct medical) and lifetime costs. RESULTS: Hazards associated with childhood cancer risks included tobacco smoke, residential exposures, and parental occupational exposures. Estimated EAFs for leukemia, lymphoma, and brain or central nervous system cancer were 21.3% (range = 11.7%-30.9%), 16.1% (range = 15.0%-17.2%), and 2.0% (range = 1.7%-2.2%), respectively. The combined EAF was 15.1% (range = 9.4%-20.7%), representing $18.6 million (range = $11.6 to $25.5 million) in annual costs and $31 million in lifetime costs. CONCLUSIONS: Reducing environmental hazards and exposures in California could substantially reduce the human burden of childhood cancer and result in significant annual and lifetime savings.

Quantifying the importance of inhaler attributes corresponding to items in the patient satisfaction and preference questionnaire in patients using Combivent Respimat.

BACKGROUND: Physicians consider ease of use, satisfaction, and preferences when prescribing an inhaler device. These factors may impact appropriate usage and compliance. METHODS: The objectives were to quantify the relative importance of inhaler attributes in patients currently using Combivent Respimat by eliciting preferences for performance and convenience attributes assessed by items in the Patient Satisfaction and Preference Questionnaire (PASAPQ). Using a pharmacy database, 19,964 adults in the United States who filled ≥2 Combivent Respimat prescriptions were identified. Of those, 8150 patients were randomly selected to receive invitation letters. The online cross-sectional survey included the PASAPQ and best-worst scaling (BWS) questions. The PASAPQ measures satisfaction with medication attributes across two domains: performance and convenience. BWS questions asked participants to select the most and least important device attributes. A descriptive statistics analysis of the PASAPQ and a random-parameters logit model of BWS responses were conducted. RESULTS: The survey was completed by 503 participants. Most were female (57.3%), white (88.5%), and 51-70 years old (67.6%). Approximately 47% reported a chronic obstructive pulmonary disease diagnosis, 21.9% asthma, 8.2% other lung disease, and 23.1% more than one lung disease. PASAPQ scores indicated that the majority were satisfied or very satisfied; up to 20% reported being dissatisfied with Combivent Respimat. The three most important inhaler attributes were Feeling that your medicine gets into your lungs, Inhaler works reliably, and Inhaler makes inhaling your medicine easy. The most important attributes corresponded to six of seven items in the PASAPQ performance domain. CONCLUSIONS: Most participants reported satisfaction with Combivent Respimat. Performance attributes were more important than convenience attributes.

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.