Bias correction models for electronic health records data in the presence of non-random sampling.

Electronic health records (EHRs) contain rich clinical information for millions of patients and are increasingly used for public health research. However, non-random inclusion of subjects in EHRs can result in selection bias, with factors such as demographics, socioeconomic status, healthcare referral patterns, and underlying health status playing a role. While this issue has been well documented, little work has been done to develop or apply bias-correction methods, often due to the fact that most of these factors are unavailable in EHRs. To address this gap, we propose a series of Heckman type bias correction methods by incorporating social determinants of health selection covariates to model the EHR non-random sampling probability. Through simulations under various settings, we demonstrate the effectiveness of our proposed method in correcting biases in both the association coefficient and the outcome mean. Our method augments the utility of EHRs for public health inferences, as we show by estimating the prevalence of cardiovascular disease and its correlation with risk factors in the New York City network of EHRs.

Using electronic health records to enhance surveillance of diabetes in children, adolescents and young adults: a study protocol for the DiCAYA Network.

INTRODUCTION: Traditional survey-based surveillance is costly, limited in its ability to distinguish diabetes types and time-consuming, resulting in reporting delays. The Diabetes in Children, Adolescents and Young Adults (DiCAYA) Network seeks to advance diabetes surveillance efforts in youth and young adults through the use of large-volume electronic health record (EHR) data. The network has two primary aims, namely: (1) to refine and validate EHR-based computable phenotype algorithms for accurate identification of type 1 and type 2 diabetes among youth and young adults and (2) to estimate the incidence and prevalence of type 1 and type 2 diabetes among youth and young adults and trends therein. The network aims to augment diabetes surveillance capacity in the USA and assess performance of EHR-based surveillance. This paper describes the DiCAYA Network and how these aims will be achieved. METHODS AND ANALYSIS: The DiCAYA Network is spread across eight geographically diverse US-based centres and a coordinating centre. Three centres conduct diabetes surveillance in youth aged 0-17 years only (component A), three centres conduct surveillance in young adults aged 18-44 years only (component B) and two centres conduct surveillance in components A and B. The network will assess the validity of computable phenotype definitions to determine diabetes status and type based on sensitivity, specificity, positive predictive value and negative predictive value of the phenotypes against the gold standard of manually abstracted medical charts. Prevalence and incidence rates will be presented as unadjusted estimates and as race/ethnicity, sex and age-adjusted estimates using Poisson regression. ETHICS AND DISSEMINATION: The DiCAYA Network is well positioned to advance diabetes surveillance methods. The network will disseminate EHR-based surveillance methodology that can be broadly adopted and will report diabetes prevalence and incidence for key demographic subgroups of youth and young adults in a large set of regions across the USA.

Global Longitudinal Strain as Predictor of Inducible Ischemia in No Obstructive Coronary Artery Disease in the CIAO-ISCHEMIA Study.

BACKGROUND: Global longitudinal strain (GLS) is a sensitive marker for identifying subclinical myocardial dysfunction in obstructive coronary artery disease (CAD). Little is known about the relationship between GLS and ischemia in patients with myocardial ischemia and no obstructive CAD (INOCA). OBJECTIVES: To investigate the relationship between resting GLS and ischemia on stress echocardiography (SE) in patients with INOCA. METHODS: Left ventricular GLS was calculated offline on resting SE images at enrollment (n = 144) and 1-year follow-up (n = 120) in the CIAO-ISCHEMIA (Changes in Ischemia and Angina over One year in International Study of Comparative Health Effectiveness with Medical and Invasive Approaches trial screen failures with no obstructive CAD on computed tomography [CT] angiography) study, which enrolled participants with moderate or severe ischemia by local SE interpretation (≥3 segments with new or worsening wall motion abnormality and no obstructive (<50% stenosis) on coronary computed tomography angiography. RESULTS: Global longitudinal strain values were normal in 83.3% at enrollment and 94.2% at follow-up. Global longitudinal strain values were not associated with a positive SE at enrollment (GLS = -21.5% positive SE vs GLS = -19.9% negative SE, P = .443) or follow-up (GLS = -23.2% positive SE vs GLS = -23.1% negative SE, P = .859). Significant change in GLS was not associated with positive SE in follow-up (P = .401). Regional strain was not associated with colocalizing ischemia at enrollment or follow-up. Changes in GLS and number of ischemic segments from enrollment to follow-up showed a modest but not clinically meaningful correlation (ß = 0.41; 95% CI, 0.16, 0.67; P = .002). CONCLUSIONS: In this cohort of INOCA patients, resting GLS values were largely normal and did not associate with the presence, severity, or location of stress-induced ischemia. These findings may suggest the absence of subclinical myocardial dysfunction detectable by echocardiographic strain analysis at rest in INOCA.

Biomarkers and cardiovascular events in patients with stable coronary disease in the ISCHEMIA Trials.

IMPORTANCE: Biomarkers may improve prediction of cardiovascular events for patients with stable coronary artery disease (CAD), but their importance in addition to clinical tests of inducible ischemia and CAD severity is unknown. OBJECTIVES: To evaluate the prognostic value of multiple biomarkers in stable outpatients with obstructive CAD and moderate or severe inducible ischemia. DESIGN AND SETTING: The ISCHEMIA and ISCHEMIA CKD trials randomized 5,956 participants with CAD to invasive or conservative management from July 2012 to January 2018; 1,064 participated in the biorepository. MAIN OUTCOME MEASURES: Primary outcome was cardiovascular death, myocardial infarction (MI), or hospitalization for unstable angina, heart failure, or resuscitated cardiac arrest. Secondary outcome was cardiovascular death or MI. Improvements in prediction were assessed by cause-specific hazard ratios (HR) and area under the receiver operating characteristics curve (AUC) for an interquartile increase in each biomarker, controlling for other biomarkers, in a base clinical model of risk factors, left ventricular ejection fraction (LVEF) and ischemia severity. Secondary analyses were performed among patients in whom core-lab confirmed severity of CAD was ascertained by computed cardiac tomographic angiography (CCTA). EXPOSURES: Baseline levels of interleukin-6 (IL-6), high sensitivity troponin T (hsTnT), growth differentiation factor 15 (GDF-15), N-terminal pro-B-type natriuretic peptide (NT-proBNP), lipoprotein a (Lp[a]), high sensitivity C-reactive protein (hsCRP), Cystatin C, soluble CD 40 ligand (sCD40L), myeloperoxidase (MPO), and matrix metalloproteinase 3 (MMP3). RESULTS: Among 757 biorepository participants, median (IQR) follow-up was 3 (2-5) years, age was 67 (61-72) years, and 144 (19%) were female; 508 had severity of CAD by CCTA available. In an adjusted multimarker model with hsTnT, GDF-15, NT-proBNP and sCD40L, the adjusted HR for the primary outcome per interquartile increase in each biomarker was 1.58 (95% CI 1.22, 2.205), 1.60 (95% CI 1.16, 2.20), 1.61 (95% 1.22, 2.14), and 1.46 (95% 1.12, 1.90), respectively. The adjusted multimarker model also improved prediction compared with the clinical model, increasing the AUC from 0.710 to 0.792 (P < .01) and 0.714 to 0.783 (P < .01) for the primary and secondary outcomes, respectively. Similar findings were observed after adjusting for core-lab confirmed atherosclerosis severity. CONCLUSIONS AND RELEVANCE: Among ISCHEMIA biorepository participants, biomarkers of myocyte injury/distension, inflammation, and platelet activity improved cardiovascular event prediction in addition to risk factors, LVEF, and assessments of ischemia and atherosclerosis severity. These biomarkers may improve risk stratification for patients with stable CAD.

Survival After Invasive or Conservative Management of Stable Coronary Disease.

BACKGROUND: The ISCHEMIA trial (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches) compared an initial invasive versus an initial conservative management strategy for patients with chronic coronary disease and moderate or severe ischemia, with no major difference in most outcomes during a median of 3.2 years. Extended follow-up for mortality is ongoing. METHODS: ISCHEMIA participants were randomized to an initial invasive strategy added to guideline-directed medical therapy or a conservative strategy. Patients with moderate or severe ischemia, ejection fraction ≥35%, and no recent acute coronary syndromes were included. Those with an unacceptable level of angina were excluded. Extended follow-up for vital status is being conducted by sites or through central death index search. Data obtained through December 2021 are included in this interim report. We analyzed all-cause, cardiovascular, and noncardiovascular mortality by randomized strategy, using nonparametric cumulative incidence estimators, Cox regression models, and Bayesian methods. Undetermined deaths were classified as cardiovascular as prespecified in the trial protocol. RESULTS: Baseline characteristics for 5179 original ISCHEMIA trial participants included median age 65 years, 23% women, 16% Hispanic, 4% Black, 42% with diabetes, and median ejection fraction 0.60. A total of 557 deaths accrued during a median follow-up of 5.7 years, with 268 of these added in the extended follow-up phase. This included a total of 343 cardiovascular deaths, 192 noncardiovascular deaths, and 22 unclassified deaths. All-cause mortality was not different between randomized treatment groups (7-year rate, 12.7% in invasive strategy, 13.4% in conservative strategy; adjusted hazard ratio, 1.00 [95% CI, 0.85-1.18]). There was a lower 7-year rate cardiovascular mortality (6.4% versus 8.6%; adjusted hazard ratio, 0.78 [95% CI, 0.63-0.96]) with an initial invasive strategy but a higher 7-year rate of noncardiovascular mortality (5.6% versus 4.4%; adjusted hazard ratio, 1.44 [95% CI, 1.08-1.91]) compared with the conservative strategy. No heterogeneity of treatment effect was evident in prespecified subgroups, including multivessel coronary disease. CONCLUSIONS: There was no difference in all-cause mortality with an initial invasive strategy compared with an initial conservative strategy, but there was lower risk of cardiovascular mortality and higher risk of noncardiovascular mortality with an initial invasive strategy during a median follow-up of 5.7 years. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04894877.

Guideline-Directed Medical Therapy Attainment and Outcomes in Dialysis-Requiring Versus Nondialysis Chronic Kidney Disease in the ISCHEMIA-CKD Trial.

BACKGROUND: Patients with chronic kidney disease (CKD) on dialysis (CKD G5D) have worse cardiovascular outcomes than patients with advanced nondialysis CKD (CKD G4-5: estimated glomerular filtration rate <30 mL/[min·1.73m2]). Our objective was to evaluate the relationship between achievement of cardiovascular guideline-directed medical therapy (GDMT) goals and clinical outcomes for CKD G5D versus CKD G4-5. METHODS: This was a subgroup analysis of ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease) participants with CKD G4-5 or CKD G5D and moderate-to-severe myocardial ischemia on stress testing. Exposures included dialysis requirement at randomization and GDMT goal achievement during follow-up. The composite outcome was all-cause mortality or nonfatal myocardial infarction. Individual GDMT goal (smoking cessation, systolic blood pressure <140 mm Hg, low-density lipoprotein cholesterol <70 mg/dL, statin use, aspirin use) trajectory was modeled. Percentage point difference was estimated for each GDMT goal at 24 months between CKD G5D and CKD G4-5, and for association with key predictors. Probability of survival free from all-cause mortality or nonfatal myocardial infarction by GDMT goal achieved was assessed for CKD G5D versus CKD G4-5. RESULTS: A total of 415 CKD G5D and 362 CKD G4-5 participants were randomized. Participants with CKD G5D were less likely to receive statin (-6.9% [95% CI, -10.3% to -3.7%]) and aspirin therapy (-3.0% [95% CI, -5.6% to -0.6%]), with no difference in other GDMT goal attainment. Cumulative exposure to GDMT achieved during follow-up was associated with reduction in all-cause mortality or nonfatal myocardial infarction (hazard ratio, 0.88 [95% CI, 0.87-0.90]; per each GDMT goal attained over 60 days), irrespective of dialysis status. CONCLUSIONS: CKD G5D participants received statin or aspirin therapy less often. Cumulative exposure to GDMT goals achieved was associated with lower incidence of all-cause mortality or nonfatal myocardial infarction in participants with advanced CKD and chronic coronary disease, regardless of dialysis status. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01985360.

ISCHEMIA-EXTEND studies: Rationale and design.

BACKGROUND: The ISCHEMIA and the ISCHEMIA-CKD trials found no statistical difference in the primary clinical endpoint between initial invasive management and initial conservative management of patients with chronic coronary disease and moderate to severe ischemia on stress testing without or with advanced chronic kidney disease (CKD). In ISCHEMIA, there was numerically lower cardiovascular mortality but higher non-cardiovascular mortality with no significant difference in all-cause death with an initial invasive strategy when compared with a conservative strategy. However, an invasive strategy increased peri-procedural myocardial infarction (MI) but decreased spontaneous MI with continued separation of curves over time, which potentially may lead to reduced risk of cardiovascular and all-cause mortality. Thus, the long-term effect of invasive management strategy on mortality remains unclear. In ISCHEMIA-CKD, the treatment and cause-specific mortality rates were similar during follow-up. METHODS: Funded by the National Heart, Lung, and Blood Institute, the ISCHEMIA-EXTEND observational study is the long-term follow-up of surviving participants (projected median of 10 years) with chronic coronary disease from the ISCHEMIA trial. In the ISCHEMIA trial, 5,179 participants with moderate or severe stress-induced ischemia were randomized to initial invasive management with angiography, revascularization when feasible, and guideline-directed medical therapy (GDMT), or initial conservative management with GDMT alone and angiography reserved for failure of medical therapy. ISCHEMIA-CKD EXTEND is the long-term follow-up of surviving participants (projected median of 9 years) from the ISCHEMIA-CKD trial, a companion trial that included 777 patients with advanced CKD. Ascertainment of death will be conducted via direct participant contact, medical record review, and/or vital status registry search. The overarching objective of long-term follow-up is to assess whether there are between-group differences in long-term all-cause, cardiovascular, and non-cardiovascular mortality, and increase precision around the treatment effect estimates for risk of all-cause, cardiovascular, and non-cardiovascular mortality. We will conduct Bayesian survival modeling to take advantage of rich inferences using the posterior distribution of the treatment effect. CONCLUSIONS: The long-term effect of an initial invasive versus conservative strategy on all-cause, cardiovascular, and non-cardiovascular mortality will be assessed. The findings of ISCHEMIA-EXTEND and ISCHEMIA-CKD EXTEND will inform patients, practitioners, practice guidelines, and health policy.

Decreased basal ganglia and thalamic iron in early psychotic spectrum disorders are associated with increased psychotic and schizotypal symptoms.

Iron deficits have been reported as a risk factor for psychotic spectrum disorders (PSD). However, examinations of brain iron in PSD remain limited. The current study employed quantitative MRI to examine iron content in several iron-rich subcortical structures in 49 young adult individuals with PSD (15 schizophrenia, 17 schizoaffective disorder, and 17 bipolar disorder with psychotic features) compared with 35 age-matched healthy controls (HC). A parametric approach based on a two-pool magnetization transfer model was applied to estimate longitudinal relaxation rate (R1), which reflects both iron and myelin, and macromolecular proton fraction (MPF), which is specific to myelin. To describe iron content, a synthetic effective transverse relaxation rate (R2*) was modeled using a linear fitting of R1 and MPF. PSD patients compared to HC showed significantly reduced R1 and synthetic R2* across examined regions including the pallidum, ventral diencephalon, thalamus, and putamen areas. This finding was primarily driven by decreases in the subgroup with schizophrenia, followed by schizoaffective disorder. No significant group differences were noted for MPF between PSD and HC while for regional volume, significant reductions in patients were only observed in bilateral caudate, suggesting that R1 and synthetic R2* reductions in schizophrenia and schizoaffective patients likely reflect iron deficits that either occur independently or precede structural and myelin changes. Subcortical R1 and synthetic R2* were also found to be inversely related to positive symptoms within the PSD group and to schizotypal traits across the whole sample. These findings that decreased iron in subcortical regions are associated with PSD risk and symptomatology suggest that brain iron deficiencies may play a role in PSD pathology and warrant further study.

Cardiovascular and Renal Implications of Myocardial Infarction in the ISCHEMIA-CKD Trial.

BACKGROUND: ISCHEMIA-CKD (International Study of Comparative Health Effectiveness With Medical and Invasive Approaches-Chronic Kidney Disease) reported an initial invasive treatment strategy did not reduce the risk of death or nonfatal myocardial infarction (MI) compared with a conservative treatment strategy in patients with advanced chronic kidney disease, stable coronary disease, and moderate or severe myocardial ischemia. The cumulative frequency of different MI type after randomization and subsequent prognosis have not been reported. METHODS: MI classification was based on the Third Universal Definition for MI. For procedural MI, the primary MI definition used creatine kinase-MB as the preferred biomarker, whereas the secondary MI definition used cTn (cardiac troponin); both definitions included elevated biomarker-only events with higher thresholds than nonprocedural MIs. The cumulative frequency of MI type according to treatment strategy was determined. The association of MI with subsequent all-cause death and new dialysis initiation was assessed by treating MI as a time-dependent covariate. RESULTS: The 3-year incidence of type 1 or 2 MI with the primary MI definition was 11.2% in invasive treatment strategy and 13.6% in conservative treatment strategy (hazard ratio [HR], 0.66 [95% CI, 0.42-1.02]). Procedural MIs were more frequent in invasive treatment strategy and accounted for 9.8% and 28.3% of all MIs with the primary and secondary MI definitions, respectively. Patients had an increased risk of all-cause death after type 1 MI (adjusted HR, 4.35 [95% CI, 2.73-6.93]) and after procedural MI with the primary (adjusted HR, 2.75 [95% CI, 0.99-7.60]) and secondary MI definitions (adjusted HR, 2.91 [95% CI, 1.73-4.88]). Dialysis initiation was increased after a type 1 MI (HR, 6.45 [95% CI, 2.59-16.08]) compared with patients without an MI. CONCLUSIONS: In ISCHEMIA-CKD, the invasive treatment strategy had higher rates of procedural MIs, particularly with the secondary MI definition, and lower rates of type 1 and 2 MIs. Procedural MIs, type 1 MIs, and type 2 MIs were associated with increased risk of subsequent death. Type 1 MI increased the risk of dialysis initiation. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01985360.

Comparison of Prostate Imaging and Reporting Data System V2.0 and V2.1 for Evaluation of Transition Zone Lesions: A 5-Reader 202-Patient Analysis.

OBJECTIVE: The aim of the study was to compare the distribution of Prostate Imaging and Reporting Data System (PI-RADS) scores, interreader agreement, and diagnostic performance of PI-RADS v2.0 and v2.1 for transition zone (TZ) lesions. METHODS: The study included 202 lesions in 202 patients who underwent 3T prostate magnetic resonance imaging showing a TZ lesion that was later biopsied with magnetic resonance imaging/ultrasound fusion. Five abdominal imaging faculty reviewed T2-weighted imaging and high b value/apparent diffusion coefficient images in 2 sessions. Cases were randomized using a crossover design whereby half in the first session were reviewed using v2.0 and the other half using v2.1, and vice versa for the 2nd session. Readers provided T2-weighted imaging and DWI scores, from which PI-RADS scores were derived. RESULTS: Interreader agreement for all PI-RADS scores had κ of 0.37 (v2.0) and 0.26 (v2.1). For 4 readers, the percentage of lesions retrospectively scored PI-RADS 1 increased greater than 5% and PI-RADS 2 score decreased greater than 5% from v2.0 to v2.1. For 2 readers, the percentage scored PI-RADS 3 decreased greater than 5% and, for 2 readers, increased greater than 5%. The percentage of PI-RADS 4 and 5 lesions changed less than 5% for all readers. For the 4 readers with increased frequency of PI-RADS 1 using v2.1, 4% to 16% were Gleason score ≥3 + 4 tumor. Frequency of Gleason score ≥3 + 4 in PI-RADS 3 lesions increased for 2 readers and decreased for 1 reader. Sensitivity of PI-RADS of 3 or greater for Gleason score ≥3 + 4 ranged 76% to 90% (v2.0) and 69% to 96% (v2.1). Specificity ranged 32% to 64% (v2.0) and 25% to 72% (v2.1). Positive predictive value ranged 43% to 55% (v2.0) and 41% to 58% (v2.1). Negative predictive value ranged 82% to 87% (v2.0) and 81% to 91% (v2.1). CONCLUSIONS: Poor interreader agreement and lack of improvement in diagnostic performance indicate an ongoing need to refine evaluation of TZ lesions.

Predictors of outcome in the ISCHEMIA-CKD trial: Anatomy versus ischemia.

BACKGROUND: The ISCHEMIA-CKD (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches-Chronic Kidney Disease) trial found no advantage to an invasive strategy compared to conservative management in reducing all-cause death or myocardial infarction (D/MI). However, the prognostic influence of angiographic coronary artery disease (CAD) burden and ischemia severity remains unknown in this population. We compared the relative impact of CAD extent and severity of myocardial ischemia on D/MI in patients with advanced chronic kidney disease (CKD). METHODS: Participants randomized to invasive management with available data on coronary angiography and stress testing were included. Extent of CAD was defined by the number of major epicardial vessels with ≥50% diameter stenosis by quantitative coronary angiography. Ischemia severity was assessed by site investigators as moderate or severe using trial definitions. The primary endpoint was D/MI. RESULTS: Of the 388 participants, 307 (79.1%) had complete coronary angiography and stress testing data. D/MI occurred in 104/307 participants (33.9%). Extent of CAD was associated with an increased risk of D/MI (P < .001), while ischemia severity was not (P = .249). These relationships persisted following multivariable adjustment. Using 0-vessel disease (VD) as reference, the adjusted hazard ratio (HR) for 1VD was 1.86, 95% confidence interval (CI) 0.94 to 3.68, P = .073; 2VD: HR 2.13, 95% CI 1.10 to 4.12, P = .025; 3VD: HR 4.00, 95% CI 2.06 to 7.76, P < .001. Using moderate ischemia as the reference, the HR for severe ischemia was 0.84, 95% CI 0.54 to 1.30, P = .427. CONCLUSION: Among ISCHEMIA-CKD participants randomized to the invasive strategy, extent of CAD predicted D/MI whereas severity of ischemia did not.

Using Lung Base Covid-19 Findings to Predict Future Disease Trends and New Variant Outbreaks: Study of First New York City (NYC) Outbreak.

RATIONALE AND OBJECTIVES: Asymptomatic COVID-19 carriers and insufficient testing make containment of the virus difficult. The purpose of this study was to determine if unexpected lung base findings on abdominopelvic CTs concerning for COVID-19 infection could serve as a surrogate for the diagnosis of COVID-19 in the community. MATERIALS AND METHODS: A database search of abdominopelvic CT reports from March 1,2020 to May 2,2020 was performed for keywords suggesting COVID-19 infection by lung base findings. COVID-19 status, respiratory symptoms, laboratory parameters and patient outcomes (hospitalization, ICU admission and/or intubation, and death) were recorded. The trend in cases of unexpected concerning lung base findings on abdominopelvic CT at our institution was compared to the total number of confirmed new cases in NYC over the same time period. RESULTS: The trend in abnormal lung base findings on abdominopelvic CT at our institution correlated with the citywide number of confirmed new cases, including rise and subsequent fall in total cases. The trend was not mediated by COVID-19 testing status or number of tests performed. Patients with respiratory symptoms had significantly higher ferritin (median = 995ng/ml vs 500ng/ml, p = 0.027) and death rate (8/24, 33% vs 4/54, 9%, p = 0.018) compared to those without. CONCLUSION: The rise and fall of unexpected lung base findings suggestive of COVID-19 infection on abdominopelvic CT in patients without COVID-19 symptoms correlated with the number of confirmed new cases throughout NYC from the same time period. A model using abdominopelvic CT lung base findings can serve as a surrogate for future COVID-19 outbreaks.

Optimal medical therapy in patients with stable coronary artery disease in Poland: the ISCHEMIA trial experience.

Introduction: Optimal medical therapy (OMT) is the cornerstone of treatment for stable coronary disease with the ISCHEMIA trial showing similar outcomes using OMT with or without an initial invasive approach. Objectives: To describe OMT goal attainment in Polish ISCHEMIA participants compared with other countries. Patients and methods: Among 5179 trial participants, 333 were randomized in Poland. The median follow-up was 3.2 years. OMT targets were: not smoking, high-intensity statin therapy, low-density lipoprotein cholesterol (LDL-C) of less than 70 mg/dl, systolic blood pressure of less than 140 mm Hg, aspirin therapy, and ACEI / ARB, and ß-blocker therapy if indicated. Results: Compared with 36 other countries, at randomization, patients in Poland were older (67 [62­75] y vs 65 [58­71] y); P <⁠0.001), more often female (30% vs 22%; P = 0.002), with a longer history of angina (3 [1­9] y vs 1 [0­3] y; P <⁠0.001), and there were more cases of prior myocardial infarction (32% vs 18%; P <⁠0.01) and revascularization (PCI, 40% vs 19%; CABG, 11% vs 3%; P <⁠0.001 for both). The number of OMT goals attained increased from baseline to follow-up visits (5 [4­5] vs 6 [5­6]; P <⁠0.001) in Poland and other countries alike (P = 0.89 vs P = 0.14). In Poland, significant improvements were achieved regarding high-intensity statin therapy (27% vs 50%), LDL-C <⁠70 mg/dl (29% vs 65%), and systolic blood pressure of less than 140 mm Hg (63% vs 81%) (P <⁠0.001 for all), whereas not-smoking (89% vs 89%), aspirin (90% vs 88%), ACEI / ARB (93% vs 95%), and ß-blocker therapy (94% vs 90%) remained high. Conclusions: With regular surveillance and contemporary medical therapy, high OMT goal attainment was achievable among the participants of the ISCHEMIA trial in Poland relative to other countries. There is still room for improvement in LDL-C and blood pressure management.

Outcomes of Participants With Diabetes in the ISCHEMIA Trials.

BACKGROUND: Among patients with diabetes and chronic coronary disease, it is unclear if invasive management improves outcomes when added to medical therapy. METHODS: The ISCHEMIA (International Study of Comparative Health Effectiveness with Medical and Invasive Approaches) trials (ie, ISCHEMIA and ISCHEMIA-Chronic Kidney Disease) randomized chronic coronary disease patients to an invasive (medical therapy + angiography and revascularization if feasible) or a conservative approach (medical therapy alone with revascularization if medical therapy failed). Cohorts were combined after no trial-specific effects were observed. Diabetes was defined by history, hemoglobin A1c ≥6.5%, or use of glucose-lowering medication. The primary outcome was all-cause death or myocardial infarction (MI). Heterogeneity of effect of invasive management on death or MI was evaluated using a Bayesian approach to protect against random high or low estimates of treatment effect for patients with versus without diabetes and for diabetes subgroups of clinical (female sex and insulin use) and anatomic features (coronary artery disease severity or left ventricular function). RESULTS: Of 5900 participants with complete baseline data, the median age was 64 years (interquartile range, 57-70), 24% were female, and the median estimated glomerular filtration was 80 mL·min-1·1.73-2 (interquartile range, 64-95). Among the 2553 (43%) of participants with diabetes, the median percent hemoglobin A1c was 7% (interquartile range, 7-8), and 30% were insulin-treated. Participants with diabetes had a 49% increased hazard of death or MI (hazard ratio, 1.49 [95% CI, 1.31-1.70]; P<0.001). At median 3.1-year follow-up the adjusted event-free survival was 0.54 (95% bootstrapped CI, 0.48-0.60) and 0.66 (95% bootstrapped CI, 0.61-0.71) for patients with diabetes versus without diabetes, respectively, with a 12% (95% bootstrapped CI, 4%-20%) absolute decrease in event-free survival among participants with diabetes. Female and male patients with insulin-treated diabetes had an adjusted event-free survival of 0.52 (95% bootstrapped CI, 0.42-0.56) and 0.49 (95% bootstrapped CI, 0.42-0.56), respectively. There was no difference in death or MI between strategies for patients with diabetes versus without diabetes, or for clinical (female sex or insulin use) or anatomic features (coronary artery disease severity or left ventricular function) of patients with diabetes. CONCLUSIONS: Despite higher risk for death or MI, chronic coronary disease patients with diabetes did not derive incremental benefit from routine invasive management compared with initial medical therapy alone. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01471522.

Effect of health systems context on infant and child mortality in sub-Saharan Africa from 1995 to 2015, a longitudinal cohort analysis.

Each year, > 3 million children die in sub-Saharan Africa before their fifth birthday. Most deaths are preventable or avoidable through interventions delivered in the primary healthcare system. However, evidence regarding the impact of health system characteristics on child survival is sparse. We assembled a retrospective cohort of > 250,000 children in seven countries in sub-Saharan Africa. We described their health service context at the subnational level using standardized surveys and employed parametric survival models to estimate the effect of three major domains of health services-quality, access, and cost-on infant and child survival, after adjusting for child, maternal, and household characteristics. Between 1995 and 2015 we observed 13,629 deaths in infants and 5149 in children. In fully-adjusted models, the largest effect sizes were related to fees for services. Immunization fees were correlated with poor child survival (HR = 1.20, 95% CI 1.12-1.28) while delivery fees were correlated with poor infant survival (HR = 1.11, 95% CI 1.01-1.21). Accessibility of facilities and greater concentrations of private facilities were associated with improved infant and child survival. The proportion of facilities with a doctor was correlated with increased risk of death in children and infants. We quantify the impact of health service environment on survival up to five years of age. Reducing health care costs and improving the accessibility of health facilities should remain a priority for improving infant and child survival. In the absence of these fundamental investments, more specialized interventions may not achieve their desired impact.

Natural History of Patients With Ischemia and No Obstructive Coronary Artery Disease: The CIAO-ISCHEMIA Study.

BACKGROUND: Ischemia with no obstructive coronary artery disease (INOCA) is common and has an adverse prognosis. We set out to describe the natural history of symptoms and ischemia in INOCA. METHODS: CIAO-ISCHEMIA (Changes in Ischemia and Angina over One Year in ISCHEMIA Trial Screen Failures With INOCA) was an international cohort study conducted from 2014 to 2019 involving angina assessments (Seattle Angina Questionnaire) and stress echocardiograms 1 year apart. This was an ancillary study that included patients with a history of angina who were not randomly assigned in the ISCHEMIA trial. Stress-induced wall motion abnormalities were determined by an echocardiographic core laboratory blinded to symptoms, coronary artery disease status, and test timing. Medical therapy was at the discretion of treating physicians. The primary outcome was the correlation between the changes in the Seattle Angina Questionnaire angina frequency score and changes in echocardiographic ischemia. We also analyzed predictors of 1-year changes in both angina and ischemia, and we compared CIAO participants with ISCHEMIA participants with obstructive coronary artery disease who had stress echocardiography before enrollment, as CIAO participants did. RESULTS: INOCA participants in CIAO were more often female (66% of 208 versus 26% of 865 ISCHEMIA participants with obstructive coronary artery disease, P<0.001), but the magnitude of ischemia was similar (median 4 ischemic segments [interquartile range, 3-5] both groups). Ischemia and angina were not significantly correlated at enrollment in CIAO (P=0.46) or ISCHEMIA stress echocardiography participants (P=0.35). At 1 year, the stress echocardiogram was normal in half of CIAO participants, and 23% had moderate or severe ischemia (≥3 ischemic segments). Angina improved in 43% and worsened in 14%. Change in ischemia over 1 year was not significantly correlated with change in angina (ρ=0.029). CONCLUSIONS: Improvement in ischemia and angina were common in INOCA but not correlated. Our INOCA cohort had a degree of inducible wall motion abnormalities similar to concurrently enrolled ISCHEMIA participants with obstructive coronary artery disease. Our results highlight the complex nature of INOCA pathophysiology and the multifactorial nature of angina. Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02347215.

Accelerated single-shot T2-weighted fat-suppressed (FS) MRI of the liver with deep learning-based image reconstruction: qualitative and quantitative comparison of image quality with conventional T2-weighted FS sequence.

OBJECTIVE: To compare the image quality of an accelerated single-shot T2-weighted fat-suppressed (FS) MRI of the liver with deep learning-based image reconstruction (DL HASTE-FS) with conventional T2-weighted FS sequence (conventional T2 FS) at 1.5 T. METHODS: One hundred consecutive patients who underwent clinical MRI of the liver at 1.5 T including the conventional T2-weighted fat-suppressed sequence (T2 FS) and accelerated single-shot T2-weighted MRI of the liver with deep learning-based image reconstruction (DL HASTE-FS) were included. Images were reviewed independently by three blinded observers who used a 5-point confidence scale for multiple measures regarding the artifacts and image quality. Descriptive statistics and McNemar's test were used to compare image quality scores and percentage of lesions detected by each sequence, respectively. Intra-class correlation coefficient (ICC) was used to assess consistency in reader scores. RESULTS: Acquisition time for DL HASTE-FS was 51.23 +/ 10.1 s, significantly (p < 0.001) shorter than conventional T2-FS (178.9 ± 85.3 s). DL HASTE-FS received significantly higher scores than conventional T2-FS for strength and homogeneity of fat suppression; sharpness of liver margin; sharpness of intra-hepatic vessel margin; in-plane and through-plane respiratory motion; other ghosting artefacts; liver-fat contrast; and overall image quality (all, p < 0.0001). DL HASTE-FS also received higher scores for lesion conspicuity and sharpness of lesion margin (all, p < .001), without significant difference for liver lesion contrast (p > 0.05). CONCLUSIONS: Accelerated single-shot T2-weighted MRI of the liver with deep learning-based image reconstruction showed superior image quality compared to the conventional T2-weighted fat-suppressed sequence despite a 4-fold reduction in acquisition time. KEY POINTS: • Conventional fat-suppressed T2-weighted sequence (conventional T2 FS) can take unacceptably long to acquire and is the most commonly repeated sequence in liver MRI due to motion. • DL HASTE-FS demonstrated superior image quality, improved respiratory motion and other ghosting artefacts, and increased lesion conspicuity with comparable liver-to-lesion contrast compared to conventional T2FS sequence. • DL HASTE- FS has the potential to replace conventional T2 FS sequence in routine clinical MRI of the liver, reducing the scan time, and improving the image quality.

Kidney Transplant List Status and Outcomes in the ISCHEMIA-CKD Trial.

BACKGROUND: Patients with chronic kidney disease (CKD) and coronary artery disease frequently undergo preemptive revascularization before kidney transplant listing. OBJECTIVES: In this post hoc analysis from ISCHEMIA-CKD (International Study of Comparative Health Effectiveness of Medical and Invasive Approaches-Chronic Kidney Disease), we compared outcomes of patients not listed versus those listed according to management strategy. METHODS: In the ISCHEMIA-CKD trial (n = 777), 194 patients (25%) with chronic coronary syndromes and at least moderate ischemia were listed for transplant. The primary (all-cause mortality or nonfatal myocardial infarction) and secondary (death, nonfatal myocardial infarction, hospitalization for unstable angina, heart failure, resuscitated cardiac arrest, or stroke) outcomes were analyzed using Cox multivariable modeling. Heterogeneity of randomized treatment effect between listed versus not listed groups was assessed. RESULTS: Compared with those not listed, listed patients were younger (60 years vs 65 years), were less likely to be of Asian race (15% vs 29%), were more likely to be on dialysis (83% vs 44%), had fewer anginal symptoms, and were more likely to have coronary angiography and coronary revascularization irrespective of treatment assignment. Among patients assigned to an invasive strategy versus conservative strategy, the adjusted hazard ratios for the primary outcome were 0.91 (95% confidence interval [CI]: 0.54-1.54) and 1.03 (95% CI: 0.78-1.37) for those listed and not listed, respectively (pinteraction= 0.68). Adjusted hazard ratios for secondary outcomes were 0.89 (95% CI: 0.55-1.46) in listed and 1.17 (95% CI: 0.89-1.53) in those not listed (pinteraction = 0.35). CONCLUSIONS: In ISCHEMIA-CKD, an invasive strategy in kidney transplant candidates did not improve outcomes compared with conservative management. These data do not support routine coronary angiography or revascularization in patients with advanced CKD and chronic coronary syndromes listed for transplant. (ISCHEMIA-Chronic Kidney Disease Trial [ISCHEMIA-CKD]; NCT01985360).

Characteristics of the built environment and spatial patterning of type 2 diabetes in the urban core of Durham, North Carolina.

BACKGROUND: Few studies examine relationships between built environment (BE) and type 2 diabetes mellitus (T2DM) using spatial models, investigate BE domains apart from food environment or physical activity resources or conduct sensitivity analysis of methodological choices made in measuring BE. We examine geographic heterogeneity of T2DM, describe how heterogeneity in T2DM relates to BE and estimate associations of T2DM with BE. METHODS: Individual-level electronic health records (n=41 203) from the Duke Medicine Enterprise Data Warehouse (2007-2011) were linked to BE based on census block. Data on housing damage, property disorder, territoriality, vacancy and public nuisances were used to estimate BE based on four different construction methods (CMs). We used race-stratified aspatial and spatial Bayesian models to assess geographic heterogeneity in T2DM and associations of T2DM with BE. RESULTS: Among whites, a 1 SD increase in poor quality BE was associated with a 1.03 (95% credible interval 1.01 to 1.06) and 1.06 (95 % credible interval 1.02 to 1.11) increased risk of T2DM for poor quality BE CM1 and CM2, respectively. Among blacks/African Americans, associations between T2DM and BE overlapped with the null for all CMs. The addition of BE to white models reduced residual geographic heterogeneity in T2DM by 4%-15%, depending on CM. In black/African-American models, BE did not affect residual heterogeneity. CONCLUSION: Associations of T2DM with BE were sensitive to CM and geographic heterogeneity in T2DM differed by race/ethnicity. Findings underscore the need to consider multiple methods of estimating BE and consider differences in relationships by race/ethnicity.

Residential Racial Isolation and Spatial Patterning of Type 2 Diabetes Mellitus in Durham, North Carolina.

Neighborhood characteristics such as racial segregation may be associated with type 2 diabetes mellitus, but studies have not examined these relationships using spatial models appropriate for geographically patterned health outcomes. We constructed a local, spatial index of racial isolation (RI) for black residents in a defined area, measuring the extent to which they are exposed only to one another, to estimate associations of diabetes with RI and examine how RI relates to spatial patterning in diabetes. We obtained electronic health records from 2007-2011 from the Duke Medicine Enterprise Data Warehouse. Patient data were linked to RI based on census block of residence. We used aspatial and spatial Bayesian models to assess spatial variation in diabetes and relationships with RI. Compared with spatial models with patient age and sex, residual geographic heterogeneity in diabetes in spatial models that also included RI was 29% and 24% lower for non-Hispanic white and black residents, respectively. A 0.20-unit increase in RI was associated with an increased risk of diabetes for white (risk ratio = 1.24, 95% credible interval: 1.17, 1.31) and black (risk ratio = 1.07, 95% credible interval: 1.05, 1.10) residents. Improved understanding of neighborhood characteristics associated with diabetes can inform development of policy interventions.