Temporal trends in cardiovascular outcomes and costs among patients with type 2 diabetes.

BACKGROUND: Type 2 diabetes (T2D) is a strong risk factor for cardiovascular (CV) disease. CV outcomes in T2D have generally been improving over time but recent data from the US suggest attenuation of trends in older adults with reversal of trends in younger adults. However, published data are only reported through 2015. OBJECTIVES: To quantify trends over time in CV outcomes from 2001 to 2018, and describe changes over time in health care costs in T2D. METHODS: This retrospective cohort study incorporated data from a regional health insurance plan. Study outcomes included acute myocardial infarction (AMI), ischemic stroke, hemorrhagic stroke, heart failure hospitalization (HFH), percutaneous coronary intervention, coronary artery bypass surgery, and all-cause mortality. Poisson regression estimated rate ratios across the entire 17-year study period (RR17). RESULTS: Among 79,392 T2D members tracked on average 4.1 years, overall trends in AMI (RR17 = 0.69; 95% CI: 0.64, 0.74), HFH (RR17 = 0.82; 0.79, 0.86), and all-cause mortality (RR17 = 0.87; 0.84, 0.91) improved while ischemic stroke (RR17 = 2.36; 2.16, 2.57) worsened. For AMI, HFH, and all-cause mortality, trends in older age groups were significantly better than in younger age groups (interaction P-values < .001). Health care costs related to pharmaceuticals (+15%/year) and emergency department (ED) visits (>15%/year) increased at faster rates than other utilization metrics (+10%/year). CONCLUSIONS: In T2D, overall trends in most CV outcomes improved but smaller improvements or worsening trends were observed in younger patients. Health care costs accelerated at faster rates for medications and ED visits.

Changes over time in the cardiovascular risk profile of type 2 diabetes from 2007 to 2020: A community-based study.

AIMS: To quantify changes over time in cardiovascular (CV) risk factor control and in the uptake of glucagon-like peptide-1 receptor agonists (GLP-1RAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors from 2007 to 2020 in a real-world community-based cohort of type 2 diabetes (T2D) patients. MATERIALS AND METHODS: This study identified 95 461 T2D patients, who were followed for an average of 6.4 years through a single healthcare organization's electronic health record. The primary outcome was global risk factor control according to four factors ("ABCS"): glycated haemoglobin (HbA1c [<8%]); Blood pressure (systolic/diastolic <140/90 mmHg); Cholesterol (non-HDL cholesterol <130 mg/dL); and Smoking (not). Concomitant presence of microvascular complications and commonly used medication classes were tracked. RESULTS: According to the ABCS metric, global risk factor control did not appreciably change over time; in 2020, 40.9% (95% confidence interval 40.2, 41.5) of patients had all four factors controlled. Among individual components, HbA1c control (<8%) worsened over time from 84% in 2007 to 78% in 2020, while lipid control (non-HDL cholesterol <130 mg/dL) improved from 59% to 72%. Coexisting microvascular complications were more prevalent over time; for example, neuropathy prevalence increased from 21% (2007) to 35% (2020). Use of thiazolidinediones and sulphonylureas decreased over time while metformin, insulin, dipeptidyl peptidase-4 inhibitor, GLP-1RA and SGLT2 inhibitor use increased. In 2020, GLP-1RAs and SGLT2 inhibitors were each used by 13% of T2D patients. CONCLUSIONS: In this community-based study, global CV risk factor control in T2D did not improve, although glycaemic control worsened and lipid control improved. Given increased uptake of GLP-1RAs and SGLT2 inhibitors, the collective effect of these changes on CV outcomes warrants evaluation.

CD16+NK-92 and anti-CD123 monoclonal antibody prolongs survival in primary human acute myeloid leukemia xenografted mice.

Patients with acute myeloid leukemia (AML) often relapse after initial therapy because of persistence of leukemic stem cells that frequently express the IL-3 receptor alpha chain CD123. Natural killer (NK) cell-based therapeutic strategies for AML show promise and we explore the NK cell lines, NK-92 and CD16+ NK-92, as a treatment for AML. NK-92 has been tested in phase I clinical trials with minimal toxicity; irradiation prior to infusion prevents risk of engraftment. The CD16 negative NK-92 parental line was genetically modified to express the high affinity Fc gamma receptor, enabling antibody-dependent cell-mediated cytotoxicity, which we utilized in combination with an anti-CD123 antibody to target leukemic stem cells. NK-92 was preferentially cytotoxic against leukemic stem and progenitor cells compared with bulk leukemia in in vitro assays, while CD16+ NK-92 in combination with an anti-CD123 mAb mediated antibody-dependent cell-mediated cytotoxicity against CD123+ leukemic targets. Furthermore, NK-92 infusions (with or without prior irradiation) improved survival in a primary AML xenograft model. Mice xenografted with primary human AML cells had a superior survival when treated with irradiated CD16+NK-92 cells and an anti-CD123 monoclonal antibody (7G3) versus treatment with irradiated CD16+NK-92 cells combined with an isotype control antibody. In this proof-of-principle study, we show for the first time that a CD16+NK-92 cell line combined with an antibody that targets a leukemic stem cell antigen can lead to improved survival in a relevant pre-clinical model of AML.

Prognostic value of vasodilator response using rubidium-82 positron emission tomography myocardial perfusion imaging in patients with coronary artery disease.

BACKGROUND: Prognostic value of positron emission tomography (PET) myocardial perfusion imaging (MPI) is well established. There is paucity of data on how the prognostic value of PET relates to the hemodynamic response to vasodilator stress. We hypothesize that inadequate hemodynamic response will affect the prognostic value of PET MPI. METHODS AND RESULTS: Using a multicenter rubidium (Rb)-82 PET registry, 3406 patients who underwent a clinically indicated rest/stress PET MPI with a vasodilator agent were analyzed. Patients were categorized as, "responders" [increase in heart rate ≥ 10 beats per minute (bpm) and decrease in systolic blood pressure (SBP) ≥10 mmHg], "partial responders" (either a change in HR or SBP), and "non-responders" (no change in HR or SBP). Primary outcome was all-cause death (ACD), and secondary outcome was cardiac death (CD). Ischemic burden was measured using summed stress score (SSS) and % left ventricular (LV) ischemia. After a median follow-up of 1.68 years (interquartile range = 1.17- 2.55), there were 7.9% (n = 270) ACD and 2.6% (n = 54) CD. Responders with a normal PET MPI had an annualized event rate (AER) of 1.22% (SSS of 0-3) and 1.58% (% LV ischemia = 0). Partial and non-responders had higher AER with worsening levels of ischemic burden. In the presence of severe SSS ≥12 and LV ischemia of ≥10%, partial responders had an AER of 10.79% and 10.36%, compared to non-responders with an AER of 19.4% and 12.43%, respectively. Patient classification was improved when SSS was added to a model containing clinical variables (NRI: 42%, p < 0.001) and responder category was added (NRI: 61%, p < 0.001). The model including clinical variables, SSS and hemodynamic response has good discrimination ability (Harrell C statistics: 0.77 [0.74-0.80]). CONCLUSION: Hemodynamic response during a vasodilator Rb-82 PET MPI is predictive of ACD. Partial and non-responders may require additional risk stratification leading to altered patient management.

Applying the Seattle Heart Failure Model in the Office Setting in the Era of Electronic Medical Records.

BACKGROUND: Prediction models such as the Seattle Heart Failure Model (SHFM) can help guide management of heart failure (HF) patients, but the SHFM has not been validated in the office environment. This retrospective cohort study assessed the predictive performance of the SHFM among patients with new or pre-existing HF in the context of an office visit.Methods and Results:SHFM elements were ascertained through electronic medical records at an office visit. The primary outcome was all-cause mortality. A "warranty period" for the baseline SHFM risk estimate was sought by examining predictive performance over time through a series of landmark analyses. Discrimination and calibration were estimated according to the proposed warranty period. Low- and high-risk thresholds were proposed based on the distribution of SHFM estimates. Among 26,851 HF patients, 14,380 (54%) died over a mean 4.7-year follow-up period. The SHFM lost predictive performance over time, with C=0.69 and C<0.65 within 3 and beyond 12 months from baseline respectively. The diminishing predictive value was attributed to modifiable SHFM elements. Discrimination (C=0.66) and calibration for 12-month mortality were acceptable. A low-risk threshold of ∼5% mortality risk within 12 months reflects the 10% of HF patients in the office setting with the lowest risk. CONCLUSIONS: The SHFM has utility in the office environment.

Prognostic significance of blood pressure response during vasodilator stress Rb-82 positron emission tomography myocardial perfusion imaging.

BACKGROUND: A drop in blood pressure (BP) or blunted BP response is an established high-risk marker during exercise myocardial perfusion imaging (MPI); however, data are sparse regarding the prognostic value of BP response in patients undergoing vasodilator stress rubidium-82 (Rb-82) Positron Emission Tomography (PET) MPI. METHODS AND RESULTS: From the PET Prognosis Multicenter Registry, a cohort of 3413 patients underwent vasodilator stress Rb-82 PET MPI with dipyridamole or adenosine. We used multivariable Cox proportional hazard regression to analyze the association with mortality of four BP variables: stress minus rest systolic BP (∆SBP), stress minus rest diastolic BP (∆DBP), resting systolic BP (rSBP), and resting diastolic BP (rDBP). Covariates that had univariate P values <.10 were entered into the multivariable model. After median 1.7 years follow-up, 270 patients died. In univariate analyses, ∆SBP (P = .082), rSBP (P = .008), and rDBP (P < .001) were of potential prognostic value (P < .10), but ∆DBP was not (P = .96). After adjustment for other clinical and MPI variables, ∆SBP no longer independently predicted mortality (P = .082); only lower rSBP (P = .026) and lower rDBP (P = .045) remained independently prognostic. CONCLUSIONS: In patients undergoing vasodilator stress MPI, only lower resting BP is an independent predictor of mortality along with other clinical and MPI variables; BP response does not appear to add to risk stratification in these patients.

The clinical epidemiology of fatigue in newly diagnosed heart failure.

BACKGROUND: Fatigue is a common and distressing but poorly understood symptom among patients with heart failure (HF). This study sought to evaluate the prevalence, predictors, and prognostic value of clinically documented fatigue in newly diagnosed HF patients from the community. METHODS: This retrospective cohort study consisted of 12,285 newly diagnosed HF patients receiving health care services through the Geisinger Health System, with passive data collection through electronic medical records (EMR). Incident HF, fatigue, and other study variables were derived from coded data within EMRs. A collection of 87 candidate predictors were evaluated to ascertain the strongest independent predictors of fatigue using logistic regression. Patients were followed for all-cause mortality for an average of 4.8 years. The associations between fatigue and 6-month, 12-month, and overall mortality were evaluated via Cox proportional hazards regression models. RESULTS: Clinically documented fatigue was found in 4827 (39%) newly diagnosed HF patients. Depression demonstrated the strongest association with fatigue. Fatigue was often part of a symptom cluster, as other HF symptoms including dyspnea, chest pain, edema, syncope, and palpitations were significant predictors of fatigue. Volume depletion, lower body mass index, and abnormal weight loss were also strong predictors of fatigue. Fatigue was not significantly associated with either 6-month (HR = 1.12, p = 0.16) or overall mortality (HR = 1.00, p = 0.89) in adjusted models. CONCLUSIONS: Fatigue is a commonly documented symptom among newly diagnosed HF patients, and its origins may lie in both psychologic and physiologic factors. Though fatigue did provide a prognostic signal in the short-term, this was largely explained by physiologic confounders. Proper therapeutic remediation of fatigue in HF relies on identifying underlying factors.

Prevalence of heart failure signs and symptoms in a large primary care population identified through the use of text and data mining of the electronic health record.

BACKGROUND: The electronic health record (EHR) contains a tremendous amount of data that if appropriately detected can lead to earlier identification of disease states such as heart failure (HF). Using a novel text and data analytic tool we explored the longitudinal EHR of over 50,000 primary care patients to identify the documentation of the signs and symptoms of HF in the years preceding its diagnosis. METHODS AND RESULTS: Retrospective analysis consisted of 4,644 incident HF cases and 45,981 group-matched control subjects. Documentation of Framingham HF signs and symptoms within encounter notes were carried out with the use of a previously validated natural language processing procedure. A total of 892,805 affirmed criteria were documented over an average observation period of 3.4 years. Among eventual HF cases, 85% had ≥1 criterion within 1 year before their HF diagnosis, as did 55% of control subjects. Substantial variability in the prevalence of individual signs and symptoms were found in both case and control subjects. CONCLUSIONS: HF signs and symptoms are frequently documented in a primary care population as identified through automated text and data mining of EHRs. Their frequent identification demonstrates the rich data available within EHRs that will allow for future work on automated criterion identification to help develop predictive models for HF.

Prognostic significance of impaired chronotropic response to pharmacologic stress Rb-82 PET.

BACKGROUND: An impaired chronotropic response to exercise is an accepted risk marker but the relationship between heart rate reserve (HRR) with pharmacologic stress is less well-established. The primary aim of this analysis was to evaluate the prognostic significance of HRR in patients undergoing rest/stress myocardial perfusion positron emission tomography (PET) in estimating coronary artery disease (CAD) mortality. METHODS: This subset analysis from the PET Prognosis Multicenter Registry includes a total of 2,398 patients undergoing rest/stress Rb-PET from three participating sites. The HRR from rest to peak stress was categorized into tertiles of ≤ 4, 5-14, and ≥ 15 beats per minute (bpm). At stress, the % abnormal myocardium was categorized as <5%, 5-9.9%, and ≥ 10%. We estimated CAD mortality using univariable and multivariable Cox proportional hazard models. RESULTS: CAD mortality was 12.8%, 3.4%, and 0.8%, respectively, for HRR measurements of ≤ 4, 5-14, and ≥ 15 bpm (P < 0.0001). In a multivariable model, the HRR was independently predictive of CAD mortality (P < 0.0001) with adjusted hazard ratios elevated 3.5- and 8.4-fold for HRR of 5-14 and ≤ 4 versus ≥ 15 bpm. In a multivariable model, both the HRR and stress MPI % abnormal myocardium were independently and highly predictive of CAD mortality. Moreover, the net reclassification improvement was 0.18 for the HRR when compared to a model including risk factors, symptoms, rest HR, and PET variables (P = 0.0008). For those with ≥ 10% abnormal myocardium on stress PET, there was a graded relationship between HRR and CAD mortality with adjusted hazards exceeding 50-fold for measurements of 5-14 and ≤ 4 bpm (P < 0.0001) compared to stress MPI with <5% abnormal myocardium and a HRR ≥ 15 bpm. CONCLUSION: A diminished HRR to vasodilator stress is a novel but increasingly important predictor of CAD mortality. HRR measurements of ≤ 4, 5-14, and ≥ 15 bpm were independently predictive of CAD mortality and underscore the importance of optimizing readily available novel markers of risk as highly relevant to identifying high and low risk patient subsets.

Echocardiographic Differences in Women Across Subtypes of Hypertensive Disorders of Pregnancy.

Background: Hypertensive disorders of pregnancy (HDP) can be classified into gestational hypertension, preeclampsia (PRE), and chronic hypertension with superimposed preeclampsia (SPE). Objectives: The purpose of this study was to retrospectively examine the echocardiographic differences in biventricular structure and function in 3 HDP groups of women in comparison to normotensive pregnant controls. Methods: Women with an echocardiogram during or within the first year of pregnancy were identified within our integrated health network. Exclusion criteria included age <18 years, diagnosis of pulmonary embolism, malignancy, autoimmune disease, and structural heart disease. Results: We identified a total of 706 subjects (cases: n = 427, normotensive controls: n = 279). Cases were divided into 3 groups: gestational hypertension (n = 57), PRE (n = 291), and SPE (n = 79). In adjusted analyses, echocardiographic parameters demonstrated a graded difference in left ventricular (LV) mass index, relative wall thickness, mitral inflow E, mitral inflow A, septal e', lateral e', E/e', left atrial volume index, tricuspid velocity, and lateral e' velocities with the most profound findings noted in the SPE group. Specifically, adjusted LV mass index (adjusted ß = 14.45, 95% CI: 9.00-19.90) and E/e' (adjusted ß = 2.97, 95% CI: 2.27-3.68) was highest in the SPE group in comparison to controls (P < 0.001). Conclusions: LV remodeling and diastolic filling abnormalities are more common in HDP and are most evident in SPE and PRE. Echocardiography during or immediately after pregnancy may be useful in these high-risk women to identify these abnormalities. The long-term implications of these echocardiographic abnormalities require further study.

Association between the diagnostic classification of newly diagnosed coronary artery disease and future heart failure development.

OBJECTIVE: The first clinical manifestation of coronary artery disease (CAD) varies widely from unheralded myocardial infarction (MI) to mild, incidentally detected disease. The primary objective of this study was to quantify the association between different initial CAD diagnostic classifications and future heart failure. METHODS: This retrospective study incorporated the electronic health record of a single integrated health care system. Newly diagnosed CAD was classified into a mutually exclusive hierarchy as MI, CAD with coronary artery bypass graft (CABG), CAD with percutaneous coronary intervention, CAD only, unstable angina, and stable angina. An acute CAD presentation was defined when the diagnosis was associated with a hospital admission. New heart failure was identified after the CAD diagnosis. RESULTS: Among 28 693 newly diagnosed CAD patients, initial presentation was acute in 47% and manifested as MI in 26%. Within 30 days of CAD diagnosis, MI [hazard ratio (HR) = 5.1; 95% confidence interval: 4.1-6.5] and unstable angina (3.2; 2.4-4.4) classifications were associated with the highest heart failure risk (compared to stable angina), as was acute presentation (2.9; 2.7-3.2). Among stable, heart failure-free CAD patients followed on average 7.4 years, initial MI (adjusted HR = 1.6; 1.4-1.7) and CAD with CABG (1.5; 1.2-1.8) were associated with higher long-term heart failure risk, but an initial acute presentation was not (1.0; 0.9-1.0). CONCLUSION: Nearly 50% of initial CAD diagnoses are associated with hospitalization, and these patients are at high risk of early heart failure. Among stable CAD patients, MI remained the diagnostic classification associated with the highest long-term heart failure risk, however, having an initial acute CAD presentation was not associated with long-term heart failure.

Association between diseases of despair and atherosclerotic cardiovascular disease among insured adults in the USA: a retrospective cohort study from 2017 to 2021.

OBJECTIVES: To assess associations between diseases of despair (DoD) and incident atherosclerotic cardiovascular disease (ASCVD) among insured adults in the USA. DESIGN: Retrospective cohort study. SETTING: Highmark insurance claims data in the USA from 2017 to 2021. PARTICIPANTS: Adults with at least 10 months of continuous insurance enrolment, no record of ASCVD in the 2016 baseline year and no missing data on study variables. PRIMARY AND SECONDARY OUTCOME MEASURES: Cox proportional hazard regression was used to calculate crude and adjusted hazard ratios (HR) and 95% confidence intervals (CI) to assess risk of ASCVD (composite of ischaemic cardiomyopathy, non-fatal ischaemic stroke, peripheral arterial disease or non-fatal acute myocardial infarction) by baseline DoD overall, and by the component conditions comprising DoD (alcohol-related disorders, substance-related disorders, suicidality) individually and in combination. RESULTS: The DoD-exposed group had an age-adjusted rate of 20.5 ASCVD events per 1000 person-years, compared with 11.7 among the unexposed. In adjusted models, overall DoD was associated with increased risk of incident ASCVD (HR 1.42, 95% CI 1.36 to 1.47). Individually and in combination, component conditions of DoD were associated with higher risk for ASCVD relative to no DoD. Substance-related disorders were associated with 50% higher risk of incident ASCVD (HR 1.5, 95% CI 1.41 to 1.59), alcohol-related disorders and suicidality/intentional self-harm were associated with 33% and 30% higher risk, respectively (HR 1.33, 95% CI 1.26 to 1.41; HR 1.30, 95% CI 1.11 to 1.52). Co-occurring DoD components conferred higher risk still. The highest risk combination was substance-related disorders+suicidality (HR 2.01, 95% CI 1.44 to 2.82). CONCLUSIONS: Among this cohort of insured adults, documented DoD was associated with increased ASCVD risk. Further research to understand and address cardiovascular disease prevention in those with DoD could reduce costs, morbidity and mortality. Further examination of overlapping structural factors that may be contributing to concurrent rises in ASCVD and DoD in the USA is needed.

Natural killer cell lines preferentially kill clonogenic multiple myeloma cells and decrease myeloma engraftment in a bioluminescent xenograft mouse model.

BACKGROUND: Novel therapies capable of targeting drug resistant clonogenic MM cells are required for more effective treatment of multiple myeloma. This study investigates the cytotoxicity of natural killer cell lines against bulk and clonogenic multiple myeloma and evaluates the tumor burden after NK cell therapy in a bioluminescent xenograft mouse model. DESIGN AND METHODS: The cytotoxicity of natural killer cell lines was evaluated against bulk multiple myeloma cell lines using chromium release and flow cytometry cytotoxicity assays. Selected activating receptors on natural killer cells were blocked to determine their role in multiple myeloma recognition. Growth inhibition of clonogenic multiple myeloma cells was assessed in a methylcellulose clonogenic assay in combination with secondary replating to evaluate the self-renewal of residual progenitors after natural killer cell treatment. A bioluminescent mouse model was developed using the human U266 cell line transduced to express green fluorescent protein and luciferase (U266eGFPluc) to monitor disease progression in vivo and assess bone marrow engraftment after intravenous NK-92 cell therapy. RESULTS: Three multiple myeloma cell lines were sensitive to NK-92 and KHYG-1 cytotoxicity mediated by NKp30, NKp46, NKG2D and DNAM-1 activating receptors. NK-92 and KHYG-1 demonstrated 2- to 3-fold greater inhibition of clonogenic multiple myeloma growth, compared with killing of the bulk tumor population. In addition, the residual colonies after treatment formed significantly fewer colonies compared to the control in a secondary replating for a cumulative clonogenic inhibition of 89-99% at the 20:1 effector to target ratio. Multiple myeloma tumor burden was reduced by NK-92 in a xenograft mouse model as measured by bioluminescence imaging and reduction in bone marrow engraftment of U266eGFPluc cells by flow cytometry. CONCLUSIONS: This study demonstrates that NK-92 and KHYG-1 are capable of killing clonogenic and bulk multiple myeloma cells. In addition, multiple myeloma tumor burden in a xenograft mouse model was reduced by intravenous NK-92 cell therapy. Since multiple myeloma colony frequency correlates with survival, our observations have important clinical implications and suggest that clinical studies of NK cell lines to treat MM are warranted.

Establishing a National Cardiovascular Disease Surveillance System in the United States Using Electronic Health Record Data: Key Strengths and Limitations.

Cardiovascular disease surveillance involves quantifying the evolving population-level burden of cardiovascular outcomes and risk factors as a data-driven initial step followed by the implementation of interventional strategies designed to alleviate this burden in the target population. Despite widespread acknowledgement of its potential value, a national surveillance system dedicated specifically to cardiovascular disease does not currently exist in the United States. Routinely collected health care data such as from electronic health records (EHRs) are a possible means of achieving national surveillance. Accordingly, this article elaborates on some key strengths and limitations of using EHR data for establishing a national cardiovascular disease surveillance system. Key strengths discussed include the: (1) ubiquity of EHRs and consequent ability to create a more "national" surveillance system, (2) existence of a common data infrastructure underlying the health care enterprise with respect to data domains and the nomenclature by which these data are expressed, (3) longitudinal length and detail that define EHR data when individuals repeatedly patronize a health care organization, and (4) breadth of outcomes capable of being surveilled with EHRs. Key limitations discussed include the: (1) incomplete ascertainment of health information related to health care-seeking behavior and the disconnect of health care data generated at separate health care organizations, (2) suspect data quality resulting from the default information-gathering processes within the clinical enterprise, (3) questionable ability to surveil patients through EHRs in the absence of documented interactions, and (4) the challenge in interpreting temporal trends in health metrics, which can be obscured by changing clinical and administrative processes.

Transient leukemia in newborns without down syndrome: diagnostic and management challenges.

Transient leukemia (TL), defined by circulating nonlymphoid blast in the peripheral blood, occurs in approximately 10% of infants with constitutional trisomy 21 (Down syndrome). The TL phenotype may also occur in newborns who do not have clinical signs of Down syndrome but nonconstitutional trisomy 21 due to mosaicism. We report the cases of 3 infants to highlight the specific parental concerns, diagnostic and counseling requirements for this group of infants and their families and suggest a practical approach to diagnosis, follow-up, anticipatory guidance, and discussion of prognosis for families with newborns diagnosed with TL and nonconstitutional trisomy 21.

Constructing Epidemiologic Cohorts from Electronic Health Record Data.

In the United States, electronic health records (EHR) are increasingly being incorporated into healthcare organizations to document patient health and services rendered. EHRs serve as a vast repository of demographic, diagnostic, procedural, therapeutic, and laboratory test data generated during the routine provision of health care. The appeal of using EHR data for epidemiologic research is clear: EHRs generate large datasets on real-world patient populations in an easily retrievable form permitting the cost-efficient execution of epidemiologic studies on a wide array of topics. Constructing epidemiologic cohorts from EHR data involves as a defining feature the development of data machinery, which transforms raw EHR data into an epidemiologic dataset from which appropriate inference can be drawn. Though data machinery includes many features, the current report focuses on three aspects of machinery development of high salience to EHR-based epidemiology: (1) selecting study participants; (2) defining "baseline" and assembly of baseline characteristics; and (3) follow-up for future outcomes. For each, the defining features and unique challenges with respect to EHR-based epidemiology are discussed. An ongoing example illustrates key points. EHR-based epidemiology will become more prominent as EHR data sources continue to proliferate. Epidemiologists must continue to improve the methods of EHR-based epidemiology given the relevance of EHRs in today's healthcare ecosystem.

Burden and Predictors of Chest Pain-Related Health-Care Utilization Following Percutaneous Coronary Intervention.

Chest pain (CP) has been reported in 20% to 40% of patients 1 year after percutaneous coronary intervention (PCI), though rates of post-PCI health-care utilization (HCU) for CP in nonclinical trial populations are unknown. Furthermore, the contribution of noncardiac factors - such as pulmonary, gastrointestinal, and psychological - to post-PCI CP HCU is unclear. Accordingly, the objectives of this study were to describe long-term trajectories and identify predictors of post-PCI CP-related HCU in real-world patients undergoing PCI for any indication. This retrospective cohort study included patients receiving PCI for any indication from 2003 to 2017 through a single integrated health-care system. Post-PCI CP-related HCU tracked through electronic medical records included (1) office visits, (2) emergency department (ED) visits, and (3) hospital admissions with CP or angina as the primary diagnosis. The strongest predictors of CP-related HCU were identified from >100 candidate variables. Among 6386 patients followed an average of 6.7 years after PCI, 73% received PCI for acute coronary syndrome (ACS), 19% for stable angina, and 8% for other indications. Post-PCI CP-related HCU was common with 26%, 16%, and 5% of patients having ≥1 office visits, ED visits, and hospital admissions for CP within 2 years of PCI. The following factors were significant predictors of all 3 CP outcomes: ACS presentation, documented CP >7 days prior to the index PCI, anxiety, depression, and syncope. In conclusion, CP-related HCU following PCI was common, especially within the first 2 years. The strongest predictors of CP-related HCU included coronary disease attributes and psychological factors.

Quantifying the Risk Continuum for Cardiovascular Death in Adults with Type 2 Diabetes.

OBJECTIVES: In type 2 diabetes (T2D), the most common causes of death are cardiovascular (CV) related, accounting for >50% of deaths in some reports. As novel diabetes therapies reduce CV death risk, identifying patients with T2D at highest CV death risk allows for cost-effective prioritization of these therapies. Accordingly, the primary goal of this study was to quantify the risk continuum for CV death in a real-world T2D population as a means to identify patients with the greatest expected benefit from cardioprotective antidiabetes therapies. METHODS: This retrospective study included patients with T2D receiving services through an integrated health-care system and used data generated through electronic medical records (EMRs). Quantifying the risk continuum entailed developing a prediction model for CV death, creating an integer risk score based on the final prediction model and estimating future CV death risk according to risk score ranking. RESULTS: Among 59,180 patients with T2D followed for an average of 7.5 years, 15,691 deaths occurred, 6,033 (38%) of which were CV related. The EMR-based prediction model included age, established CV disease and risk factors and glycemic indices (c statistic = 0.819). The 10% highest-risk patients according to prediction model elements had an annual CV death risk of ∼5%; the 25% highest-risk patients had an annual risk of ∼2%. CONCLUSIONS: This study incorporated a prediction modelling approach to quantify the risk continuum for CV death in T2D. Prospective application allows us to rank individuals with T2D according to their CV death risk, and may guide prioritization of novel diabetes therapies with cardioprotective properties.

Occupational exposure to terbufos and the incidence of cancer in the Agricultural Health Study.

OBJECTIVE: Terbufos is the fourth most commonly used organophosphate insecticide (OP) in the United States. Terbufos has not been demonstrated to be carcinogenic in rodents, although non-arsenical insecticides, including OPs, have been associated with excess cancer in epidemiologic studies. We investigated associations between use of terbufos and the incidence of cancer. METHODS: The Agricultural Health Study is a prospective cohort study of 57,310 licensed pesticide applicators from Iowa and North Carolina. Detailed information about 50 pesticides, including terbufos, and potential confounders was obtained from self-administered questionnaires. Terbufos intensity-weighted lifetime exposure-days were defined as (lifetime exposure-days) x (exposure intensity score). Cases include all first primary cancers diagnosed between enrollment and December 31, 2005. Hazard ratios (HR) and 95% CI were calculated with Cox proportional hazards models, adjusting for potential confounders. RESULTS: Overall cancer risk was slightly increased among terbufos users [HR 1.21 (1.06-1.37)]. Suggestive associations were observed between terbufos use and cancers of the prostate (HR(highest tertile) = 1.21; 95% CI = 0.99-1.47) and lung (HR(middle tertile) = 1.45; 95% CI = 0.95-2.22) and leukemia (HR(middle tertile) = 2.38; 95% CI = 1.35-4.21) and non-Hodgkin's lymphoma (HR(middle tertile) = 1.94; 95% CI = 1.16-3.22), although the exposure-response gradients were non-monotonic and p for trends were not significant. CONCLUSION: We found suggestive associations between occupational terbufos use and several cancer sites. However, cautious interpretation of these results is warranted by the lack of existing experimental and epidemiologic evidence to support carcinogenic effects of terbufos.

Clonogenic assays measure leukemia stem cell killing not detectable by chromium release and flow cytometric cytotoxicity assays.

BACKGROUND AIMS: NK-92, a permanent natural killer (NK) cell line, shows cytotoxicity against a variety of tumors and has been tested in a phase I trial. We tested the toxicity of NK-92 and chemotherapy drugs against the stem cell capacity of the acute leukemia cell line, KG1. While the chromium-release assay is the most common method for assessing cytotoxicity of immune effectors, and flow cytometry is increasingly used, the relationship of either assay to clonogenic readouts remains unknown. METHODS: KG1 was assessed for stem cell frequency by serial dilution, single-cell sorting and colony growth in methylcellulose. KG1 was sorted into CD34(+) CD38(+) and CD34(+) CD38⁻ populations and recultured in liquid medium or methylcellulose to determine the proliferative capacity of each fraction. Cytotoxicity of NK-92, daunorubicin and cytarabine against KG1 was measured using the chromium-release assay, flow cytometry and clonogenic assays. RESULTS: The culture-initiating cell frequency of whole KG1 was between 1 in 100 to 1000 by serial dilution and single-cell sorting. Although a rare (1-3%) CD34(+) CD38⁻ population could be demonstrated in KG1, both fractions had equivalent proliferative capacity. The cumulative flow cytotoxicity assay was more sensitive than the chromium-release assay in detecting target cell killing. At a 10:1 ratio NK-92 eliminated the clonogenic capacity of KG1, which was not predicted by the chromium-release assay. CONCLUSIONS: Clonogenic assays provide a more sensitive means of assessing the effect of a cytotoxic agent against putative cancer stem cells within cell lines, provided that they grow well in liquid culture medium or methylcellulose.