Huiman X. Barnhart

Reducing Frailty and Falls in Older Persons: An Investigation of Tai Chi and Computerized Balance Training

OBJECTIVE: To evaluate the effects of two exercise approaches, Tai Chi (TC) and computerized balance training (BT), on specified primary outcomes (biomedical, functional, and psychosocial indicators of frailty) and secondary outcomes (occurrence of falls).

Secondary analysis of the CHOIR trial epoetin-α dose and achieved hemoglobin outcomes

Trials of anemia correction in chronic kidney disease have found either no benefit or detrimental outcomes of higher targets. We did a secondary analysis of patients with chronic kidney disease enrolled in the Correction of Hemoglobin in the Outcomes in Renal Insufficiency trial to measure the potential for competing benefit and harm from achieved hemoglobin and epoetin dose trials. In the 4 month analysis, significantly more patients in the high-hemoglobin compared to the low-hemoglobin arm were unable to achieve target hemoglobin and required high-dose epoetin-alpha. In unadjusted analyses, the inability to achieve a target hemoglobin and high-dose epoetin-alpha were each significantly associated with increased risk of a primary endpoint (death, myocardial infarction, congestive heart failure or stroke). In adjusted models, high-dose epoetin-alpha was associated with a significant increased hazard of a primary endpoint but the risk associated with randomization to the high hemoglobin arm did not suggest a possible mediating effect of higher target via dose. Similar results were seen in the 9 month analysis. Our study demonstrates that patients achieving their target had better outcomes than those who did not; and among subjects who achieved their randomized target, no increased risk associated with the higher hemoglobin goal was detected. Prospective studies are needed to confirm this relationship and determine safe dosing algorithms for patients unable to achieve target hemoglobin.

Intra-aortic balloon counterpulsation and infarct size in patients with acute anterior myocardial infarction without shock: the CRISP AMI randomized trial.

CONTEXT Intra-aortic balloon counterpulsation (IABC) is an adjunct to revascularization in patients with cardiogenic shock and reduces infarct size when placed prior to reperfusion in animal models. OBJECTIVE To determine if routine IABC placement prior to reperfusion in patients with anterior ST-segment elevation myocardial infarction (STEMI) without shock reduces myocardial infarct size. DESIGN, SETTING, AND PATIENTS An open, multicenter, randomized controlled trial, the Counterpulsation to Reduce Infarct Size Pre-PCI Acute Myocardial Infarction (CRISP AMI) included 337 patients with acute anterior STEMI but without cardiogenic shock at 30 sites in 9 countries from June 2009 through February 2011. INTERVENTION Initiation of IABC before primary percutaneous coronary intervention (PCI) and continuation for at least 12 hours (IABC plus PCI) vs primary PCI alone. MAIN OUTCOME MEASURES Infarct size expressed as a percentage of left ventricular (LV) mass and measured by cardiac magnetic resonance imaging performed 3 to 5 days after PCI. Secondary end points included all-cause death at 6 months and vascular complications and major bleeding at 30 days. Multiple imputations were performed for missing infarct size data. RESULTS The median time from first contact to first coronary device was 77 minutes (interquartile range, 53 to 114 minutes) for the IABC plus PCI group vs 68 minutes (interquartile range, 40 to 100 minutes) for the PCI alone group (P = .04). The mean infarct size was not significantly different between the patients in the IABC plus PCI group and in the PCI alone group (42.1% [95% CI, 38.7% to 45.6%] vs 37.5% [95% CI, 34.3% to 40.8%], respectively; difference of 4.6% [95% CI, -0.2% to 9.4%], P = .06; imputed difference of 4.5% [95% CI, -0.3% to 9.3%], P = .07) and in patients with proximal left anterior descending Thrombolysis in Myocardial Infarction flow scores of 0 or 1 (46.7% [95% CI, 42.8% to 50.6%] vs 42.3% [95% CI, 38.6% to 45.9%], respectively; difference of 4.4% [95% CI, -1.0% to 9.7%], P = .11; imputed difference of 4.8% [95% CI, -0.6% to 10.1%], P = .08). At 30 days, there were no significant differences between the IABC plus PCI group and the PCI alone group for major vascular complications (n = 7 [4.3%; 95% CI, 1.8% to 8.8%] vs n = 2 [1.1%; 95% CI, 0.1% to 4.0%], respectively; P = .09) and major bleeding or transfusions (n = 5 [3.1%; 95% CI, 1.0% to 7.1%] vs n = 3 [1.7%; 95% CI, 0.4% to 4.9%]; P = .49). By 6 months, 3 patients (1.9%; 95% CI, 0.6% to 5.7%) in the IABC plus PCI group and 9 patients (5.2%; 95% CI, 2.7% to 9.7%) in the PCI alone group had died (P = .12). CONCLUSION Among patients with acute anterior STEMI without shock, IABC plus primary PCI compared with PCI alone did not result in reduced infarct size. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT00833612.

An Overview on Assessing Agreement with Continuous Measurements

Reliable and accurate measurements serve as the basis for evaluation in many scientific disciplines. Issues related to reliable and accurate measurement have evolved over many decades, dating back to the nineteenth century and the pioneering work of Galton (1886), Pearson (1896 1899 1901), and Fisher (1925). Requiring a new measurement to be identical to the truth is often impractical, either because (1) we are willing to accept a measurement up to some tolerable (or acceptable) error, or (2) the truth is simply not available to us, either because it is not measurable or is only measurable with some degree of error. To deal with issues related to both (1) and (2), a number of concepts, methods, and theories have been developed in various disciplines. Some of these concepts have been used across disciplines, while others have been limited to a particular field but may have potential uses in other disciplines. In this paper, we elucidate and contrast fundamental concepts employed in different disciplines and unite these concepts into one common theme: assessing closeness (agreement) of observations. We focus on assessing agreement with continuous measurements and classify different statistical approaches as (1) descriptive tools; (2) unscaled summary indices based on absolute differences of measurements; and (3) scaled summary indices attaining values between –1 and 1 for various data structures, and for cases with and without a reference. We also identify gaps that require further research and discuss future directions in assessing agreement.

Liver injury from herbals and dietary supplements in the U.S. Drug‐Induced Liver Injury Network

The Drug‐Induced Liver Injury Network (DILIN) studies hepatotoxicity caused by conventional medications as well as herbals and dietary supplements (HDS). To characterize hepatotoxicity and its outcomes from HDS versus medications, patients with hepatotoxicity attributed to medications or HDS were enrolled prospectively between 2004 and 2013. The study took place among eight U.S. referral centers that are part of the DILIN. Consecutive patients with liver injury referred to a DILIN center were eligible. The final sample comprised 130 (15.5%) of all subjects enrolled (839) who were judged to have experienced liver injury caused by HDS. Hepatotoxicity caused by HDS was evaluated by expert opinion. Demographic and clinical characteristics and outcome assessments, including death and liver transplantation (LT), were ascertained. Cases were stratified and compared according to the type of agent implicated in liver injury; 45 had injury caused by bodybuilding HDS, 85 by nonbodybuilding HDS, and 709 by medications. Liver injury caused by HDS increased from 7% to 20% (P < 0.001) during the study period. Bodybuilding HDS caused prolonged jaundice (median, 91 days) in young men, but did not result in any fatalities or LT. The remaining HDS cases presented as hepatocellular injury, predominantly in middle‐aged women, and, more frequently, led to death or transplantation, compared to injury from medications (13% vs. 3%; P < 0.05). Conclusions: The proportion of liver injury cases attributed to HDS in DILIN has increased significantly. Liver injury from nonbodybuilding HDS is more severe than from bodybuilding HDS or medications, as evidenced by differences in unfavorable outcomes (death and transplantation). (Hepatology 2014;60:1399–1408)

Hepatic histological findings in suspected drug‐induced liver injury: Systematic evaluation and clinical associations

Drug‐induced liver injury (DILI) is considered to be a diagnosis of exclusion. Liver biopsy may contribute to diagnostic accuracy, but the histological features of DILI and their relationship to biochemical parameters and outcomes are not well defined. We have classified the pathological pattern of liver injury and systematically evaluated histological changes in liver biopsies obtained from 249 patients with suspected DILI enrolled in the prospective, observational study conducted by the Drug Induced Liver Injury Network. Histological features were analyzed for their frequency within different clinical phenotypes of liver injury and to identify associations between clinical and laboratory findings and histological features. The most common histological patterns were acute (21%) and chronic hepatitis (14%), acute (9%) and chronic cholestasis (10%), and cholestatic hepatitis (29%). Liver histology from 128 patients presenting with hepatocellular injury had more severe inflammation, necrosis, and apoptosis and more frequently demonstrated lobular disarray, rosette formation, and hemorrhage than those with cholestasis. Conversely, histology of the 73 patients with cholestatic injury more often demonstrated bile plugs and duct paucity. Severe or fatal hepatic injury in 46 patients was associated with higher degrees of necrosis, fibrosis stage, microvesicular steatosis, and ductular reaction among other findings, whereas eosinophils and granulomas were found more often in those with milder injury. Conclusion: We describe an approach for evaluating liver histology in DILI and demonstrate numerous associations between pathological findings and clinical presentations that may serve as a foundation for future studies correlating DILI pathology with its causality and outcome. (Hepatology 2014;59:661–670)

Angioplasty or Surgery for Multivessel Coronary Artery Disease: Comparison of Eligible Registry and Randomized Patients in the EAST Trial and Influence of Treatment Selection on Outcomes

The Emory Angioplasty versus Surgery Trial (EAST) showed that multivessel patients eligible for both percutaneous transluminal coronary angioplasty (PTCA) and coronary bypass surgery (CABG) had equivalent 3-year outcomes regarding survival, myocardial infarction, and major myocardial ischemia. Patients eligible for the trial who were not randomized because of physician or patient refusal were followed in a registry. This study compares the outcomes of the randomized and registry patients. Of the 842 eligible patients, 450 did not enter the trial. Their baseline features closely resembled those of the randomized patients and follow up was performed using the same methods. In the registry there was a bias toward selecting CABG in patients with 3-vessel disease (84%) and PTCA in patients with 2-vessel disease (54%). Three-year survival for the registry patients was 96.4%, which was better than the randomized patients, 93.4% (p = 0.044). Angina relief in the registry was equal for CABG and PTCA patients and was better for the PTCA registry (12.4%) than PTCA randomized patients (19.6%) (p = 0.079). Thus, the registry confirms that EAST is representative of all eligible patients and does not represent a low-risk subgroup. Since baseline differences were small, improved survival in the registry may be due to treatment selection. Physician judgment, even in patients judged appropriate for clinical trials, remains a potentially important predictor of outcomes.

Repeatability and reproducibility of phase analysis of gated single-photon emission computed tomography myocardial perfusion imaging used to quantify cardiac dyssynchrony.

BackgroundA novel method to quantify dyssynchrony has been developed using phase analysis of gated single-photon emission computed tomography perfusion imaging. We report on the effect of variability in image reconstruction on the phase analysis results (repeatability) and on the interobserver and intraobserver reproducibility of the technique. MethodsPhase standard deviation (SD) and bandwidth are phase indices that quantify dyssynchrony. To evaluate repeatability, raw data sets were processed twice in 50 patients with left ventricular dysfunction and 50 normal controls. To determine the optimal processing method, two replicated phase analysis results were obtained using automated and manual base parameter placement. Reproducibility of the phase analysis was determined using the data from 20 patients. ResultsIn normal controls, manual base parameter placement improves repeatability of the phase analysis as measured by the mean absolute difference between two reads for phase SD (12.0° vs. 1.2°, P<0.0001) and bandwidth (33.7° vs. 3.6°, P<0.0001). Repeatability is better for normal controls than for patients with left ventricular dysfunction for phase SD (1.2° vs. 6.0°, P<0.0001) and bandwidth (3.6° vs. 26.5°, P<0.0001). Reproducibility of the phase analysis is high as measured by the intraclass correlation coefficients for phase SD and bandwidth of 0.99 and 0.99 for the interobserver comparisons and 1.00 and 1.00 for the intraobserver comparisons. ConclusionA novel method to quantify dyssynchrony has been developed using gated single-photon emission computed tomography perfusion imaging. Manual base parameter placement reduces the effect that variability in image reconstruction has on phase analysis. A high degree of reproducibility of phase analysis is observed.

The emerging science of quantitative imaging biomarkers terminology and definitions for scientific studies and regulatory submissions

The development and implementation of quantitative imaging biomarkers has been hampered by the inconsistent and often incorrect use of terminology related to these markers. Sponsored by the Radiological Society of North America, an interdisciplinary group of radiologists, statisticians, physicists, and other researchers worked to develop a comprehensive terminology to serve as a foundation for quantitative imaging biomarker claims. Where possible, this working group adapted existing definitions derived from national or international standards bodies rather than invent new definitions for these terms. This terminology also serves as a foundation for the design of studies that evaluate the technical performance of quantitative imaging biomarkers and for studies of algorithms that generate the quantitative imaging biomarkers from clinical scans. This paper provides examples of research studies and quantitative imaging biomarker claims that use terminology consistent with these definitions as well as examples of the rampant confusion in this emerging field. We provide recommendations for appropriate use of quantitative imaging biomarker terminological concepts. It is hoped that this document will assist researchers and regulatory reviewers who examine quantitative imaging biomarkers and will also inform regulatory guidance. More consistent and correct use of terminology could advance regulatory science, improve clinical research, and provide better care for patients who undergo imaging studies.

Premature atherosclerosis in pediatric systemic lupus erythematosus: Risk factors for increased carotid intima‐media thickness in the atherosclerosis prevention in pediatric lupus erythematosus cohort

OBJECTIVE To evaluate risk factors for subclinical atherosclerosis in a population of patients with pediatric systemic lupus erythematosus (SLE). METHODS In a prospective multicenter study, a cohort of 221 patients underwent baseline measurements of carotid intima-media thickness (CIMT) as part of the Atherosclerosis Prevention in Pediatric Lupus Erythematosus (APPLE) trial. SLE disease measures, medications, and traditional risk factors for atherosclerosis were assessed. A standardized protocol was used to assess the thickness of the bilateral common carotid arteries and the mean maximal IMT of 12 segments. Univariable analysis identified potential associations with CIMT, which were examined in multivariable linear regression modeling. RESULTS Based on the mean-mean common or the mean-max CIMT as the dependent variable, univariable analysis showed significant associations of the following variables with increased CIMT: increasing age, longer SLE duration, minority status, higher body mass index (BMI), male sex, increased creatinine clearance, higher lipoprotein(a) level, proteinuria, azathioprine treatment, and prednisone dose. In multivariable modeling, both azathioprine use (P=0.005 for the mean-mean model and P=0.102 for the mean-max model) and male sex (P<0.001) were associated with increases in the mean-max CIMT. A moderate dosage of prednisone (0.15-0.4 mg/kg/day) was associated with decreases in the mean-max CIMT (P=0.024), while high-dose and low-dose prednisone were associated with increases in the mean-mean common CIMT (P=0.021) and the mean-max CIMT (P=0.064), respectively. BMI (P<0.001) and creatinine clearance (P=0.031) remained associated with increased mean-mean common CIMT, while increasing age (P<0.001) and increasing lipoprotein(a) level (P=0.005) were associated with increased mean-max CIMT. CONCLUSION Traditional as well as nontraditional risk factors were associated with increased CIMT in this cohort of patients in the APPLE trial. Azathioprine treatment was associated with increased CIMT. The relationship between CIMT and prednisone dose may not be linear.