Liver Transplant Listing in Pediatric Acute Liver Failure: Practices and Participant Characteristics.

Liver transplant (LT) decisions in pediatric acute liver failure (PALF) are complex. Three phases of the PALF registry, containing data on 1,144 participants over 15 years, were interrogated to characterize clinical features associated with listing status. A decrease in the cumulative incidence of listing (P < 0.005) and receiving (P < 0.05) LT occurred without an increase in the cumulative incidence of death (P = 0.67). Time to listing was constant and early (1 day; quartiles 1-3 = 0-2; P = 0.88). The most frequent reasons for not listing were "not sick enough" and "medically unsuitable." Participants listed for LT were more likely male, with coma grade scores >0; had higher international normalized ratio, bilirubin, lactate, and venous ammonia; and had lower peripheral lymphocytes and transaminase levels compared to those deemed "not sick enough." Participants listed versus those deemed "medically unsuitable" were older; had higher serum aminotransferase levels, bilirubin, platelets, and albumin; and had lower lactate, venous ammonia, and lymphocyte count. An indeterminate diagnosis was more prevalent in listed participants. Ventilator (23.8%) and vasopressor (9.2%) support occurred in a significant portion of listed participants but less frequently than in those who were not "medically suitable." Removal from the LT list was a rare event. Conclusion: The cumulative incidence of listing for and receiving LT decreased throughout the PALF study without an increase in the cumulative incidence of death. While all participants fulfilled entry criteria for PALF, significant differences were noted between participants listed for LT and those deemed "not sick enough" as well as those who were "medically unsuitable." Having an indeterminate diagnosis and a requirement for cardiopulmonary support appeared to influence decisions toward listing; optimizing listing decisions in PALF may reduce the frequency of LT without increasing the frequency of death.

Hepatic Encephalopathy in Children With Acute Liver Failure: Utility of Serum Neuromarkers.

BACKGROUND: Pediatric acute liver failure (PALF) is a public heath burden, often requiring prolonged hospitalization and liver transplantation. Hepatic encephalopathy (HE) is a complication of PALF with limited diagnostic tools to predict outcomes. Serum neurological markers (neuron-specific enolase, S100ß, and myelin basic protein) can be elevated in traumatic or ischemic brain injury. We hypothesized that these neuromarkers would be associated with the development of HE in PALF. METHODS: PALF study participants enrolled between May 2012 and December 2014 by 12 participating centers were the subjects of this analysis. Daily HE assessments were determined by study investigators. Neurological and inflammatory markers were measured using enzyme-linked immunosorbent assay and MILLIPLEX techniques, respectively. To model encephalopathy, these markers were log2 transformed and individually examined for association with HE using a generalized linear mixed model with a logit link and random intercept. RESULTS: Eighty-two children had neurological and inflammatory marker levels and HE assessments recorded, with the majority having assessments for 3 days during their illness. An indeterminate diagnosis (29%) was most common and the median age was 2.9 years. Significant associations were observed for HE with S100ß (odds ratio 1.16, 95% confidence interval [1.03-1.29], P = 0.04) and IL-6 (odds ratio 1.24 [1.11-1.38], P = 0.006). CONCLUSIONS: Serum S100ß and IL-6 are associated with HE in children with PALF. Measuring these markers may assist in assessing neurological injury in PALF, impacting clinical decisions.

A Learning Collaborative Approach Increases Specificity of Diagnosis of Acute Liver Failure in Pediatric Patients.

BACKGROUND & AIMS: Many pediatric patients with acute liver failure (PALF) do not receive a specific diagnosis (such as herpes simplex virus or Wilson disease or fatty acid oxidation defects)-they are left with an indeterminate diagnosis and are more likely to undergo liver transplantation, which is contraindicated for some disorders. Strategies to facilitate complete diagnostic testing should increase identification of specific liver diseases and might reduce liver transplantation. We investigated whether performing recommended age-specific diagnostic tests (AS-DTs) at the time of hospital admission reduces the percentage PALFs with an indeterminate diagnosis. METHODS: We performed a multinational observational cohort study of 658 PALF participants in the United States and Canada, enrolled at 10 medical centers, during 3 study phases from December 1999 through December 2014. A learning collaborative approach was used to implement AS-DT using an electronic medical record admission order set at hospital admission in phase 3 of the study. Data from 10 study sites participating in all 3 phases were compared before (phases 1 and 2) and after (phase 3) diagnostic test recommendations were inserted into electronic medical record order sets. RESULTS: The percentage of subjects with an indeterminate diagnosis decreased significantly between phases 1-2 (48.0%) and phase 3 (to 30.8%) (P = .0003). The 21-day cumulative incidence rates for liver transplantation were significantly different among phase 1 (34.6%), phase 2 (31.9%), and phase 3 (20.2%) (P = .030). The 21-day cumulative incidence rates for death did not differ significantly among phase 1 (17.9%), phase 2 (11.9%), and phase 3 (11.3%) (P = .20). CONCLUSIONS: In a multinational study of children with acute liver failure, we found that incorporating diagnostic test recommendations into electronic medical record order sets accessed at time of admission reduced the percentage with an indeterminate diagnosis that may have reduced liver transplants without increasing mortality. Widespread use of this approach could significantly enhance care of acute liver failure in children.

Health Related Quality of Life and Neurocognitive Outcomes in the First Year after Pediatric Acute Liver Failure.

OBJECTIVE: To determine health-related quality of life (HRQoL) and neurocognitive impairment in survivors of pediatric acute liver failure (PALF). STUDY DESIGN: A longitudinal prospective study was conducted. At 6 and 12 months after PALF presentation, surveys of HRQoL were completed for 2- to 19-year-olds and executive functioning for ages 2-16 years. At 12 months, patients 3-16 years of age completed neurocognitive testing. HRQoL scores were compared with a healthy, matched sample. Neurocognitive scores were compared with norms; executive functioning scores were examined categorically. RESULTS: A total of 52 parent-report HRQoL surveys were completed at 6 months, 48 at 12 months; 25 patients completed neurocognitive testing. The median age at 6 months was 7.9 years (range 3.5-15.0), and final diagnosis was indeterminate for 46.2% (n = 24). Self and parent-report on Pediatric Quality of Life Inventory Generic and Multidimensional Fatigue scales fell below the healthy sample at 6 months and 12 months (almost all P < .001). Children reported lower mean scores on cognitive fatigue at 12 months (60.91 ± 22.99) compared with 6 months (73.61 ± 27.49, P = .006) . The distribution of Behavior Rating Inventory of Executive Function scores was shifted downward on parent-report (preschool) for all indices at 6 months (n = 14, P ≤ .003); Global Executive Composite and Emergent Metacognition at 12 months (n = 10, P = .03). Visual Motor Integration (VMI-6) Copying (mean = 90.3 ± 13.8, P = .0002) and VMI-6 Motor Coordination (mean = 85.1 ± 15.2 P = .0002) fell below norms, but full scale IQ (Wechsler Scales) and Attention (Conners' Continuous Performance Test) did not. CONCLUSIONS: Survivors of PALF appear to show deficits in motor skills, executive functioning, HRQoL, and evidence for worsening cognitive fatigue from 6 to 12 months following PALF presentation.

Lactate and Lactate: Pyruvate Ratio in the Diagnosis and Outcomes of Pediatric Acute Liver Failure.

OBJECTIVES: To assess the accuracy of blood lactate and lactate: pyruvate molar ratio (L:P) as a screen for mitochondrial, respiratory chain, or fatty acid oxidation disorders in children with pediatric acute liver failure (PALF); to determine whether serum lactate ≥ 2.5 mmol/L or L:P ≥ 25 correlated with biochemical variables of clinical severity; and to determine whether lactate or L:P is associated with clinical outcome at 21 days. STUDY DESIGN: Retrospective review of demographic, clinical, laboratory, and outcome data for PALF study group participants who had lactate and pyruvate levels collected on the same day. RESULTS: Of 986 participants, 110 had lactate and pyruvate levels collected on the same day. Of the 110, the etiology of PALF was a mitochondrial disorder in 8 (7%), indeterminate in 65 (59%), and an alternative diagnosis in 37 (34%). Lactate, pyruvate, and L:P were similar among the 3 etiologic groups. There was no significant association between the initial lactate or L:P and biochemical variables of clinical severity or clinical outcome at 21 days. CONCLUSIONS: A serum lactate ≥ 2.5 mmol/L and/or elevated L:P was common in all causes of PALF, not limited to those with a mitochondrial etiology, and did not predict 21-day clinical outcome. TRIAL REGISTRATION: ClinicalTrials.gov: NCT00986648.

Prevalence and Significance of Autoantibodies in Children With Acute Liver Failure.

OBJECTIVES: The purpose of the present study is to estimate autoantibody (auto-AB) frequency, clinical characteristics, and 21-day outcome of participants in the Pediatric Acute Liver Failure Study Group (PALFSG) by antinuclear antibody, smooth muscle antibody, and liver-kidney microsomal (LKM) antibody status. METHODS: Auto-ABs were determined at local and/or central laboratories. Subjects were assigned to autoimmune hepatitis (AIH), indeterminate, and other diagnoses groups. RESULTS: Between 1999 and 2010, 986 subjects were enrolled in the PALFSG. At least 1 auto-AB result was available for 722 (73.2%). At least 1 auto-AB was positive for 202 (28.0%). Diagnoses for auto-AB+ subjects were AIH (63), indeterminate (75), and other (64). Auto-ABs were more common in Wilson disease (12/32, 37.5%) compared with other known diagnoses (52/253, 20.6%, P = 0.03). LKM+ subjects were younger (median 2.4 vs 9.1 years, P < 0.001) and more likely to undergo liver transplantation (53.3% vs 31.4% P = 0.02) than other auto-AB+/LKM- subjects. Steroid treatment of subjects who were auto-AB+ was not significantly associated with survival and the subgroup with known diagnoses other than AIH had a higher risk of death. CONCLUSIONS: Auto-ABs are common in children with acute liver failure, occurring in 28%. Auto-AB+ subjects have similar outcomes to auto-AB negative subjects. LKM+ children are younger and more likely to undergo liver transplantation compared with other auto-AB+ subjects. Although auto-AB may indicate a treatable condition, positivity does not eliminate the need for a complete diagnostic evaluation because auto-ABs are present in other conditions. The significance of auto-AB in pediatric acute liver failure remains uncertain, but LKM+ appears to identify a unique population of children who merit further study.

The effects of normal aging on amyloid-ß deposition in nondemented adults with Down syndrome as imaged by carbon 11-labeled Pittsburgh compound B.

INTRODUCTION: In Down syndrome (DS), the overproduction of amyloid precursor protein is hypothesized to predispose young adults to early expression of Alzheimer-like neuropathology. METHODS: PET imaging with carbon 11-labeled Pittsburgh compound B examined the pattern of amyloid-ß deposition in 68 nondemented adults with DS (30-53 years) to determine the relationship between deposition and normal aging. Standard uptake value ratio (SUVR) images were created with cerebellar gray matter as the reference region. RESULTS: Multiple linear regression revealed slight but highly significant (corrected P < .05) positive correlations between SUVR and age. The striatum showed the strongest correlation, followed by precuneus, parietal cortex, anterior cingulate, frontal cortex, and temporal cortex. CONCLUSION: There is an age-related amyloid-ß deposition in the DS population, but as a pattern of elevated cortical retention becomes apparent, the correlation of SUVR with age ceases to be significant. Factors unrelated to aging may drive an increase in deposition during early Alzheimer's disease pathogenesis.

Cognitive functioning in relation to brain amyloid-ß in healthy adults with Down syndrome.

Nearly all adults with Down syndrome show neuropathology of Alzheimer's disease, including amyloid-ß deposition, by their fifth decade of life. In the current study, we examined the association between brain amyloid-ß deposition, assessed via in vivo assessments of neocortical Pittsburgh compound B, and scores on an extensive neuropsychological battery of measures of cognitive functioning in 63 adults (31 male, 32 female) with Down syndrome aged 30-53 years who did not exhibit symptoms of dementia. Twenty-two of the adults with Down syndrome were identified as having elevated neocortical Pittsburgh compound B retention levels. There was a significant positive correlation (r = 0.62, P < 0.0001) between age and neocortical Pittsburgh compound B retention. This robust association makes it difficult to discriminate normative age-related decline in cognitive functioning from any potential effects of amyloid-ß deposition. When controlling for chronological age in addition to mental age, there were no significant differences between the adults with Down syndrome who had elevated neocortical Pittsburgh compound B retention levels and those who did not on any of the neuropsychological measures. Similarly, when examining Pittsburgh compound B as a continuous variable, after controlling for mental age and chronological age, only the Rivermead Picture Recognition score was significantly negatively associated with neocortical Pittsburgh compound B retention. Our findings indicate that many adults with Down syndrome can tolerate amyloid-ß deposition without deleterious effects on cognitive functioning. However, we may have obscured true effects of amyloid-ß deposition by controlling for chronological age in our analyses. Moreover, our sample included adults with Down syndrome who were most 'resistant' to the effects of amyloid-ß deposition, as adults already exhibiting clinical symptoms of dementia symptoms were excluded from the study.

Clinical and angiographic risk stratification and differential impact on treatment outcomes in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.

BACKGROUND: The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial assigned patients with type 2 diabetes mellitus to prompt coronary revascularization plus intensive medical therapy versus intensive medical therapy alone and reported no significant difference in mortality. Among patients selected for coronary artery bypass graft surgery, prompt coronary revascularization was associated with a significant reduction in death/myocardial infarction/stroke compared with intensive medical therapy. We hypothesized that clinical and angiographic risk stratification would affect the effectiveness of the treatments overall and within revascularization strata. METHODS AND RESULTS: An angiographic risk score was developed from variables assessed at randomization; independent prognostic factors were myocardial jeopardy index, total number of coronary lesions, prior coronary revascularization, and left ventricular ejection fraction. The Framingham Risk Score for patients with coronary disease was used to summarize clinical risk. Cardiovascular event rates were compared by assigned treatment within high-risk and low-risk subgroups. Overall, no outcome differences between the intensive medical therapy and prompt coronary revascularization groups were seen in any risk stratum. The 5-year risk of death/myocardial infarction/stroke was 36.8% for intensive medical therapy compared with 24.8% for prompt coronary revascularization among the 381 coronary artery bypass graft surgery-selected patients in the highest angiographic risk tertile (P=0.005); this treatment effect was amplified in patients with both high angiographic and high Framingham risk (47.3% intensive medical therapy versus 27.1% prompt coronary revascularization; P=0.010; hazard ratio=2.10; P=0.009). Treatment group differences were not significant in other clinical-angiographic risk groups within the coronary artery bypass graft surgery stratum, or in any subgroups within the percutaneous coronary intervention stratum. CONCLUSION: Among patients with diabetes mellitus and stable ischemic heart disease, a strategy of prompt coronary artery bypass graft surgery significantly reduces the rate of death/myocardial infarction MI/stroke in those with extensive coronary artery disease or impaired left ventricular function. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

Liberal versus restrictive transfusion thresholds for patients with symptomatic coronary artery disease.

BACKGROUND: Prior trials suggest it is safe to defer transfusion at hemoglobin levels above 7 to 8 g/dL in most patients. Patients with acute coronary syndrome may benefit from higher hemoglobin levels. METHODS: We performed a pilot trial in 110 patients with acute coronary syndrome or stable angina undergoing cardiac catheterization and a hemoglobin <10 g/dL. Patients in the liberal transfusion strategy received one or more units of blood to raise the hemoglobin level ≥10 g/dL. Patients in the restrictive transfusion strategy were permitted to receive blood for symptoms from anemia or for a hemoglobin <8 g/dL. The predefined primary outcome was the composite of death, myocardial infarction, or unscheduled revascularization 30 days post randomization. RESULTS: Baseline characteristics were similar between groups except age (liberal, 67.3; restrictive, 74.3). The mean number of units transfused was 1.6 in the liberal group and 0.6 in the restrictive group. The primary outcome occurred in 6 patients (10.9%) in the liberal group and 14 (25.5%) in the restrictive group (risk difference = 15.0%; 95% confidence interval of difference 0.7% to 29.3%; P = .054 and adjusted for age P = .076). Death at 30 days was less frequent in liberal group (n = 1, 1.8%) compared to restrictive group (n = 7, 13.0%; P = .032). CONCLUSIONS: The liberal transfusion strategy was associated with a trend for fewer major cardiac events and deaths than a more restrictive strategy. These results support the feasibility of and the need for a definitive trial.

Profibrinolytic, antithrombotic, and antiinflammatory effects of an insulin-sensitizing strategy in patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial.

BACKGROUND: Effects were compared in patients in the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial of 2 mechanistically different strategies for treatment of hyperglycemia, insulin-sensitizing and insulin-providing strategies, on biomarker profiles reflecting the balance between fibrinolysis and thrombosis and the intensity of inflammation implicated in diabetic vasculopathy. METHODS AND RESULTS: A total of 2368 patients with type 2 diabetes mellitus and clinically stable, angiographically documented coronary artery disease were randomized to treatment with 1 of the 2 strategies and followed for an average of 5 years. Plasminogen activator inhibitor type 1 antigen and activity, tissue plasminogen activator antigen, fibrinogen, D-dimer, C-reactive protein, insulin, and hemoglobin A(1c) were assayed in blood samples acquired at baseline and at 12 regular intervals throughout the follow-up interval. Higher baseline D-dimer, fibrinogen, and C-reactive protein portended a poor prognosis in patients in both groups. In contrast to the insulin-providing strategy, the insulin-sensitizing strategy led to (1) lower plasma insulin; (2) lower plasminogen activator inhibitor type 1 antigen and activity and lower tissue plasminogen activator antigen (known to track with plasminogen activator inhibitor type 1); and (3) lower C-reactive protein and fibrinogen at all intervals after baseline (P<0.001 for each). CONCLUSIONS: The insulin-sensitizing treatment strategy led to changes in biomarker profiles indicative of decreased insulin resistance, an altered balance between thrombosis and fibrinolysis favoring fibrinolysis, and diminished intensity of the systemic inflammatory state, factors that have been associated with cardiovascular risk. CLINICAL TRIAL REGISTRATION: http://www.clinicaltrials.gov. Unique identifier: NCT00006305.

A randomized trial of therapies for type 2 diabetes and coronary artery disease.

BACKGROUND: Optimal treatment for patients with both type 2 diabetes mellitus and stable ischemic heart disease has not been established. METHODS: We randomly assigned 2368 patients with both type 2 diabetes and heart disease to undergo either prompt revascularization with intensive medical therapy or intensive medical therapy alone and to undergo either insulin-sensitization or insulin-provision therapy. Primary end points were the rate of death and a composite of death, myocardial infarction, or stroke (major cardiovascular events). Randomization was stratified according to the choice of percutaneous coronary intervention (PCI) or coronary-artery bypass grafting (CABG) as the more appropriate intervention. RESULTS: At 5 years, rates of survival did not differ significantly between the revascularization group (88.3%) and the medical-therapy group (87.8%, P=0.97) or between the insulin-sensitization group (88.2%) and the insulin-provision group (87.9%, P=0.89). The rates of freedom from major cardiovascular events also did not differ significantly among the groups: 77.2% in the revascularization group and 75.9% in the medical-treatment group (P=0.70) and 77.7% in the insulin-sensitization group and 75.4% in the insulin-provision group (P=0.13). In the PCI stratum, there was no significant difference in primary end points between the revascularization group and the medical-therapy group. In the CABG stratum, the rate of major cardiovascular events was significantly lower in the revascularization group (22.4%) than in the medical-therapy group (30.5%, P=0.01; P=0.002 for interaction between stratum and study group). Adverse events and serious adverse events were generally similar among the groups, although severe hypoglycemia was more frequent in the insulin-provision group (9.2%) than in the insulin-sensitization group (5.9%, P=0.003). CONCLUSIONS: Overall, there was no significant difference in the rates of death and major cardiovascular events between patients undergoing prompt revascularization and those undergoing medical therapy or between strategies of insulin sensitization and insulin provision. (ClinicalTrials.gov number, NCT00006305.)

The Bypass Angioplasty Revascularization Investigation 2 Diabetes randomized trial of different treatment strategies in type 2 diabetes mellitus with stable ischemic heart disease: impact of treatment strategy on cardiac mortality and myocardial infarction.

BACKGROUND: The Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) trial in 2368 patients with stable ischemic heart disease assigned before randomization to percutaneous coronary intervention or coronary artery bypass grafting strata reported similar 5-year all-cause mortality rates with insulin sensitization versus insulin provision therapy and with a strategy of prompt initial coronary revascularization and intensive medical therapy or intensive medical therapy alone with revascularization reserved for clinical indication(s). In this report, we examine the predefined secondary end points of cardiac death and myocardial infarction (MI). METHODS AND RESULTS: Outcome data were analyzed by intention to treat; the Kaplan-Meier method was used to assess 5-year event rates. Nominal P values are presented. During an average 5.3-year follow-up, there were 316 deaths (43% were attributed to cardiac causes) and 279 first MI events. Five-year cardiac mortality did not differ between revascularization plus intensive medical therapy (5.9%) and intensive medical therapy alone groups (5.7%; P=0.38) or between insulin sensitization (5.7%) and insulin provision therapy (6%; P=0.76). In the coronary artery bypass grafting stratum (n=763), MI events were significantly less frequent in revascularization plus intensive medical therapy versus intensive medical therapy alone groups (10.0% versus 17.6%; P=0.003), and the composite end points of all-cause death or MI (21.1% versus 29.2%; P=0.010) and cardiac death or MI (P=0.03) were also less frequent. Reduction in MI (P=0.001) and cardiac death/MI (P=0.002) was significant only in the insulin sensitization group. CONCLUSIONS: In many patients with type 2 diabetes mellitus and stable ischemic coronary disease in whom angina symptoms are controlled, similar to those enrolled in the percutaneous coronary intervention stratum, intensive medical therapy alone should be the first-line strategy. In patients with more extensive coronary disease, similar to those enrolled in the coronary artery bypass grafting stratum, prompt coronary artery bypass grafting, in the absence of contraindications, intensive medical therapy, and an insulin sensitization strategy appears to be a preferred therapeutic strategy to reduce the incidence of MI.

An Aggregate Biomarker Risk Score Predicts High Risk of Near-Term Myocardial Infarction and Death: Findings From BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes).

BACKGROUND: In a previous study, we found that a biomarker risk score (BRS) comprised of C-reactive protein, fibrin-degradation products, and heat shock protein-70 predicts risk of myocardial infarction and death in coronary artery disease patients. We sought to: (1) validate the BRS in the independent BARI 2D (Bypass Angioplasty Revascularization Investigation 2 Diabetes) cohort, (2) investigate whether 1 year of intensive medical therapy is associated with improved BRS, and (3) elucidate whether an altered BRS parallels altered risk. METHODS AND RESULTS: Two thousand thirty-two subjects with coronary artery disease were followed for 5.3±1.1 years for cardiovascular events. Biomarkers were measured at baseline and retested in 1304 subjects at 1 year. BRS was determined as the biomarker number above previously defined cut-off values (C-reactive protein >3 mg/L, heat shock protein-70 >0.313 ng/mL, and fibrin-degradation products >1 µg/mL). After adjustment for covariates, those with a BRS of 3 had a 4-fold increased risk of all-cause death and a 6.8-fold increased risk of cardiac death compared with those with a BRS of 0 (95% CI, 2.9-16.0; P<0.0001). All individual biomarkers decreased by 1 year, with ≈80% of patients decreasing their BRS. BRS recalibrated at 1 year also predicted risk. Those with 1-year BRS of 2 to 3 had a 4-year mortality rate of 21.1% versus 7.4% for those with BRS of 0 to 1 (P<0.0001). CONCLUSIONS: Our results validate the ability of the BRS to identify coronary artery disease patients at very high near-term risk of myocardial infarction/death. After 1 year of intensive medical therapy, the BRS decreased significantly, and the reclassified BRS continued to track with risk. Our results suggest that repeated BRS measurements might be used to assess risk and recalibrate therapy.

Cognitive decline and brain amyloid-ß accumulation across 3 years in adults with Down syndrome.

Adults with Down syndrome (DS) have a high incidence of Alzheimer's disease (AD), providing a unique opportunity to explore the early, preclinical stages of AD neuropathology. We examined change in brain amyloid-ß accumulation via the positron emission tomography tracer [11C] Pittsburgh compound B (PiB) across 2 data collection cycles, spaced 3 years apart, and decline in cognitive functioning in 58 adults with DS without clinical AD. PiB retention increased in the anterior cingulate gyrus, precuneus cortex, parietal cortex, and anterior ventral striatum. Across the 2 cycles, 14 (27.5%) participants were consistently PiB+, 31 (60.8%) were consistently PiB-, and 6 (11.7%) converted from PiB- at cycle 1 to PiB+ at cycle 2. Increased global amyloid-ß was related to decline in verbal episodic memory, visual episodic memory, executive functioning, and fine motor processing speed. Participants who were consistently PiB+ demonstrated worsening of episodic memory, whereas participants who were consistently PiB- evidenced stable or improved performance. Amyloid-ß accumulation may be a contributor to or biomarker of declining cognitive functioning in preclinical AD in DS.

Non-high-density lipoprotein cholesterol levels predict five-year outcome in the Bypass Angioplasty Revascularization Investigation (BARI).

BACKGROUND: Current National Cholesterol Education Program guidelines recommend that non-high-density lipoprotein cholesterol (non-HDL-C) be considered a secondary target of therapy among individuals with triglycerides >2.26 mmol/L. It is not known whether non-HDL-C relates to prognosis among patients with coronary heart disease. METHODS AND RESULTS: Lipid levels were available at baseline among 1514 patients (73% men; mean age, 61 years) enrolled in the Bypass Angioplasty Revascularization Investigation (BARI); all had multivessel coronary artery disease. Patients were followed for 5 years. Outcomes of death, nonfatal myocardial infarction, and death or myocardial infarction were modeled using univariate and multivariate time-dependent proportional hazards methods; angina pectoris at 5 years was modeled using univariate and multivariate logistic regression. Non-HDL-C was a strong and independent predictor of nonfatal myocardial infarction (multivariate relative risk, 1.049 [95% confidence intervals, 1.006 to 1.093] for every 0.26 mmol/L increase) and angina pectoris (multivariate odds ratio, 1.049 [95% confidence intervals, 1.004 to 1.096] for every 0.26 mmol/L increase), but it did not relate to mortality. HDL-C and LDL-C did not predict events during follow-up. CONCLUSIONS: Among patients with lipid values in BARI, non-HDL-C is a strong and independent predictor of nonfatal myocardial infarction and angina pectoris at 5 years, even after consideration of powerful clinical variables. Our data suggest that non-HDL-C is an appropriate treatment target among patients with coronary heart disease.

Analysis of the bypass angioplasty revascularization investigation trial using a multistate model of clinical outcomes.

Current cardiovascular randomized trials typically use composite outcomes. We hypothesized that the Bypass Angioplasty Revascularization Investigation (BARI) outcomes and conclusions would differ using a multistate model relative to the intervention for the composite outcome of death (D) and nonfatal Q-wave myocardial infarction (MI). We used a multistate model which uses transition paths to simultaneously assess multiple end points. Using the 10-year follow-up BARI data, we post hoc analyzed outcomes according to 3 transition paths: (1) from intervention to MI; (2) from intervention to death; and (3) from MI to death. Of 1,829 patients randomized to the intervention of percutaneous transluminal coronary angioplasty or coronary artery bypass grafting (CABG), 700 (38%) experienced the composite event D/MI which included 230 (13%) nonfatal MI and 470 (26%) death without antecedent nonfatal MI, whereas 79 of 230 (34%) experienced death after nonfatal MI. Outcomes of the 3 individual transition paths were analyzed by a multistate model. In contrast to standard survival analyses, after adjustment for baseline clinical covariates, outcomes after percutaneous transluminal coronary angioplasty or CABG were not significantly different for intervention to MI (p = 0.33) or intervention to death (p = 0.23), but MI to death favored CABG (p = 0.02). Deconstruction of the BARI data using a multistate model identifies a significant difference in individual transition-stage outcomes and therefore trial conclusions in contrast to the standard methods of survival analysis. These observations suggest multistate models should be considered in the design and analysis of randomized cardiovascular trials which use composite outcomes.

Coronary artery bypass in patients with type 2 diabetes: experience from the Bypass Angioplasty Revascularization Investigation 2 Diabetes trial.

OBJECTIVE: Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) was a study of management strategies for diabetic patients with myocardial ischemia and coronary artery disease. In a 2×2 design, early revascularization versus medical management with or without late revascularization and insulin sensitization versus insulin provision were examined. No advantage for either strategy was seen, except in the group undergoing early coronary artery bypass grafting (CABG). In that group, a reduction in subsequent myocardial infarction was noted. The purpose of our report was to characterize the conduct and short-term outcomes for CABG that led to this result. METHODS: Data from the BARI 2D CABG stratum were collected, including the baseline demographic and cardiovascular characteristics, technical details of the operation, and perioperative morbidity and mortality, and analyzed. RESULTS: A total of 347 patients were studied. The average cardiac function was normal, and most had multivessel disease. Almost all had undergone CABG by way of a median sternotomy using an internal mammary artery, and one third were off pump. The perioperative morbidity and mortality were low and compared well with larger outcomes databases. CONCLUSIONS: BARI 2D showed that early CABG in patients with type 2 diabetes and myocardial ischemia and multivessel disease reduced the subsequent myocardial infarction rates. The present results have demonstrated that this was achieved using off-pump surgery in certain cases, standard myocardial protection, and routine use of the internal mammary artery or other arterial grafts.

Extubating in the operating room after adult cardiac surgery safely improves outcomes and lowers costs.

OBJECTIVE: Prolonged intubation has been implicated in the poor outcomes after adult cardiac surgery. Accelerated postoperative extubation has been a quality focus, but operating room (OR) extubation after cardiopulmonary bypass is rare. We examined the outcomes and direct costs of protocolized OR extubation versus early postoperative intensive care unit (ICU) extubation after nonemergency open cardiac surgery. METHODS: From January 2012 to June 2013, 652 consecutive patients who had undergone various cardiac operations, including redo and multivalve operations, were extubated within 12 hours, 165 in the OR. The OR extubation patients were propensity matched from multivariable logistic regression to derive 106 matched pairs for OR extubation versus extubation < 12 hours (group 1) and 98 independently matched pairs for OR extubation versus extubation < 6 hours (group 2). RESULTS: OR versus ICU extubation conveyed significant reductions in ICU hours (26.3, interquartile range [IQR], 22.0-31.0; vs 29.0, IQR, 25.0-51.0; P = .001, for group 1; 27.0, IQR, 22.0-32.0; vs 29.0, IQR, 25.0-54.0; P = .0002, for group 2) and postoperative length of stay (5 days, IQR, 4-6; vs 6 days, IQR, 5-7; P = .0008, for group 1; 5 days, IQR, 4-6; vs 6 days, IQR, 4-7; P = .0002, for group 2) but did not affect the reintubation rate (1.9% [2 of 106] vs 0.0% [0 of 106], P = .5, group 1; 3.1% [3 of 98] vs 2.0% [2 of 98], P = 1.0, group 2). OR versus ICU extubation conferred a >20% cost reduction from surgery completion to discharge ($3055, IQR, $2576-$3964; vs $3977, IQR, $3028-$4947; P = .0007, group 1; $3025, IQR, $2598-$3965, vs $3877, IQR, $2998-$5458; P = .007, group 2). CONCLUSIONS: After cardiac surgery, OR extubation is safe and might provide improvement in length of stay and cost compared with early postoperative ICU extubation.

Change in albuminuria and eGFR following insulin sensitization therapy versus insulin provision therapy in the BARI 2D study.

BACKGROUND AND OBJECTIVES: In the Bypass Angioplasty Revascularization Investigation 2 Diabetes randomized trial, glycemic control with insulin-sensitization therapy was compared with insulin-provision therapy in patients with type 2 diabetes and coronary artery disease. This study examined differences in albumin excretion and renal function in the insulin-sensitization group versus the insulin-provision group over 5 years. DESIGN, SETTING, PARTICIPANTS & MEASUREMENTS: In total, 1799 patients with measurements of creatinine and urine albumin/creatinine ratio at baseline and at least two follow-up visits were included. Management of BP, lipids, and lifestyle counseling was uniform. Progression of albuminuria was defined as doubling of baseline albumin/creatinine ratio to at least 100 mg/g or worsening of albumin/creatinine ratio status on two or more visits. Worsening renal function was defined as >25% decline in estimated GFR and annualized decline of >3 ml/min per 1.73 m(2) per year. RESULTS: By 6 months and thereafter, the mean glycated hemoglobin levels were lower in the insulin-sensitization group compared with the insulin-provision group (P<0.002 for each time point; absolute difference=0.4%). Albumin/creatinine ratio increased over time in the insulin-sensitization group (P value for trend<0.001) and was stable in the insulin-provision group. Risk for progression of albumin/creatinine ratio was higher in the insulin-sensitization group compared with the insulin-provision group (odds ratio, 1.59; 95% confidence interval, 1.25 to 2.02; P=0.02). Over 5 years, albumin/creatinine ratio increased from 11.5 (interquartile range=5.0-46.7) to 15.7 mg/g (interquartile range=6.2-55.4) in the insulin-sensitization group (P<0.001) and from 12.1 (interquartile range=5.3-41.3) to 12.4 mg/g (interquartile range=5.8-50.6) in the insulin-provision group (P=0.21). Estimated GFR declined from 75.0±20.6 to 66.3±22.6 ml/min per 1.73 m(2) in the insulin-sensitization group (P<0.001) and from 76.1±29.5 to 66.8±22.1 ml/min per 1.73 m(2) in the insulin-provision group (P<0.001). CONCLUSION: Over 5 years, despite lower glycated hemoglobin levels, the insulin-sensitization treatment group had greater progression of albumin/creatinine ratio compared with the insulin-provision treatment group. Decline in estimated GFR was similar.