Pharmacodynamic evaluation and safety assessment of treatment with antibodies to serum amyloid P component in patients with cardiac amyloidosis: an open-label Phase 2 study and an adjunctive immuno-PET imaging study.

BACKGROUND: In a Phase I study treatment with the serum amyloid P component (SAP) depleter miridesap followed by monoclonal antibody to SAP (dezamizumab) showed removal of amyloid from liver, spleen and kidney in patients with systemic amyloidosis. We report results from a Phase 2 study and concurrent immuno-positron emission tomography (PET) study assessing efficacy, pharmacodynamics, pharmacokinetics, safety and cardiac uptake (of dezamizumab) following the same intervention in patients with cardiac amyloidosis. METHODS: Both were uncontrolled open-label studies. After SAP depletion with miridesap, patients received ≤ 6 monthly doses of dezamizumab in the Phase 2 trial (n = 7), ≤ 2 doses of non-radiolabelled dezamizumab plus [89Zr]Zr-dezamizumab (total mass dose of 80 mg at session 1 and 500 mg at session 2) in the immuno-PET study (n = 2). Primary endpoints of the Phase 2 study were changed from baseline to follow-up (at 8 weeks) in left ventricular mass (LVM) by cardiac magnetic resonance imaging and safety. Primary endpoint of the immuno-PET study was [89Zr]Zr-dezamizumab cardiac uptake assessed via PET. RESULTS: Dezamizumab produced no appreciable or consistent reduction in LVM nor improvement in cardiac function in the Phase 2 study. In the immuno-PET study, measurable cardiac uptake of [89Zr]Zr-dezamizumab, although seen in both patients, was moderate to low. Uptake was notably lower in the patient with higher LVM. Treatment-associated rash with cutaneous small-vessel vasculitis was observed in both studies. Abdominal large-vessel vasculitis after initial dezamizumab dosing (300 mg) occurred in the first patient with immunoglobulin light chain amyloidosis enrolled in the Phase 2 study. Symptom resolution was nearly complete within 24 h of intravenous methylprednisolone and dezamizumab discontinuation; abdominal computed tomography imaging showed vasculitis resolution by 8 weeks. CONCLUSIONS: Unlike previous observations of visceral amyloid reduction, there was no appreciable evidence of amyloid removal in patients with cardiac amyloidosis in this Phase 2 trial, potentially related to limited cardiac uptake of dezamizumab as demonstrated in the immuno-PET study. The benefit-risk assessment for dezamizumab in cardiac amyloidosis was considered unfavourable after the incidence of large-vessel vasculitis and development for this indication was terminated. Trial registration NCT03044353 (2 February 2017) and NCT03417830 (25 January 2018).

Outcomes following formation of a dedicated pediatric liver transplant anesthesia team.

BACKGROUND: Given the complex nature of liver transplant surgery, adult centers typically use a dedicated liver transplant anesthesia team, which has improved patient outcomes. AIMS: Our goal was to determine whether a dedicated pediatric liver transplant anesthesia team was associated with improved patient outcomes. METHODS: This retrospective cohort study analyzed patients who underwent liver transplantation from April 2013 to September 2020 at St. Louis Children's Hospital. The general group (April 2013-December 2016) was compared with the liver group (January 2017-September 2020). Outcomes measured included cases per anesthesiologist, early extubation, ventilator days, fluid and blood administration, postoperative events, and intensive care unit and hospital length of stay (LOS). RESULTS: Patients in both groups had similar demographics. The average number of cases/anesthesiologist/year was 2.9 times higher in the liver group (mean (SD) general 0.7 (0.5), liver 2.0 (0.6), and difference in mean [95% CI] 1.3 [0.8, 1.8]). The rate of extubation in the operating room was higher for patients in the liver group (general 56%, liver 80%, and difference in proportion [95% CI] 24.7 [7.0, 42.4]), while the number of ventilator days was lower (mean (SD) general 2.1 (4.4), liver 1.1 (3.6), and difference in proportion [95%CI] -0.9 [-2.6, 0.7]). Colloid administration was higher in the liver group (mean (SD) general 23.9 (14.5) ml/kg, liver 48.4 (37.7) ml/kg, and difference in mean [95% CI] 24.6 [12.7, 36.4]), while fresh frozen plasma administration was lower in the liver group (mean (SD) general 15.3 (23.9) ml/kg, liver 6.2 (14) ml/kg, and difference in mean [95% CI] -9.0 [-16.8, -1.3]). There were no significant differences between the groups in postoperative events including blood product transfusions, vasopressor use, and thromboses, or in the intensive care unit and hospital LOS. CONCLUSIONS: The liver group was associated with increased early extubations, decreased ventilator days, and decreased fresh frozen plasma use.

Clinical moderators and predictors of cognitive-behavioral therapy by guided-self-help versus therapist-led for binge-eating disorder: Analysis of aggregated clinical trials.

OBJECTIVE: Cognitive-behavioral therapy (CBT)-therapist-led (CBTth) and guided-self-help (CBTgsh)-has efficacy for binge-eating disorder (BED) but many patients do not benefit sufficiently. We examined predictors and moderators for these two CBT methods. METHOD: Data were aggregated from randomized controlled trials (RCTs) testing psychosocial treatments for BED in the U.S. Predictors and moderators of outcomes (treatment completion and binge-eating remission) were examined in N = 457 participants who received either CBTgsh (N = 164) or CBTth (N = 293). RESULTS: Analyses, adjusting for demographic/clinical variables, indicated CBTth was significantly superior to CBTgsh for treatment completion (odds ratio [OR] = 20.0) and remission (OR = 14.6). For remission, analyses revealed significant predictors (age, treatment length, Weight Concern), a moderator (weight concern [OR = 5.13]), and a significant interaction between CBT-type and treatment length (OR = 2.66). For CBTgsh, longer treatment was associated with less remission, whereas for CBTth, longer treatment was associated with greater remission. For CBTgsh, 44.1% with low weight concern versus 56.3% with high weight concern achieved remission whereas for CBTth, 43.5% with high weight concern and 61.0% with low weight concern achieved remission. DISCUSSION: Analyses of aggregated RCT BED data, adjusting for demographic/clinical characteristics, indicated superiority (large effect-sizes) in treatment outcomes of CBTth over CBTgsh and that Weight Concern moderated outcomes.

Effect of ileal bile acid transporter inhibitor GSK2330672 on pruritus in primary biliary cholangitis: a double-blind, randomised, placebo-controlled, crossover, phase 2a study.

BACKGROUND: Up to 70% of patients with primary biliary cholangitis develop pruritus (itch) during the course of their disease. Treatment of pruritus in primary biliary cholangitis is challenging and novel therapies are needed. Ursodeoxycholic acid, the standard first-line treatment for primary biliary cholangitis, is largely ineffective for pruritus. We investigated the efficacy and safety of GSK2330672, a selective inhibitor of human ileal bile acid transporter (IBAT), in patients with primary biliary cholangitis with pruritus. METHODS: We conducted this phase 2a, double-blind, randomised, placebo-controlled, crossover trial in two UK medical centres. Following 2 weeks of open placebo run-in, patients were randomly assigned in a 1:1 ratio with a block size of 4 to receive GSK2330672 or placebo twice daily during two consecutive 14-day treatment periods in a crossover sequence. The treatment periods were followed by a 14-day single-blinded placebo follow-up period. The primary endpoints were safety of GSK2330672, assessed using clinical and laboratory parameters, and tolerability as rated by the Gastrointestinal Symptom Rating Scale. The secondary endpoints were changes in pruritus scores measured using the 0 to 10 numerical rating scale (NRS), primary biliary cholangitis-40 (PBC-40) itch domain score and 5-D itch scale, changes in serum total bile acids and 7 alpha hydroxy-4-cholesten-3-one (C4), and changes in the pharmacokinetic parameters of ursodeoxycholic acid and its conjugates. The trial was registered with ClinicalTrials.gov, number NCT01899703. FINDINGS: Between March 10, 2014, and Oct 7, 2015, we enrolled 22 patients. 11 patients were assigned to receive intervention followed by placebo (sequence 1), and 11 patients were assigned to receive placebo followed by intervention (sequence 2). One patient assigned to sequence 2 withdrew consent prior to receiving randomised therapy. One patient did not attend the placebo follow-up period, but was included in the final analysis. GSK2330672 treatment for 14 days was safe with no serious adverse events reported. Diarrhoea was the most frequent adverse event during treatment with GSK2330672 (seven with GSK2330672 vs one with placebo) and headache was the most frequent adverse event during treatment with placebo (seven with placebo vs six with GSK2330672). After GSK2330672 treatment, the percentage changes from baseline itch scores were -57% (95% CI -73 to -42, p<0·0001) in the NRS, -31% (-42 to -20, p<0·0001) in the PBC-40 itch domain and -35% (-45 to -25, p<0·0001) in the 5-D itch scale. GSK2330672 produced significantly greater reduction from baseline than the double-blind placebo in the NRS (-23%, 95% CI -45 to -1; p=0·037), PBC-40 itch domain, (-14%, -26 to -1; p=0·034), and 5-D itch scale (-20%, -34 to -7; p=0·0045). After GSK2330672 treatment, serum total bile acid concentrations declined by 50% (95% CI -37 to -61, p<0·0001) from 30 to 15 µM, with a significant 3·1-times increase (95% CI 2·4 to 4·0, p<0·0001) in serum C4 concentrations from 7·9 to 24·7ng/mL. INTERPRETATION: In patients with primary biliary cholangitis with pruritus, 14 days of ileal bile acid transporter inhibition by GSK2330672 was generally well tolerated without serious adverse events, and demonstrated efficacy in reducing pruritus severity. GSK2330672 has the potential to be a significant and novel advance for the treatment of pruritus in primary biliary cholangitis. Diarrhoea, the most common adverse event associated with GSK2330672 treatment, might limit the long-term use of this drug. FUNDING: GlaxoSmithKline and National Institute for Health Research.

Extracellular volume with bolus-only technique in amyloidosis patients: Diagnostic accuracy, correlation with other clinical cardiac measures, and ability to track changes in amyloid load over time.

BACKGROUND: Extracellular volume (ECV) by T1 mapping requires the contrast agent distribution to be at equilibrium. This can be achieved either definitively with a primed contrast infusion (infusion ECV), or sufficiently with a delay postbolus (bolus-only ECV). For large ECV, the bolus-only approach measures higher than the infusion ECV, causing some uncertainty in diseases such as amyloidosis. PURPOSE: To characterize the relationship between the bolus-only and current gold-standard infusion ECV in patients with amyloidosis. STUDY TYPE: Bolus-only and infusion ECV were prospectively measured. POPULATION: In all, 186 subjects with systemic amyloidosis attending our clinic and 23 subjects with systemic amyloidosis who were participating in an open-label, two-part, dose-escalation, phase 1 trial. FIELD STRENGTH: Avanto 1.5T, Siemens Medical Solutions, Erlangen, Germany. ASSESSMENT: Bolus-only and infusion ECV were measured in all subjects using shortened modified Look-Locker inversion recovery (ShMOLLI) T1 mapping sequence. STATISTICAL TESTS: Pearson correlation coefficient (r); Bland-Altman; receiver operating characteristic (ROC) curve analysis. Linear regression model with a fractional polynomial transformation. RESULTS: The difference between the bolus-only and infusion myocardial ECV increased as the average of the two measures increased, with the bolus-ECV measuring higher. For an average ECV of 0.4, the difference was 0.013. The 95% limits of agreement for the two methods, after adjustment for the bias, were ±0.056. However, cardiac diagnostic accuracy was comparable (bolus-only vs. infusion ECV area under the curve [AUC] = 0.839 vs. 0.836), as were correlations with other clinical cardiac measures, and, in the trial patients, the ability to track changes in the liver/spleen with therapy. DATA CONCLUSION: In amyloidosis, with large ECVs, the bolus-only technique reads higher than the infusion technique, but clinical performance by any measure is the same. Given the work-flow advantages, these data suggest that the bolus-only approach might be acceptable for amyloidosis, and might support its use as a surrogate endpoint in future clinical trials. LEVEL OF EVIDENCE: 1 Technical Efficacy: Stage 4 J. Magn. Reson. Imaging 2018;47:1677-1684.

Endoscopic Versus Open Repair for Craniosynostosis in Infants Using Propensity Score Matching to Compare Outcomes: A Multicenter Study from the Pediatric Craniofacial Collaborative Group.

BACKGROUND: The North American Pediatric Craniofacial Collaborative Group (PCCG) established the Pediatric Craniofacial Surgery Perioperative Registry to evaluate outcomes in infants and children undergoing craniosynostosis repair. The goal of this multicenter study was to utilize this registry to assess differences in blood utilization, intensive care unit (ICU) utilization, duration of hospitalization, and perioperative complications between endoscopic-assisted (ESC) and open repair in infants with craniosynostosis. We hypothesized that advantages of ESC from single-center studies would be validated based on combined data from a large multicenter registry. METHODS: Thirty-one institutions contributed data from June 2012 to September 2015. We analyzed 1382 infants younger than 12 months undergoing open (anterior and/or posterior cranial vault reconstruction, modified-Pi procedure, or strip craniectomy) or endoscopic craniectomy. The primary outcomes included transfusion data, ICU utilization, hospital length of stay, and perioperative complications; secondary outcomes included anesthesia and surgical duration. Comparison of unmatched groups (ESC: N = 311, open repair: N = 1071) and propensity score 2:1 matched groups (ESC: N = 311, open repair: N = 622) were performed by conditional logistic regression analysis. RESULTS: Imbalances in baseline age and weight are inherent due to surgical selection criteria for ESC. Quality of propensity score matching in balancing age and weight between ESC and open groups was assessed by quintiles of the propensity scores. Analysis of matched groups confirmed significantly reduced utilization of blood (26% vs 81%, P < .001) and coagulation (3% vs 16%, P < .001) products in the ESC group compared to the open group. Median blood donor exposure (0 vs 1), anesthesia (168 vs 248 minutes) and surgical duration (70 vs 130 minutes), days in ICU (0 vs 2), and hospital length of stay (2 vs 4) were all significantly lower in the ESC group (all P < .001). Median volume of red blood cell administered was significantly lower in ESC (19.6 vs 26.9 mL/kg, P = .035), with a difference of approximately 7 mL/kg less for the ESC (95% confidence interval for the difference, 3-12 mL/kg), whereas the median volume of coagulation products was not significantly different between the 2 groups (21.2 vs 24.6 mL/kg, P = .73). Incidence of complications including hypotension requiring treatment with vasoactive agents (3% vs 4%), venous air embolism (1%), and hypothermia, defined as <35°C (22% vs 26%), was similar between the 2 groups, whereas postoperative intubation was significantly higher in the open group (2% vs 10%, P < .001). CONCLUSIONS: This multicenter study of ESC versus open craniosynostosis repair represents the largest comparison to date. It demonstrates striking advantages of ESC for young infants that may result in improved clinical outcomes, as well as increased safety.

Practical experiences of adopting assurance as a quantitative framework to support decision making in drug development.

All clinical trials are designed for success of their primary objectives. Hence, evaluating the probability of success (PoS) should be a key focus at the design stage both to support funding approval from sponsor governance boards and to inform trial design itself. Use of assurance-that is, expected success probability averaged over a prior probability distribution for the treatment effect-to quantify PoS of a planned study has grown across the industry in recent years, and has now become routine within the authors' company. In this paper, we illustrate some of the benefits of systematically adopting assurance as a quantitative framework to support decision making in drug development through several case-studies where evaluation of assurance has proved impactful in terms of trial design and in supporting governance-board reviews of project proposals. In addition, we describe specific features of how the assurance framework has been implemented within our company, highlighting the critical role that prior elicitation plays in this process, and illustrating how the overall assurance calculation may be decomposed into a sequence of conditional PoS estimates which can provide greater insight into how and when different development options are able to discharge risk.

Perioperative Outcomes and Management in Pediatric Complex Cranial Vault Reconstruction: A Multicenter Study from the Pediatric Craniofacial Collaborative Group.

BACKGROUND: The Pediatric Craniofacial Collaborative Group established the Pediatric Craniofacial Surgery Perioperative Registry to elucidate practices and outcomes in children with craniosynostosis undergoing complex cranial vault reconstruction and inform quality improvement efforts. The aim of this study is to determine perioperative management, outcomes, and complications in children undergoing complex cranial vault reconstruction across North America and to delineate salient features of current practices. METHODS: Thirty-one institutions contributed data from June 2012 to September 2015. Data extracted included demographics, perioperative management, length of stay, laboratory results, and blood management techniques employed. Complications and outlier events were described. Outcomes analyzed included total blood donor exposures, intraoperative and perioperative transfusion volumes, and length of stay outcomes. RESULTS: One thousand two hundred twenty-three cases were analyzed: 935 children aged less than or equal to 24 months and 288 children aged more than 24 months. Ninety-five percent of children aged less than or equal to 24 months and 79% of children aged more than 24 months received at least one transfusion. There were no deaths. Notable complications included cardiac arrest, postoperative seizures, unplanned postoperative mechanical ventilation, large-volume transfusion, and unplanned second surgeries. Utilization of blood conservation techniques was highly variable. CONCLUSIONS: The authors present a comprehensive description of perioperative management, outcomes, and complications from a large group of North American children undergoing complex cranial vault reconstruction. Transfusion remains the rule for the vast majority of patients. The occurrence of numerous significant complications together with large variability in perioperative management and outcomes suggest targets for improvement.

Preoperative malnutrition is associated with increased mortality and adverse outcomes after paediatric cardiac surgery.

BACKGROUND: Malnutrition is common in children with CHD and is likely to place them at an increased risk for adverse surgical outcomes. We sought to evaluate the impact of preoperative malnutrition on outcomes after paediatric cardiac surgery. METHODS: We conducted a retrospective analysis of patients from age 0 to 5 years undergoing cardiac surgery at Seattle Children's Hospital from 2006 to 2015. We used regression modelling to examine the impact of malnutrition on surgical outcomes. RESULTS: We found a non-linear relationship between low height-for-age and weight-for-age z-scores and mortality after surgery. In the range of z-score ⩽-2, each additional unit decrease in height-for-age or weight-for-age z-score was associated with a 2.9 or 2.1% increased risk for mortality, respectively. Each unit decrease in height-for-age z-score was associated with a 1.2% increased risk for cardiac arrest, 1.1% increased risk for infection, and an average of 1.7 additional hours of mechanical ventilation, 6 hours longer ICU stay, and 13 hours longer hospital stay. Each unit decrease in weight-for-age z-score was associated with a 0.7% increased risk for cardiac arrest, 0.8% increased risk for infection, and an average of 1.9 additional hours of mechanical ventilation and 5.3 additional hours of ICU stay. CONCLUSIONS: This study is unique in demonstrating a significant association between malnutrition and 30-day mortality and other adverse outcomes after paediatric cardiac surgery in a mixed population of CHD patients. By evaluating nutritional status as a continuous variable, we were able to clearly distinguish the point at which malnutrition begins to affect mortality.

Focused vs. Broad enhanced cognitive behavioral therapy for bulimia nervosa with comorbid borderline personality: A randomized controlled trial.

OBJECTIVE: A subset of individuals with bulimia nervosa (BN) have borderline personality disorder (BPD) symptoms, including chronic negative affect and interpersonal problems. These symptoms predict poor BN treatment outcome in some studies. The broad version of Enhanced Cognitive Behavior Therapy (CBT-E) was developed to address co-occurring problems that interfere with treatment response. The current study investigated the relative effects, predictors, and moderators of CBT-E for BN with BPD and co-occurring mood/anxiety disorders. METHOD: Fifty patients with BN and threshold or sub-threshold BPD and current or recent Axis I mood or anxiety disorders were randomly assigned to receive focused CBT-E (CBT-Ef) or broad CBT-E (CBT-Eb) specifically including an interpersonal module and additional attention to mood intolerance. RESULTS: Forty-two percent of the sample reported remission from binge eating and purging at termination. Significant changes across symptom domains were observed at termination and at 6-month follow-up. Though CBT-Ef predicted good outcomes in multivariate models, the severity of affective/interpersonal problems moderated treatment effects: participants with higher severity showed better ED outcomes in CBT-Eb, whereas those with lower severity showed better outcomes in CBT-Ef. Severity of affective/interpersonal BPD symptoms at baseline predicted negative outcomes overall. Follow-up BPD affective/interpersonal problems were predicted by baseline affective/interpersonal problems and by termination EDE score. DISCUSSION: This study supports the utility of CBT-E for patients with BN and complex comorbidity. CBT-Ef appears to be more efficacious for patients with relatively less severe BPD symptoms, whereas CBT-Eb appears to be more efficacious for patients with more severe BPD symptoms.

Large-volume vitrification of human biopsied and non-biopsied blastocysts: a simple, robust technique for cryopreservation.

PURPOSE: To evaluate the transition from a proven slow-cooling cryopreservation method to a commercial large-volume vitrification system for human blastocysts. METHODS: Retrospective analysis of de-identified laboratory and clinical data from January 2012 to present date for all frozen embryo replacement (FET) cycles was undertaken. Cryopreservation of trophectoderm-biopsied or non-biopsied blastocysts utilized during this time period was logged as either slow-cooling, small-volume vitrification, or large-volume vitrification. Blastocyst survival post-warm or post-thaw, clinical pregnancy following FET, and implantation rates were identified for each respective cryopreservation method. RESULTS: Embryo survival was highest for large-volume vitrification compared to micro-volume vitrification and slow-cooling; 187/193 (96.9 %), 27/32 (84.4 %), and 244/272 (89.7 %), respectively. Survival of biopsied and non-biopsied blastocysts vitrified using the large-volume system was 105/109 (96.3 %) and 82/84 (97.6 %), respectively. Survival for micro-volume biopsied and non-biopsied blastocysts was 16/30 (83.3 %) and 2/2 (100.0 %) respectively. Slow-cooling post-thaw embryo survival was 272/244 (89.7 %). Clinical pregnancy and implantation rates outcomes for non-biopsied embryos were similar between large-volume and slow-cooling cryopreservation methods, 18/39 (46.2 %) clinical pregnancy and 24/82 (29.3 %) implantation/embryo, and 52/116 (44.8 %) clinical pregnancy and 67/244 (27.5 %) implantation/embryo, respectively. Comparing outcomes for biopsied embryos, clinical pregnancy and implantation rates were 39/67 (58.2 %) clinical pregnancy and 50/105 (47.6 %) implantation/embryo and 4/16 (25 %) clinical pregnancy and 6/25 (24.0 %) implantation/embryo, respectively. CONCLUSIONS: The LifeGlobal large-volume vitrification system proved to be very reliable, simple to learn and implement in the laboratory. Clinically large-volume vitrification was as, or more effective compared to slow-cooling cryopreservation in terms of recovery of viable embryos in this laboratory.

Effect of alteplase within 6 hours of acute ischemic stroke on all-cause mortality (third International Stroke Trial).

BACKGROUND AND PURPOSE: Prompt thrombolytic therapy with intravenous alteplase reduces disability after acute ischemic stroke. In an exploratory analysis, we examined whether long-term survival varied by baseline characteristics after alteplase. METHODS: In this open-treatment, international, randomized, controlled trial, ischemic stroke patients were randomly allocated <6 hours of onset to intravenous alteplase (0.9 mg/kg) plus standard care (n=1515) or standard care alone (n=1520). We followed patients to death, censoring when last known to be alive. We grouped patients by delay to randomization, and good or poor predicted prognosis (calculated from baseline National Institutes of Health Stroke Scale [NIHSS] score and age). We present absolute mortality differences between treated and control groups at 7 days, 6 months, and 18 months poststroke. RESULTS: Alteplase was not associated with a significant increase in mortality within 18 months (0.6% [95% confidence interval (CI), -2.9% to +4.2] P=0.72] in all patients with complete vital status (99.9%, 3034/3035). In patients randomized <3 hours of stroke, 18-month mortality was lower in the alteplase-treated group than the control group (40.6% [95% CI, 42.6-52.7] versus 47.8% [95% CI, 35.5-45.3]; P=0.0434]. The difference in 18-month mortality between alteplase-treated and control patients was greater in patients who were randomized early (<3 hours) compared with late (3-6 hours; +9% [95% CI, 1-17]; P=0.0317). Alteplase led to a greater improvement in 18-month survival in patients with a poor prognosis than in patients with a good prognosis (+8% [95% CI, 2-14]; P=0.0091). CONCLUSIONS: These exploratory analyses of the third International Stroke Trial (IST-3) trial support improving acute stroke patients' access to earlier alteplase treatment, treatment of patients with poor prognosis, and further randomized controlled trials in minor stroke to replicate these findings. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN25765518.

Targeting recombinant tissue-type plasminogen activator in acute ischemic stroke based on risk of intracranial hemorrhage or poor functional outcome: an analysis of the third international stroke trial.

BACKGROUND AND PURPOSE: Intravenous recombinant tissue-type plasminogen activator (r-tPA), despite a risk of early symptomatic intracranial hemorrhage (sICH), is of net clinical benefit to acute stroke patients. We tested if predictive models could identify patients least likely to be harmed by sICH or those who gained no net benefit. METHODS: We used the Third International Stroke Trial (IST-3) trial data set, an international, multicenter, open treatment randomized trial of 0.9 mg/kg r-tPA versus control in 3035 patients with acute ischemic stroke. We compared the discrimination and calibration of previously developed predictive models for ICH and poststroke poor outcome and developed a new model using variables selected by systematic review. We calculated the absolute and relative risk reduction of death or dependency with r-tPA in patients at a low, medium, or high predicted risk of sICH or poor functional outcome. RESULTS: Prediction models for sICH or poor outcome (Hemorrhage After Thrombolysis [HAT]; Sugar, Early Infarct Signs, Dense Artery, Age, National Institutes of Health (NIH) Stroke Score (SEDAN); Glucose Race Age Sex Pressure Stroke Severity [GRASPS]; Stroke Thrombolytic Predictive Instrument; Dense Artery, Rankin Score, Age, Glucose, Onset to Treatment Time, NIHSS [DRAGON]; Totaled Health Risks in Vascular Events [THRIVE]; our new model; and a model with National Institutes of Health Stroke Scale and age) had similar area under receiver operator characteristic curves (AUROCC) to predict sICH (P for difference >0.05). The simplest model (with covariates National Institutes of Health Stroke Scale and age) predicted both sICH (AUROCC, 0.63; 95% CI, 0.58-0.68) and poststroke poor functional outcome (AUROCC, 0.80; 95% CI, 0.77-0.82) similarly to complex models. There was no evidence that the effect of r-tPA in patients at high predicted risk of sICH or poor functional outcome after stroke was less than in those at lower risk. CONCLUSIONS: There is a clinically relevant net positive effect of r-tPA in patients with acute stroke at a high predicted risk of sICH or poor functional outcome. CLINICAL TRIAL REGISTRATION URL: http://www.controlled-trials.com. Unique identifier: ISRCTN25765518.

Formal and informal prediction of recurrent stroke and myocardial infarction after stroke: a systematic review and evaluation of clinical prediction models in a new cohort.

BACKGROUND: The objective of this study was to: (1) systematically review the reporting and methods used in the development of clinical prediction models for recurrent stroke or myocardial infarction (MI) after ischemic stroke; (2) to meta-analyze their external performance; and (3) to compare clinical prediction models to informal clinicians' prediction in the Edinburgh Stroke Study (ESS). METHODS: We searched Medline, EMBASE, reference lists and forward citations of relevant articles from 1980 to 19 April 2013. We included articles which developed multivariable clinical prediction models for the prediction of recurrent stroke and/or MI following ischemic stroke. We extracted information to assess aspects of model development as well as metrics of performance to determine predictive ability. Model quality was assessed against a pre-defined set of criteria. We used random-effects meta-analysis to pool performance metrics. RESULTS: We identified twelve model development studies and eleven evaluation studies. Investigators often did not report effective sample size, regression coefficients, handling of missing data; typically categorized continuous predictors; and used data dependent methods to build models. A meta-analysis of the area under the receiver operating characteristic curve (AUROCC) was possible for the Essen Stroke Risk Score (ESRS) and for the Stroke Prognosis Instrument II (SPI-II); the pooled AUROCCs were 0.60 (95% CI 0.59 to 0.62) and 0.62 (95% CI 0.60 to 0.64), respectively. An evaluation among minor stroke patients in the ESS demonstrated that clinicians discriminated poorly between those with and those without recurrent events and that this was similar to clinical prediction models. CONCLUSIONS: The available models for recurrent stroke discriminate poorly between patients with and without a recurrent stroke or MI after stroke. Models had a similar discrimination to informal clinicians' predictions. Formal prediction may be improved by addressing commonly encountered methodological problems.

Thrombotic complications in children from short-term percutaneous central venous catheters: what can we do?

The reported incidence of venous thromboembolism (VTE) in children has increased dramatically over the past decade, and the primary risk factor for VTE in neonates and infants is the presence of a central venous catheter (CVC). Although the associated morbidity and mortality are significant, very few trials have been conducted in children to guide clinicians in the prophylaxis, diagnosis, and treatment of CVC-related VTE. Furthermore, pediatric guidelines for prophylaxis and management of VTE are largely extrapolated from adult data. How then should the anesthesiologist approach central access in children of different ages to lessen the risk of CVC-related VTE or in children with prior thrombosis and vessel occlusion? A comprehensive review of the pediatric and adult literature is presented with the goal of assisting anesthesiologists with point-of-care decision-making regarding the risk factors, diagnosis, and treatment of CVC-related VTE. Illustrative cases are also provided to highlight decision-making in varying situations. The only risk factor strongly associated with CVC-related VTE formation in children is the duration of the indwelling CVC. Several other factors show a trend toward altering the incidence of CVC-related VTE formation and may be under the control of the anesthesiologist placing and managing the catheter. In particular, because children with VTE may live decades with its sequelae and chronic vein thrombosis, careful consideration of lessening the risk of VTE is warranted in every child. Further studies are needed to form a clearer understanding of the risk factors, prophylaxis, and management of CVC-related VTE in children and to guide the anesthesiologist in lessening the risk of VTE.

Use of a standard urine assay for measuring the phosphate content of beverages.

Hyperphosphatemia is strongly associated with cardiovascular morbidity and mortality in patients with chronic kidney disease. Phosphate in beverages is readily absorbed and could have a significant impact on serum phosphate levels. Patients are routinely warned about the phosphoric acid in colas, but information on the phosphate content of other beverages is difficult to find. We have shown that the phosphomolybdate method, which is used in the vast majority of hospital laboratories for measuring phosphate in urine, can give an accurate measurement of the phosphate content of beer, cider, wine, and soft drinks. No change to the standard assay protocol is required. There was considerable variation between different types of wine and beer, probably due to the methods of production. The information the assay provides could enable staff providing dietary advice to compare locally available beverages and help patients to avoid or limit their intake of those with high phosphate content.

Culturally adapted cognitive behavioral guided self-help for binge eating: a feasibility study with Mexican Americans.

Objective was to test feasibility and preliminary efficacy of a culturally adapted cognitive-behavioral self-help program to treat binge eating and related problems in Mexican Americans. Participants were 31 women recruited from the Los Angeles area and diagnosed with binge eating disorder, recurrent binge eating, or bulimia nervosa. Participants completed a culturally adapted version of a CBT-based self-help program with 8 guidance sessions over a 3-month period. Treatment efficacy was evaluated in terms of binge eating, psychological functioning, and weight loss. Intent-to-treat analyses revealed 35.5% abstinence from binge eating at posttreatment and 38.7% diagnostic remission. Results indicated significant pretreatment to posttreatment improvement on distress level, BMI, eating disorder psychopathology, and self-esteem. Satisfaction with the program was high. Findings demonstrate that the program is acceptable, feasible, and efficacious in reducing binge eating and associated symptoms for Mexican American women. Study provides "proof of concept" for implementation of culturally adapted forms of evidence-based programs.

Early experience of a safety net provider reorganizing into an accountable care organization.

Although safety net providers will benefit from health insurance expansions under the Affordable Care Act, they also face significant challenges in the postreform environment. Some have embraced the concept of the accountable care organization to help improve quality and efficiency while addressing financial shortfalls. The experience of Cambridge Health Alliance (CHA) in Massachusetts, where health care reform began six years ago, provides insight into the opportunities and challenges of this approach in the safety net. CHA's strategies include care redesign, financial realignment, workforce transformation, and development of external partnerships. Early results show some improvement in access, patient experience, quality, and utilization; however, the potential efficiencies will not eliminate CHA's current operating deficit. The patient population, payer mix, service mix, cost structure, and political requirements reduce the likelihood of financial sustainability without significant changes in these factors, increased public funding, or both. Thus the future of safety net institutions, regardless of payment and care redesign success, remains at risk.

Serum aminoacylase-1 is a novel biomarker with potential prognostic utility for long-term outcome in patients with delayed graft function following renal transplantation.

Early identification and prognostic stratification of delayed graft function following renal transplantation has significant potential to improve outcome. Mass spectrometry analysis of serum samples, before and on day 2 post transplant from five patients with delayed graft function and five with an uncomplicated transplant, identified aminoacylase-1 (ACY-1) as a potential outcome biomarker. Following assay development, analysis of longitudinal samples from an initial validation cohort of 55 patients confirmed that the ACY-1 level on day 1 or 2 was a moderate predictor of delayed graft function, similar to serum creatinine, complementing the strongest predictor cystatin C. A further validation cohort of 194 patients confirmed this association with area under ROC curves (95% CI) for day 1 serum (138 patients) of 0.74 (0.67-0.85) for ACY-1, 0.9 (0.84-0.95) for cystatin C, and 0.93 (0.88-0.97) for both combined. Significant differences in serum ACY-1 levels were apparent between delayed, slow, and immediate graft function. Analysis of long-term follow-up for 54 patients with delayed graft function showed a highly significant association between day 1 or 3 serum ACY-1 and dialysis-free survival, mainly associated with the donor-brain-dead transplant type. Thus, proteomic analysis provides novel insights into the potential clinical utility of serum ACY-1 levels immediately post transplantation, enabling subdivision of patients with delayed graft function in terms of long-term outcome. Our study requires independent confirmation.

MRI and the Critical Care Patient: Clinical, Operational, and Financial Challenges.

Neuroimaging in conjunction with a neurologic examination has become a valuable resource for today's intensive care unit (ICU) physicians. Imaging provides critical information during the assessment and ongoing neuromonitoring of patients for toxic-metabolic or structural injury of the brain. A patient's condition can change rapidly, and interventions may require imaging. When making this determination, the benefit must be weighed against possible risks associated with intrahospital transport. The patient's condition is assessed to decide if they are stable enough to leave the ICU for an extended period. Intrahospital transport risks include adverse events related to the physical nature of the transport, the change in the environment, or relocating equipment used to monitor the patient. Adverse events can be categorized as minor (e.g., clinical decompensation) or major (e.g., requiring immediate intervention) and may occur in preparation or during transport. Regardless of the type of event experienced, any intervention during transport impacts the patient and may lead to delayed treatment and disruption of critical care. This review summarizes the commentary on the current literature on the associated risks and provides insight into the costs as well as provider experiences. Approximately, one-third of patients who are transported from the ICU to an imaging suite may experience an adverse event. This creates an additional risk for extending a patient's stay in the ICU. The delay in obtaining imaging can negatively impact the patient's treatment plan and affect long-term outcomes as increased disability or mortality. Disruption of ICU therapy can decrease respiratory function after the patient returns from transport. Because of the complex care team needed for patient transport, the staff time alone can cost $200 or more. New technologies and advancements are needed to reduce patient risk and improve safety.