A modified ELISA assay differentiates CCL20 locked dimers from wild-type monomers.

A novel engineered CCL20 locked dimer (CCL20LD) is nearly identical to the naturally occurring chemokine CCL20 but blocks CCR6-mediated chemotaxis and offers a new approach to treat the diseases of psoriasis and psoriatic arthritis. Methods for quantifying CCL20LD serum levels are needed to assess pharmacokinetics parameters and evaluate drug delivery, metabolism, and toxicity. Existing ELISA kits fail to discriminate between CCL20LD and the natural chemokine, CCL20WT (the wild type monomer). Herein, we tested several available CCL20 monoclonal antibodies to be able to identify one clone that can be used both as a capture and a detection antibody (with biotin-labeling) to specifically detect CCL20LD with high specificity. After validation using recombinant proteins, the CCL20LD-selective ELISA was used to analyze blood samples from CCL20LD treated mice, demonstrating the utility of this novel assay for preclinical development of a biopharmaceutical lead compound for psoriatic disease.

Phase 3 trial of human islet-after-kidney transplantation in type 1 diabetes.

Allogeneic islet transplant offers a minimally invasive option for ß cell replacement in the treatment of type 1 diabetes (T1D). The CIT consortium trial of purified human pancreatic islets (PHPI) in patients with T1D after kidney transplant (CIT06), a National Institutes of Health-sponsored phase 3, prospective, open-label, single-arm pivotal trial of PHPI, was conducted in 24 patients with impaired awareness of hypoglycemia while receiving intensive insulin therapy. PHPI were manufactured using standardized processes. PHPI transplantation was effective with 62.5% of patients achieving the primary endpoint of freedom from severe hypoglycemic events and HbA1c  ≤ 6.5% or reduced by ≥ 1 percentage point at 1 year posttransplant. Median HbA1c declined from 8.1% before to 6.0% at 1 year and 6.3% at 2 and 3 years following transplant (P < .001 for all vs baseline), with related improvements in hypoglycemia awareness and glucose variability. The improved metabolic control was associated with better health-related and diabetes-related quality of life. The procedure was safe and kidney allograft function remained stable after 3 years. These results add to evidence establishing allogeneic islet transplant as a safe and effective treatment for patients with T1D and unstable glucose control despite intensive insulin treatment, supporting the indication for PHPI in the post-renal transplant setting.

CLPTM1L/CRR9 ectodomain interaction with GRP78 at the cell surface signals for survival and chemoresistance upon ER stress in pancreatic adenocarcinoma cells.

Altered regulation of endoplasmic reticulum (ER) homeostasis has been implicated in many cancers and has recently become a therapeutic and chemosensitization target of interest. We have identified Cleft Lip and Palate Transmembrane 1-Like (CLPTM1L)/Cisplatin Resistance Related Protein 9 (CRR9) as an ER stress related mediator of cytoprotection in pancreatic cancer. We recently demonstrated that CLPTM1L is highly expressed in pancreatic ductal adenocarcinoma and associated with poor outcome. Furthermore, we have discovered that CLPTM1L interacts with phosphoinositol-3-kinase-alpha at the tumor cell surface and causes up-regulation of Bcl-xL and pAkt mediated survival signaling. Here, we demonstrate surface relocalization and survival signaling by CLPTM1L triggered by endoplasmic reticular (ER) stress. We demonstrate the interaction of CLPTM1L with the central ER stress survival mediator, Glucose Regulated Protein 78 (GRP78)/Binding Immunoglobulin Protein (BiP) and PI3K-alpha /p110α. This interaction and surface relocalization of CLPTM1L and GRP78 is induced by ER stress, including that caused by treatment with gemcitabine. We demonstrate that the extracellular loop of CLPTM1L is required for gemcitabine resistance and interaction with GRP78. This interaction and the chemoresistance effect conferred by this pathway is targetable with our recently developed inhibitory CLPTM1L antibodies, which may represent novel modalities of chemosensitization and treatment of pancreatic adenocarcinoma. Anchorage independent growth, GRP78-mediated chemoresistance, and Akt phosphorylation were abrogated by inhibition of CLPTM1L. These findings demonstrate a novel and potentially targetable mechanism of cytoprotection and chemoresistance in pancreatic tumors.

National Institutes of Health-Sponsored Clinical Islet Transplantation Consortium Phase 3 Trial: Manufacture of a Complex Cellular Product at Eight Processing Facilities.

Eight manufacturing facilities participating in the National Institutes of Health-sponsored Clinical Islet Transplantation (CIT) Consortium jointly developed and implemented a harmonized process for the manufacture of allogeneic purified human pancreatic islet (PHPI) product evaluated in a phase 3 trial in subjects with type 1 diabetes. Manufacturing was controlled by a common master production batch record, standard operating procedures that included acceptance criteria for deceased donor organ pancreata and critical raw materials, PHPI product specifications, certificate of analysis, and test methods. The process was compliant with Current Good Manufacturing Practices and Current Good Tissue Practices. This report describes the manufacturing process for 75 PHPI clinical lots and summarizes the results, including lot release. The results demonstrate the feasibility of implementing a harmonized process at multiple facilities for the manufacture of a complex cellular product. The quality systems and regulatory and operational strategies developed by the CIT Consortium yielded product lots that met the prespecified characteristics of safety, purity, potency, and identity and were successfully transplanted into 48 subjects. No adverse events attributable to the product and no cases of primary nonfunction were observed.

Phase 3 Trial of Transplantation of Human Islets in Type 1 Diabetes Complicated by Severe Hypoglycemia.

OBJECTIVE: Impaired awareness of hypoglycemia (IAH) and severe hypoglycemic events (SHEs) cause substantial morbidity and mortality in patients with type 1 diabetes (T1D). Current therapies are effective in preventing SHEs in 50-80% of patients with IAH and SHEs, leaving a substantial number of patients at risk. We evaluated the effectiveness and safety of a standardized human pancreatic islet product in subjects in whom IAH and SHEs persisted despite medical treatment. RESEARCH DESIGN AND METHODS: This multicenter, single-arm, phase 3 study of the investigational product purified human pancreatic islets (PHPI) was conducted at eight centers in North America. Forty-eight adults with T1D for >5 years, absent stimulated C-peptide, and documented IAH and SHEs despite expert care were enrolled. Each received immunosuppression and one or more transplants of PHPI, manufactured on-site under good manufacturing practice conditions using a common batch record and standardized lot release criteria and test methods. The primary end point was the achievement of HbA1c <7.0% (53 mmol/mol) at day 365 and freedom from SHEs from day 28 to day 365 after the first transplant. RESULTS: The primary end point was successfully met by 87.5% of subjects at 1 year and by 71% at 2 years. The median HbA1c level was 5.6% (38 mmol/mol) at both 1 and 2 years. Hypoglycemia awareness was restored, with highly significant improvements in Clarke and HYPO scores (P > 0.0001). No study-related deaths or disabilities occurred. Five of the enrollees (10.4%) experienced bleeds requiring transfusions (corresponding to 5 of 75 procedures), and two enrollees (4.1%) had infections attributed to immunosuppression. Glomerular filtration rate decreased significantly on immunosuppression, and donor-specific antibodies developed in two patients. CONCLUSIONS: Transplanted PHPI provided glycemic control, restoration of hypoglycemia awareness, and protection from SHEs in subjects with intractable IAH and SHEs. Safety events occurred related to the infusion procedure and immunosuppression, including bleeding and decreased renal function. Islet transplantation should be considered for patients with T1D and IAH in whom other, less invasive current treatments have been ineffective in preventing SHEs.

Consistency of quantitative scores of hypoglycemia severity and glycemic lability and comparison with continuous glucose monitoring system measures in long-standing type 1 diabetes.

BACKGROUND: In long-standing type 1 diabetes (T1D), loss of endogenous insulin secretion and glucose dysregulation can lead to severe hypoglycemia and associated complications. Here, we report the serial consistency and the correlation between different scores that characterize glucose dysregulation using self-monitoring of blood glucose (SMBG), in a cohort of T1D individuals being evaluated for transplant eligibility in Clinical Islet Transplantation Consortium trials. SUBJECTS AND METHODS: In total, 152 C-peptide-negative T1D subjects with at least one severe hypoglycemia episode in the prior year documented SMBG at enrollment and every 6 months until deemed ineligible or transplanted. SMBG was used to calculate the HYPO score, Lability Index (LI), and mean amplitude of glycemic excursion (MAGE). Additionally, a blinded continuous glucose monitoring system (CGMS) was worn for 72 h at enrollment and every 12 months. RESULTS: In this cohort, LI was the most consistent (intraclass correlation coefficient=0.70) over time, followed by the HYPO score (0.51), with MAGE being the least consistent (0.36). Although MAGE and LI were highly correlated with each other, neither correlated with CGMS SD or glucose coefficient of variation (CV). Subjects spent a median of 97 min/day at <54 mg/dL using CGMS. The HYPO score correlated with CGMS time below 54 mg/dL and glucose CV. CONCLUSIONS: The HYPO score and LI are more consistent than MAGE in patients with established T1D experiencing severe hypoglycemic events and may be especially useful both for identifying subjects experiencing the greatest difficulty in maintaining glycemic control and for longitudinal assessment of novel interventions.

Lower stroke risk with lower blood pressure in hemodynamic cerebral ischemia.

OBJECTIVE: To determine whether strict blood pressure (BP) control is the best medical management for patients with symptomatic carotid artery occlusion and hemodynamic cerebral ischemia. METHODS: In this prospective observational cohort study, we analyzed data from 91 participants in the nonsurgical group of the Carotid Occlusion Surgery Study (COSS) who had recent symptomatic internal carotid artery occlusion and hemodynamic cerebral ischemia manifested by ipsilateral increased oxygen extraction fraction. The target BP goal in COSS was ≤130/85 mm Hg. We compared the occurrence of ipsilateral ischemic stroke during follow-up in the 41 participants with mean BP ≤130/85 mm Hg to the remaining 50 with higher BP. RESULTS: Of 16 total ipsilateral ischemic strokes that occurred during follow-up, 3 occurred in the 41 participants with mean follow-up BP of ≤130/85 mm Hg, compared to 13 in the remaining 50 participants with mean follow-up BP >130/85 mm Hg (hazard ratio 3.742, 95% confidence interval 1.065-13.152, log-rank p = 0.027). CONCLUSION: BPs ≤130/85 mm Hg were associated with lower subsequent stroke risk in these patients. CLASSIFICATION OF EVIDENCE: This study provides Class III evidence that control of hypertension ≤130/85 mm Hg is associated with a reduced risk of subsequent ipsilateral ischemic stroke in patients with recently symptomatic carotid occlusion and hemodynamic cerebral ischemia (increased oxygen extraction fraction).

Randomized Evaluation of Carotid Occlusion and Neurocognition (RECON) trial: main results.

OBJECTIVE: To determine whether extracranial-intracranial (EC-IC) bypass can improve cognition over 2 years compared to best medical therapy alone in patients with symptomatic internal carotid artery (ICA) occlusion and increased oxygen extraction fraction (OEF) on PET. METHODS: Patients underwent (15)O PET and were randomized if OEF ratio was >1.13 on the occluded side. Using blinded baseline and 2-year cognitive assessments, age-adjusted composite z scores were generated from subtests sensitive to right/left hemisphere plus global cognitive functioning. Multiple regression predicted 2-year cognitive change. RESULTS: Eighty-nine patients were enrolled; 41 had increased OEF and were randomized. Two died, 2 were lost to follow-up, and 2 refused 2-year testing. Of the 35 remaining, 6 had ipsilateral stroke or death, leaving 13 surgical and 16 medical patients. Controlling for age, education, and depression, there was no difference in 2-year cognitive change between the medical and surgical arms (95% confidence interval -0.5 to 0.5, p = 0.9). In post hoc analysis of 26 patients with no stroke in the follow-up period, cognitive improvement was associated with less impaired PET OEF at baseline (p = 0.045). CONCLUSION: Cognitive improvement following bypass surgery was not superior to medical therapy among patients with recently symptomatic carotid occlusion and increased OEF. Among those with no recurrent stroke, less hemodynamic impairment at baseline was associated with greater cognitive gain in both groups. Reversing cognitive impairment in hemodynamic failure remains an open challenge. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that for patients with symptomatic ICA occlusion and increased OEF on PET, EC-IC bypass compared to no bypass does not improve cognitive function after 2 years.

Investigating the mechanisms of perioperative ischemic stroke in the Carotid Occlusion Surgery Study.

OBJECT: The Carotid Occlusion Surgery Study (COSS) was a large, prospective clinical trial that examined whether superficial temporal artery-middle cerebral artery (STA-MCA) bypass, in addition to best medical therapy, reduced the risk of ipsilateral ischemic stroke in patients with carotid artery occlusion and hemodynamic cerebral ischemia. Despite improved cerebral hemodynamics and excellent bypass graft patency rates, COSS failed to show a benefit for the surgical group with respect to ipsilateral stroke recurrence at 2 years after treatment. This was due to a lower than expected rate of recurrent ipsilateral stroke in the medically treated group and a high rate of perioperative ipsilateral strokes in the surgical group. Critics of the trial have cited surgeon inexperience and technical difficulties related to the performance of the bypass graft as a leading cause of failure of the trial. METHODS: The authors retrospectively identified all patients from the COSS with an ipsilateral, perioperative (< 30 days) ischemic stroke after STA-MCA cortical branch anastomosis. Study records, operative notes, stroke adjudication forms, and imaging studies were reviewed. Ischemic strokes were characterized as bypass graft related or non-bypass graft related based on clinical and radiographic findings. RESULTS: Fourteen of 93 surgically treated patients experienced an ipsilateral, perioperative ischemic stroke. Postoperatively, the mean oxygen extraction fraction (OEF) ratio between the symptomatic and asymptomatic cerebral hemisphere significantly improved in these patients (1.30 ± 0.18 preoperative vs 1.12 ± 0.11 postoperative; p = 0.02), but did not normalize. In this cohort, total MCA occlusion time during the anastomosis (54.3 ± 23.5 minutes) was no different from the MCA occlusion time in those surgical patients who did not have a perioperative stroke (45.4 ± 24.2 minutes, p = 0.2). Bypass graft patency rates in patients with a perioperative stroke were 92% at 30 days (11 of 12 patients with patency data) and 83% at last follow-up visit (10 of 12 patients with patency data). These patency rates were not significantly different from those achieved at 30 days (100%; 76 of 76 patients with patency data; p = 0.14) and at last follow-up (99%; 71 of 72 patients with patency data; p = 0.052) in patients without a perioperative stroke. Eighty-six percent (12 of 14 patients) of strokes were likely attributable to factors unrelated to the STA-MCA anastomosis. Only 21% of strokes (3 of 14 patients) were in the territory of the recipient vessel and likely related to technical performance of the anastomosis itself. One patient was thought to have dual stroke mechanisms. CONCLUSIONS: Only a small minority of ipsilateral, perioperative ischemic strokes in the COSS could be attributed to technical problems of the bypass anastomosis. The majority of ischemic strokes could not be ascribed to this cause and were most likely due to patient hemodynamic fragility and the inability of patients to tolerate surgery.

Surgical results of the Carotid Occlusion Surgery Study.

OBJECT: The Carotid Occlusion Surgery Study (COSS) was conducted to determine if superficial temporal artery-middle cerebral artery (STA-MCA) bypass, when added to the best medical therapy, would reduce subsequent ipsilateral stroke in patients with complete internal carotid artery (ICA) occlusion and an elevated oxygen extraction fraction (OEF) in the cerebral hemisphere distal to the occlusion. A recent publication documented the methodology of the COSS in detail and briefly outlined the major findings of the trial. The surgical results of the COSS are described in detail in this report. METHODS: The COSS was a prospective, parallel-group, 1:1 randomized, open-label, blinded-adjudication treatment trial. Participants, who had angiographically demonstrated complete occlusion of the ICA causing either a transient ischemic attack or ischemic stroke within 120 days and hemodynamic cerebral ischemia indicated by an increased OEF measured by PET, were randomized to either surgical or medical treatment. One hundred ninety-five patients were randomized: 97 to the surgical group and 98 to the medical group. The surgical patients underwent an STA-MCA cortical branch anastomosis. RESULTS: In the intention-to-treat analysis, the 2-year rates for the primary end point were 21% for the surgical group and 22.7% for the medical group (p = 0.78, log-rank test). Fourteen (15%) of the 93 patients who had undergone an arterial bypass had a primary end point ipsilateral hemispheric stroke in the 30-day postoperative period, 12 within 2 days after surgery. The STA-MCA arterial bypass patency rate was 98% at the 30-day postoperative visit and 96% at the last follow-up examination. The STA-MCA arterial bypass markedly improved, although it did not normalize, the level of elevated OEF in the symptomatic cerebral hemisphere. Five surgically treated and 1 nonsurgically treated patients in the surgical group had a primary end point ipsilateral hemispheric stroke after the 30-day postoperative period. No baseline characteristics or intraoperative variables revealed those who would experience a procedure-related stroke. CONCLUSIONS: Despite excellent bypass graft patency and improved cerebral hemodynamics, STA-MCA anastomosis did not provide an overall benefit regarding ipsilateral 2-year stroke recurrence, mainly because of a much better than expected stroke recurrence rate (22.7%) in the medical group, but also because of a significant postoperative stroke rate (15%). Clinical trial registration no.: NCT00029146.

Case report: giant cardiac malignancy in a nine-year-old female.

PURPOSE: To describe the management of a giant cardiac malignancy initially diagnosed as an anterior mediastinal mass. CLINICAL FEATURES: A nine-year-old female with right facial swelling and chronic cough was diagnosed with a large right mediastinal mass. Intermittent ventricular and supraventricular arrhythmias were noted on admission electrocardiograms. Empiric corticosteroid and radiation therapy did not reduce the size of the tumour, and initial tissue biopsies were non-diagnostic. Due to worsening tamponade physiology and persistent arrhythmias, the patient was scheduled for tumour debulking with potential resection. Prior to surgery, a multidisciplinary team was assembled to delineate team member responsibilities and treatment algorithms. The procedure was performed under general anesthesia with spontaneous ventilation preserved during endotracheal intubation and invasive line placement. The team was prepared to provide extracorporeal mechanical support if needed. The child required inotropic and vasoactive medications after transitioning to positive pressure ventilation, but her hemodynamics improved with sternotomy. The lesion was identified as a malignant cardiac clear-cell tumour that was unresectable. Her sternum was left open, as attempted closure led to the re-creation of tamponade physiology. She underwent delayed sternal closure days later. After months of chemotherapy that resulted in significant tumour involution, she underwent successful surgical resection. CONCLUSION: Giant primary cardiac tumours may present similarly to large anterior mediastinal masses. The care of patients with these lesions requires an understanding of the risks associated with mediastinal masses as well as those unique to cardiac tumours. A multidisciplinary approach is critical to providing safe and effective care throughout this process.

Extracranial-intracranial bypass surgery for stroke prevention in hemodynamic cerebral ischemia: the Carotid Occlusion Surgery Study randomized trial.

CONTEXT: Patients with symptomatic atherosclerotic internal carotid artery occlusion (AICAO) and hemodynamic cerebral ischemia are at high risk for subsequent stroke when treated medically. OBJECTIVE: To test the hypothesis that extracranial-intracranial (EC-IC) bypass surgery, added to best medical therapy, reduces subsequent ipsilateral ischemic stroke in patients with recently symptomatic AICAO and hemodynamic cerebral ischemia. DESIGN: Parallel-group, randomized, open-label, blinded-adjudication clinical treatment trial conducted from 2002 to 2010. SETTING: Forty-nine clinical centers and 18 positron emission tomography (PET) centers in the United States and Canada. The majority were academic medical centers. PARTICIPANTS: Patients with arteriographically confirmed AICAO causing hemispheric symptoms within 120 days and hemodynamic cerebral ischemia identified by ipsilateral increased oxygen extraction fraction measured by PET. Of 195 patients who were randomized, 97 were randomized to receive surgery and 98 to no surgery. Follow-up for the primary end point until occurrence, 2 years, or termination of trial was 99% complete. No participant withdrew because of adverse events. INTERVENTIONS: Anastomosis of superficial temporal artery branch to a middle cerebral artery cortical branch for the surgical group. Antithrombotic therapy and risk factor intervention were recommended for all participants. MAIN OUTCOME MEASURE: For all participants who were assigned to surgery and received surgery, the combination of (1) all stroke and death from surgery through 30 days after surgery and (2) ipsilateral ischemic stroke within 2 years of randomization. For the nonsurgical group and participants assigned to surgery who did not receive surgery, the combination of (1) all stroke and death from randomization to randomization plus 30 days and (2) ipsilateral ischemic stroke within 2 years of randomization. RESULTS: The trial was terminated early for futility. Two-year rates for the primary end point were 21.0% (95% CI, 12.8% to 29.2%; 20 events) for the surgical group and 22.7% (95% CI, 13.9% to 31.6%; 20 events) for the nonsurgical group (P = .78, Z test), a difference of 1.7% (95% CI, -10.4% to 13.8%). Thirty-day rates for ipsilateral ischemic stroke were 14.4% (14/97) in the surgical group and 2.0% (2/98) in the nonsurgical group, a difference of 12.4% (95% CI, 4.9% to 19.9%). CONCLUSION: Among participants with recently symptomatic AICAO and hemodynamic cerebral ischemia, EC-IC bypass surgery plus medical therapy compared with medical therapy alone did not reduce the risk of recurrent ipsilateral ischemic stroke at 2 years. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT00029146.

Quantification of CLR1401, a novel alkylphosphocholine anticancer agent, in rat plasma by hydrophilic interaction liquid chromatography-tandem mass spectrometric detection.

A rapid and specific LC-MS/MS based bioanalytical method was developed and validated for the determination of 18-(p-iodophenyl)octadecyl phosphocholine (CLR1401), a novel phosphocholine drug candidate, in rat plasma. The optimal chromatographic behavior of CLR1401 was achieved on a Kromasil silica column (50 mm x 3 mm, 5 microm) under hydrophilic interaction chromatography. The total LC analysis time per injection was 2.8 min with a flow rate of 1.5 mL/min under gradient elution. Liquid-liquid extraction in a 96-well format using ethyl acetate was developed and applied for method validation and sample analysis. The method validation was conducted over the curve range of 2.00-1000 ng/mL using 0.0500 mL of plasma sample. The intra- and inter-day precision and accuracy of the quality control samples at low, medium, and high concentration levels showed < or = 5.9% relative standard deviation (RSD) and -10.8 to -1.4% relative error (RE). The method was successfully applied to determine the toxicokinetics of CLR1401 in rats from three dose groups of 0.4, 4.0, and 10.0 mg/kg/day via intravenous administration.

A flexible futility monitoring method with time-varying conditional power boundary.

BACKGROUND: In an ongoing multi-center randomized control clinical trial, the Carotid Occlusion Surgery Study (COSS), the study protocol specifies multiple interim analyses whose results will be reviewed by an independent DSMB to determine if the trial needs to be stopped early due to either efficacy or futility. Conditional power is used as the decision rule for the DSMB to recommend stopping the trial for futility. An aggressive rule for futility stopping sets a relatively high threshold for the conditional power which may result in significant loss of overall power of the study. A conservative rule using a lower threshold may not be able to stop the trial early when there is indeed no treatment efficacy. PURPOSE: The goal of this article is to develop a flexible futility monitoring plan with a time-varying conditional power boundary that maintains the overall power of the study well, but has a better chance to stop the trial earlier for futility compared to a futility stopping rule with a fixed value for the minimum conditional power to continue. METHODS: The conditional power boundary for futility is developed using the beta-spending function method for sequential test statistics and assuming no interim analysis for efficacy. It is then modified to account for the repeated interim analyses for efficacy. RESULTS: Simulation studies that mirror the design of the COSS trial show that the proposed method with sample size calculated without considering interim analyses will maintain the designed size and power well when the designed effect size holds, but will have a better chance to exit the trial earlier if the true effect size is smaller than the designed size such that it is not clinically meaningful to conduct the trial. LIMITATIONS: The method is valid for sequential test statistics that constitute of a stochastic process which approximates the Brownian motion. It is not applicable to the monitored process that behaves quire differently from the Brownian motion. CONCLUSIONS: The proposed conditional power method facilitates a flexible futility monitoring plan that can be easily implemented in long-term clinical trials where multiple interim analyses are required. It provides the DSMB an objective guideline to use in considering early stopping for futility. Clinical Trials 2010; 7: 209. http:// ctj.sagepub.com.

Perioperative fever and outcome in surgical patients with aneurysmal subarachnoid hemorrhage.

OBJECTIVE: We examined the incidence of perioperative fever and its relationship to outcome among patients enrolled in the Intraoperative Hypothermia for Aneurysm Surgery Trial. METHODS: One thousand patients with initial World Federation of Neurological Surgeons grades of I to III undergoing clipping of intracranial aneurysms after subarachnoid hemorrhage were randomized to intraoperative normothermia (36 degrees C-37 degrees C) or hypothermia (32.5 degrees C-33.5 degrees C). Fever (> or =38.5 degrees C) and other complications (including infections) occurring between admission and discharge (or death) were recorded. Functional and neuropsychologic outcomes were assessed 3 months postoperatively. The primary outcome variable for the trial was dichotomized Glasgow Outcome Scale (good outcome versus all others). RESULTS: Fever was reported in 41% of patients. In 97% of these, fever occurred in the postoperative period. The median time from surgery to first fever was 3 days. All measures of outcome were worse in patients who developed fever, even in those without infections or who were World Federation of Neurological Surgeons grade I. Logistic regression analyses were performed to adjust for differences in preoperative factors (e.g., age, Fisher grade, initial neurological status). This demonstrated that fever continued to be significantly associated with most outcome measures, even when infection was added to the model. An alternative stepwise model selection process including all fever-related measures from the preoperative and intraoperative period (e.g., hydrocephalus, duration of surgery, intraoperative blood loss) resulted in the loss of significance for dichotomized Glasgow Outcome Scale, but significant associations between fever and several other outcome measures remained. After adding postoperative delayed ischemic neurological deficits to the model, only worsened National Institutes of Health Stroke Scale score, Barthel Activities of Daily Living index, and discharge destination (home versus other) remained independently associated with fever. CONCLUSION: These findings suggest that fever is associated with worsened outcome in surgical subarachnoid hemorrhage patients, although, because the association between fever and the primary outcome measure for the trial is dependent on the covariates used in the analysis (particularly operative events and delayed ischemic neurological deficits), we cannot rule out the possibility that fever is a marker for other events. Only a formal trial of fever treatment or prevention can address this issue.

Translating research into practice intervention improves management of acute pain in older hip fracture patients.

OBJECTIVE: To test an interdisciplinary, multifaceted, translating research into practice (TRIP) intervention to (a) promote adoption, by physicians and nurses, of evidence-based (EB) acute pain management practices in hospitalized older adults, (b) decrease barriers to use of EB acute pain management practices, and (c) decrease pain intensity of older hospitalized adults. STUDY DESIGN: Experimental design with the hospital as the unit of randomization. STUDY SETTING: Twelve acute care hospitals in the Midwest. DATA SOURCES: (a) Medical records (MRs) of patients > or =65 years or older with a hip fracture admitted before and following implementation of the TRIP intervention and (b) physicians and nurses who care for those patients. DATA COLLECTION: Data were abstracted from MRs and questions distributed to nurses and physicians. PRINCIPAL FINDINGS: The Summative Index for Quality of Acute Pain Care (0-18 scale) was significantly higher for the experimental (10.1) than comparison group (8.4) at the end of the TRIP implementation phase. At the end of the TRIP implementation phase, patients in the experimental group had a lower mean pain intensity rating than those in the comparison group ( p<.0001). CONCLUSION: The TRIP intervention improved quality of acute pain management of older adults hospitalized with a hip fracture.