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Rationale: Outcome measures that integrate mortality and morbidity, like quality-adjusted life years (QALYs), have been proposed for critical care clinical trials. Objectives: We sought to describe the distribution of QALYs in critically ill patients and estimate sample size requirements for a hypothetical trial using QALYs as the primary outcome. Methods: We used data from a prospective cohort study of survivors of acute respiratory distress syndrome to generate utility values and calculate QALYs at 6 and 12 months. Using multiple simulations, we estimated the required sample sizes for multiple outcome scenarios in a hypothetical trial, including a base-case wherein the intervention improved both mortality and QALYs among survivors. Measurements and Main Results: From 195 enrolled patients, follow-up was sufficient to generate QALY outcomes for 168 (86.2%) at 6 months and 159 (81.5%) at 1 year. For a hypothetical intervention that reduced mortality from 48 to 44% and improved QALYs by 0.025 in survivors at 6 months, the required per-group sample size was 571 (80% power; two-sided [alpha] = 0.05), compared with 2,436 patients needed for a comparison focusing on mortality alone. When only mortality or QALY in survivors (but not both) showed improvement by these amounts, 3,426 and 1,827 patients per group were needed, respectively. When mortality and morbidity effects moved in opposite directions, simulation results became impossible to interpret. Conclusions: QALYs may be a feasible outcome in critical care trials yielding a patient-centered result and major gains in statistical power under certain conditions, but this approach is susceptible to several threats, including loss to follow-up. [ABSTRACT FROM AUTHOR]

Purpose: Our aim was to evaluate the potential effect of imatinib mesylate (IM), a small molecule that specifically inhibits the tyrosine quinase receptors, on the proliferation and invasive abilities of two human retinoblastoma (Rb) cell lines. Furthermore, the ability of IM to radiosensitize Rb cells was evaluated. The potential targets of IM (C-kit, PDGRF-α and -β, and c-Abl) were also investigated in these cell lines.Methods: Two human Rb cell lines (WERI-RB-1 and Y79) were cultured under normal growth conditions. An MTT-based proliferation assay and a Matrigel invasion assay were performed with and without exposure to 10 μM of IM. The cells were also irradiated with graded dosages of 0, 2, 4, 6, 8, and 10 Gy with and without IM and their proliferations rates were analyzed. Western blot and immunocytochemical analysis of cytospins were performed to evaluate the expression of C-kit, PDGRF-α and -β, and c-Abl.Results: When IM was added to both cell lines a statistically significant (P<0.05) reduction in proliferation and invasive ability were observed. Exposure to IM also significantly increased the radiosensitivity of both Rb cell lines. The c-Abl expression was strongly positive, PDGRF-α and -β expression were also positive but the C-kit expression was negative in both cell lines.Conclusions: These results indicate that Gleevec may be useful as an adjuvant treatment in Rb patients, specially those considered for radiation therapy. [ABSTRACT FROM AUTHOR]

Background and Objectives: Sepsis is the leading cause of morbidity and mortality for patients admitted to an intensive care unit. The evaluation of new therapies has been hampered by the underdevelopment of outcome measures used to detect biological activity and patient-centered benefit in a complex and highly heterogeneous patient population. We sought to evaluate existing approaches and to draw on insights from other disciplines to propose a comprehensive approach to outcome evaluation in sepsis clinical trials.Methods: An expert colloquium organized by the International Sepsis Forum brought together sepsis researchers, clinical epidemiologists, and experts in the development and implementation of outcome measures in rheumatology, neurology, and oncology.Results: The translation of an evolving understanding of the biology of sepsis into effective new therapies for critically ill patients requires a reevaluation of the end points used to determine response to intervention. These represent a continuum that measures biological activity against the target at one end and sustained improvement in survival or quality of life at the other. Early phase research should determine whether an intervention works in vivo, using measures that are responsive and informative to provide proof of principle, to aid in selecting optimal patient populations for study, and to gain insights into optimal dose and duration of therapy. After in vivo biology has been demonstrated and the possibility of efficacy inferred by plausible improvements in surrogate physiologic measures, definitive studies should seek robust evidence of benefit using end points that measure important, patient-centered benefit, including intermediate and longer term survival and health-related quality of life. Nonmortal measures of benefit assume particular importance for populations, such as children, whose mortality risk is low, or who have significant rates of comorbidities that independently limit survival. Composite measures that integrate morbidity and mortality effects may provide the most meaningful information about therapeutic efficacy.Conclusions: The development of explicit, hypothesis-driven, and iterative approaches to outcome measure development, patterned on approaches used in the fields of rheumatology and oncology, may improve the conduct of clinical studies in the critically ill. [ABSTRACT FROM AUTHOR]

Objective: To evaluate whether administration of afelimomab, an anti-tumor necrosis factor F(ab')2 monoclonal antibody fragment, would reduce 28-day all-cause mortality in patients with severe sepsis and elevated serum levels of IL-6.Design: Prospective, randomized, double-blind, placebo-controlled, multiple-center, phase III clinical trial.Setting: One hundred fifty-seven intensive care units in the United States and Canada.Patients: Subjects were 2,634 patients with severe sepsis secondary to documented infection, of whom 998 had elevated interleukin-6 levels.Interventions: Patients were stratified into two groups by means of a rapid qualitative interleukin-6 test kit designed to identify patients with serum interleukin-6 levels above (test positive) or below (test negative) approximately 1000 pg/mL. Of the 2,634 patients, 998 were stratified into the test-positive group, 1,636 into the test-negative group. They were then randomly assigned 1:1 to receive afelimomab 1 mg/kg or placebo for 3 days and were followed for 28 days. The a priori population for efficacy analysis was the group of patients with elevated baseline interleukin-6 levels as defined by a positive rapid interleukin-6 test result.Measurements and Main Results: In the group of patients with elevated interleukin-6 levels, the mortality rate was 243 of 510 (47.6%) in the placebo group and 213 of 488 (43.6%) in the afelimomab group. Using a logistic regression analysis, treatment with afelimomab was associated with an adjusted reduction in the risk of death of 5.8% (p = .041) and a corresponding reduction of relative risk of death of 11.9%. Mortality rates for the placebo and afelimomab groups in the interleukin-6 test negative population were 234 of 819 (28.6%) and 208 of 817 (25.5%), respectively. In the overall population of interleukin-6 test positive and negative patients, the placebo and afelimomab mortality rates were 477 of 1,329 (35.9%)and 421 of 1,305 (32.2%), respectively. Afelimomab resulted in a significant reduction in tumor necrosis factor and interleukin-6 levels and a more rapid improvement in organ failure scores compared with placebo. The safety profile of afelimomab was similar to that of placebo.Conclusions: Afelimomab is safe, biologically active, and well tolerated in patients with severe sepsis, reduces 28-day all-cause mortality, and attenuates the severity of organ dysfunction in patients with elevated interleukin-6 levels. [ABSTRACT FROM AUTHOR]

OBJECTIVE: To review the biologic characteristics of, and management approaches to, intra-abdominal infection in the critically ill patient. DESIGN: Narrative review. SETTING: Medline review focussed on intra-abdominal infection in the critically ill patient. PATIENTS AND SUBJECTS: Restricted to studies involving human subjects. INTERVENTIONS: None. RESULTS: Intra-abdominal infections are an important cause of morbidity and mortality in the intensive care unit (ICU). Peritonitis can be classified as primary, secondary, or tertiary, the unique pathologic features reflecting the complex nature of the endogenous gut flora and the gut-associated immune system, and the alterations of these that occur in critical illness. Outcome is dependent on timely and accurate diagnosis, vigorous resuscitation and antibiotic support, and decisive implementation of optimal source control measures, specifically the drainage of abscesses and collections of infected fluid, the debridement of necrotic infected tissue, and the use of definitive measures to prevent further contamination and to restore anatomy and function. CONCLUSIONS: Optimal management of intra-abdominal infection in the critically ill patient is based on the synthesis of evidence, an understanding of biologic principles, and clinical experience. An algorithm outlining a clinical approach to the ICU patient with complex intra-abdominal infection is presented. [ABSTRACT FROM AUTHOR]

Background: Sepsis is not a single disease but a complex and heterogeneous process. Its expression is variable, and its severity is influenced by the nature of the infection, the genetic background of the patient, the time to clinical intervention, the supportive care provided by the clinician, and a number of factors as yet unknown. The evaluation of effective therapies has been hampered by limitations in our ability to characterize the process and to stratify patients into more homogeneous groups with respect to pathogenesis.Objectives: To develop a taxonomy of markers relevant to clinical research in sepsis and to propose a testable candidate system for stratifying patients into more therapeutically homogeneous groups.Data Source: An expert roundtable discussion and a MEDLINE review using search terms "marker" and "sepsis."Results: Markers provide information in one or more of three domains: diagnosis, prognosis, and response to therapy. More than 80 putative markers of sepsis have been described. All correlate with the risk of mortality (prognosis), yet none has shown utility in stratifying patients with respect to therapy (diagnosis) or in titrating that therapy (response). Their limitations arise from the challenges of establishing causality in a complex disease process such as sepsis and of stratifying patients into more homogeneous populations. The former limitation may be addressed through a modification of Koch's postulates to differentiate causality from simple association. The latter suggests the need for a staging system analogous to those used in other complex disease processes such as cancer. A candidate framework for such a system, based on the infection, the host response, and the extent of organ dysfunction (the IRO system) is described.Conclusions: Advances in the understanding and management of patients with sepsis will necessitate more rigorous approaches to disease description and stratification. Models should be developed, tested, and modified through clinical studies rather than through consensus. [ABSTRACT FROM AUTHOR]

Foreign accent syndrome (FAS) refers to a disorder that involves foreign sounding speech, usually following stroke. This paper presents a case study of an English patient allegedly speaking with a Scottish English accent after right-hemisphere stroke. The results of detailed impressionistic and acoustic analyses are reported, based on a direct comparison of the patient's pre-stroke and post-stroke speech samples. The emphasis is on a comparison of the typical features of Scottish English and phonetic features actually found in the patient's post-stroke speech. The respective roles of prosodic and segmental features in the post-stroke speech sample are also discussed. Rather untypically, prosodic features seem to be affected to a much lesser extent than segmental phonetic features in the patient's post-stroke speech. They are, therefore, less likely to contribute to the perception of a foreign accent. [ABSTRACT FROM AUTHOR]