Portland VA Medical Center

BACKGROUND: Constitutive activation of KIT receptor tyrosine kinase is critical in the pathogenesis of gastrointestinal stromal tumors. Imatinib mesylate, a selective tyrosine kinase inhibitor, has been shown in preclinical models and preliminary clinical studies to have activity against such tumors. METHODS: We conducted an open-label, randomized, multicenter trial to evaluate the activity of imatinib in patients with advanced gastrointestinal stromal tumor. We assessed antitumor response and the safety and tolerability of the drug. Pharmacokinetics were assessed in a subgroup of patients. RESULTS: A total of 147 patients were randomly assigned to receive 400 mg or 600 mg of imatinib daily. Overall, 79 patients (53.7 percent) had a partial response, 41 patients (27.9 percent) had stable disease, and for technical reasons, response could not be evaluated in 7 patients (4.8 percent). No patient had a complete response to the treatment. The median duration of response had not been reached after a median follow-up of 24 weeks after the onset of response. Early resistance to imatinib was noted in 20 patients (13.6 percent). Therapy was well tolerated, although mild-to-moderate edema, diarrhea, and fatigue were common. Gastrointestinal or intraabdominal hemorrhage occurred in approximately 5 percent of patients. There were no significant differences in toxic effects or response between the two doses. Imatinib was well absorbed, with pharmacokinetics similar to those reported in patients with chronic myeloid leukemia. CONCLUSIONS: Imatinib induced a sustained objective response in more than half of patients with an advanced unresectable or metastatic gastrointestinal stromal tumor. Inhibition of the KIT signal-transduction pathway is a promising treatment for advanced gastrointestinal stromal tumors, which resist conventional chemotherapy.

This document represents the first collaboration between 2 organizations-the American Society for Parenteral and Enteral Nutrition and the Society of Critical Care Medicine-to describe best practices in nutrition therapy in critically ill children. The target of these guidelines is intended to be the pediatric critically ill patient (>1 month and <18 years) expected to require a length of stay >2-3 days in a PICU admitting medical, surgical, and cardiac patients. In total, 2032 citations were scanned for relevance. The PubMed/MEDLINE search resulted in 960 citations for clinical trials and 925 citations for cohort studies. The EMBASE search for clinical trials culled 1661 citations. In total, the search for clinical trials yielded 1107 citations, whereas the cohort search yielded 925. After careful review, 16 randomized controlled trials and 37 cohort studies appeared to answer 1 of the 8 preidentified question groups for this guideline. We used the GRADE criteria (Grading of Recommendations, Assessment, Development, and Evaluation) to adjust the evidence grade based on assessment of the quality of study design and execution. These guidelines are not intended for neonates or adult patients. The guidelines reiterate the importance of nutrition assessment-particularly, the detection of malnourished patients who are most vulnerable and therefore may benefit from timely intervention. There is a need for renewed focus on accurate estimation of energy needs and attention to optimizing protein intake. Indirect calorimetry, where feasible, and cautious use of estimating equations and increased surveillance for unintended caloric underfeeding and overfeeding are recommended. Optimal protein intake and its correlation with clinical outcomes are areas of great interest. The optimal route and timing of nutrient delivery are areas of intense debate and investigations. Enteral nutrition remains the preferred route for nutrient delivery. Several strategies to optimize enteral nutrition during critical illness have emerged. The role of supplemental parenteral nutrition has been highlighted, and a delayed approach appears to be beneficial. Immunonutrition cannot be currently recommended. Overall, the pediatric critical care population is heterogeneous, and a nuanced approach to individualizing nutrition support with the aim of improving clinical outcomes is necessary.

Characterization of the genetic landscape of Alzheimer's disease (AD) and related dementias (ADD) provides a unique opportunity for a better understanding of the associated pathophysiological processes. We performed a two-stage genome-wide association study totaling 111,326 clinically diagnosed/'proxy' AD cases and 677,663 controls. We found 75 risk loci, of which 42 were new at the time of analysis. Pathway enrichment analyses confirmed the involvement of amyloid/tau pathways and highlighted microglia implication. Gene prioritization in the new loci identified 31 genes that were suggestive of new genetically associated processes, including the tumor necrosis factor alpha pathway through the linear ubiquitin chain assembly complex. We also built a new genetic risk score associated with the risk of future AD/dementia or progression from mild cognitive impairment to AD/dementia. The improvement in prediction led to a 1.6- to 1.9-fold increase in AD risk from the lowest to the highest decile, in addition to effects of age and the APOE ε4 allele.

Most gastrointestinal stromal tumors (GISTs) have activating mutations in the KIT receptor tyrosine kinase, and most patients with GISTs respond well to Gleevec, which inhibits KIT kinase activity. Here we show that approximately 35% (14 of 40) of GISTs lacking KIT mutations have intragenic activation mutations in the related receptor tyrosine kinase, platelet-derived growth factor receptor alpha (PDGFRA). Tumors expressing KIT or PDGFRA oncoproteins were indistinguishable with respect to activation of downstream signaling intermediates and cytogenetic changes associated with tumor progression. Thus, KIT and PDGFRA mutations appear to be alternative and mutually exclusive oncogenic mechanisms in GISTs.

DESCRIPTION: The American College of Physicians (ACP) developed this guideline to present the evidence and provide clinical recommendations on the management of chronic insomnia disorder in adults. METHODS: This guideline is based on a systematic review of randomized, controlled trials published in English from 2004 through September 2015. Evaluated outcomes included global outcomes assessed by questionnaires, patient-reported sleep outcomes, and harms. The target audience for this guideline includes all clinicians, and the target patient population includes adults with chronic insomnia disorder. This guideline grades the evidence and recommendations by using the ACP grading system, which is based on the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. RECOMMENDATION 1: ACP recommends that all adult patients receive cognitive behavioral therapy for insomnia (CBT-I) as the initial treatment for chronic insomnia disorder. (Grade: strong recommendation, moderate-quality evidence). RECOMMENDATION 2: ACP recommends that clinicians use a shared decision-making approach, including a discussion of the benefits, harms, and costs of short-term use of medications, to decide whether to add pharmacological therapy in adults with chronic insomnia disorder in whom cognitive behavioral therapy for insomnia (CBT-I) alone was unsuccessful. (Grade: weak recommendation, low-quality evidence).

BACKGROUND AND METHODS: The role of colonoscopy in screening for colorectal cancer is uncertain. At 13 Veterans Affairs Medical Centers, we performed colonoscopy to determine the prevalence and location of advanced colonic neoplasms and the risk of advanced proximal neoplasia in asymptomatic patients (age range, 50 to 75 years) with or without distal neoplasia. Advanced colonic neoplasia was defined as an adenoma that was 10 mm or more in diameter, a villous adenoma, an adenoma with high-grade dysplasia, or invasive cancer. In patients with more than one neoplastic lesion, classification was based on the most advanced lesion. RESULTS: Of 17,732 patients screened for enrollment, 3196 were enrolled; 3121 of the enrolled patients (97.7 percent) underwent complete examination of the colon. The mean age of the patients was 62.9 years, and 96.8 percent were men. Colonoscopic examination showed one or more neoplastic lesions in 37.5 percent of the patients, an adenoma with a diameter of at least 10 mm or a villous adenoma in 7.9 percent, an adenoma with high-grade dysplasia in 1.6 percent, and invasive cancer in 1.0 percent. Of the 1765 patients with no polyps in the portion of the colon that was distal to the splenic flexure, 48 (2.7 percent) had advanced proximal neoplasms. Patients with large adenomas (> or = 10 mm) or small adenomas (< 10 mm) in the distal colon were more likely to have advanced proximal neoplasia than were patients with no distal adenomas (odds ratios, 3.4 [95 percent confidence interval, 1.8 to 6.5] and 2.6 (95 percent confidence interval, 1.7 to 4.1], respectively). However, 52 percent of the 128 patients with advanced proximal neoplasia had no distal adenomas. CONCLUSIONS: Colonoscopic screening can detect advanced colonic neoplasms in asymptomatic adults. Many of these neoplasms would not be detected with sigmoidoscopy.

In the United States, colorectal cancer (CRC) is the third most common cancer diagnosed among men and women and the second leading cause of death from cancer. CRC largely can be prevented by the detection and removal of adenomatous polyps, and survival is significantly better when CRC is diagnosed while still localized. In 2006 to 2007, the American Cancer Society, the US Multi Society Task Force on Colorectal Cancer, and the American College of Radiology came together to develop consensus guidelines for the detection of adenomatous polyps and CRC in asymptomatic average-risk adults. In this update of each organization's guidelines, screening tests are grouped into those that primarily detect cancer early and those that can detect cancer early and also can detect adenomatous polyps, thus providing a greater potential for prevention through polypectomy. When possible, clinicians should make patients aware of the full range of screening options, but at a minimum they should be prepared to offer patients a choice between a screening test that is effective at both early cancer detection and cancer prevention through the detection and removal of polyps and a screening test that primarily is effective at early cancer detection. It is the strong opinion of these 3 organizations that colon cancer prevention should be the primary goal of screening.

CONTEXT: Predicting hospital readmission risk is of great interest to identify which patients would benefit most from care transition interventions, as well as to risk-adjust readmission rates for the purposes of hospital comparison. OBJECTIVE: To summarize validated readmission risk prediction models, describe their performance, and assess suitability for clinical or administrative use. DATA SOURCES AND STUDY SELECTION: The databases of MEDLINE, CINAHL, and the Cochrane Library were searched from inception through March 2011, the EMBASE database was searched through August 2011, and hand searches were performed of the retrieved reference lists. Dual review was conducted to identify studies published in the English language of prediction models tested with medical patients in both derivation and validation cohorts. DATA EXTRACTION: Data were extracted on the population, setting, sample size, follow-up interval, readmission rate, model discrimination and calibration, type of data used, and timing of data collection. DATA SYNTHESIS: Of 7843 citations reviewed, 30 studies of 26 unique models met the inclusion criteria. The most common outcome used was 30-day readmission; only 1 model specifically addressed preventable readmissions. Fourteen models that relied on retrospective administrative data could be potentially used to risk-adjust readmission rates for hospital comparison; of these, 9 were tested in large US populations and had poor discriminative ability (c statistic range: 0.55-0.65). Seven models could potentially be used to identify high-risk patients for intervention early during a hospitalization (c statistic range: 0.56-0.72), and 5 could be used at hospital discharge (c statistic range: 0.68-0.83). Six studies compared different models in the same population and 2 of these found that functional and social variables improved model discrimination. Although most models incorporated variables for medical comorbidity and use of prior medical services, few examined variables associated with overall health and function, illness severity, or social determinants of health. CONCLUSIONS: Most current readmission risk prediction models that were designed for either comparative or clinical purposes perform poorly. Although in certain settings such models may prove useful, efforts to improve their performance are needed as use becomes more widespread.

Strains of mice that show characteristic patterns of behavior are critical for research in neurobehavioral genetics. Possible confounding influences of the laboratory environment were studied in several inbred strains and one null mutant by simultaneous testing in three laboratories on a battery of six behaviors. Apparatus, test protocols, and many environmental variables were rigorously equated. Strains differed markedly in all behaviors, and despite standardization, there were systematic differences in behavior across labs. For some tests, the magnitude of genetic differences depended upon the specific testing lab. Thus, experiments characterizing mutants may yield results that are idiosyncratic to a particular laboratory.

Tumor necrosis factor (TNF) is a proinflammatory cytokine involved in the pathogenesis of rheumatoid arthritis, and antagonism of TNF may reduce the activity of the disease. This study evaluated the safety and efficacy of a novel TNF antagonist — a recombinant fusion protein that consists of the soluble TNF receptor (p75) linked to the Fc portion of human IgG1 (TNFR:Fc).

PRELIMINARY REMARKS (INTENT OF GUIDELINES) A.S.P.E.N. and SCCM are both nonprofit organizations composed of multidisciplinary healthcare professionals. The mission of A.S.P.E.N. is to improve patient care by advancing the science and practice of clinical nutrition and metabolism. The mission of SCCM is to secure the highest quality care for all critically ill and injured patients. Guideline Limitations: These A.S.P.E.N.−SCCM Clinical Guidelines are based on general conclusions of health professionals who, in developing such guidelines, have balanced potential benefits to be derived from a particular mode of medical therapy against certain risks inherent with such therapy. However, practice guidelines are not intended as absolute requirements. The use of these practice guidelines does not in any way project or guarantee any specific benefit in outcome or survival. The judgment of the healthcare professional based on individual circumstances of the patient must always take precedence over the recommendations in these guidelines. The guidelines offer basic recommendations that are supported by review and analysis of the current literature, other national and international guidelines, and a blend of expert opinion and clinical practicality. The population of critically ill patients in an intensive care unit (ICU) is not homogeneous. Many of the studies on which the guidelines are based are limited by sample size, patient heterogeneity, variability in disease severity, lack of baseline nutritional status, and insufficient statistical power for analysis. Periodic Guideline Review and Update: This particular report is an update and expansion of guidelines published by A.S.P.E.N. and SCCM in 2009 (1). Governing bodies of both A.S.P.E.N. and SCCM have mandated that these guidelines be updated every three to five years. The database of randomized controlled trials (RCTs) that served as the platform for the analysis of the literature was assembled in a joint "harmonization process" with the Canadian Clinical Guidelines group. Once completed, each group operated separately in their interpretation of the studies and derivation of guideline recommendations (2). The current A.S.P.E.N. and SCCM guidelines included in this paper were derived from data obtained via literature searches by the authors through December 31, 2013. Although the committee was aware of landmark studies published after this date, these data were not included in this manuscript. The process by which the literature was evaluated necessitated a common end date for the search review. Adding a last-minute landmark trial would have introduced bias unless a formalized literature search was re-conducted for all sections of the manuscript. Target Patient Population for Guideline: The target of these guidelines is intended to be the adult (≥ 18 years) critically ill patient expected to require a length of stay (LOS) greater than 2 or 3 days in a medical ICU (MICU) or surgical ICU (SICU). The current guidelines were expanded to include a number of additional subsets of patients who met the above criteria, but were not included in the previous 2009 guidelines. Specific patient populations addressed by these expanded and updated guidelines include organ failure (pulmonary, renal, and liver), acute pancreatitis, surgical subsets (trauma, traumatic brain injury [TBI], open abdomen [OA], and burns), sepsis, postoperative major surgery, chronic critically ill, and critically ill obese. These guidelines are directed toward generalized patient populations but, like any other management strategy in the ICU, nutrition therapy should be tailored to the individual patient. Target Audience: The intended use of these guidelines is for all healthcare providers involved in nutrition therapy of the critically ill, primarily physicians, nurses, dietitians, and pharmacists. Methodology: The authors compiled clinical questions reflecting key management issues in nutrition therapy. A committee of multidisciplinary experts in clinical nutrition composed of physicians, nurses, pharmacists, and dietitians was jointly convened by the two societies. Literature searches were then performed using key words (critically ill, critical care, intensive care, nutrition, enteral, parenteral, tube feeding, and those related to assigned topics such as pancreatitis, sepsis, etc.) to evaluate the quality of evidence supporting a response to those questions, which were then used to derive a subsequent treatment recommendation. The literature search included MEDLINE, PubMed, Cochrane Database of Systemic Reviews, the National Guidelines Clearing House and an Internet search using the Google search engine for scholarly articles through an end date of December 31, 2013 (including ePub publications). While preference was given to RCTs, other forms of resource material were used to support the response, including nonrandomized cohort trials, prospective observational studies, and retrospective case series. Use of publications was limited to full-text articles available in English on adult humans. For all included RCTs, two readers completed data abstraction forms (DAFs) examining the data and assessing the quality of the research methodology to produce a shared evaluation achieved by consensus for each study (example of DAF provided in the supplemental data, Supplemental Digital Content 1, https://links.lww.com/CCM/B571). DAFs were constructed only for RCTs. When the strongest available evidence was a published meta-analysis, the studies from the meta-analysis were used to determine the quality of the evidence and assessed by two evidence assessors. The data from included trials were entered into Review Manager 5.2 software to create forest plots aggregating the effect size for each intervention and outcome (3). The key forest plots supporting the recommendation are included throughout the text and in the supplement data (Supplemental Digital Content 1, https://links.lww.com/CCM/B571). No new forest plots were created when a meta-analysis was evaluated. Since release of the 2009 A.S.P.E.N. and SCCM Clinical Guidelines, the concepts of the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) Working Group have been adopted (4–7). A full description of the methodology has been previously published (4). The data from the Review Manager analysis was uploaded to GRADEPro software (8), where the body of evidence for a given intervention and outcome was evaluated for overall quality. One analyst created each GRADE table that was then independently confirmed by a second analyst. The GRADE tables are provided in the supplement data (Supplemental Digital Content 1, https://links.lww.com/CCM/B571). Due to the inordinately large number of RCTs evaluated, observational studies were critically reviewed, but not utilized to construct the GRADE tables. However, in the few cases where observational studies were the only available evidence in a population, their quality of evidence was reviewed, using GRADE (Table 1). When no RCT or observational study was available to answer a question directly, consensus of the author group on the best clinical practice approach was used, and the recommendation was designated "based on expert consensus."TABLE 1: Type of EvidenceA recommendation for clinical practice was based on both the best available evidence and the risks and benefits to patients. While small author teams developed each recommendation and provided the supporting rationale, a full discussion by the entire author group followed, and every committee member was polled anonymously for their agreement with the recommendation. Achievement of consensus was arbitrarily set at 70% agreement of authors with a particular recommendation. Only one recommendation (H3a) did not meet this level of agreement, with a final consensus of 64%. All other consensus-based recommendations reached a level of agreement of 80% or higher. As with all A.S.P.E.N. and SCCM clinical guidelines, this manuscript was subjected to rigorous peer review by clinical content experts from all the practice disciplines that would use the guidelines, both internal and external to the organizations. A summary of the guidelines is presented in the supplement data (Supplemental Digital Content 1, https://links.lww.com/CCM/B571). A nutrition bundle based on the top guidelines (as voted on by the committee) for the bedside practitioner is presented in Table 2.TABLE 2: Bundle StatementsCONFLICT OF INTEREST All authors completed both an A.S.P.E.N. and SCCM conflict of interest form for copyright assignment and financial disclosure. There was no input or funding from industry, nor were any industry representatives present at any of the committee meetings. DEFINITIONS Nutrition Therapy refers specifically to the provision of either enteral nutrition (EN) by enteral access device and/or parenteral nutrition (PN) by central venous access. Standard therapy (STD) refers to provision of IV fluids, no EN or PN, and advancement to oral diet as tolerated. INTRODUCTION The significance of nutrition in the hospital setting (and especially the ICU) cannot be overstated. Critical illness is typically associated with a catabolic stress state in which patients demonstrate a systemic inflammatory response coupled with complications of increased infectious morbidity, multiple organ dysfunction, prolonged hospitalization, and disproportionate mortality. Over the past three decades, exponential advances have been made in the understanding of the molecular and biological effects of nutrients in maintaining homeostasis in the critically ill population. Traditionally, nutrition support in the critically ill population was regarded as adjunctive care designed to provide exogenous fuels to preserve lean body mass and support the patient throughout the stress response. Recently this strategy has evolved to represent nutrition therapy, in which the feeding is thought to help attenuate the metabolic response to stress, prevent oxidative cellular injury, and favorably modulate immune responses. Improvement in the clinical course of critical illness may be achieved by early EN, appropriate macro- and micronutrient delivery, and meticulous glycemic control. Delivering early nutrition support therapy, primarily by the enteral route, is seen as a proactive therapeutic strategy that may reduce disease severity, diminish complications, decrease LOS in the ICU, and favorably impact patient outcomes. A. NUTRITION ASSESSMENT Question: Does the use of a nutrition risk indicator identify patients who will most likely benefit from nutrition therapy? A1. Based on expert consensus, we suggest a determination of nutrition risk (for example, Nutritional Risk Score [NRS-2002], NUTRIC score) be performed on all patients admitted to the ICU for whom volitional intake is anticipated to be insufficient. High nutrition risk identifies those patients most likely to benefit from early EN therapy. Rationale: Poor outcomes have been associated with inflammation generated by critical illness that leads to deterioration of nutrition status and malnutrition (9). However, malnutrition in the critically ill has always been difficult to define. An international consensus group modified definitions to recognize the impact of inflammation. Objective measures of baseline nutrition status have been described by A.S.P.E.N. and the Academy of Nutrition and Dietetics (10, 11). On the other hand, nutrition risk is easily defined and more readily determined by evaluation of baseline nutrition status and assessment of disease severity. All hospitalized patients are required to undergo an initial nutrition screen within 48 hours of admission. However, patients at higher nutrition risk in an ICU setting require a full nutrition assessment. Many screening and assessment tools are used to evaluate nutrition status, such as the Mini Nutritional Assessment (MNA), the Malnutrition Universal Screening Tool (MUST), the Short Nutritional Assessment Questionnaire (SNAQ), the Malnutrition Screening Tool (MST), and the Subjective Global Assessment (SGA) (12). However, only the NRS-2002 and the NUTRIC score determine both nutrition status and disease severity. Although both scoring systems were based on retrospective analysis, they have been used to define nutrition risk in RCTs in critically ill patients (13–16). Patients at "risk" are defined by an NRS-2002 > 3 and those at "high risk" with a score ≥ 5; or a NUTRIC score ≥ 5 (if interleukin-6 is not included, otherwise ≥ 6) (13, 18). Interleukin-6 is rarely available as a component for the NUTRIC score; therefore, Heyland et al has shown a NUTRIC score ≥ 5 still indicates high nutrition risk (19). Two prospective nonrandomized studies show that patients at high nutrition risk are more likely to benefit from early EN with improved outcome (reduced nosocomial infection, total complications, and mortality) than patients at low nutrition risk (13, 18). While widespread use and supportive evidence is somewhat lacking to date, improvement in these scoring systems may increase their applicability in the future by providing guidance as to the role of EN and PN in the ICU. Question: What additional tools, components or surrogate markers provide useful information when performing nutrition assessments in critically ill adult patients? A2. Based on expert consensus, we suggest that nutritional assessment include an evaluation of comorbid conditions, function of the gastrointestinal (GI) tract, and risk of aspiration. We suggest not using traditional nutrition indicators or surrogate markers, as they are not validated in critical care. Rationale: In the critical care setting, the traditional serum protein markers (albumin, prealbumin, transferrin, retinol-binding protein) are a reflection of the acute phase response (increases in vascular permeability and reprioritization of hepatic protein synthesis) and do not accurately represent nutrition status in the ICU setting (20). Anthropometrics are not reliable in assessment of nutrition status or adequacy of nutrition therapy (21). Individual levels of calcitonin, C-reactive protein (CRP), IL-1, tumor necrosis factor (TNF), IL-6, and citrulline are still investigational and should not be used as surrogate markers. Ultrasound is emerging as a tool to expediently measure muscle mass and determine changes in muscle tissue at bedside in the ICU, given its ease of use and availability (22, 23). A CT scan provides a precise quantification of skeletal muscle and adipose tissue depots; however it is quite costly unless a scan taken for other purposes is used to determine body composition (24, 25). Both may be valuable future tools to incorporate into nutrition assessment; however, validation and reliability studies in ICU patients are still pending. Assessment of muscle function is still in its infancy. Its measurement, reproducibility, and applicability are still being validated for use in critically ill patients, and may be of value in the future. Question: What is the best method for determining energy needs in the critically ill adult patient? A3a. We suggest that indirect calorimetry (IC) be used to determine energy requirements, when available and in the absence of variables that affect the accuracy of measurement. [Quality of Evidence: Very Low] A3b. Based on expert consensus, in the absence of IC, we suggest that a published predictive equation or a simplistic weight-based equation (25–30 kcal/kg/day) be used to determine energy requirements. (See section Q for obesity recommendations.) Rationale: Clinicians should determine energy requirements in order to establish the goals of nutrition therapy. Energy requirements may be calculated either through simplistic formulas (25–30 kcal/kg/day), published predictive equations, or IC. The applicability of IC may be limited at most institutions by availability and cost. Variables in the ICU that affect the timing and accuracy of IC measurements include the presence of air leaks or chest tubes, supplemental oxygen (e.g., nasal cannula, bilevel positive airway pressure), ventilator settings (fractional inspiratory oxygen and positive end-expiratory pressure), continuous renal replacement therapy (CRRT), anesthesia, physical therapy, and excessive movement (26). More than 200 predictive equations have been published in the literature, with accuracy rates ranging from 40–75% when compared to IC, and no single equation emerges as being more accurate in an ICU (27–32). Predictive equations are less accurate in obese and underweight patients (33–36). Equations derived from testing hospital patients (Penn State, Ireton-Jones, Swinamer) are no more accurate than equations derived from testing normal volunteers (Harris-Benedict, Mifflin St. Jeor) (37). The poor accuracy of predictive equations is related to many non-static variables affecting energy expenditure in the critically ill patient, such as weight, medications, treatments, and body temperature. The only advantage of using weight-based equations over other predictive equations is simplicity. However, in critically ill patients following aggressive volume resuscitation or in the presence of edema or anasarca, clinicians should use dry or usual body weight in these equations. Additional energy provided by dextrose-containing fluids and lipid-based medications such as propofol should be accounted for when deriving nutrition therapy regimens to meet target energy goals. Achieving energy balance as guided by IC measurements compared to predictive equations may lead to more appropriate nutrition intake. While two RCTs (38, 39) that met our inclusion criteria (with data from 161 patients) showed that higher mean intake of energy and protein were provided in IC-directed study patients compared to controls whose nutrition therapy was directed by predictive equations, issues with study design prevent a stronger recommendation for use of IC. In a study of burn patients, use of IC-directed nutrition therapy helped provide the minimal effective intake, avoiding the excesses of overfeeding seen in controls whose therapy was directed by the Curreri formula. Complications between groups (diarrhea and hyperglycemia) were no different, but traditional outcome parameters were not evaluated (38). A second study in general ICU patients used both EN and PN to meet target energy goals determined by IC measurement or a weight-based predictive equation (25 kcal/kg/day) (39). While the IC-directed energy goal was no different than the value obtained by predictive equation (1976 ± 468 vs 1838 ± 468 kcal/day, respectively, p = 0.60), only study patients were monitored vigilantly by an ICU dietitian, while controls were managed by standard of care (less frequent ICU dietitian monitoring), which led to significantly more energy and protein per in the study patients. The toward in study patients compared to controls = p = is difficult to in of their increased with to ICU LOS vs p = and of vs p = (38, by IC or by predictive equations, energy expenditure should be more than per and to energy and protein intake should be used Question: protein provision be monitored independently from energy provision in critically ill adult patients? Based on expert consensus, we suggest an evaluation of adequacy of protein provision be Rationale: In the critical care setting, protein to be the most for supporting immune and maintaining lean body For most critically ill patients, protein requirements are higher than energy requirements and are not easily met by provision of enteral have a high Patients with EN to frequent may benefit from protein The to protein should be based on an assessment of adequacy of protein intake. equations (e.g., may be used to adequacy of protein provision by the of protein to that especially when balance studies are not available to needs section protein markers (albumin, prealbumin, transferrin, are not validated for determining adequacy of protein provision and should not be used in the critical care setting in this EN Question: What is the benefit of early EN in critically ill adult patients compared to or this therapy? We that nutrition support therapy in the form of early EN be within hours in the critically ill patient who is to volitional intake. [Quality of Evidence: Very Low] Rationale: EN the of the by maintaining between the and the release of as and EN by maintaining and supporting the mass of and that the tissue and in to tissue at such as the and in permeability from of is a that is within hours of the major or The of the permeability changes include increased of with risk for systemic infection, and greater of multiple organ As disease in permeability are and the enteral of feeding is more likely to favorably impact outcome parameters of infection, organ and hospital LOS The specific for providing EN are to modulate stress and the systemic immune response, and attenuate disease Additional of EN therapy may include use of the as a for the of and use of enteral as an effective for stress previous data from RCTs early One meta-analysis of trials by Heyland showed a toward = p = when EN was within 48 hours compared to of EN after that A second meta-analysis of trials by showed in infectious = p = and hospital LOS p = when early EN was on within hours of ICU A meta-analysis of trials by showed a in = p = and = p = but no in multiple organ failure when early EN was within hours of to the ICU, compared to EN after that an updated meta-analysis of RCTs that met our inclusion criteria the provision of early EN EN, all on with on of early EN was associated with a in = p = and infectious = p = compared to early EN EN or 1: enteral nutrition (EN) vs EN, 2: enteral nutrition (EN) vs EN, infectious a in outcome between the use of EN or PN for adult critically ill patients? We suggest the use of EN over PN in critically ill patients who require nutrition support therapy. [Quality of Evidence: to Very Low] Rationale: In the of critically ill patients it is and to use EN of The effects of EN compared to PN are in RCTs a of patient populations in critical including injury, major surgery, and acute While few studies have shown a effect on the most outcome effect from EN is a in infectious and central in most patient and in patients) and ICU previous EN to PN showed in infectious with use of EN complications = p = and hospital LOS mean = p = were seen with use of EN compared to PN in one of the by of the showed no in between the two of nutrition support therapy One meta-analysis by showed a significantly = p = a significantly higher of infectious complications = p = with use of PN compared to EN In studies patients that met our inclusion criteria, on which was shown to be significantly less with EN than PN = p ICU LOS was with EN compared to PN by one full = to p = LOS and were not significantly These in outcome from the of feeding from studies and may diminish in the future with in glycemic medical management and new nutrition (EN) vs parenteral nutrition infectious the clinical evidence of required to EN in critically ill adult patients? 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BACKGROUND: Patients with heart failure who receive an implantable cardioverter-defibrillator (ICD) for primary prevention (i.e., prevention of a first life-threatening arrhythmic event) may later receive therapeutic shocks from the ICD. Information about long-term prognosis after ICD therapy in such patients is limited. METHODS: Of 829 patients with heart failure who were randomly assigned to ICD therapy, we implanted the ICD in 811. ICD shocks that followed the onset of ventricular tachycardia or ventricular fibrillation were considered to be appropriate. All other ICD shocks were considered to be inappropriate. RESULTS: Over a median follow-up period of 45.5 months, 269 patients (33.2%) received at least one ICD shock, with 128 patients receiving only appropriate shocks, 87 receiving only inappropriate shocks, and 54 receiving both types of shock. In a Cox proportional-hazards model adjusted for baseline prognostic factors, an appropriate ICD shock, as compared with no appropriate shock, was associated with a significant increase in the subsequent risk of death from all causes (hazard ratio, 5.68; 95% confidence interval [CI], 3.97 to 8.12; P<0.001). An inappropriate ICD shock, as compared with no inappropriate shock, was also associated with a significant increase in the risk of death (hazard ratio, 1.98; 95% CI, 1.29 to 3.05; P=0.002). For patients who survived longer than 24 hours after an appropriate ICD shock, the risk of death remained elevated (hazard ratio, 2.99; 95% CI, 2.04 to 4.37; P<0.001). The most common cause of death among patients who received any ICD shock was progressive heart failure. CONCLUSIONS: Among patients with heart failure in whom an ICD is implanted for primary prevention, those who receive shocks for any arrhythmia have a substantially higher risk of death than similar patients who do not receive such shocks.

BACKGROUND: Deep-brain stimulation is the surgical procedure of choice for patients with advanced Parkinson's disease. The globus pallidus interna and the subthalamic nucleus are accepted targets for this procedure. We compared 24-month outcomes for patients who had undergone bilateral stimulation of the globus pallidus interna (pallidal stimulation) or subthalamic nucleus (subthalamic stimulation). METHODS: At seven Veterans Affairs and six university hospitals, we randomly assigned 299 patients with idiopathic Parkinson's disease to undergo either pallidal stimulation (152 patients) or subthalamic stimulation (147 patients). The primary outcome was the change in motor function, as blindly assessed on the Unified Parkinson's Disease Rating Scale, part III (UPDRS-III), while patients were receiving stimulation but not receiving antiparkinsonian medication. Secondary outcomes included self-reported function, quality of life, neurocognitive function, and adverse events. RESULTS: Mean changes in the primary outcome did not differ significantly between the two study groups (P=0.50). There was also no significant difference in self-reported function. Patients undergoing subthalamic stimulation required a lower dose of dopaminergic agents than did those undergoing pallidal stimulation (P=0.02). One component of processing speed (visuomotor) declined more after subthalamic stimulation than after pallidal stimulation (P=0.03). The level of depression worsened after subthalamic stimulation and improved after pallidal stimulation (P=0.02). Serious adverse events occurred in 51% of patients undergoing pallidal stimulation and in 56% of those undergoing subthalamic stimulation, with no significant between-group differences at 24 months. CONCLUSIONS: Patients with Parkinson's disease had similar improvement in motor function after either pallidal or subthalamic stimulation. Nonmotor factors may reasonably be included in the selection of surgical target for deep-brain stimulation. (ClinicalTrials.gov numbers, NCT00056563 and NCT01076452.)

BACKGROUND: Combination therapy with angiotensin-converting-enzyme (ACE) inhibitors and angiotensin-receptor blockers (ARBs) decreases proteinuria; however, its safety and effect on the progression of kidney disease are uncertain. Methods We provided losartan (at a dose of 100 mg per day) to patients with type 2 diabetes, a urinary albumin-to-creatinine ratio (with albumin measured in milligrams and creatinine measured in grams) of at least 300, and an estimated glomerular filtration rate (GFR) of 30.0 to 89.9 ml per minute per 1.73 m(2) of body-surface area and then randomly assigned them to receive lisinopril (at a dose of 10 to 40 mg per day) or placebo. The primary end point was the first occurrence of a change in the estimated GFR (a decline of ≥ 30 ml per minute per 1.73 m(2) if the initial estimated GFR was ≥ 60 ml per minute per 1.73 m(2) or a decline of ≥ 50% if the initial estimated GFR was <60 ml per minute per 1.73 m(2)), end-stage renal disease (ESRD), or death. The secondary renal end point was the first occurrence of a decline in the estimated GFR or ESRD. Safety outcomes included mortality, hyperkalemia, and acute kidney injury. Results The study was stopped early owing to safety concerns. Among 1448 randomly assigned patients with a median follow-up of 2.2 years, there were 152 primary end-point events in the monotherapy group and 132 in the combination-therapy group (hazard ratio with combination therapy, 0.88; 95% confidence interval [CI], 0.70 to 1.12; P=0.30). A trend toward a benefit from combination therapy with respect to the secondary end point (hazard ratio, 0.78; 95% CI, 0.58 to 1.05; P=0.10) decreased with time (P=0.02 for nonproportionality). There was no benefit with respect to mortality (hazard ratio for death, 1.04; 95% CI, 0.73 to 1.49; P=0.75) or cardiovascular events. Combination therapy increased the risk of hyperkalemia (6.3 events per 100 person-years, vs. 2.6 events per 100 person-years with monotherapy; P<0.001) and acute kidney injury (12.2 vs. 6.7 events per 100 person-years, P<0.001). Conclusions Combination therapy with an ACE inhibitor and an ARB was associated with an increased risk of adverse events among patients with diabetic nephropathy. (Funded by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development; VA NEPHRON-D ClinicalTrials.gov number, NCT00555217.).

PURPOSE: To synthesize new data on breast cancer screening for the U.S. Preventive Services Task Force. DATA SOURCES: MEDLINE; the Cochrane Controlled Trials Registry; and reference lists of reviews, editorials, and original studies. STUDY SELECTION: Eight randomized, controlled trials of mammography and 2 trials evaluating breast self-examination were included. One hundred fifty-four publications of the results of these trials, as well as selected articles about the test characteristics and harms associated with screening, were examined. DATA EXTRACTION: Predefined criteria were used to assess the quality of each study. Meta-analyses using a Bayesian random-effects model were conducted to provide summary relative risk estimates and credible intervals (CrIs) for the effectiveness of screening with mammography in reducing death from breast cancer. DATA SYNTHESIS: For studies of fair quality or better, the summary relative risk was 0.84 (95% CrI, 0.77 to 0.91) and the number needed to screen to prevent one death from breast cancer after approximately 14 years of observation was 1224 (CrI, 665 to 2564). Among women younger than 50 years of age, the summary relative risk associated with mammography was 0.85 (CrI, 0.73 to 0.99) and the number needed to screen to prevent one death from breast cancer after 14 years of observation was 1792 (CrI, 764 to 10 540). For clinical breast examination and breast self-examination, evidence from randomized trials is inconclusive. CONCLUSIONS: In the randomized, controlled trials, mammography reduced breast cancer mortality rates among women 40 to 74 years of age. Greater absolute risk reduction was seen among older women. Because these results incorporate several rounds of screening, the actual number of mammograms needed to prevent one death from breast cancer is higher. In addition, each screening has associated risks and costs.

BACKGROUND: HHT is an autosomal dominant disease with an estimated prevalence of at least 1/5000 which can frequently be complicated by the presence of clinically significant arteriovenous malformations in the brain, lung, gastrointestinal tract and liver. HHT is under-diagnosed and families may be unaware of the available screening and treatment, leading to unnecessary stroke and life-threatening hemorrhage in children and adults. OBJECTIVE: The goal of this international HHT guidelines process was to develop evidence-informed consensus guidelines regarding the diagnosis of HHT and the prevention of HHT-related complications and treatment of symptomatic disease. METHODS: The overall guidelines process was developed using the AGREE framework, using a systematic search strategy and literature retrieval with incorporation of expert evidence in a structured consensus process where published literature was lacking. The Guidelines Working Group included experts (clinical and genetic) from eleven countries, in all aspects of HHT, guidelines methodologists, health care workers, health care administrators, HHT clinic staff, medical trainees, patient advocacy representatives and patients with HHT. The Working Group determined clinically relevant questions during the pre-conference process. The literature search was conducted using the OVID MEDLINE database, from 1966 to October 2006. The Working Group subsequently convened at the Guidelines Conference to partake in a structured consensus process using the evidence tables generated from the systematic searches. RESULTS: The outcome of the conference was the generation of 33 recommendations for the diagnosis and management of HHT, with at least 80% agreement amongst the expert panel for 30 of the 33 recommendations.

STI 571 (formerly known as CGP 57148B) is a known inhibitor of the c-abl, bcr-abl, and platelet-derived growth-factor receptor (PDGFR) tyrosine kinases. This compound is being evaluated in clinical trials for the treatment of chronic myelogenous leukemia. We sought to extend the activity profile of STI 571 by testing its ability to inhibit the tyrosine kinase activity of c-kit, a receptor structurally similar to PDGFR. We treated a c-kit expressing a human myeloid leukemia cell line, M-07e, with STI 571 before stimulation with Steel factor (SLF). STI 571 inhibited c-kit autophosphorylation, activation of mitogen-activated protein (MAP) kinase, and activation of Akt without altering total protein levels of c-kit, MAP kinase, or Akt. The concentration that produced 50% inhibition for these effects was approximately 100 nmol/L. STI 571 also significantly decreased SLF-dependent growth of M-07e cells in a dose-dependent manner and blocked the antiapoptotic activity of SLF. In contrast, the compound had no effect on MAP kinase activation or cellular proliferation in response to granulocyte-macrophage colony-stimulating factor. We also tested the activity of STI 571 in a human mast cell leukemia cell line (HMC-1), which has an activated mutant form of c-kit. STI 571 had a more potent inhibitory effect on the kinase activity of this mutant receptor than it did on ligand-dependent activation of the wild-type receptor. These findings show that STI 571 selectively inhibits c-kit tyrosine kinase activity and downstream activation of target proteins involved in cellular proliferation and survival. This compound may be useful in treating cancers associated with increased c-kit kinase activity.

Abstract Most estimates of osteoporosis in older U.S. adults have been based on its occurrence in white women, even though it is known to affect men and minority women. In the present study, we used dual-energy X-ray absorptiometry measurements of femoral bone mineral density (BMD) from the third National Health and Nutrition Examination Survey (NHANES III, 1988–1994) to estimate the overall scope of the disease in the older U.S. population. Specifically, we estimate prevalences of low femoral BMD in women 50 years and older and explore different approaches for defining low BMD in older men in that age range. Low BMD levels were defined in accordance with an approach proposed by an expert panel of the World Health Organization and used BMD data from 382 non-Hispanic white (NHW) men or 409 NHW women ages 20–29 years from the NHANES III dataset. For women, estimates indicate 13–18%, or 4–6 million, have osteoporosis (i.e., BMD &amp;gt;2.5 standard deviations [SD] below the mean of young NHW women) and 37–50%, or 13–17 million, have osteopenia (BMD between 1 and 2.5 SD below the mean of young NHW women). For men, these numbers depend on the gender of the reference group used to define cutoff values. When based on male cutoffs, 3–6% (1–2 million) of men have osteoporosis and 28–47% (8–13 million) have osteopenia; when based on female cutoffs, 1–4% (280,000–1 million) have osteoporosis and 15–33% (4–9 million) have osteopenia. Most of the older U.S. adults with low femur BMD are women, but, regardless of which cutoffs are used, the number of men is substantial.

Imatinib, a Bcr-Abl tyrosine kinase inhibitor, is a highly effective therapy for patients with chronic myelogenous leukemia (CML). Despite durable responses in most chronic phase patients, relapses have been observed and are much more prevalent in patients with advanced disease. The most common mechanism of acquired imatinib resistance has been traced to Bcr-Abl kinase domain mutations with decreased imatinib sensitivity. Thus, alternate Bcr-Abl kinase inhibitors that have activity against imatinib-resistant mutants would be useful for patients who relapse on imatinib therapy. Two such Bcr-Abl inhibitors are currently being evaluated in clinical trials: the improved potency, selective Abl inhibitor AMN107 and the highly potent dual Src/Abl inhibitor BMS-354825. In the current article, we compared imatinib, AMN107, and BMS-354825 in cellular and biochemical assays against a panel of 16 kinase domain mutants representing >90% of clinical isolates. We report that AMN107 and BMS-354825 are 20-fold and 325-fold more potent than imatinib against cells expressing wild-type Bcr-Abl and that similar improvements are maintained for all imatinib-resistant mutants tested, with the exception of T315I. Thus, both inhibitors hold promise for treating imatinib-refractory CML.

OBJECTIVE: Rituximab, a monoclonal antibody selectively depleting CD20+ B cells, has demonstrated efficacy in reducing disease activity in relapsing-remitting multiple sclerosis (MS). We evaluated rituximab in adults with primary progressive MS (PPMS) through 96 weeks and safety through 122 weeks. METHODS: Using 2:1 randomization, 439 PPMS patients received two 1,000 mg intravenous rituximab or placebo infusions every 24 weeks, through 96 weeks (4 courses). The primary endpoint was time to confirmed disease progression (CDP), a prespecified increase in Expanded Disability Status Scale sustained for 12 weeks. Secondary endpoints were change from baseline to week 96 in T2 lesion volume and total brain volume on magnetic resonance imaging scans. RESULTS: Differences in time to CDP between rituximab and placebo did not reach significance (96-week rates: 38.5% placebo, 30.2% rituximab; p = 0.14). From baseline to week 96, rituximab patients had less (p < 0.001) increase in T2 lesion volume; brain volume change was similar (p = 0.62) to placebo. Subgroup analysis showed time to CDP was delayed in rituximab-treated patients aged <51 years (hazard ratio [HR] = 0.52; p = 0.010), those with gadolinium-enhancing lesions (HR = 0.41; p = 0.007), and those aged <51 years with gadolinium-enhancing lesions (HR = 0.33; p = 0.009) compared with placebo. Adverse events were comparable between groups; 16.1% of rituximab and 13.6% of placebo patients reported serious events. Serious infections occurred in 4.5% of rituximab and <1.0% of placebo patients. Infusion-related events, predominantly mild to moderate, were more common with rituximab during the first course, and decreased to rates comparable to placebo on successive courses. INTERPRETATION: Although time to CDP between groups was not significant, overall subgroup analyses suggest selective B-cell depletion may affect disease progression in younger patients, particularly those with inflammatory lesions.