Showing papers by "Oregon Health & Science University published in 2009"
University of Colorado Boulder1, Harvard University2, Mayo Clinic3, Boston University4, University of Pennsylvania5, University of Pittsburgh6, University of Siena7, University Health Network8, Institut Gustave Roussy9, Oregon Health & Science University10, University of Texas MD Anderson Cancer Center11, Duke University12, University of Cincinnati13, Memorial Sloan Kettering Cancer Center14, MedStar Washington Hospital Center15
TL;DR: Evidence-based recommendations are developed to inform clinical decision-making in the management of thyroid nodules and differentiated thyroid cancer and represent, in the authors' opinion, contemporary optimal care for patients with these disorders.
Abstract: Background: Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Association's (ATA's) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer. Methods: The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles on adults were eligible for inclusion. The American College of Physicians Guideline Gr...
10,501 citations
Oregon Health & Science University1, Dartmouth College2, University of Utah3, Harvard University4, Seattle Cancer Care Alliance5, Kaiser Permanente6, University of Miami7, Memorial Sloan Kettering Cancer Center8, Albany College of Pharmacy and Health Sciences9, University of Wisconsin-Madison10, California Health and Human Services Agency11, Yale University12, Yeshiva University13, University of California, Davis14, University of California, San Francisco15
TL;DR: Safe and effective chronic opioid therapy for chronic noncancer pain requires clinical skills and knowledge in both the principles of opioid prescribing and on the assessment and management of risks associated with opioid abuse, addiction, and diversion.
2,051 citations
TL;DR: The diarylthiohydantoins RD162 and MDV3100 are characterized, two compounds optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased androgen receptor expression that appear to be promising candidates for treatment of advanced prostate cancer.
Abstract: Metastatic prostate cancer is treated with drugs that antagonize androgen action, but most patients progress to a more aggressive form of the disease called castration-resistant prostate cancer, driven by elevated expression of the androgen receptor. Here we characterize the diarylthiohydantoins RD162 and MDV3100, two compounds optimized from a screen for nonsteroidal antiandrogens that retain activity in the setting of increased androgen receptor expression. Both compounds bind to the androgen receptor with greater relative affinity than the clinically used antiandrogen bicalutamide, reduce the efficiency of its nuclear translocation, and impair both DNA binding to androgen response elements and recruitment of coactivators. RD162 and MDV3100 are orally available and induce tumor regression in mouse models of castration-resistant human prostate cancer. Of the first 30 patients treated with MDV3100 in a Phase I/II clinical trial, 13 of 30 (43%) showed sustained declines (by >50%) in serum concentrations of prostate-specific antigen, a biomarker of prostate cancer. These compounds thus appear to be promising candidates for treatment of advanced prostate cancer.
2,046 citations
TL;DR: These 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 that are directed toward generalized patient populations.
Abstract: 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.
1,734 citations
TL;DR: This update contains revisions to the diagnosis and staging and management strategies and highlights the status of basic science research.
1,727 citations
Ohio State University1, National Institutes of Health2, George Washington University3, Brown University4, University of Texas Health Science Center at Houston5, University of Texas Southwestern Medical Center6, Columbia University7, University of Utah8, University of Alabama at Birmingham9, University of North Carolina at Chapel Hill10, Drexel University11, Case Western Reserve University12, Wake Forest University13, University of Texas Medical Branch14, University of Pittsburgh15, Wayne State University16, Northwestern University17, Oregon Health & Science University18
TL;DR: Treatment of mild gestational diabetes mellitus did not significantly reduce the frequency of a composite outcome that included stillbirth or perinatal death and several neonatal complications, but it did reduce the risks of fetal overgrowth, shoulder dystocia, cesarean delivery, and hypertensive disorders.
Abstract: Background It is uncertain whether treatment of mild gestational diabetes mellitus improves pregnancy outcomes. Methods Women who were in the 24th to 31st week of gestation and who met the criteria for mild gestational diabetes mellitus (i.e., an abnormal result on an oral glucose-tolerance test but a fasting glucose level below 95 mg per deciliter [5.3 mmol per liter]) were randomly assigned to usual prenatal care (control group) or dietary intervention, self-monitoring of blood glucose, and insulin therapy, if necessary (treatment group). The primary outcome was a composite of stillbirth or perinatal death and neonatal complications, including hyperbilirubinemia, hypoglycemia, hyperinsulinemia, and birth trauma. Results A total of 958 women were randomly assigned to a study group — 485 to the treatment group and 473 to the control group. We observed no significant difference between groups in the frequency of the composite outcome (32.4% and 37.0% in the treatment and control groups, respectively; P=0.1...
1,587 citations
TL;DR: Over development, the organization of multiple functional networks shifts from a local anatomical emphasis in children to a more “distributed” architecture in young adults, and it is argued that this “local to distributed” developmental characterization has important implications for understanding the development of neural systems underlying cognition.
Abstract: The mature human brain is organized into a collection of specialized functional networks that flexibly interact to support various cognitive functions. Studies of development often attempt to identify the organizing principles that guide the maturation of these functional networks. In this report, we combine resting state functional connectivity MRI (rs-fcMRI), graph analysis, community detection, and spring-embedding visualization techniques to analyze four separate networks defined in earlier studies. As we have previously reported, we find, across development, a trend toward ‘segregation’ (a general decrease in correlation strength) between regions close in anatomical space and ‘integration’ (an increased correlation strength) between selected regions distant in space. The generalization of these earlier trends across multiple networks suggests that this is a general developmental principle for changes in functional connectivity that would extend to large-scale graph theoretic analyses of large-scale brain networks. Communities in children are predominantly arranged by anatomical proximity, while communities in adults predominantly reflect functional relationships, as defined from adult fMRI studies. In sum, over development, the organization of multiple functional networks shifts from a local anatomical emphasis in children to a more “distributed” architecture in young adults. We argue that this “local to distributed” developmental characterization has important implications for understanding the development of neural systems underlying cognition. Further, graph metrics (e.g., clustering coefficients and average path lengths) are similar in child and adult graphs, with both showing “small-world”-like properties, while community detection by modularity optimization reveals stable communities within the graphs that are clearly different between young children and young adults. These observations suggest that early school age children and adults both have relatively efficient systems that may solve similar information processing problems in divergent ways.
1,358 citations
TL;DR: The overall risk of death and other adverse outcomes after bariatric surgery was low and varied considerably according to patient characteristics, andExtreme values of body-mass index were significantly associated with an increased risk of the composite end point, whereas age, sex, race, ethnic group, and other coexisting conditions were not.
Abstract: BACKGROUND To improve decision making in the treatment of extreme obesity, the risks of bariatric surgical procedures require further characterization. METHODS We performed a prospective, multicenter, observational study of 30-day outcomes in consecutive patients undergoing bariatric surgical procedures at 10 clinical sites in the United States from 2005 through 2007. A composite end point of 30-day major adverse outcomes (including death; venous thromboembolism; percutaneous, endoscopic, or operative reintervention; and failure to be discharged from the hospital) was evaluated among patients undergoing first-time bariatric surgery. RESULTS There were 4776 patients who had a first-time bariatric procedure (mean age, 44.5 years; 21.1% men; 10.9% nonwhite; median body-mass index [the weight in kilograms divided by the square of the height in meters], 46.5). More than half had at least two coexisting conditions. A Roux-en-Y gastric bypass was performed in 3412 patients (with 87.2% of the procedures performed laparoscopically), and laparoscopic adjustable gastric banding was performed in 1198 patients; 166 patients underwent other procedures and were not included in the analysis. The 30-day rate of death among patients who underwent a Roux-en-Y gastric bypass or laparoscopic adjustable gastric banding was 0.3%; a total of 4.3% of patients had at least one major adverse outcome. A history of deep-vein thrombosis or pulmonary embolus, a diagnosis of obstructive sleep apnea, and impaired functional status were each independently associated with an increased risk of the composite end point. Extreme values of body-mass index were significantly associated with an increased risk of the composite end point, whereas age, sex, race, ethnic group, and other coexisting conditions were not. CONCLUSIONS The overall risk of death and other adverse outcomes after bariatric surgery was low and varied considerably according to patient characteristics. In helping patients make appropriate choices, short-term safety should be considered in conjunction with both the long-term effects of bariatric surgery and the risks associated with being extremely obese. (ClinicalTrials.gov number, NCT00433810.)
1,297 citations
University of North Carolina at Chapel Hill1, University of Kansas2, Mayo Clinic3, Veterans Health Administration4, Cleveland Clinic5, Oregon Health & Science University6, Medical University of South Carolina7, Dartmouth College8, United States Department of Veterans Affairs9, University of California, Irvine10, University of Washington11, University of Texas Southwestern Medical Center12, Thomas Jefferson University13, Case Western Reserve University14, Columbia University15
TL;DR: In patients with dysplastic Barrett's esophagus, radiofrequency ablation was associated with a high rate of complete eradication of both dysplasia and intestinal metaplasia, and a reduced risk of disease progression.
Abstract: Background Barrett’s esophagus, a condition of intestinal metaplasia of the esophagus, is associated with an increased risk of esophageal adenocarcinoma. We assessed whether endoscopic radiofrequency ablation could eradicate dysplastic Barrett’s esophagus and decrease the rate of neoplastic progression. Methods In a multicenter, sham-controlled trial, we randomly assigned 127 patients with dysplastic Barrett’s esophagus in a 2:1 ratio to receive either radiofrequency ablation (ablation group) or a sham procedure (control group). Randomization was stratified according to the grade of dysplasia and the length of Barrett’s esophagus. Primary outcomes at 12 months included the complete eradication of dysplasia and intestinal metaplasia. Results In the intention-to-treat analyses, among patients with low-grade dysplasia, complete eradication of dysplasia occurred in 90.5% of those in the ablation group, as compared with 22.7% of those in the control group (P<0.001). Among patients with highgrade dysplasia, complete eradication occurred in 81.0% of those in the ablation group, as compared with 19.0% of those in the control group (P<0.001). Overall, 77.4% of patients in the ablation group had complete eradication of intestinal metaplasia, as compared with 2.3% of those in the control group (P<0.001). Patients in the ablation group had less disease progression (3.6% vs. 16.3%, P = 0.03) and fewer cancers (1.2% vs. 9.3%, P = 0.045). Patients reported having more chest pain after the ablation procedure than after the sham procedure. In the ablation group, one patient had upper gastrointestinal hemorrhage, and five patients (6.0%) had esophageal stricture. Conclusions In patients with dysplastic Barrett’s esophagus, radiofrequency ablation was associated with a high rate of complete eradication of both dysplasia and intestinal metaplasia and a reduced risk of disease progression. (ClinicalTrials.gov number, NCT00282672.)
1,231 citations
Northwestern University1, Veterans Health Administration2, University of Nebraska Omaha3, University of Pennsylvania4, University of California, San Francisco5, University of Michigan6, National Institutes of Health7, University of Kansas8, Portland VA Medical Center9, Oregon Health & Science University10, United States Department of Veterans Affairs11, Baylor College of Medicine12, Virginia Commonwealth University13, University of Iowa14
TL;DR: Deep brain stimulation was more effective than best medical therapy in improving on time without troubling dyskinesias, motor function, and quality of life at 6 months, but was associated with an increased risk of serious adverse events.
Abstract: Context Deep brain stimulation is an accepted treatment for advanced Parkinson disease (PD), although there are few randomized trials comparing treatments, and most studies exclude older patients. Objective To compare 6-month outcomes for patients with PD who received deep brain stimulation or best medical therapy. Design, Setting, and Patients Randomized controlled trial of patients who received either deep brain stimulation or best medical therapy, stratified by study site and patient age ( Intervention Bilateral deep brain stimulation of the subthalamic nucleus (n = 60) or globus pallidus (n = 61). Patients receiving best medical therapy (n = 134) were actively managed by movement disorder neurologists. Main Outcome Measures The primary outcome was time spent in the “on” state (good motor control with unimpeded motor function) without troubling dyskinesia, using motor diaries. Other outcomes included motor function, quality of life, neurocognitive function, and adverse events. Results Patients who received deep brain stimulation gained a mean of 4.6 h/d of on time without troubling dyskinesia compared with 0 h/d for patients who received best medical therapy (between group mean difference, 4.5 h/d [95% CI, 3.7-5.4 h/d]; P Conclusion In this randomized controlled trial of patients with advanced PD, deep brain stimulation was more effective than best medical therapy in improving on time without troubling dyskinesias, motor function, and quality of life at 6 months, but was associated with an increased risk of serious adverse events. Trial Registration clinicaltrials.gov Identifier: NCT00056563
1,218 citations
TL;DR: New studies and evidence gaps that were unresolved at the time of the 2002 USPSTF recommendation are focused on, including the effectiveness of mammography screening in decreasing breast cancer mortality among average-risk women aged 40 to 49 years and 70 years or older.
Abstract: To inform the USPSTF recommendations about breast cancer screening, Nelson and coworkers reviewed evidence on the effectiveness of mammography screening in decreasing breast cancer mortality among ...
TL;DR: The updated STAIR preclinical recommendations reinforce the previous suggestions that reproducibly defining dose response and time windows with both histological and functional outcomes in multiple animal species with appropriate physiological monitoring is appropriate.
Abstract: The initial Stroke Therapy Academic Industry Roundtable (STAIR) recommendations published in 1999 were intended to improve the quality of preclinical studies of purported acute stroke therapies Although recognized as reasonable, they have not been closely followed nor rigorously validated Substantial advances have occurred regarding the appropriate quality and breadth of preclinical testing for candidate acute stroke therapies for better clinical translation The updated STAIR preclinical recommendations reinforce the previous suggestions that reproducibly defining dose response and time windows with both histological and functional outcomes in multiple animal species with appropriate physiological monitoring is appropriate The updated STAIR recommendations include: the fundamentals of good scientific inquiry should be followed by eliminating randomization and assessment bias, a priori defining inclusion/exclusion criteria, performing appropriate power and sample size calculations, and disclosing potential conflicts of interest After initial evaluations in young, healthy male animals, further studies should be performed in females, aged animals, and animals with comorbid conditions such as hypertension, diabetes, and hypercholesterolemia Another consideration is the use of clinically relevant biomarkers in animal studies Although the recommendations cannot be validated until effective therapies based on them emerge from clinical trials, it is hoped that adherence to them might enhance the chances for success
TL;DR: Design and preclinical evaluation of AP24534, a potent, orally available multitargeted kinase inhibitor active against T315I and other BCR-ABL mutants, and clinical evaluation ofAP24534 as a pan-BCR-ABl inhibitor for treatment of CML are reported.
TL;DR: The crystal structure of the α-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive, homotetrameric, rat GluA2 receptor is reported at 3.6 Å resolution in complex with a competitive antagonist to exploit mechanisms of ion channel activation, desensitization and inhibition by non-competitive antagonists and pore blockers.
Abstract: Ionotropic glutamate receptors mediate most excitatory neurotransmission in the central nervous system and function by opening a transmembrane ion channel upon binding of glutamate. Despite their crucial role in neurobiology, the architecture and atomic structure of an intact ionotropic glutamate receptor are unknown. Here we report the crystal structure of the alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA)-sensitive, homotetrameric, rat GluA2 receptor at 3.6 A resolution in complex with a competitive antagonist. The receptor harbours an overall axis of two-fold symmetry with the extracellular domains organized as pairs of local dimers and with the ion channel domain exhibiting four-fold symmetry. A symmetry mismatch between the extracellular and ion channel domains is mediated by two pairs of conformationally distinct subunits, A/C and B/D. Therefore, the stereochemical manner in which the A/C subunits are coupled to the ion channel gate is different from the B/D subunits. Guided by the GluA2 structure and site-directed cysteine mutagenesis, we suggest that GluN1 and GluN2A NMDA (N-methyl-d-aspartate) receptors have a similar architecture, with subunits arranged in a 1-2-1-2 pattern. We exploit the GluA2 structure to develop mechanisms of ion channel activation, desensitization and inhibition by non-competitive antagonists and pore blockers.
Columbia University1, University of Miami2, University of North Carolina at Chapel Hill3, SUNY Downstate Medical Center4, University College London5, Cambridge University Hospitals NHS Foundation Trust6, University of California, San Francisco7, University of California, Los Angeles8, University of Alabama at Birmingham9, Rio de Janeiro State University10, University of Guadalajara11, University of Düsseldorf12, New York University13, University of Barcelona14, Shanghai Jiao Tong University15, University of Lisbon16, Stellenbosch University17, Guy's and St Thomas' NHS Foundation Trust18, Oregon Health & Science University19, University of Padua20, University of Leeds21, North Shore-LIJ Health System22, Northwestern University23, Medical University of South Carolina24, University of Birmingham25, Sun Yat-sen University26, Lille University of Science and Technology27, Charité28, Rutgers University29, Federal University of São Paulo30, University of Debrecen31, Imperial College London32, Emory University33, University of Liège34, University of Pittsburgh35, University of Paris36, University of the Witwatersrand37, California State University, Long Beach38, Royal Melbourne Hospital39, University of Texas Southwestern Medical Center40, Autonomous University of Barcelona41, Pennsylvania State University42, Johns Hopkins University43, University of Szeged44, Duke University45, University of Colorado Denver46, Harvard University47, University of Cape Town48, University of Malaya49, Peking Union Medical College50
TL;DR: Although most patients in both treatment groups experienced clinical improvement, the study did not meet its primary objective of showing that MMF was superior to IVC as induction treatment for lupus nephritis.
Abstract: Recent studies have suggested that mycophenolate mofetil (MMF) may offer advantages over intravenous cyclophosphamide (IVC) for the treatment of lupus nephritis, but these therapies have not been compared in an international randomized, controlled trial. Here, we report the comparison of MMF and IVC as induction treatment for active lupus nephritis in a multinational, two-phase (induction and maintenance) study. We randomly assigned 370 patients with classes III through V lupus nephritis to open-label MMF (target dosage 3 g/d) or IVC (0.5 to 1.0 g/m(2) in monthly pulses) in a 24-wk induction study. Both groups received prednisone, tapered from a maximum starting dosage of 60 mg/d. The primary end point was a prespecified decrease in urine protein/creatinine ratio and stabilization or improvement in serum creatinine. Secondary end points included complete renal remission, systemic disease activity and damage, and safety. Overall, we did not detect a significantly different response rate between the two groups: 104 (56.2%) of 185 patients responded to MMF compared with 98 (53.0%) of 185 to IVC. Secondary end points were also similar between treatment groups. There were nine deaths in the MMF group and five in the IVC group. We did not detect significant differences between the MMF and IVC groups with regard to rates of adverse events, serious adverse events, or infections. Although most patients in both treatment groups experienced clinical improvement, the study did not meet its primary objective of showing that MMF was superior to IVC as induction treatment for lupus nephritis.
TL;DR: The epidemiology and choice of therapy for candidemia are rapidly changing and additional study is warranted to differentiate host factors and differences in virulence among Candida species and to determine the best therapeutic regimen.
Abstract: Background. Candidemia remains a major cause of morbidity and mortality in the health care setting, and the epidemiology of Candida infection is changing. Methods. Clinical data from patients with candidemia were extracted from the Prospective Antifungal Therapy (PATH) Alliance database, a comprehensive registry that collects information regarding invasive fungal infections. A total of 2019 patients, enrolled from 1 July 2004 through 5 March 2008, were identified. Data regarding the candidemia episode were analyzed, including the specific fungal species and patient survival at 12 weeks after diagnosis. Results. The incidence of candidemia caused by non-Candida albicans Candida species (54.4%) was higher than the incidence of candidemia caused by C. albicans (45.6%). The overall, crude 12-week mortality rate was 35.2%. Patients with Candida parapsilosis candidemia had the lowest mortality rate (23.7%; P<.001) and were less likely to be neutropenic (5.1%; P<.001) and to receive corticosteroids (33.5%; P<.001) or other immunosuppressive drugs (7.9%; P = .002), compared with patients infected with other Candida species. Candida krusei candidemia was most commonly associated with prior use of antifungal agents (70.6%; P<.001), hematologic malignancy (52.9%; P<.001) or stem cell transplantation (17.7%; P<.001), neutropenia (45.1%; P<.001), and corticosteroid treatment (60.8%; P<.001). Patients with C. krusei candidemia had the highest crude 12-week mortality in this series (52.9%; P<.001). Fluconazole was the most commonly administered antimicrobial, followed by the echinocandins, and amphotericin B products were infrequently administered. Conclusions. The epidemiology and choice of therapy for candidemia are rapidly changing. Additional study is warranted to differentiate host factors and differences in virulence among Candida species and to determine the best therapeutic regimen.
TL;DR: The theoretical framework, interrater reliability, and preliminary concurrent validity for this new instrument, the Balance Evaluation Systems Test (BESTest), which aims to target 6 different balance control systems so that specific rehabilitation approaches can be designed for different balance deficits are presented.
Abstract: Background: Current clinical balance assessment tools do not aim to help therapists identify the underlying postural control systems responsible for poor functional balance. By identifying the disordered systems underlying balance control, therapists can direct specific types of intervention for different types of balance problems.
Objective: The goal of this study was to develop a clinical balance assessment tool that aims to target 6 different balance control systems so that specific rehabilitation approaches can be designed for different balance deficits. This article presents the theoretical framework, interrater reliability, and preliminary concurrent validity for this new instrument, the Balance Evaluation Systems Test (BESTest).
Design: The BESTest consists of 36 items, grouped into 6 systems: “Biomechanical Constraints,” “Stability Limits/Verticality,” “Anticipatory Postural Adjustments,” “Postural Responses,” “Sensory Orientation,” and “Stability in Gait.”
Methods: In 2 interrater trials, 22 subjects with and without balance disorders, ranging in age from 50 to 88 years, were rated concurrently on the BESTest by 19 therapists, students, and balance researchers. Concurrent validity was measured by correlation between the BESTest and balance confidence, as assessed with the Activities-specific Balance Confidence (ABC) Scale.
Results: Consistent with our theoretical framework, subjects with different diagnoses scored poorly on different sections of the BESTest. The intraclass correlation coefficient (ICC) for interrater reliability for the test as a whole was .91, with the 6 section ICCs ranging from .79 to .96. The Kendall coefficient of concordance among raters ranged from .46 to 1.00 for the 36 individual items. Concurrent validity of the correlation between the BESTest and the ABC Scale was r =.636, P <.01.
Limitations: Further testing is needed to determine whether: (1) the sections of the BESTest actually detect independent balance deficits, (2) other systems important for balance control should be added, and (3) a shorter version of the test is possible by eliminating redundant or insensitive items.
Conclusions: The BESTest is easy to learn to administer, with excellent reliability and very good validity. It is unique in allowing clinicians to determine the type of balance problems to direct specific treatments for their patients. By organizing clinical balance test items already in use, combined with new items not currently available, the BESTest is the most comprehensive clinical balance tool available and warrants further development.
TL;DR: Analysis of the circuitry within the RVM reveals that the neural basis for bidirectional control from the midline system is two populations of neurons, ON-cells and OFF-cells, that are differentially recruited by higher structures important in fear, illness and psychological stress to enhance or inhibit pain.
TL;DR: During the sixth year of study treatment, there were no reports of disease progression to accelerated phase (AP) or blast crisis (BC), and the toxicity profile was unchanged.
Abstract: Imatinib mesylate is considered standard of care for first-line treatment of chronic phase chronic myeloid leukemia (CML-CP). In the phase III, randomized, open-label International Randomized Study of Interferon vs STI571 (IRIS) trial, previously untreated CML-CP patients were randomized to imatinib (n=553) or interferon-alpha (IFN) plus cytarabine (n=553). This 6-year update focuses on patients randomized to receive imatinib as first-line therapy for newly diagnosed CML-CP. During the sixth year of study treatment, there were no reports of disease progression to accelerated phase (AP) or blast crisis (BC). The toxicity profile was unchanged. The cumulative best complete cytogenetic response (CCyR) rate was 82%; 63% of all patients randomized to receive imatinib and still on study treatment showed CCyR at last assessment. The estimated event-free survival at 6 years was 83%, and the estimated rate of freedom from progression to AP and BC was 93%. The estimated overall survival was 88% -- or 95% when only CML-related deaths were considered. This 6-year update of IRIS underscores the efficacy and safety of imatinib as first-line therapy for patients with CML.
TL;DR: IA remains the most commonly identified IFI among HSCT recipients, but rates of survival in persons with IA appear to have improved, compared with previously reported data.
Abstract: BACKGROUND With use of data from the Prospective Antifungal Therapy (PATH) Alliance registry, we performed this multicenter, prospective, observational study to assess the epidemiologic characters and outcomes of invasive fungal infection (IFI) in hematopoietic stem cell transplant (HSCT) recipients. METHODS Sixteen medical centers from North America reported data on adult HSCT recipients with proven or probable IFI during the period July 2004 through September 2007. The distribution of IFIs and rates of survival at 6 and 12 weeks after diagnosis were studied. We used logistic regression models to determine risk factors associated with 6-week mortality for allogeneic HSCT recipients with invasive aspergillosis (IA). RESULTS Two hundred thirty-four adult HSCT recipients with a total of 250 IFIs were included in this study. IA (59.2%) was the most frequent IFI, followed by invasive candidiasis (24.8%), zygomycosis (7.2%), and IFI due to other molds (6.8%). Voriconazole was the most frequently administered agent (68.4%); amphotericin B deoxycholate was administered to a few patients (2.1%). Ninety-three (46.7%) of 199 HSCT recipients with known outcome had died by week 12. The 6-week survival rate was significantly greater for patients with IA than for those with invasive candidiasis and for those with IFI due to the Zygomycetes or other molds (P < .07). The 6-week mortality rate for HSCT recipients with IA was 21.5%. At 6 weeks, there was a trend toward a worse outcome among allogeneic HSCT recipients with IA who received myeloablative conditioning (P = .07); absence of mechanical ventilation or/and hemodialysis (P = .01) were associated with improved survival. CONCLUSIONS IA remains the most commonly identified IFI among HSCT recipients, but rates of survival in persons with IA appear to have improved, compared with previously reported data. Invasive candidiasis and IFI due to molds other than Aspergillus species remain a significant problem in HSCT recipients.
Washington University in St. Louis1, University of Pennsylvania2, City of Hope National Medical Center3, Mayo Clinic4, Loyola University Chicago5, Emory University6, Oregon Health & Science University7, University of Texas MD Anderson Cancer Center8, Heidelberg University9, Duke University10, Yale University11, Genzyme12
TL;DR: Plerixafor and G- CSF were well tolerated, and significantly more patients collected the optimal CD34(+) cell/kg target for transplantation earlier compared with G-CSF alone.
TL;DR: There is a need for a better understanding of the basic science of pain mechanisms, more rigorous and independent trials of many treatments, a stronger regulatory stance toward approval and post-marketing surveillance of new drugs and devices for chronic pain, and a chronic disease model for managing chronic back pain.
Abstract: Chronic back pain is among the most common patient complaints. Its prevalence and impact have spawned a rapidly expanding range of tests and treatments. Some of these have become widely used for indications that are not well validated, leading to uncertainty about efficacy and safety, increasing complication rates, and marketing abuses. Recent studies document a 629% increase in Medicare expenditures for epidural steroid injections; a 423% increase in expenditures for opioids for back pain; a 307% increase in the number of lumbar magnetic resonance images among Medicare beneficiaries; and a 220% increase in spinal fusion surgery rates. The limited studies available suggest that these increases have not been accompanied by population-level improvements in patient outcomes or disability rates. We suggest a need for a better understanding of the basic science of pain mechanisms, more rigorous and independent trials of many treatments, a stronger regulatory stance toward approval and post-marketing surveillance of new drugs and devices for chronic pain, and a chronic disease model for managing chronic back pain.
TL;DR: This work defines the location of three non-canonical, intersubunit ATP-binding sites, and suggests that ATP binding promotes subunit rearrangement and ion channel opening.
Abstract: P2X receptors are cation-selective ion channels gated by extracellular ATP, and are implicated in diverse physiological processes, from synaptic transmission to inflammation to the sensing of taste and pain. Because P2X receptors are not related to other ion channel proteins of known structure, there is at present no molecular foundation for mechanisms of ligand-gating, allosteric modulation and ion permeation. Here we present crystal structures of the zebrafish P2X4 receptor in its closed, resting state. The chalice-shaped, trimeric receptor is knit together by subunit–subunit contacts implicated in ion channel gating and receptor assembly. Extracellular domains, rich in β-strands, have large acidic patches that may attract cations, through fenestrations, to vestibules near the ion channel. In the transmembrane pore, the ‘gate’ is defined by an ∼8 A slab of protein. We define the location of three non-canonical, intersubunit ATP-binding sites, and suggest that ATP binding promotes subunit rearrangement and ion channel opening. P2X receptors are ATP-gated non-selective cation channels involved in nociception and inflammatory responses, whose structures were unknown. Kawate et al. now present the crystal structure of the zebrafish P2X4 receptor in a closed state. The trimeric structure reveals some of the molecular underpinnings of ligand-binding, cation entry and channel gating. A related paper presents the structure of chicken acid-sensing ion channel 1 (ASIC1) in a desensitized state. Like P2X receptors, ASICs are trimeric, but they belong to an entirely different family of ion channels. The structure determination of ASIC1 shows how ion permeation and desensitization may occur, and comparison of ASIC and P2X structures suggests that these functionally distinct channels employ similar mechanistic principles. P2X receptors are ATP-gated cation channels that are implicated in diverse physiological processes, from synaptic transmission to inflammation to the sensing of taste and pain. The crystal structure of the zebrafish P2X4 channel is now solved in its closed state, revealing some of the molecular underpinnings of ligand-binding, cation entry and channel gating.
TL;DR: These studies suggest that neighborhood environment is important for older adults' health and functioning.
TL;DR: CML-CP pts responding to IM had a low overall risk of progression to AP/BC and the safety profile of IM remains unchanged after 8 yr, with no previously unreported AEs identified over the past 36 mo.
TL;DR: Cognitive function in nondemented aging appears to be degraded by the presence of NFTs and SPs, and neuropathological processes related to AD in persons without dementia appear to be associated with subtle cognitive dysfunction and may represent a preclinical stage of the illness.
University of Washington1, University of Pennsylvania2, Colorado Department of Public Health and Environment3, Brown University4, Washington State Department of Health5, University of California, San Francisco6, Blue Cross Blue Shield Association7, Oregon Health & Science University8, Johns Hopkins University9, Emory University10, Merck & Co.11
TL;DR: The EGAPP Working Group constructed a chain of evidence that linked genetic testing for Lynch syndrome in patients with newly diagnosed CRC with improved health outcomes in their relatives, and concluded that there is moderate certainty that such a testing strategy would provide moderate population benefit.
University of Nebraska Medical Center1, Carlos III Health Institute2, University of Oxford3, University of Oslo4, Oregon Health & Science University5, National Institutes of Health6, University of British Columbia7, University of Würzburg8, Bosch9, University of Arizona10, University of Barcelona11, Emory University12
TL;DR: A new algorithm using GCET1, CD10, BCL6, MUM1, and FOXP1 was derived that closely approximated the GEP classification with 93% concordance and will facilitate risk stratification of DLBCL patients and futureDLBCL research using archival materials.
Abstract: Purpose: Hans and coworkers previously developed an immunohistochemical algorithm with ∼80% concordance with the gene expression profiling (GEP) classification of diffuse large B-cell lymphoma (DLBCL) into the germinal center B-cell–like (GCB) and activated B-cell–like (ABC) subtypes. Since then, new antibodies specific to germinal center B-cells have been developed, which might improve the performance of an immunostain algorithm. Experimental Design: We studied 84 cases of cyclophosphamide-doxorubicin-vincristine-prednisone (CHOP)–treated DLBCL (47 GCB, 37 ABC) with GCET1, CD10, BCL6, MUM1, FOXP1, BCL2, MTA3, and cyclin D2 immunostains, and compared different combinations of the immunostaining results with the GEP classification. A perturbation analysis was also applied to eliminate the possible effects of interobserver or intraobserver variations. A separate set of 63 DLBCL cases treated with rituximab plus CHOP (37 GCB, 26 ABC) was used to validate the new algorithm. Results: A new algorithm using GCET1, CD10, BCL6, MUM1, and FOXP1 was derived that closely approximated the GEP classification with 93% concordance. Perturbation analysis indicated that the algorithm was robust within the range of observer variance. The new algorithm predicted 3-year overall survival of the validation set [GCB (87%) versus ABC (44%); P Conclusion: Our new algorithm is significantly more accurate than the Hans9 algorithm and will facilitate risk stratification of DLBCL patients and future DLBCL research using archival materials. (Clin Cancer Res 2009;15(17):5494–502)
TL;DR: An objective, empirically based index that can be used to identify the statistically estimated risk of in-hospital mortality by procedure and to group procedures into risk categories is created and represents an improvement over existing consensus-based methods.
TL;DR: It is found that fetal offspring from both lean and obese mothers chronically consuming a HFD had a 3-fold increase in liver triglycerides (TGs), and exposure to this may increase the risk of pediatric NAFLD.
Abstract: Maternal obesity is thought to increase the offspring's risk of juvenile obesity and metabolic diseases; however, the mechanism(s) whereby excess maternal nutrition affects fetal development remain poorly understood. Here, we investigated in nonhuman primates the effect of chronic high-fat diet (HFD) on the development of fetal metabolic systems. We found that fetal offspring from both lean and obese mothers chronically consuming a HFD had a 3-fold increase in liver triglycerides (TGs). In addition, fetal offspring from HFD-fed mothers (O-HFD) showed increased evidence of hepatic oxidative stress early in the third trimester, consistent with the development of nonalcoholic fatty liver disease (NAFLD). O-HFD animals also exhibited elevated hepatic expression of gluconeogenic enzymes and transcription factors. Furthermore, fetal glycerol levels were 2-fold higher in O-HFD animals than in control fetal offspring and correlated with maternal levels. The increased fetal hepatic TG levels persisted at P180, concurrent with a 2-fold increase in percent body fat. Importantly, reversing the maternal HFD to a low-fat diet during a subsequent pregnancy improved fetal hepatic TG levels and partially normalized gluconeogenic enzyme expression, without changing maternal body weight. These results suggest that a developing fetus is highly vulnerable to excess lipids, independent of maternal diabetes and/or obesity, and that exposure to this may increase the risk of pediatric NAFLD.