Microarray-based classifiers and prognosis models identify subgroups with distinct clinical outcomes and high risk of AML transformation of myelodysplastic syndrome

The diagnosis of myelodysplastic syndrome (MDS) currently relies primarily on the morphologic assessment of the patient's bone marrow and peripheral blood cells. Moreover, prognostic scoring systems rely on observer-dependent assessments of blast percentage and dysplasia. Gene expression profiling could enhance current diagnostic and prognostic systems by providing a set of standardized, objective gene signatures. Within the Microarray Innovations in LEukemia study, a diagnostic classification model was investigated to distinguish the distinct subclasses of pediatric and adult leukemia, as well as MDS. Overall, the accuracy of the diagnostic classification model for subtyping leukemia was approximately 93%, but this was not reflected for the MDS samples giving only approximately 50% accuracy. Discordant samples of MDS were classified either into acute myeloid leukemia (AML) or

Effect of intravenous beta-2 agonist treatment on clinical outcomes in acute respiratory distress syndrome (BALTI-2): a multicentre, randomised controlled trial

BACKGROUND:
In a previous randomised controlled phase 2 trial, intravenous infusion of salbutamol for up to 7 days in patients with acute respiratory distress syndrome (ARDS) reduced extravascular lung water and plateau airway pressure. We assessed the effects of this intervention on mortality in patients with ARDS.
METHODS:
We did a multicentre, placebo-controlled, parallel-group, randomised trial at 46 UK intensive-care units between December, 2006, and March, 2010. Intubated and mechanically ventilated patients (aged =16 years) within 72 h of ARDS onset were randomly assigned to receive either salbutamol (15 µg/kg ideal bodyweight per h) or placebo for up to 7 days. Randomisation was done by a central telephone or web-based randomisation service with minmisation by centre, pressure of arterial oxygen to fractional inspired oxygen concentration (PaO(2)/F(I)O(2)) ratio, and age. All participants, caregivers, and investigators were masked to group allocation. The primary outcome was death within 28 days of randomisation. Analysis was by intention-to-treat. This trial is registered, ISRCTN38366450 and EudraCT number 2006-002647-86.
FINDINGS:
We randomly assigned 162 patients to the salbutamol group and 164 to the placebo group. One patient in each group withdrew consent. Recruitment was stopped after the second interim analysis because of safety concerns. Salbutamol increased 28-day mortality (55 [34%] of 161 patients died in the salbutamol group vs 38 (23%) of 163 in the placebo group; risk ratio [RR] 1·47, 95% CI 1·03-2·08).
INTERPRETATION:
Treatment with intravenous salbutamol early in the course of ARDS was poorly tolerated. Treatment is unlikely to be beneficial, and could worsen outcomes. Routine use of ß-2 agonist treatment in ventilated patients with this disorder cannot be recommended.

Clinical outcomes and inflammatory biomarkers in current smokers and exsmokers with severe asthma

Clinical outcomes are worse in current smokers and exsmokers with mild-to-moderate asthma compared with never smokers, but little is known about the influence of smoking status in patients with severe asthma.

Variation of clinical outcomes used in glaucoma randomised controlled trials:a systematic review

Purpose: In randomised clinical trials (RCTs) the selection of appropriate outcomes is crucial to the assessment of whether one intervention is better than another. The purpose of this review is to identify different clinical outcomes reported in glaucoma trials.

Methods We conducted a systematic review of glaucoma RCTs. A sample or selection of glaucoma trials were included bounded by a time frame (between 2006 and March 2012). Only studies in English language were considered. All clinical measured and reported outcomes were included. The possible variations of clinical outcomes were defined prior to data analysis. Information on reported clinical outcomes was tabulated and analysed using descriptive statistics. Other data recorded included type of intervention and glaucoma, duration of the study, defined primary outcomes, and outcomes used for sample size calculation, if nominated.

Results The search strategy identified 4323 potentially relevant abstracts. There were 315 publications retrieved, of which 233 RCTs were included. A total of 967 clinical measures were reported. There were large variations in the definitions used to describe different outcomes and their measures. Intraocular pressure was the most commonly reported outcome (used in 201 RCTs, 86%) with a total of 422 measures (44%). Safety outcomes were commonly reported in 145 RCTs (62%) whereas visual field outcomes were used in 38 RCTs (16%).

Conclusions There is a large variation in the reporting of clinical outcomes in glaucoma RCTs. This lack of standardisation may impair the ability to evaluate the evidence of glaucoma interventions.

XBP1s levels are implicated in the biology and outcome of myeloma mediating different clinical outcomes to thalidomide-based treatments.

Immunoglobulin production by myeloma plasma cells depends on the unfolded protein response for protein production and folding. Recent studies have highlighted the importance of IRE1alpha and X box binding protein 1 (XBP1), key members of this pathway, in normal B-plasma cell development. We have determined the gene expression levels of IRE1alpha, XBP1, XBP1UNSPLICED (XBP1u), and XBP1SPLICED (XBP1s) in a series of patients with myeloma and correlated findings with clinical outcome. We show that IRE1alpha and XBP1 are highly expressed and that patients with low XBP1s/u ratios have a significantly better overall survival. XBP1s is an independent prognostic marker and can be used with beta2 microglobulin and t(4;14) to identify a group of patients with a poor outcome. Furthermore, we show the beneficial therapeutic effects of thalidomide in patients with low XBP1s/u ratios. This study highlights the importance of XBP1 in myeloma and its significance as an independent prognostic marker and as a predictor of thalidomide response.

Clinical Outcomes in 3343 Children and Adults with Rheumatic Heart Disease from 14 Low and Middle Income Countries: 2-Year Follow-up of the Global Rheumatic Heart Disease Registry (the REMEDY study)

BACKGROUND: -There are few contemporary data on the mortality and morbidity associated with rheumatic heart disease (RHD) or information on their predictors. We report the two year follow-up of individuals with RHD from 14 low and middle income countries in Africa and Asia.

METHODS: -Between January 2010 and November 2012, we enrolled 3343 patients from 25 centers in 14 countries and followed them for two years to assess mortality, congestive heart failure (CHF), stroke or transient ischemic attack (TIA), recurrent acute rheumatic fever (ARF), and infective endocarditis (IE).

RESULTS: -Vital status at 24 months was known for 2960 (88.5%) patients. Two thirds were female. Although patients were young (median age 28 years, interquartile range 18 to 40), the two year case fatality rate was high (500 deaths, 16.9%). Mortality rate was 116.3/1000 patient-years in the first year and 65.4/1000 patient-years in the second year. Median age at death was 28.7 years. Independent predictors of death were severe valve disease (hazard ratio (HR) 2.36, 95% confidence interval (CI) 1.80-3.11), CHF (HR 2.16, 95% CI 1.70-2.72), New York Heart Association functional class III/IV (HR 1.67, 95% CI 1.32-2.10), atrial fibrillation (AF) (HR 1.40, 95% CI 1.10-1.78) and older age (HR 1.02, 95% CI 1.01-1.02 per year increase) at enrolment. Post-primary education (HR 0.67, 95% CI 0.54-0.85) and female sex (HR 0.65, 95%CI 0.52-0.80) were associated with lower risk of death. 204 (6.9%) had new CHF (incidence, 38.42/1000 patient-years), 46 (1.6%) had a stroke or TIA (8.45/1000 patient-years), 19 (0.6%) had ARF (3.49/1000 patient-years), and 20 (0.7%) had IE (3.65/1000 patient-years). Previous stroke and older age were independent predictors of stroke/TIA or systemic embolism. Patients from low and lower-middle income countries had significantly higher age- and sex-adjusted mortality compared to patients from upper-middle income countries. Valve surgery was significantly more common in upper-middle income than in lower-middle- or low-income countries.

CONCLUSIONS: -Patients with clinical RHD have high mortality and morbidity despite being young; those from low and lower-middle income countries had a poorer prognosis associated with advanced disease and low education. Programs focused on early detection and treatment of clinical RHD are required to improve outcomes.

Communicating clinical trial outcomes: Effects of presentation method on physicians’ evaluations of new treatments

Physicians expect a treatment to be more effective when its clinical outcomes are described as relative rather than as absolute risk reductions. We examined whether effects of presentation method (relative vs. absolute risk reduction)
remain when physicians are provided the baseline risk information, a vital piece of statistical information omitted in previous studies. Using a between-subjects design, ninety five physicians were presented the risk reduction associated
with a fictitious treatment for hypertension either as an absolute risk reduction or as a relative risk reduction, with or without including baseline risk information. Physicians reported that the treatment would be more effective and that they would be more willing to prescribe it when its risk reduction was presented to them in relative rather than in absolute terms. The relative risk reduction was perceived as more effective than absolute risk reduction even when the baseline risk information was explicitly reported. We recommend that information about absolute risk reduction be made available to physicians in the reporting of clinical outcomes. Moreover, health professionals should be cognizant of the potential biasing effects of risk information presented in relative risk terms

A prospective clinical trial of a real-time polymerase chain reaction assay for the diagnosis of candidemia in nonneutropenic, critically ill adults

Background. Invasive Candida infection among nonneutropenic, critically ill adults is a clinical problem that has received increasing attention in recent years. Poor performance of extant diagnostic modalities has promoted risk-based, preemptive prescribing in view of the poor outcomes associated with inadequate or delayed antifungal therapy; this risks unnecessary overtreatment. A rapid, reliable diagnostic test could have a substantial impact on therapeutic practice in this patient population.

Methods. Three TaqMan-based real-time polymerase chain reaction assays were developed that are capable of detecting the main medically important Candida species, categorized according to the likelihood of fluconazole susceptibility. Assay 1 detected Candida albicans, Candida parapsilosis, Candida tropicalis, and Candida dubliniensis. Assays 2 and 3 detected Candida glabrata and Candida krusei, respectively. The clinical performance of these assays, applied to serum, was evaluated in a prospective trial of nonneutropenic adults in a single intensive care unit.

Results. In all, 527 specimens were obtained from 157 participants. All 3 assays were run in parallel for each specimen; they could be completed within 1 working day. Of these, 23 specimens were obtained from 23 participants categorized as having proven Candida infection at the time of sampling. If a single episode of Candida famata candidemia was excluded, the estimated clinical sensitivity, specificity, and positive and negative predictive values of the assays in this trial were 90.9%, 100%, 100% and 99.8%, respectively.

Conclusions. These data suggest that the described assays perform well in this population for enhancing the diagnosis of candidemia. The extent to which they may affect clinical outcomes, prescribing practice, and cost-effectiveness of care remains to be ascertained.

Effect of a clinical pathway to reduce hospitalizations in nursing home residents with pneumonia:A randomized controlled trial

Context: Nursing home residents with pneumonia are frequently hospitalized. Such transfers may be associated with multiple hazards of hospitalization as well as economic costs. Objective: To assess whether using a clinical pathway for on-site treatment of pneumonia and other lower respiratory tract infections in nursing homes could reduce hospital admissions, related complications, and costs. Design, Setting, and Participants: A cluster randomized controlled trial of 680 residents aged 65 years or older in 22 nursing homes in Hamilton, Ontario, Canada. Nursing homes began enrollment between January 2, 2001, and April 18, 2002, with the last resident follow-up occurring July 4, 2005. Residents were eligible if they met a standardized definition of lower respiratory tract infection. Interventions: Treatment in nursing homes according to a clinical pathway, which included use of oral antimicrobials, portable chest radiographs, oxygen saturation monitoring, rehydration, and close monitoring by a research nurse, or usual care. Main Outcome Measures: Hospital admissions, length of hospital stay, mortality, health-related quality of life, functional status, and cost. Results: Thirty-four (10%) of 327 residents in the clinical pathway group were hospitalized compared with 76 (22%) of 353 residents in the usual care group. Adjusting for clustering of residents in nursing homes, the weighted mean reduction in hospitalizations was 12% (95% confidence interval [CI], 5%-18%; P=.001). The mean number of hospital days per resident was 0.79 in the clinical pathway group vs 1.74 in the usual care group, with a weighted mean difference of 0.95 days per resident (95% CI, 0.34-1.55 days; P=.004). The mortality rate was 8% (24 deaths) in the clinical pathway group vs 9% (32 deaths) in the usual care group, with a weighted mean difference of 2.9% (95% CI, -2.0% to 7.9%; P=.23). There were no significant differences between the groups in health-related quality of life or functional status. The clinical pathway resulted in an overall cost savings of US $1016 per resident (95% CI, $207-$1824) treated. Conclusion: Treating residents of nursing homes with pneumonia and other lower respiratory tract infections with a clinical pathway can result in comparable clinical outcomes, while reducing hospitalizations and health care costs. ©2006 American Medical Association. All rights reserved.

Overview of clinical outcome measures used in glaucoma randomised controlled trials (RCTs)

Background: In clinical trials the selection of appropriate outcomes is crucial to the assessment of whether one intervention is better than another. Glaucoma is a chronic eye disease and the leading cause of irreversible blindness in the world. A variety of outcomes has been used and reported in glaucoma RCTs.

Objectives: The purpose of this review is to identify different clinical outcome measures used in glaucoma RCTs between January 2006 and March 2012.

Methods: A systematic review was conducted using standard methodology. We searched for RCTs in glaucoma published in English with no restrictions on the population type or size, or applied interventions. All clinical outcomes were included. Patient-reported, pharmacokinetic and economic outcomes were excluded.

Results: The search strategy identified 4288 potentially relevant abstracts. There were 315 publications retrieved, of which 233 RCTs were included. A total of 967 clinical measures were reported. There were large variations in the definitions used to describe different outcomes and their measures. Intraocular pressure (IOP) was the most commonly reported outcome (used in 201 RCTs, 86%) with a total of 422 measures (44%). Amongst the IOPrelated measures, the most commonly used was mean IOP (n=143, 15% of all measures). Safety outcomes were commonly reported, in 145 RCTs (62%) whereas visual field outcomes were utilized in 38 RCTs (16%).

Conclusions: There is a large variability in clinical outcomes used for glaucoma RCTs and in the way each outcome is reported. This lack of standardisation may impair the ability to evaluate the evidence of glaucoma interventions.

Genomic lesions associated with a different clinical outcome in diffuse large B-Cell lymphoma treated with R-CHOP-21

Despite recent therapeutic improvements, the clinical course of diffuse large B-cell lymphoma (DLBCL) still differs considerably among patients. We conducted this retrospective multi-centre study to evaluate the impact of genomic aberrations detected using a high-density genome wide-single nucleotide polymorphism-based array on clinical outcome in a population of DLBCL patients treated with R-CHOP-21 (rituximab, cyclophosphamide, doxorubicine, vincristine and prednisone repeated every 21_d). 166 DNA samples were analysed using the GeneChip Human Mapping 250K NspI. Genomic anomalies were analysed regarding their impact on the clinical course of 124 patients treated with R-CHOP-21. Unsupervised clustering was performed to identify genetically related subgroups of patients with different clinical outcomes. Twenty recurrent genetic lesions showed an impact on the clinical course. Loss of genomic material at 8p23.1 showed the strongest statistical significance and was associated with additional aberrations, such as 17p- and 15q-. Unsupervised clustering identified five DLBCL clusters with distinct genetic profiles, clinical characteristics and outcomes. Genetic features and clusters, associated with a different outcome in patients treated with R-CHOP, have been identified by arrayCGH.

Design characteristic of randomised controlled trials for geographic atrophy in age-related macular degeneration: selection of outcomes and sample size calculation

PurposeThe selection of suitable outcomes and sample size calculation are critical factors in the design of a randomised controlled trial (RCT). The goal of this study was to identify the range of outcomes and information on sample size calculation in RCTs on geographic atrophy (GA).MethodsWe carried out a systematic review of age-related macular degeneration (AMD) RCTs. We searched MEDLINE, EMBASE, Scopus, Cochrane Library, www.controlled-trials.com, and www.ClinicalTrials.gov. Two independent reviewers screened records. One reviewer collected data and the second reviewer appraised 10% of collected data. We scanned references lists of selected papers to include other relevant RCTs.ResultsLiterature and registry search identified 3816 abstracts of journal articles and 493 records from trial registries. From a total of 177 RCTs on all types of AMD, 23 RCTs on GA were included. Eighty-one clinical outcomes were identified. Visual acuity (VA) was the most frequently used outcome, presented in 18 out of 23 RCTs and followed by the measures of lesion area. For sample size analysis, 8 GA RCTs were included. None of them provided sufficient Information on sample size calculations.ConclusionsThis systematic review illustrates a lack of standardisation in terms of outcome reporting in GA trials and issues regarding sample size calculation. These limitations significantly hamper attempts to compare outcomes across studies and also perform meta-analyses.

Clinical evaluation of three incision size-dependent phacoemulsification systems.

PURPOSE:

To compare the outcomes of cataract surgery performed with 3 incision size-dependent phacoemulsification groups (1.8, 2.2, and 3.0 mm).

DESIGN:

Prospective randomized comparative study.

METHODS:

One hundred twenty eyes of 120 patients with age-related cataract (grades 2 to 4) were categorized according to the Lens Opacities Classification System III. Eligible subjects were randomly assigned to 3 surgical groups using coaxial phacoemulsification through 3 clear corneal incision sizes (1.8, 2.2, and 3.0 mm). Different intraoperative and postoperative outcome measures were obtained, with corneal incision size and surgically induced astigmatism as the main clinical outcomes.

RESULTS:

There were no statistically significant differences in most of the intraoperative and postoperative outcome measures among the 3 groups. However, the mean cord length of the clear corneal incision was increased in each group after surgery. The mean maximal clear corneal incision thickness in the 1.8-mm group was significantly greater than for the other groups at 1 month. The mean surgically induced astigmatism in the 1.8- and 2.2-mm groups was significantly less than that in the 3.0-mm group after 1 month, without significant difference between the 1.8- and 2.2-mm groups.

CONCLUSIONS:

With appropriate equipment, smaller incisions may result in less astigmatism, but the particular system used will influence incision stress and wound integrity, and may thus limit the reduction in incision size and astigmatism that is achievable.

The association between anticholinergic medication burden and health related outcomes in the ‘oldest old’: A systematic review of the literature

Background: Increased exposure to anticholinergic medication is problematic, particularly in those aged 80 years and older.

Objective: The aim of this systematic review was to identify tools used to quantify anticholinergic medication burden and determine the most appropriate tool for use in longitudinal research, conducted in those aged 80 years and older.

Methods: A systematic literature search was conducted across six electronic databases to identify existing tools. Data extraction was conducted independently by two researchers; studies describing the development of each tool were also retrieved and relevant data extracted. An assessment of quality was completed for all studies. Tools were assessed in terms of their measurement of the association between anticholinergic medication burden and a defined set of clinical outcomes, their development and their suitability for use in longitudinal research; the latter was evaluated on the basis of criteria defined as the key attributes of an ideal anticholinergic risk tool.

Results: In total, 807 papers were retrieved, 13 studies were eligible for inclusion and eight tools were identified. Included studies were classed as ‘very good’ or ‘good’ following the quality assessment analysis; one study was unclassified. Anticholinergic medication burden as measured in studies was associated with impaired cognitive and physical function, as well as an increased frequency of falls. The Drug Burden Index (DBI) exhibited most of the key attributes of an ideal anticholinergic risk tool.

Conclusion: This review identified the DBI as the most appropriate tool for use in longitudinal research focused on older people and their exposure to anticholinergic medication burden.