Several lines of evidence indicate that a range of measures obtained in cognitively normal individuals are significantly related to time to onset of clinical symptoms of Alzheimer's disease (AD) that develop many years later. This suggests that combinations of biomarkers might be useful for selecting individuals to include in clinical trials and for assessing disease progression in response to treatment. Using data from the BIOCARD study, which includes serial assessment of CSF, MRI and cognitive measures, we used time-dependent ROC methods to examine combinations of measures that were significant predictors of which cognitively normal individuals had a high likelihood of progressing to mild cognitive impairment (MCI) due to AD over time. The best model was selected using the AIC criterion. Using data from baseline in 189 participants, and predicting onset of clinical symptoms up to 5 years later, sets of biomarkers were examined using several approaches: (1) the least costly to the most costly, (2) the least invasive to the most invasive, and (3) the best fit model. The best fit model included 6 variables: two cognitive measures (Digit Symbol and Paired Associates Immediate Recall), two CSF measures (Abeta and ptau) and two MRI measures (right entorhinal cortex thickness and right hippocampal volume), adjusted for demographics (AUC=0.886, sensitivity = 0.85, specificity = 0.70). Moreover, the addition of each domain (cognitive + CSF + MRI) added significantly to the accuracy of prediction. Combinations of biomarkers obtained at least 5 years prior to symptom onset can be used to identify which cognitively normal individuals will progress to MCI due to AD. Additionally, these findings demonstrate that biomarkers useful for prediction later in the disease course are useful in preclinical AD. Clinical trials aimed at delaying the onset of symptoms could utilize such an approach for determining which individuals might be most likely to benefit from inclusion in a clinical trial aimed at individuals with preclinical AD and/or tracking response to treatment.
Purpose The selection and design of control conditions are critical factors in minimizing the influence of unwanted variables in randomized controlled trials (RCTs). This article describes the rationale, design, and content of a standard of care control condition in a Phase III RCT of tinnitus retraining therapy. Method Existing tinnitus practices at military hospitals were identified and aligned with the American Speech-Language-Hearing Association's (2006) preferred practice patterns for tinnitus management and counseling and embedded in a patient-centered protocol to ensure uniformity and treatment fidelity. Results For those involved in the design of behavioral RCTs, the article identifies options and methods to consider in the selection and design of control conditions. Conclusion For those who provide tinnitus services, the standard of care protocol developed for the tinnitus retraining therapy trial constitutes a patient-centered approach to intervention that can be implemented clinically. Supplemental Material https://doi.org/10.23641/asha.9342503
—To assess the safety and efficacy of optic nerve decompression surgery compared with careful follow-up alone in patients with nonarteritic anterior ischemic optic neuropathy (NAION).
Design.
—The Ischemic Optic Neuropathy Decompression Trial (IONDT) is a randomized, single-masked, multicenter trial.
Setting.
—Twenty-five US clinical centers.
Participants.
—The IONDT ceased recruitment on October 20, 1994, on the recommendation of its Data and Safety Monitoring Committee. The preliminary results presented herein are based on data as of September 8,1994, from 244 patients with NAION and visual acuity of 20/64 or worse. One hundred twenty-five patients had been randomized to careful follow-up, and 119 had been randomized to surgery, with 91 and 95, respectively, having completed 6 months of follow-up.
Intervention.
—Patients in the surgery group received optic nerve decompression surgery and follow-up ophthalmologic examinations; those in the careful follow-up group received ophthalmologic examinations at the same times as the surgery group.
Main Outcome Measures.
—Gain or loss of three or more lines of visual acuity on the New York Lighthouse chart at 6 months after randomization, as measured by a technician masked to treatment assignment.
Results.
—Patients assigned to surgery did no better when compared with patients assigned to careful follow-up regarding improved visual acuity of three or more lines at 6 months: 32.6% of the surgery group improved compared with 42.7% of the careful follow-up group. The odds ratio (OR) for three or more lines better, adjusted for baseline visual acuity and diabetes, was 0.74 (95% confidence interval [CI], 0.39 to 1.38). Patients receiving surgery had a significantly greater risk of losing three or more lines of vision at 6 months: 23.9% in the surgery group worsened compared with 12.4% in the careful follow-up group. The 6-month adjusted OR for three or more lines worse was 1.96 (95% CI, 0.87 to 4.41). No difference in treatment effect was observed between patients with progressive NAION and all others.
Conclusion.
—Results from the IONDT indicate that optic nerve decompression surgery for NAION is not effective, may be harmful, and should be abandoned. The spontaneous improvement rate is better than previously reported. (JAMA. 1995;273:625-632)
Methodological research has found that non-published studies often have different results than those that are published, a phenomenon known as publication bias. When results are not published, or are published selectively based on the direction or the strength of the findings, healthcare professionals and consumers of healthcare cannot base their decision-making on the full body of current evidence.As part of the OPEN project (http://www.open-project.eu) we will conduct a systematic review with the following objectives:1. To determine the proportion and/or rate of non-publication of studies by systematically reviewing methodological research projects that followed up a cohort of studies that a. received research ethics committee (REC) approval,b. were registered in trial registries, orc. were presented as abstracts at conferences.2. To assess the association of study characteristics (for example, direction and/or strength of findings) with likelihood of full publication.To identify reports of relevant methodological research projects we will conduct electronic database searches, check reference lists, and contact experts. Published and unpublished projects will be included. The inclusion criteria are as follows:a. RECs: methodological research projects that examined the subsequent proportion and/or rate of publication of studies that received approval from RECs;b. Trial registries: methodological research projects that examine the subsequent proportion and/or rate of publication of studies registered in trial registries;c. Conference abstracts: methodological research projects that examine the subsequent proportion and/or rate of full publication of studies which were initially presented at conferences as abstracts.Proportion/rate of published studies; time to full publication (mean/median; cumulative publication rate by time).Association of study characteristics with full publication.The different questions (a, b, and c) will be investigated separately. Data synthesis will involve a combination of descriptive and statistical summaries of the included methodological research projects.Results are expected to be publicly available in mid 2013.
The National Academy of Sciences (NAS) Review of the Environmental Protection Agency's Draft IRIS Assessment of Formaldehyde proposed a "roadmap" for reform and improvement of the Agency's risk assessment process. Specifically, it called for development of a transparent and defensible methodology for weight-of-evidence (WoE) assessments. To facilitate development of an improved process, we developed a white paper that reviewed approximately 50 existing WoE frameworks, seeking insights from their variations and nominating best practices for WoE analyses of causation of chemical risks. Four phases of WoE analysis were identified and evaluated in each framework: (1) defining the causal question and developing criteria for study selection, (2) developing and applying criteria for review of individual studies, (3) evaluating and integrating evidence and (4) drawing conclusions based on inferences. We circulated the draft white paper to stakeholders and then held a facilitated, multi-disciplinary invited stakeholder workshop to broaden and deepen the discussion on methods, rationales, utility and limitations among the surveyed WoE frameworks. The workshop developed recommendations for improving the conduct of WoE evaluations. Based on the analysis of the 50 frameworks and discussions at the workshop, best practices in conducting WoE analyses were identified for each of the four phases. Many of these best practices noted from the analysis and workshop could be implemented immediately, while others may require additional refinement as part of the ongoing discussions for improving the scientific basis of chemical risk assessments.
Department of Anaesthesiology and Intensive Care Medicine, Clemens Hospital, Miinster, FRC Abbreviations ECG– electrocardiogram; ECG– eletroencephalogram; SAM–subarachnoid haemorrhage
Methylphenidate is a psychostimulant widely used by geriatric psychiatrists but with a limited evidence base for efficacy and safety. We conducted a randomized double-blind placebo-controlled trial (RCT) of methyphenidate treatment of apathy in 60 participants with Alzheimer's Disease, Apathy in Dementia Methylphenidate Trial (ADMET), and here report safety data and adverse events from the trial. Patients with apathy and AD were recruited for ADMET at 3 university sites. Included participants had a diagnosis of AD (NINCDS-ADRDA criteria) with MMSE scores >10, and were apathetic (apathy score on Neuropsychiatric Inventory “very frequently” or “frequent/often” AND severity “moderate” or “marked”). Patients were randomized to 6 weeks treatment with placebo vs methyphenidate with dose titrated up as tolerated and a target dose of 20 mg daily. Assessments were at baseline, 2, 4, and 6 weeks after randomization. Adverse events (AEs) were recorded using a symptom checklist. Serious adverse events (SAEs) were defined as events leading to hospitalization or death. The results of the ADMET trial will be expected in April 2012. A total of 60 patients were recruited (62% female, and 92% Caucasian, non-Hispanic). At baseline, patients were, on average (± SD), 76 ± 8 years of age and had an MMSE score of 20 ± 5. AEs reported by > 1/3 of participants at least one follow up visit included: 52% agitation, 47% anxiety, 41% depressed mood, 40% drowsiness, 35% anthralgia, 33% distractibility. All other solicited symptoms were reported by less than 1/3 of the participants, including angina, distractibility, dyskinesia, impulsivity, palpitations, and tachycardia. There were two SAEs for “abdominal pain” and “drop in hemoglobin” and no deaths reported. AEs and SAEs will be presented stratified by treatment assignment at AAIC. The results of ADMET will be useful to clinicians and investigators to better understand the safety profile of methyphenidate administered in an RCT. Although results stratified by treatment assignment are not yet available, it is notable that AEs thought to be specific to methylphenidate were not highly prevalent in ADMET.
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