Search

Abstract Background To model the progression of geographic atrophy (GA) in patients with age-related macular degeneration (AMD) by building a suitable statistical regression model for GA size measurements obtained from fundus autofluorescence imaging. Methods Based on theoretical considerations, we develop a linear mixed-effects model for GA size progression that incorporates covariable-dependent enlargement rates as well as correlations between longitudinally collected GA size measurements. To capture nonlinear progression in a flexible way, we systematically assess Box-Cox transformations with different transformation parameters λ. Model evaluation is performed on data collected for two longitudinal, prospective multi-center cohort studies on GA size progression. Results A transformation parameter of λ=0.45 yielded the best model fit regarding the Akaike information criterion (AIC). When hypertension and hypercholesterolemia were included as risk factors in the model, they showed an association with progression of GA size. The mean estimated age-of-onset in this model was 67.21±6.49 years. Conclusions We provide a comprehensive framework for modeling the course of uni- or bilateral GA size progression in longitudinal observational studies. Specifically, the model allows for age-of-onset estimation, identification of risk factors and prediction of future GA size. A square-root transformation of atrophy size is recommended before model fitting.

Abstract Background Vestibular migraine (VM) is the most frequent cause of recurrent spontaneous attacks of vertigo causally related to migraine. The objective of the Prophylactic treatment of vestibular migraine with metoprolol (PROVEMIG) trial was to demonstrate that metoprolol succinate is superior to placebo in the prevention of episodic vertigo- and migraine-related symptoms in patients with VM. Methods This phase III, two-arm, parallel-group, double-blind, randomized placebo-controlled trial was designed to be conducted at tertiary referral centres at neurology and ear, nose and throat departments of eight German university hospitals. The planned sample size was a total of 266 patients to be allocated. Adults aged 18 years or above diagnosed with probable or definitive VM according to the Neuhauser criteria 2001 were randomly assigned 1:1 to 6 months blinded metoprolol (maintenance dosage of 95 mg daily) or placebo. The primary efficacy outcome was the self-reported number of vertiginous attacks per 30 days documented by means of a paper-based daily symptom diary. The pre-specified time period of primary interest was defined as months 4 to 6. Secondary outcomes included the patient-reported number of migraine days and vertigo days, the Dizziness Handicap Inventory, and clinical assessments. Adverse events were reported throughout the whole 9-month study period. Results At the time of trial termination, no evidence for a difference in the incidence of vertiginous attacks between groups was detected. For the full analysis set, the incidence rate ratio was 0.983 (95% confidence interval (CI) 0.902–1.071) for metoprolol versus placebo. In both groups, there was a significant decline over time in the overall monthly vertigo attacks by a factor of 0.830 (95% CI 0.776–0.887). Results were consistent for all subjective and objective key measures of efficacy. The treatment was well tolerated with no unexpected safety findings. Conclusions After randomizing 130 patients PROVEMIG had to be discontinued because of poor participant accrual not related to the tolerability of the study medication or safety concerns; no treatment benefit of metoprolol over placebo could be established. Additional preparatory work is much needed in the development, psychometric evaluation and interpretation of clinically meaningful end points in trials on episodic syndromes like VM taking into consideration the complexity of this disease entity comprising two domains (vertigo- and headache-related disability). Trial registration EudraCT, 2009-013701-34. Prospectively registered on 8 April 2011.

Abstract Background Traumatic events like critical illness and intensive care are threats to life and bodily integrity and pose a risk factor for posttraumatic stress disorder (PTSD). PTSD affects the quality of life and morbidity and may increase health-care costs. Limited access to specialist care results in PTSD patients being treated in primary care settings. Narrative exposure therapy (NET) is based on the principles of cognitive behavioral therapy and has shown positive effects when delivered by health-care professionals other than psychologists. The primary aims of the PICTURE trial (from “PTSD after ICU survival”) are to investigate the effectiveness and applicability of NET adapted for primary care with case management in adults diagnosed with PTSD after intensive care. Methods/design This is an investigator-initiated, multi-center, primary care-based, randomized controlled two-arm parallel group, observer-blinded superiority trial conducted throughout Germany. In total, 340 adult patients with a total score of at least 20 points on the posttraumatic diagnostic scale (PDS-5) 3 months after receiving intensive care treatment will be equally randomized to two groups: NET combined with case management and improved treatment as usual (iTAU). All primary care physicians (PCPs) involved will be instructed in the diagnosis and treatment of PTSD according to current German guidelines. PCPs in the iTAU group will deliver usual care during three consultations. In the experimental group, PCPs will additionally be trained to deliver an adapted version of NET (three sessions) supported by phone-based case management by a medical assistant. At 6 and 12 months after randomization, structured blinded telephone interviews will assess patient-reported outcomes. The primary composite endpoint is the absolute change from baseline at month 6 in PTSD symptom severity measured by the PDS-5 total score, which also incorporates the death of any study patients. Secondary outcomes cover the domains depression, anxiety, disability, health-related quality-of-life, and cost-effectiveness. The principal analysis is by intention to treat. Discussion If the superiority of the experimental intervention over usual care can be demonstrated, the combination of brief NET and case management could be a treatment option to relieve PTSD-related symptoms and to improve primary care after intensive care. Trial registration ClinicalTrials.gov, NCT03315390. Registered on 10 October 2017. German Clinical Trials Register, DRKS00012589. Registered on 17 October 2017.