Rationale: Meta-analyses of case series of non-arteritic central retinal artery occlusion (CRAO) indicate beneficial effects of intravenous thrombolysis when initiated early after symptom onset. Randomized data are lacking to address this question. Aims: The REperfusion therapy with intravenous alteplase for recovery of VISION in acute central retinal artery occlusion (REVISION) investigates intravenous alteplase within 4.5 h of monocular vision loss due to acute CRAO. Methods: This study is the randomized (1:1), double-blind, placebo-controlled, multicenter adaptive phase III trial. Study outcomes: Primary outcome is functional recovery to normal or mildly impaired vision in the affected eye defined as best-corrected visual acuity of the Logarithm of the Minimum Angle of Resolution of 0.5 or less at 30 days (intention-to-treat analysis). Secondary efficacy outcomes include modified Rankin Score at 90 days and quality of life. Safety outcomes include symptomatic intracranial hemorrhage, major bleeding (International Society on Thrombosis and Haemostasis definition) and mortality. Exploratory analyses of optical coherence tomography/angiography, ultrasound and magnetic resonance imaging (MRI) biomarkers will be conducted. Sample size: Using an adaptive design with interim analysis at 120 patients, up to 422 participants (211 per arm) would be needed for 80% power (one-sided alpha = 0.025) to detect a difference of 15%, assuming functional recovery rates of 10% in the placebo arm and 25% in the alteplase arm. Discussion: By enrolling patients within 4.5 h of CRAO onset, REVISION uses insights from meta-analyses of CRAO case series and randomized thrombolysis trials in acute ischemic stroke. Increased rates of early reperfusion and good neurological outcomes in stroke may translate to CRAO with its similar pathophysiology. Trial registration: ClinicalTrials.gov: NCT04965038; EU Trial Number: 2023-507388-21-00.

Rationale: Oxygen is essential for cellular energy metabolism. Neurons are particularly vulnerable to hypoxia. Increasing oxygen supply shortly after stroke onset could preserve the ischemic penumbra until revascularization occurs. Aims: PROOF investigates the use of normobaric oxygen (NBO) therapy within 6 h of symptom onset/notice for brain-protective bridging until endovascular revascularization of acute intracranial anterior-circulation occlusion. Methods and design: Randomized (1:1), standard treatment-controlled, open-label, blinded endpoint, multicenter adaptive phase IIb trial. Study outcomes: Primary outcome is ischemic core growth (mL) from baseline to 24 h (intention-to-treat analysis). Secondary efficacy outcomes include change in NIHSS from baseline to 24 h, mRS at 90 days, cognitive and emotional function, and quality of life. Safety outcomes include mortality, intracranial hemorrhage, and respiratory failure. Exploratory analyses of imaging and blood biomarkers will be conducted. Sample size: Using an adaptive design with interim analysis at 80 patients per arm, up to 456 participants (228 per arm) would be needed for 80% power (one-sided alpha 0.05) to detect a mean reduction of ischemic core growth by 6.68 mL, assuming 21.4 mL standard deviation. Discussion: By enrolling endovascular thrombectomy candidates in an early time window, the trial replicates insights from preclinical studies in which NBO showed beneficial effects, namely early initiation of near 100% inspired oxygen during short temporary ischemia. Primary outcome assessment at 24 h on follow-up imaging reduces variability due to withdrawal of care and early clinical confounders such as delayed extubation and aspiration pneumonia. Trial registrations: ClinicalTrials.gov: NCT03500939; EudraCT: 2017-001355-31.

IntroductionNo evaluated therapeutic approaches, that can efficiently be established in routine mental healthcare, are currently available for traumatised adolescent refugees in Germany. This study evaluates the efficacy of the Stress-Traumasymptoms-Arousal-Regulation-Treatment (START) programme to reduce trauma-related symptoms and psychological distress in traumatised adolescent refugees based in Germany.Methods and analysisThis randomised, waiting-list-controlled, multicentre trial with a 12-week follow-up will include 174 refugee minors with partial or full post-traumatic stress disorder who are fluent in either Arabic, Dari, English, German or Somali. Eligible refugee minors will be randomised to the START or waiting-list control groups. The manualised 8-week START programme is based on techniques of dialectical behaviour therapy (DBT), fosters adaptive coping with emotional distress and traumatic symptoms and comprises eight therapy modules and a booster session. Study assessments are planned at baseline, post-treatment (ie, after programme participation or waiting time), booster session at week 12 or 12-week waiting time, and at the 12-week follow-up. Primary and coprimary outcomes are changes in psychological distress and traumatic symptoms at post-treatment and will be analysed as response variables in linear mixed regression models. Secondary outcomes are changes in further trauma-related and other psychopathological symptoms, emotion regulation and intermediate effects of the programme at follow-up. We will also assess effects of the programme with ecological momentary assessments and on neuroendocrine stress parameters using hair cortisol.Ethics and disseminationThis study has been approved by the lead ethics committee of Rhineland-Palatinate and the ethics committees of participating sites. The study results will be disseminated through peer-reviewed publications and scientific conferences.Trial registration numberDRKS00020771.

Background: To assess the risk of peripheral artery disease (PAD) in older adults and the contribution of traditional and novel risk factors to the incidence of PAD. Patients and methods: 344 general practitioners (GPs), trained by vascular specialists all over Germany, enrolled 6,880 unselected participants aged 65 years or older (getABI study). The onset of PAD was determined by a regression method in the course of repeated measurements of the ankle brachial index (ABI) over seven years. PAD onset was defined by the declining linear regression ABI line reaching 0.9 or by PAD symptoms. Results: The cumulative PAD incidence over seven years was 12.9%, corresponding to an incidence rate of 20.3 per 1000 person years (95% confidence interval [95%CI] 18.8 to 21.7). Logistic regression analysis showed that traditional risk factors contributed significantly to the risk of PAD: current smoker status (odds ratio 2.65, 95%CI 2.08 to 3.37), diabetes (1.35, 95%CI 1.13 to 1.62), and low-density lipoprotein >130 mg/dl (1.26, 95%CI 1.07 to 1.48). Three novel risk factor candidates showed significant impact on PAD incidence: elevated sensitive C-reactive protein level (1.23, 95%CI 1.05 to 1.45), impaired estimated glomerular filtration rate (1.27, 95%CI 1.03 to 1.56), and elevated homocysteine level (1.19, 95%CI 1.01 to 1.41). Conclusions: Older adults in Germany have a PAD risk of 12.9% per seven years. Potentially modifiable traditional PAD risk factors yield high impact on PAD incidence. Novel risk factor candidates may contribute to the risk of PAD

In nonlinear regression models the Fisher information depends on the parameters of the model. Consequently, optimal designs maximizing some functional of the information matrix cannot be implemented directly but require some preliminary knowledge about the unknown parameters. Bayesian optimality criteria provide an attractive solution to this problem. These criteria depend sensitively on a reasonable specification of a prior distribution for the model parameters which might not be available in all applications. In this paper we investigate Bayesian optimality criteria with non-informative prior distributions. In particular, we study the Jeffreys and the Berger–Bernardo prior for which the corresponding optimality criteria are not necessarily concave. Several examples are investigated where optimal designs with respect to these criteria are calculated and compared to Bayesian optimal designs based on a uniform and a functional uniform prior.

Background:There is controversial evidence with regard to the significance of peripheral arterial disease (PAD) as an indicator for future stroke risk. We aimed to quantify the risk increase for mortality and morbidity associated with PAD. Methods:In an open, prospective, noninterventional cohort study in the primary care setting, a total of 6,880 unselected patients ≧65 years were categorized according to the presence or absence of PAD and followed up for vascular events or deaths over 5 years. PAD was defined as ankle-brachial index (ABI) <0.9 or history of previous peripheral revascularization and/or limb amputation and/or intermittent claudication. Associations between known cardiovascular risk factors including PAD and cerebrovascular mortality/events were analyzed in a multivariate Cox regression model. Results:During the 5-year follow-up [29,915 patient-years (PY)], 183 patients had a stroke (incidence per 1,000 PY: 6.1 cases). In patients with PAD (n = 1,429) compared to those without PAD (n = 5,392), the incidence of all stroke types standardized per 1,000 PY, with the exception of hemorrhagic stroke, was about doubled (for fatal stroke tripled). The corresponding adjusted hazard ratios were 1.6 (95% confidence interval, CI, 1.1–2.2) for total stroke, 1.7 (95% CI 1.2–2.5) for ischemic stroke, 0.7 (95% CI 0.2–2.2) for hemorrhagic stroke, 2.5 (95% CI 1.2–5.2) for fatal stroke and 1.4 (95% CI 0.9–2.1) for nonfatal stroke. Lower ABI categories were associated with higher stroke rates. Besides high age, previous stroke and diabetes mellitus, PAD was a significant independent predictor for ischemic stroke. Conclusions:The risk of stroke is substantially increased in PAD patients, and PAD is a strong independent predictor for stroke.

The aims of this study were (1) to analyze the sport participation in a cohort of community-dwelling elderly people in Germany and (2) to evaluate associations between sport participation, sociodemographic factors, cardiovascular risk factors, and health status. In a monitored prospective cohort study (getABI), 6,880 unselected patients ≥65 years have been followed up by 344 general practitioners beginning in 2001. As part of the 5-year follow-up telephone interview, a sample of 1,376 participants was interviewed on sport participation. The association between participation in at least one sporting activity (“sporty” yes/no) during the past week (cycling) or month (other sports) and the following parameters was analyzed by logistic regression: age, sex, immigration background, education, waist circumference, smoking, self-reported health, history of vascular events, diabetes mellitus, lipometabolic disorder, and arterial hypertension. Analysis of activities ( n = 1,304; median age 76 (70–94) years; 55.1% women) showed that 27.6% of participants rode a bicycle during the previous week. During the previous month, 24.9% of participants did gymnastics or strength training, and 16.5% swam. Of all participants, 53.8% were sporty. Multivariate analysis revealed several independent factors to be associated with being sporty ( p < 0.05): younger age, male sex, higher education, nonsmoking, better self-reported health, and not being diagnosed with diabetes. Immigration background, waist circumference, history of vascular events, lipometabolic disorder, and hypertension did not show a statistically significant association ( p ≥ 0.05) with sport participation. Summing up, the most frequently performed sporting activities were cycling, gymnastics or strength training, and swimming. Sport participation was associated with, for example, age and sex.

OBJECTIVE:We aimed to investigate whether the post-exercise ankle brachial index (ABI) performed by primary care physicians offers useful information for the prediction of death or cardiovascular events, beyond the traditional resting ABI. An additional focus was on patients with intermittent claudication and normal resting ABI. METHODS:Using data from the 5-year follow-up of 6468 elderly patients in the primary care setting in Germany (getABI study) we used multivariate Cox regression models adjusted for age, gender and conventional risk factors to determine the association of resting ABI and/or post-exercise ABI and all-cause mortality/morbidity. RESULTS:Mean post-exercise ABI in the total cohort was 0.977 and resting ABI was 1.034. For post-exercise ABI, a threshold value of 0.825 had nearly the same sensitivity (28.6%) and specificity (85.7%) as the conventionally used resting ABI with a cut-off value of 0.9 to predict death. Compared to patients with normal post-exercise ABI, a low post-exercise ABI was associated with an almost identical risk increase for mortality (hazard ratio [HR] 1.56, 95% confidence interval [CI] 1.30-1.86) as a low resting ABI (HR 1.65; CI 1.39-1.97) and/or myocardial infarction/stroke. Slight differences were observed for coronary/carotid revascularisation and peripheral revascularisation/amputation. In combined models it could not be shown that post-exercise ABI yielded relevant additional information for the prognosis of mortality and/or myocardial infarction/stroke, not even in the subgroup analysis of patients with intermittent claudication and normal resting ABI. CONCLUSIONS:It could not be shown that the post-exercise ABI is a useful tool for the prognosis of mortality and/or myocardial infarction/stroke beyond the resting ABI.

s 15th Meeting of the European Society of Neurosonology and Cerebral Hemodynamics Madrid, Spain, May 22–25, 2010 Guest Editors: J. Carneado-Ruiz (Madrid); F. Diaz Otero (Madrid); L. Cziba (Debrecen); D. Russell (Oslo)

Background— Our aim was to assess the mortality and vascular morbidity risk of elderly individuals with asymptomatic versus symptomatic peripheral artery disease (PAD) in the primary care setting. Methods and Results— This prospective cohort study included 6880 representative unselected patients ≥65 years of age with monitored follow-up over 5 years. According to physician diagnosis, 5392 patients had no PAD, 836 had asymptomatic PAD (ankle brachial index <0.9 without symptoms), and 593 had symptomatic PAD (lower-extremity peripheral revascularization, amputation as a result of PAD, or intermittent claudication symptoms regardless of ankle brachial index). The risk of symptomatic compared with asymptomatic PAD patients was significantly increased for the composite of all-cause death or severe vascular event (myocardial infarction, coronary revascularization, stroke, carotid revascularization, or lower-extremity peripheral vascular events; hazard ratio, 1.48; 95% confidence interval, 1.21 to 1.80) but not for all-cause death alone (hazard ratio, 1.13; 95% confidence interval, 0.89 to 1.43), all-cause death/myocardial infarction/stroke (excluding lower-extremity peripheral vascular events and any revascularizations; hazard ratio, 1.18; 95% confidence interval, 0.92 to 1.52), cardiovascular events alone (hazard ratio, 1.20; 95% confidence interval, 0.89 to 1.60), or cerebrovascular events alone (hazard ratio, 1.33; 95% confidence interval, 0.80 to 2.20). Lower ankle brachial index categories were associated with increased risk. PAD was a strong factor for the prediction of the composite end point in an adjusted model. Conclusions— Asymptomatic PAD diagnosed through routine screening in the offices of primary care physicians carries a high mortality and/or vascular event risk. Notably, the risk of mortality was similar in symptomatic and asymptomatic patients with PAD and was significantly higher than in those without PAD. In the primary care setting, the diagnosis of PAD has important prognostic value.

Background Physical activity programmes can help to prevent functional decline in the elderly. Until now, such programmes use to target either on healthy community-dwelling seniors or on elderly living in special residences or care institutions. Sedentary or frail people, however, are difficult to reach when they live in their own homes. The general practitioner's (GP) practice offers a unique opportunity to acquire these people for participation in activity programmes. We conceptualised a multidimensional home-based exercise programme that shall be delivered to the target group through cooperation between GPs and exercise therapists. In order to prepare a randomised controlled trial (RCT), a feasibility study is being conducted. Methods The study is designed as a single arm interventional trial. We plan to recruit 90 patients aged 70 years and above through their GPs. The intervention lasts 12 weeks and consists of physical activity counselling, a home-exercise programme, and exercise consultations provided by an exercise therapist in the GP's practice and via telephone. The exercise programme consists of two main components: 1. a combination of home-exercises to improve strength, flexibility and balance, 2. walking for exercise to improve aerobic capacity. Primary outcome measures are: appraisal by GP, undesirable events, drop-outs, adherence. Secondary outcome measures are: effects (a. motor tests: timed-up-and-go, chair rising, grip strength, tandem stand, tandem walk, sit-and-reach; b. telephone interview: PRISCUS-Physical Activity Questionnaire, Short Form-8 Health Survey, three month recall of frequency of falls, Falls Efficacy Scale), appraisal by participant, exercise performance, focus group discussion. Data analyses will focus on: 1. decision-making concerning the conduction of a RCT, 2. estimation of the effects of the programme, detection of shortcomings and identification of subgroups with contrary results, 3. feedback to participants and to GPs. Conclusion A new cooperation between GPs and exercise therapists to approach community-dwelling seniors and to deliver a home-exercise programme is object of research with regard to feasibility and acceptance. In case of success, an RCT should examine the effects of the programme. A future implementation within primary medical care may take advantage from the flexibility of the programme. Trial registration Current Controlled Trials ISRCTN58562962.