Effectiveness of an intensive care telehealth programme to improve process quality (ERIC): a multicentre stepped wedge cluster randomised controlled trial.

PURPOSE: Supporting the provision of intensive care medicine through telehealth potentially improves process quality. This may improve patient recovery and long-term outcomes. We investigated the effectiveness of a multifaceted telemedical programme on the adherence to German quality indicators (QIs) in a regional network of intensive care units (ICUs) in Germany. METHODS: We conducted an investigator-initiated, large-scale, open-label, stepped-wedge cluster randomised controlled trial enrolling adult ICU patients with an expected ICU stay of ≥ 24 h. Twelve ICU clusters in Berlin and Brandenburg were randomly assigned to three sequence groups to transition from control (standard care) to the intervention condition (telemedicine). The quality improvement intervention consisted of daily telemedical rounds guided by eight German acute ICU care QIs and expert consultations. Co-primary effectiveness outcomes were patient-specific daily adherence (fulfilled yes/no) to QIs, assessed by a central end point adjudication committee. Analyses used mixed-effects logistic modelling adjusted for time. This study is completed and registered with ClinicalTrials.gov (NCT03671447). RESULTS: Between September 4, 2018, and March 31, 2020, 1463 patients (414 treated on control, 1049 on intervention condition) were enrolled at ten clusters, resulting in 14,783 evaluated days. Two randomised clusters recruited no patients (one withdrew informed consent; one dropped out). The intervention, as implemented, significantly increased QI performance for "sedation, analgesia and delirium" (adjusted odds ratio (99.375% confidence interval [CI]) 5.328, 3.395-8.358), "ventilation" (OR 2.248, 1.198-4.217), "weaning from ventilation" (OR 9.049, 2.707-30.247), "infection management" (OR 4.397, 1.482-13.037), "enteral nutrition" (OR 1.579, 1.032-2.416), "patient and family communication" (OR 6.787, 3.976-11.589), and "early mobilisation" (OR 3.161, 2.160-4.624). No evidence for a difference in adherence to "daily multi-professional and interdisciplinary clinical visits" between both conditions was found (OR 1.606, 0.780-3.309). Temporal trends related and unrelated to the intervention were detected. 149 patients died during their index ICU stay (45 treated on control, 104 on intervention condition). CONCLUSION: A telemedical quality improvement program increased adherence to seven evidence-based German performance indicators in acute ICU care. These results need further confirmation in a broader setting of regional, non-academic community hospitals and other healthcare systems.

Safety and Efficacy of Acetyl-DL-Leucine in Certain Types of Cerebellar Ataxia: The ALCAT Randomized Clinical Crossover Trial.

Importance: Cerebellar ataxia is a neurodegenerative disease impairing motor function characterized by ataxia of stance, gait, speech, and fine motor disturbances. Objective: To investigate the efficacy, safety, and tolerability of the modified essential amino acid acetyl-DL-leucine in treating patients who have cerebellar ataxia. Design, Setting, and Participants: The Acetyl-DL-leucine on Cerebellar Ataxia (ALCAT) trial was an investigator-initiated, multicenter, double-blind, randomized, placebo-controlled, clinical crossover trial. The study was conducted at 7 university hospitals in Germany and Austria between January 25, 2016, and February 17, 2017. Patients were aged at least 18 years and diagnosed with cerebellar ataxia of hereditary (suspected or genetically confirmed) or nonhereditary or unknown type presenting with a total score of at least 3 points on the Scale for the Assessment and Rating of Ataxia (SARA). Statistical analysis was performed from April 2018 to June 2018 and January 2020 to March 2020. Interventions: Patients were randomly assigned (1:1) to receive acetyl-DL-leucine orally (5 g per day after 2 weeks up-titration) followed by a matched placebo, each for 6 weeks, separated by a 4-week washout, or vice versa. The randomization was done via a web-based, permuted block-wise randomization list (block size, 2) that was stratified by disease subtype (hereditary vs nonhereditary or unknown) and site. Main Outcomes and Measures: Primary efficacy outcome was the absolute change of SARA total score from (period-dependent) baseline to week 6. Results: Among 108 patients who were randomly assigned to sequence groups (54 patients each), 55 (50.9%) were female; the mean (SD) age was 54.8 (14.4) years; and the mean (SD) SARA total score was 13.33 (5.57) points. The full analysis set included 105 patients (80 patients with hereditary, 25 with nonhereditary or unknown cerebellar ataxia). There was no evidence of a difference in the mean absolute change from baseline to week 6 in SARA total scores between both treatments (mean treatment difference: 0.23 points [95% CI, -0.40 to 0.85 points]). Conclusions and Relevance: In this large multicenter, double-blind, randomized, placebo-controlled clinical crossover trial, acetyl-DL-leucine in the investigated dosage and treatment duration was not superior to placebo for the symptomatic treatment of certain types of ataxia. The drug was well tolerated; and ALCAT yielded valuable information about the duration of treatment periods and the role of placebo response in cerebellar ataxia. These findings suggest that further symptom-oriented trials are needed for evaluating the long-term effects of acetyl-DL-leucine for well-defined subgroups of cerebellar ataxia. Trial Registration: EudraCT 2015-000460-34.

Pylorus resection versus pylorus preservation in pancreatoduodenectomy (PyloResPres): study protocol and statistical analysis plan for a German multicentre, single-blind, surgical, registry-based randomised controlled trial.

INTRODUCTION: Partial pancreatoduodenectomy (PD) is the treatment of choice for various benign and malignant tumours of the pancreatic head or the periampullary region. For reconstruction of the gastrointestinal passage, two stomach-preserving PD variants exist: pylorus preservation PD (ppPD) or pylorus resection PD (prPD) with preservation of the stomach. In pancreatic surgery, delayed gastric emptying (DGE) remains a serious complication after PD with an incidence varying between 4.5% and 45%, potentially delaying hospital discharge or further treatment, for example, adjuvant chemotherapy. Evidence is lacking to assess, which variant of PD entails fewer postoperative DGE. METHODS AND ANALYSIS: The protocol of a large-scale, multicentre, pragmatic, two-arm parallel-group, registry-based randomised controlled trial (rRCT) using a two-stage group-sequential design is presented. This patient-blind rRCT aims to demonstrate the superiority of prPD over ppPD with respect to the overall incidence of DGE within 30 days after index surgery in a German real-world setting. A total of 984 adults undergoing elective PD for any indication will be randomised in a 1:1 ratio. Patients will be recruited at about 30 hospitals being members of the StuDoQ|Pancreas registry established by the German Society of General and Visceral Surgery. The postoperative follow-up for each patient will be 30 days. The primary analysis will follow an intention-to-treat approach and applies a binary logistic random intercepts model. Secondary perioperative outcomes include overall severe morbidity (Clavien-Dindo classification), blood loss, 30-day all-cause mortality, postoperative hospital stay and operation time. Complication rates and adverse events will be closely monitored. ETHICS AND DISSEMINATION: This protocol was approved by the leading ethics committee of the Medical Faculty of the Ludwig-Maximilians-Universität, Munich (reference number 19-221). The results will be published in a peer-reviewed journal and presented at international conferences. Study findings will also be disseminated via the website (http://www.dgav.de/studoq/pylorespres/). TRIAL REGISTRATION NUMBER: DRKS-ID: DRKS00018842.

Modeling of atrophy size trajectories: variable transformation, prediction and age-of-onset estimation.

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.

Enhanced Recovery after Intensive Care (ERIC): study protocol for a German stepped wedge cluster randomised controlled trial to evaluate the effectiveness of a critical care telehealth program on process quality and functional outcomes.

INTRODUCTION: Survival after critical illness has noticeably improved over the last decades due to advances in critical care medicine. Besides, there is an increasing number of elderly patients with chronic diseases being treated in the intensive care unit (ICU). More than half of the survivors of critical illness suffer from medium-term or long-term cognitive, psychological and/or physical impairments after ICU discharge, which is recognised as post-intensive care syndrome (PICS). There are evidence-based and consensus-based quality indicators (QIs) in intensive care medicine, which have a positive influence on patients' long-term outcomes if adhered to. METHODS AND ANALYSIS: The protocol of a multicentre, pragmatic, stepped wedge cluster randomised controlled, quality improvement trial is presented. During 3 predefined steps, 12 academic hospitals in Berlin and Brandenburg, Germany, are randomly selected to move in a one-way crossover from the control to the intervention condition. After a multifactorial training programme on QIs and clinical outcomes for site personnel, ICUs will receive an adapted, interprofessional protocol for a complex telehealth intervention comprising of daily telemedical rounds at ICU. The targeted sample size is 1431 patients. The primary objective of this trial is to evaluate the effectiveness of the intervention on the adherence to eight QIs daily measured during the patient's ICU stay, compared with standard of care. Furthermore, the impact on long-term recovery such as PICS-related, patient-centred outcomes including health-related quality of life, mental health, clinical assessments of cognition and physical function, all-cause mortality and cost-effectiveness 3 and 6 months after ICU discharge will be evaluated. ETHICS AND DISSEMINATION: This protocol was approved by the ethics committee of the Charité-Universitätsmedizin, Berlin, Germany (EA1/006/18). The results will be published in a peer-reviewed scientific journal and presented at international conferences. Study findings will also be disseminated via the website (www.eric-projekt.net). TRIAL REGISTRATION NUMBER: ClinicalTrials.gov Registry (NCT03671447).

Results and lessons learnt from a randomized controlled trial: prophylactic treatment of vestibular migraine with metoprolol (PROVEMIG).

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.

Effect of a combined brief narrative exposure therapy with case management versus treatment as usual in primary care for patients with traumatic stress sequelae following intensive care medicine: study protocol for a multicenter randomized controlled trial (PICTURE).

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.

Effects of acetyl-DL-leucine on cerebellar ataxia (ALCAT trial): study protocol for a multicenter, multinational, randomized, double-blind, placebo-controlled, crossover phase III trial.

BACKGROUND: Cerebellar ataxia (CA) is a frequent and often disabling condition that impairs motor functioning and impacts on quality of life (QoL). No medication has yet been proven effective for the symptomatic or even causative treatment of hereditary or non-hereditary, non-acquired CA. So far, the only treatment recommendation is physiotherapy. Therefore, new therapeutic options are needed. Based on three observational studies, the primary objective of the acetyl-DL-leucine on ataxia (ALCAT) trial is to examine the efficacy and tolerability of a symptomatic therapy with acetyl-DL-leucine compared to placebo on motor function measured by the Scale for the Assessment and Rating of Ataxia (SARA) in patients with CA. METHODS/DESIGN: An investigator-initiated, multicenter, European, randomized, double-blind, placebo-controlled, 2-treatment 2-period crossover phase III trial will be carried out. In total, 108 adult patients who meet the clinical criteria of CA of different etiologies (hereditary or non-hereditary, non-acquired) presenting with a SARA total score of at least 3 points will be randomly assigned in a 1:1 ratio to one of two different treatment sequences, either acetyl-DL-leucine (up to 5 g per day) followed by placebo or vice versa. Each sequence consists of two 6-week treatment periods, separated by a 4-week wash-out period. A follow-up examination is scheduled 4 weeks after the end of treatment. The primary efficacy outcome is the absolute change in the SARA total score. Secondary objectives are to demonstrate that acetyl-DL-leucine is effective in improving (1) motor function measured by the Spinocerebellar Ataxia Functional Index (SCAFI) and SARA subscore items and (2) QoL (EuroQoL 5 dimensions and 5 level version, EQ-5D-5 L), depression (Beck Depression Inventory, BDI-II) and fatigue (Fatigue Severity Score, FSS). Furthermore, the incidence of adverse events will be investigated. DISCUSSION: The results of this trial will inform whether symptomatic treatment with the modified amino-acid acetyl-DL-leucine is a worthy candidate for a new drug therapy to relieve ataxia symptoms and to improve patient care. If superiority of the experimental drug to placebo can be established it will also be re-purposing of an agent that has been previously used for the symptomatic treatment of dizziness. TRIAL REGISTRATION: The trial was prospectively registered at www.clinicaltrialsregister.eu (EudraCT no. 2015-000460-34) and at https://www.germanctr.de (DRKS-ID: DRKS00009733 ).

Long-term Rehabilitation in Patients With Acquired Brain Injury.

BACKGROUND: Patients with acquired brain injury who have been discharged from inpatient neurological rehabilitation often continue to suffer from limited independence, participation, and quality of life. Participation-focused outpatient treatment (in German: teilhabeorientierte ambulan. METHODS: In a randomized, controlled trial, 53 patients who had sustained an acquired brain injury approximately four years earlier were allotted to two different sequences of treatment (26 TEAM/control, 27 control/TEAM). The primary endpoint was the achievement of an individual participation goal one month after the start of treatment. The secondary endpoints included independence in everyday activities, health-related quality of life, participation, and need for nursing care. The intervention was four weeks long and was carried out on an outpatient basis (19.4 ± 1.3 hours per week). Patients in the control group were treated in a manner resembling usual current care. All endpoints were evaluated in a per-protocol (PP) analysis of data from 47 patients. For confirmation, an intention-to-treat (ITT) analysis was also carried out for the primary endpoint and for independence in everyday activities. RESULTS: According to the PP analysis, TEAM patients achieved their individual participation goals at 1 month more frequently than control patients receiving standard treatment (61% vs. 21%; p = 0.008) and improved more with respect to independence in everyday activities. The difference between TEAM and standard treatment was +7.3 points on the FIM (Functional Independence Measure) scale (95% confidence interval [2.8; 11.8]; p = 0.0024). The superiority of TEAM was confirmed by the ITT analysis (achievement of the participation goal, TEAM vs. standard treatment: 54% vs. 19%, p = 0.0103). Moreover, improvements were seen at 12 months in quality of life, participation, and the need for nursing care. CONCLUSION: The TEAM rehabilitation program can help patients in the chronic phase of acquired brain injury achieve participation goals that are relevant to everyday life. An adjustment of the care structure in Germany to include such intensive goal-oriented rehabilitation programs would lead to a more effective mobilization of these patients' potential for long-term rehabilitation.

Combined therapy with sitagliptin plus granulocyte-colony stimulating factor in patients with acute myocardial infarction - Long-term results of the SITAGRAMI trial.

BACKGROUND: Autologous progenitor cell therapy comprising granulocyte-colony stimulating factor (G-CSF) for mobilization of bone-marrow derived progenitor cells (BMPCs) into peripheral blood and inhibition of dipeptidylpeptidase-IV by sitagliptin for enhanced myocardial recruitment of circulating BMPCs has been shown to improve survival after acute myocardial infarction (MI) in preclinical studies. In the SITAGRAMI trial we found that during short-term follow-up G-CSF plus sitagliptin (GS) failed to show a beneficial effect on cardiac function and clinical events in patients with acute MI that underwent successful PCI. The objective of the present analysis was to assess the impact of GS versus placebo treatment on long-term clinical outcomes of the SITAGRAMI trial patient population. METHODS: In the randomized, prospective, double-blind, placebo-controlled SITAGRAMI trial, 174 patients with acute MI were assigned to GS or placebo in a 1:1 ratio. The primary outcome for the present long-term analysis was the composite of death, MI or stroke on long-term follow-up. RESULTS: The median [IQR] follow-up duration was 4.50 [3.56-5.95] years. The primary outcome occurred in 12.8% of patients assigned to placebo and 9.2% assigned to GS (HR 0.69, 95% CI 0.28-1.69; p=0.42). The incidence of the combined cardiovascular outcome was 47.7% in the placebo- and 41.4% in the GS-group (HR 0.75, 95% CI 0.48-1.18; p=0.21). Overall, there was no significant difference in MACCE rates between both treatment groups (p=0.41). CONCLUSION: These long-term follow-up data indicate that GS therapy does not improve clinical outcomes of patients with acute MI.

Efficacy and safety of betahistine treatment in patients with Meniere's disease: primary results of a long term, multicentre, double blind, randomised, placebo controlled, dose defining trial (BEMED trial).

STUDY QUESTION: What is the long term efficacy of betahistine dihydrochloride on the incidence of vertigo attacks in patients with Meniere's disease, compared with placebo? METHODS: The BEMED trial is a multicentre, double blind, randomised, placebo controlled, three arm, parallel group, phase III, dose defining superiority trial conducted in 14 German tertiary referral centres (for neurology or ear, nose, and throat). Adults aged 21-80 years (mean age 56 years) with definite unilateral or bilateral Meniere's disease were recruited from March 2008 to November 2012. Participants received placebo (n=74), low dose betahistine (2 × 24 mg daily, (n=73)), or high dose betahistine (3 × 48 mg daily, (n=74)) over nine months. The primary outcome was the number of attacks per 30 days, based on patients' diaries during a three month assessment period at months seven to nine. An internet based randomisation schedule performed a concealed 1:1:1 allocation, stratified by study site. Secondary outcomes included the duration and severity of attacks, change in quality of life scores, and several observer-reported parameters to assess changes in audiological and vestibular function. STUDY ANSWER AND LIMITATIONS: Incidence of attacks related to Meniere's disease did not differ between the three treatment groups (P=0.759). Compared with placebo, attack rate ratios were 1.036 (95% confidence interval 0.942 to 1.140) and 1.012 (0.919 to 1.114) for low dose and high dose betahistine, respectively. The overall monthly attack rate fell significantly by the factor 0.758 (0.705 to 0.816; P<0.001). The population based, mean monthly incidence averaged over the assessment period was 2.722 (1.304 to 6.309), 3.204 (1.345 to 7.929), and 3.258 (1.685 to 7.266) for the placebo, low dose betahistine, and high dose betahistine groups, respectively. Results were consistent for all secondary outcomes. Treatment was well tolerated with no unexpected safety findings. Without a control group of patients who did not receive any intervention to follow the natural course of the disease, the placebo effect could not be accurately assessed and differentiated from spontaneous remission and fluctuation of symptoms. WHAT THIS STUDY ADDS: Current evidence is limited as to whether betahistine prevents vertigo attacks caused by Meniere's disease, compared with placebo. The trial provides information on symptom relief on placebo intervention which is relevant for the design of future studies on potential disease modifying treatments in patients with Meniere's disease. FUNDING, COMPETING INTERESTS, DATA SHARING: Support from the German Federal Ministry of Education and Research (BMBF support code 01KG0708). Potential competing interests have been reported in full at the end of the paper on thebmj.com. Data are available from the corresponding author (Michael.Strupp@med.uni-muenchen.de) or biostatistician (mansmann@ibe.med.uni-muenchen.de). Study registration EudraCT no 2005-000752-32; ISRCTN no ISRCTN44359668.

Sitagliptin plus granulocyte colony-stimulating factor in patients suffering from acute myocardial infarction: A double-blind, randomized placebo-controlled trial of efficacy and safety (SITAGRAMI trial).

OBJECTIVE: In animal models, G-CSF based progenitor cell mobilization combined with a DPP4 inhibitor leads to increased homing of bone marrow derived progenitor cells to the injured myocardium via the SDF1/CXCR4 axis resulting in improved ejection fraction and survival after acute myocardial infarction (AMI). RESEARCH DESIGN AND METHODS: After successful revascularization in AMI, 174 patients were randomized 1:1 in a multi-centre, prospective, placebo-controlled, parallel group, double blind, phase III efficacy and safety trial to treatment with G-CSF and Sitagliptin (GS) or placebo. Diabetic and non-diabetic patients were included in our trial. The primary efficacy endpoint hierarchically combined global left and right ventricular ejection fraction changes from baseline to 6 months of follow-up (ΔLVEF, ΔRVEF), as determined by cardiac MRI. RESULTS: At follow-up ΔLVEF as well as ΔRVEF did not differ between the GS and placebo group. Patients in the placebo group had a similar risk for a major adverse cardiac event within 12 months of follow-up as compared to patients under GS. CONCLUSION: Progenitor cell therapy comprising the use of G-CSF and Sitagliptin after successfully revascularized acute myocardial infarction fails to show a beneficial effect on cardiac function and clinical events after 12 months. (EudraCT: 2007-003,941-34; ClinicalTrials.gov: NCT00650143, funding: Heinz-Nixdorf foundation).

Esophoria or esotropia in adulthood: a sign of cerebellar dysfunction?

Convergent strabismus is a common diagnosis in early childhood, when it is mostly considered benign. If it develops later in life, strabismus can, however, be a sign of neurological disease. In these cases the underlying pathophysiological mechanisms are largely unknown. In this retrospective case-control study we analyzed the neuro-ophthalmological examination reports of 400 adult patients who presented at the German Center for Vertigo and Balance Disorders to determine an association between ocular misalignment and cerebellar dysfunction. Patients with cerebellar signs (i.e., cerebellar ataxia and/or cerebellar ocular motor signs) had a 4.49 (95 % CI [1.60; 13.78]) times higher frequency of ocular misalignment and specifically a 13.3 (95 % CI [3.80; 55.73]) times increased frequency of esophoria/esotropia (ESO) during distant gaze than patients without cerebellar dysfunction. ESO when looking into the distance was associated with saccadic smooth pursuit, dysmetria of saccades, and downbeat nystagmus (DBN) (χ (2) test, p < 0.0001 for all associations). Patients with cerebellar dysfunction also showed mildly impaired eye abduction (χ (2) test, left eye and right eye: p < 0.0001), associated with horizontal gaze-evoked nystagmus (χ (2) test, p < 0.0001). The association of ESO and DBN implicates a pathophysiological involvement of the cerebellar flocculus, while the association with dysmetric saccades suggests involvement of the oculomotor vermis. This is compatible with animal studies showing that the pathways of the flocculus/posterior interposed nucleus and vermis/nucleus fastigii are both involved in vergence movements and static binocular alignment. From a clinical point of view, a newly diagnosed esophoria/esotropia only during distant gaze may be a sign of a cerebellar disease.

Tracer kinetic modeling in myocardial perfusion quantification using MRI.

PURPOSE: To investigate and compare several quantification methods of myocardial perfusion measurements, paying special attention to the relation between the techniques and the required measurement duration. METHODS: Seven patients underwent contrast-enhanced rest and stress cardiac perfusion measurements at 3T. Three slices were acquired in each patient and were divided into 16 segments, leading to 112 rest and stress data curves, which were analyzed using various tracer kinetic models as well as a model-free deconvolution. Plasma flow, plasma volume, and myocardial perfusion reserve were analyzed for the complete acquisition as well as for the first pass data only. RESULTS: Deconvolution analysis yielded stable results for both rest and stress analysis, while Fermi and one compartment models agree well for first pass data (rest measurements only) and prolonged data acquisition (stress measurements only). More complex models do not yield satisfactory results for the short measurement times investigated in this study. CONCLUSIONS: When performing MRI-based quantification of myocardial perfusion, care must be taken that the method used is appropriate for the time frame under investigation. When a numerical deconvolution is used instead of tracer kinetic models, more stable results are obtained.

Long-term changes of central ocular motor signs in patients with vestibular migraine.

BACKGROUND: A high percentage of patients with vestibular migraine (VM) were reported to have central ocular motor dysfunctions (COMD) in the symptom-free interval. Since VM is a chronic disorder, it is of interest if COMD worsen over time. METHODS: Thirty VM patients and 11 control patients participated in an 8-year-long observational study with follow-up. All patients underwent standardized neuro-ophthalmological and neuro-otological examinations at the initial presentation and at follow-up. The primary outcome measure was change in COMD at follow-up. RESULTS: In general, COMD in the symptom-free interval were subtle, consisting of a saccadic horizontal and/or vertical pursuit. At follow-up, significantly more patients with VM had COMD (p = 0.015). The prevalence of COMD increased from 20 to 63% in VM patients. Further, the presence of COMD at follow-up had a positive predictive value of 90.5% for the diagnosis of VM. Successful treatment with prophylactic migraine medication seems to prevent the development and worsening of COMD (p = 0.008). CONCLUSION: Mild COMD occur in a large percentage of VM patients during the course of the disease. The presence of COMD is predictive of VM in patients with recurrent attacks of vertigo. Prophylactic migraine medication seems to attenuate the development and progression of COMD.

Bayesian model selection techniques as decision support for shaping a statistical analysis plan of a clinical trial: an example from a vertigo phase III study with longitudinal count data as primary endpoint.

BACKGROUND: A statistical analysis plan (SAP) is a critical link between how a clinical trial is conducted and the clinical study report. To secure objective study results, regulatory bodies expect that the SAP will meet requirements in pre-specifying inferential analyses and other important statistical techniques. To write a good SAP for model-based sensitivity and ancillary analyses involves non-trivial decisions on and justification of many aspects of the chosen setting. In particular, trials with longitudinal count data as primary endpoints pose challenges for model choice and model validation. In the random effects setting, frequentist strategies for model assessment and model diagnosis are complex and not easily implemented and have several limitations. Therefore, it is of interest to explore Bayesian alternatives which provide the needed decision support to finalize a SAP. METHODS: We focus on generalized linear mixed models (GLMMs) for the analysis of longitudinal count data. A series of distributions with over- and under-dispersion is considered. Additionally, the structure of the variance components is modified. We perform a simulation study to investigate the discriminatory power of Bayesian tools for model criticism in different scenarios derived from the model setting. We apply the findings to the data from an open clinical trial on vertigo attacks. These data are seen as pilot data for an ongoing phase III trial. To fit GLMMs we use a novel Bayesian computational approach based on integrated nested Laplace approximations (INLAs). The INLA methodology enables the direct computation of leave-one-out predictive distributions. These distributions are crucial for Bayesian model assessment. We evaluate competing GLMMs for longitudinal count data according to the deviance information criterion (DIC) or probability integral transform (PIT), and by using proper scoring rules (e.g. the logarithmic score). RESULTS: The instruments under study provide excellent tools for preparing decisions within the SAP in a transparent way when structuring the primary analysis, sensitivity or ancillary analyses, and specific analyses for secondary endpoints. The mean logarithmic score and DIC discriminate well between different model scenarios. It becomes obvious that the naive choice of a conventional random effects Poisson model is often inappropriate for real-life count data. The findings are used to specify an appropriate mixed model employed in the sensitivity analyses of an ongoing phase III trial. CONCLUSIONS: The proposed Bayesian methods are not only appealing for inference but notably provide a sophisticated insight into different aspects of model performance, such as forecast verification or calibration checks, and can be applied within the model selection process. The mean of the logarithmic score is a robust tool for model ranking and is not sensitive to sample size. Therefore, these Bayesian model selection techniques offer helpful decision support for shaping sensitivity and ancillary analyses in a statistical analysis plan of a clinical trial with longitudinal count data as the primary endpoint.

A subgroup of age-related macular degeneration is associated with mono-allelic sequence variants in the ABCA4 gene.

Purpose. Age-related macular degeneration (AMD) is a heterogeneous condition of high prevalence and complex etiology involving genetic as well as environmental factors. By fundus autofluorescence (FAF) imaging, AMD can be classified into several distinct phenotypes, with one subgroup characterized by fine granular pattern with peripheral punctate spots (GPS[+]). Some features of GPS[+] overlap with Stargardt disease (STGD1), a recessive macular dystrophy caused by biallelic sequence variants in the ATP-binding cassette transporter 4 (ABCA4) gene. The aim of this study was to investigate the role of ABCA4 in GPS[+]. Methods. The ABCA4 gene was sequenced in 25 patients with the GPS[+] phenotype and 29 with geographic atrophy (GA)-AMD but no signs of GPS (GPS[-]). In addition, frequencies of risk-increasing alleles at three known AMD susceptibility loci, including complement factor H (CFH), age-related maculopathy susceptibility 2 (ARMS2), and complement component 3 (C3), were evaluated. Results. We demonstrate that GPS[+] is associated significantly with monoallelic ABCA4 sequence variants. Moreover, frequencies of AMD risk-increasing alleles at CFH, ARMS2, and C3 are similar in GPS[+] and STGD1 patients, with risk allele frequencies in both subcategories comparable to population-based control individuals estimated from 3,510 individuals from the NHLBI Exome Sequencing Project. Conclusions. Our data suggest that the GPS[+] phenotype is accounted for by monoallelic variants in ABCA4 and unlikely by the well-established AMD risk-increasing alleles at CFH, ARMS2, and C3. These findings provide support for a complex role of ABCA4 in the etiology of a minor proportion of patients with AMD.

Progression of age-related geographic atrophy: role of the fellow eye.

PURPOSE. To evaluate the role of fellow eye status in determining progression of geographic atrophy (GA) in patients with age-related macular degeneration (AMD). METHODS. A total of 300 eyes with GA of 193 patients from the prospective, longitudinal, natural history FAM Study were classified into three groups according to the AMD manifestation in the fellow eye at baseline examination: (1) bilateral GA, (2) early/intermediate AMD, and (3) exudative AMD. GA areas were quantified based on fundus autofluorescence images using a semiautomated image-processing method, and progression rates (PR) were estimated using two-level, linear, mixed-effects models. RESULTS. Crude GA-PR in the bilateral GA group (mean, 1.64 mm(2)/y; 95% CI, 1.478-1.803) was significantly higher than in the fellow eye early/intermediate group (0.74 mm(2)/y, 0.146-1.342). Although there was a significant difference in baseline GA size (P = 0.0013, t-test), and there was a significant increase in GA-PR by 0.11 mm(2)/y (0.05-0.17) per 1 disc area (DA; 2.54 mm(2)), an additional mean change of -0.79 (-1.43 to -0.15) was given to the PR beside the effect of baseline GA size. However, this difference was only significant when GA size was ≥1 DA at baseline with a GA-PR of 1.70 mm(2)/y (1.54-1.85) in the bilateral and 0.95 mm(2)/y (0.37-1.54) in the early/intermediate group. There was no significant difference in PR compared with that in the fellow eye exudative group. CONCLUSIONS. The results indicate that the AMD manifestation of the fellow eye at baseline serves as an indicator for disease progression in eyes with GA ≥ 1 DA. Predictive characteristics not only contribute to the understanding of pathophysiological mechanisms, but also are useful for the design of future interventional trials in GA patients.

High-dosage betahistine dihydrochloride between 288 and 480 mg/day in patients with severe Menière's disease: a case series.

The objective of this study was to evaluate the clinical benefit and the side effects of high dosages of betahistine dihydrochloride (288-480 mg/day) in patients with severe Menière's disease (MD). In this case series 11 patients with MD who had not responded sufficiently to a dosage of 144 mg/day of betahistine dihydrochloride were treated on an individual basis with daily dosages between 288 and 480 mg of betahistine dihydrochloride. The number of attacks per month and the side effects were monitored. Non-parametric tests were used for statistical analysis. As a result, the frequency and the severity of vertigo were significantly reduced in all patients. The side effects were mild, self-limiting, and did not require any change in the treatment strategy. Despite the considerable limitations of an observational study--in particular in MD--high dosages of betahistine dihydrochloride between 288 and 480 mg/day seem to be effective in patients who do not sufficiently respond to lower dosages. Moreover, such dosages are well tolerated.