Preference-Based Implementation of Video Consultations in Urban and Rural Regions in Outpatient Care in Germany: Protocol for a Mixed Methods Study.

BACKGROUND: Particularly in rural regions, factors such as lower physician density and long travel distances complicate adequate outpatient care. However, urban regions can also be affected by deficits in care, for example, long waiting times. One model of care intending to improve the situation is the implementation of video consultations. The study protocol presents the methodology of the research project titled "Preference-based implementation of the video consultation in urban and rural regions" funded by the German Federal Joint Committee (funding number 01VSF20011). OBJECTIVE: This study aims to identify existing barriers to the use of video consultation and the preferences of insured individuals and physicians as well as psychotherapists in order to optimize its design and thus increase acceptance and use of video consultations in urban and rural regions. METHODS: Built on a mixed methods approach, this study first assesses the status quo of video consultation use through claims data analysis and carries out a systematic literature review on barriers and promoting factors for the use of video consultations. Based on this preliminary work, focus groups are conducted in order to prepare surveys with insureds as well as physicians and psychotherapists in the second study phase. The central element of the survey is the implementation of discrete choice experiments to elicit relevant preferences of (potential) user groups and service providers. The summarized findings are discussed in a stakeholder workshop and translated into health policy recommendations. RESULTS: The methodological approach used in this study is the focus of this paper. The study is still ongoing and will continue until March 2024. The first study phase has already been completed, in which preliminary work has been done on potential applications and hurdles for the use of video consultations. Currently, the survey is being conducted and analyses are being prepared. CONCLUSIONS: This study is intended to develop a targeted strategy for health policy makers based on actual preferences and perceived obstacles to the use of video consultations. The results of this study will contribute to further user-oriented development of the implementation of video consultations in German statutory health insurance. Furthermore, the iterative and mixed methods approach used in this study protocol is also suitable for a variety of other research projects. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/50932.

Iopromide for Contrast-Enhanced Mammography: A Systemic Review and Meta-Analysis of Pertinent Literature.

Background: Contrast-enhanced mammography (CEM) is an emerging breast imaging modality. Clinical data is scarce. Objectives: To summarize clinical evidence on the use of iopromide in CEM for the detection or by systematically analyzing the available literature on efficacy and safety. Design: Systematic review and meta-analysis. Data sources and methods: Iopromide-specific publications reporting its use in CEM were identified by a systematic search within Bayer's Product Literature Information (PLI) database and by levering a recent review publication. The literature search in PLI was performed up to January 2023. The confirmatory-supporting review publication was based on a MEDLINE/EMBASE + full text search for publications issued between September 2003 and January 2019. Relevant literature was selected based on pre-defined criteria by 2 reviewers. The comparison of CEM vs traditional mammography (XRM) was performed on published results of sensitivity and specificity. Differences in diagnostic parameters were assessed within a meta-analysis. Results: Literature search: A total of 31 studies were identified reporting data on 5194 patients. Thereof, 19 studies on efficacy and 3 studies on safety. Efficacy: in 11 studies comparing iopromide CEM vs XRM, sensitivity was up to 43% higher (range 1%-43%) for CEM. Differences in specificity were found to be in a range of -4% to 46% for CEM compared with XRM. The overall gain in sensitivity for CEM vs XRM was 7% (95% CI [4%, 11%]) with no statistically significant loss in specificity in any study assessed. In most studies, accuracy, positive predictive value, and negative predictive value were found to be in favor of CEM. In 2 studies comparing CEM with breast magnetic resonance imaging (bMRI), both imaging modalities performed either equally well or CEM tended to show better results with respect to sensitivity and specificity. Safety: eight cases of iopromide-related adverse drug reactions were reported in 1022 patients (0.8%). Conclusions: Pertinent literature provides evidence for clinical utility of iopromide in CEM for the detection or confirmation of breast cancer. The overall gain in sensitivity for iopromide CEM vs XRM was 7% with no statistically significant loss in specificity.

Long-term cardiac pathology in individuals with mild initial COVID-19 illness.

Cardiac symptoms are increasingly recognized as late complications of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in previously well individuals with mild initial illness, but the underlying pathophysiology leading to long-term cardiac symptoms remains unclear. In this study, we conducted serial cardiac assessments in a selected population of individuals with Coronavirus Disease 2019 (COVID-19) with no previous cardiac disease or notable comorbidities by measuring blood biomarkers of heart injury or dysfunction and by performing magnetic resonance imaging. Baseline measurements from 346 individuals with COVID-19 (52% females) were obtained at a median of 109 days (interquartile range (IQR), 77-177 days) after infection, when 73% of participants reported cardiac symptoms, such as exertional dyspnea (62%), palpitations (28%), atypical chest pain (27%) and syncope (3%). Symptomatic individuals had higher heart rates and higher imaging values or contrast agent accumulation, denoting inflammatory cardiac involvement, compared to asymptomatic individuals. Structural heart disease or high levels of biomarkers of cardiac injury or dysfunction were rare in symptomatic individuals. At follow-up (329 days (IQR, 274-383 days) after infection), 57% of participants had persistent cardiac symptoms. Diffuse myocardial edema was more pronounced in participants who remained symptomatic at follow-up as compared to those who improved. Female gender and diffuse myocardial involvement on baseline imaging independently predicted the presence of cardiac symptoms at follow-up. Ongoing inflammatory cardiac involvement may, at least in part, explain the lingering cardiac symptoms in previously well individuals with mild initial COVID-19 illness.

Combined Analysis of Two Parallel Randomized Trials of Sirolimus-Coated and Paclitaxel-Coated Balloons in Coronary In-Stent Restenosis Lesions.

BACKGROUND: Paclitaxel-coated balloons (PCBs) are a preferred treatment option for coronary in-stent restenosis. To date, data from randomized trials of alternative drug coatings are lacking. The aim of the randomized Malaysian and German-Swiss randomized trials was to investigate a novel sirolimus-coated balloon (SCB) compared with a PCB in in-stent restenosis. METHODS: One hundred one patients with drug-eluting stent in-stent restenosis were enrolled in 2 identical randomized trials comparing the novel SCB (SeQuent SCB, 4 µg/mm²) with the clinically proven PCB (SeQuent Please, 3 µg/mm²). Primary end point was angiographic late lumen loss at 6 months. Secondary end points included procedural success, major adverse cardiac events, and individual clinical end points such as stent thrombosis, cardiac death, target lesion myocardial infarction, clinically driven target lesion revascularization, and binary restenosis. RESULTS: Quantitative coronary angiography revealed no differences in baseline parameters. After 6 months, in-segment late lumen loss was 0.25±0.57 mm in the PCB group versus 0.26±0.60 mm in the SCB group. Mean difference between SCB and PCB was 0.01 (95% CI, -0.23 to 0.24). Noninferiority at a predefined margin of 0.35 was shown. Clinical events up to 12 months did not differ between the groups. CONCLUSIONS: This first-in man comparison of a novel SCB with a crystalline coating showed similar angiographic and clinical outcomes in the treatment of coronary drug-eluting stent in-stent restenosis compared with PCB. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT02996318, NCT03242096.

Treatment of Coronary De Novo Lesions by a Sirolimus- or Paclitaxel-Coated Balloon.

OBJECTIVES: The aim of this randomized controlled trial was to investigate a novel sirolimus-coated balloon (SCB) compared with the best investigated paclitaxel-coated balloon (PCB). BACKGROUND: There is increasing clinical evidence for the treatment of coronary de novo disease using drug-coated balloons. However, it is unclear whether paclitaxel remains the drug of choice or if sirolimus is an alternative, in analogy to drug-eluting stents. METHODS: Seventy patients with coronary de novo lesions were enrolled in a randomized, multicenter trial to compare a novel SCB (SeQuent SCB, B. Braun Melsungen; 4 µg/mm2) with a PCB (SeQuent Please, B. Braun Melsungen; 3 µg/mm2). The primary endpoint was angiographic late lumen loss (LLL) at 6 months. Secondary endpoints included major adverse cardiovascular events and individual clinical endpoints such as cardiac death, target lesion myocardial infarction, clinically driven target lesion revascularization, and binary restenosis. RESULTS: Quantitative coronary angiography revealed no differences in baseline parameters. After 6 months, in-segment LLL was 0.01 ± 0.33 mm in the PCB group versus 0.10 ± 0.32 mm in the SCB group. The mean difference between SCB and PCB was 0.08 (95% CI: -0.07 to 0.24). Noninferiority at a predefined margin of 0.35 was shown. However, negative LLL was more frequent in the PCB group (60% of lesions vs 32% in the SCB group; P = 0.019). Major adverse cardiovascular events up to 12 months also did not differ between the groups. CONCLUSIONS: This first-in-human comparison of a novel SCB with a crystalline coating showed similar angiographic outcomes in the treatment of coronary de novo disease compared with a clinically proven PCB. However, late luminal enlargement was more frequently observed after PCB treatment. (Treatment of Coronary De-Novo Stenosis by a Sirolimus Coated Balloon or a Paclitaxel Coated Balloon Catheter Malaysia [SCBDNMAL]; NCT04017364).

The Effect of Gadolinium-Based Contrast Agents on Longitudinal Changes of Magnetic Resonance Imaging Signal Intensities and Relaxation Times in the Aging Rat Brain.

OBJECTIVES: The aim of the study was to investigate the possible influence of changes in the brain caused by age on relaxometric and relaxation time-weighted magnetic resonance imaging (MRI) parameters in the deep cerebellar nuclei (DCN) and the globus pallidus (GP) of Gd-exposed and control rats over the course of 1 year. MATERIALS AND METHODS: Twenty-five Wistar-Han rats were equally subdivided into 5 groups and initially received 8 injections on 4 consecutive days per week of either 3.6 mL/kg body weight saline (group I-III) or 1.8 mmol Gd/kg body weight gadobutrol (group IV) or gadodiamide (group V). T1- and T2-weighted scans, as well as relaxation maps, were acquired at 1 week (all groups); 5, 12, 20, and 26 weeks (saline II, gadobutrol, gadodiamide); and at 35, 44, and 52 weeks (saline III, gadobutrol, gadodiamide) after the last administration. Saline I was euthanized after 1 week, saline II after 26 weeks, and the remaining groups after 52 weeks. Signal intensities (SIs) were evaluated for the DCN/pons (P) and the GP/piriform cortex (PC) ratios, and relaxation times for the DCN and the GP. Brain tissue was extracted, and the gadolinium, iron, and manganese contents were quantified with inductively coupled plasma mass spectrometry (ICP-MS) and laser ablation-ICP-MS imaging. RESULTS: T1-weighted SI ratios did not show any significant trend with age in any region. The between-group analysis at 52 weeks resulted in a significant difference for the DCN/P and GP/PC region ratio between gadodiamide and its comparators. T1 relaxation times dropped with increasing age in the GP with a 10% to 20% difference between first and last measurement for all groups, and in the DCN <10% with a significant decrease for the gadodiamide group only (DCN: P = 0.0158). Group-related differences were observed at the last measurement time point for T1 values between gadodiamide and saline III in the DCN (P = 0.0153) and gadodiamide and gadobutrol in the GP (P = 0.0287). Analysis of the SI ratios of the T2-weighted images revealed a significant increase for the DCN/P and a decrease for the GP/PC with increasing age for all groups and no differences at 52 weeks after the last injection between groups. T2 values of the GP showed a significant linear decrease over time for all groups (saline I-III: P = 0.0101; gadobutrol: P = 0.0001; gadodiamide: P = 0.0142) in the aging rat brain. Quantitative imaging of manganese and iron by laser ablation-ICP-MS showed a linear increase for the saline groups in the GP for both metals (Fe: P < 0.0001; Mn: P = 0.0306) and in the DCN for manganese only (P = 0.0187), but no differences between groups at 52 weeks. CONCLUSIONS: Extensive MRI evaluation did not reveal an indication of SI or relaxation time changes associated with multiple exposure to the macrocyclic-chelated GBCA gadobutrol in the DCN and the GP. With increasing age, a T1 and T2 shortening in the GP and an increase in T2-weighted SI ratio in the DCN/P, as well as a decrease in the GP/PC, were observed for all groups. Such age-related changes can potentially bias MRI results as an indicator for gadolinium presence in the brain.

A phase I study assessing the safety, tolerability, immunogenicity, and low-density lipoprotein cholesterol-lowering activity of immunotherapeutics targeting PCSK9.

PURPOSE: AT04A and AT06A are two AFFITOPE® peptide vaccine candidates being developed for the treatment of hypercholesterolemia by inducing proprotein convertase subtilisin/kexin type 9 (PCSK9)-specific antibodies. This study aimed to investigate safety, tolerability, antibody development, and reduction of low-density lipoprotein cholesterol (LDLc) following four subcutaneous immunizations. METHODS: This phase I, single-blind, randomized, placebo-controlled study was conducted in a total of 72 healthy subjects with a mean fasting LDLc level at baseline of 117.1 mg/dL (range 77-196 mg/dL). Each cohort enrolled 24 subjects to receive three priming immunizations at weeks 0, 4, and 8 and to receive a single booster immunization at week 60 of either AT04A, AT06A, or placebo. In addition to safety (primary objective), the antigenic peptide- and PCSK9-specific antibody response and the impact on LDLc were evaluated over a period of 90 weeks. RESULTS: The most common systemic treatment-related adverse events (AEs) reported were fatigue, headache, and myalgia in 75% of subjects in the AT06A group and 58% and 46% of subjects in the placebo and AT04A groups, respectively. Injection site reactions (ISR) representing 63% of all treatment-emergent adverse events (TEAEs), were transient and mostly of mild or moderate intensity and rarely severe (3%). Both active treatments triggered a robust, long-lasting antibody response towards the antigenic peptides used for immunization that optimally cross-reacted with the target epitope on PCSK9. In the AT04A group, a reduction in serum LDLc was observed with a mean peak reduction of 11.2% and 13.3% from baseline compared to placebo at week 20 and 70 respectively, and over the whole study period, the mean LDLc reduction for the AT04A group vs. placebo was -7.2% (95% CI [-10.4 to -3.9], P < 0.0001). In this group, PCSK9 target epitope titers above 50 were associated with clinically relevant LDLc reductions with an individual maximal decrease of 39%. CONCLUSIONS: Although both AT04A and AT06 were safe and immunogenic, only AT04A demonstrated significant LDLc-lowering activity, justifying further development. TRIAL REGISTRATION: EudraCT: 2015-001719-11. ClinicalTrials.gov Identifier: NCT02508896.

Impact of sequence type and field strength (1.5, 3, and 7T) on 4D flow MRI hemodynamic aortic parameters in healthy volunteers.

PURPOSE: 4D flow magnetic resonance imaging (4D-MRI) allows time-resolved visualization of blood flow patterns, quantification of volumes, velocities, and advanced parameters, such as wall shear stress (WSS). As 4D-MRI enters the clinical arena, standardization and awareness of confounders are important. Our aim was to evaluate the equivalence of 4D flow-derived aortic hemodynamics in healthy volunteers using different sequences and field strengths. METHODS: 4D-MRI was acquired in 10 healthy volunteers at 1.5T using three different prototype sequences, at 3T and at 7T (Siemens Healthineers). After evaluation of diagnostic quality in three segments (ascending-, descending aorta, aortic arch), peak velocity, flow volumes, and WSS were investigated. Equivalence limits for comparison of field strengths/sequences were based on the limits of Bland-Altman analyses of the intraobserver variability. RESULTS: Non-diagnostic quality was found in 10/144 segments, 9/10 were obtained at 7T. Apart for the comparison of forward flow between sequence 1 and 3, the differences in measurements between field strengths/sequences exceeded the range of agreement. Significant differences were found between field strengths/sequences for forward flow (1.5T vs. 3T, 3T vs. 7T, sequence 1 vs. 3, 2 vs. 3 [P < .001]), WSS (1.5T vs. 3T [P < .05], sequence 1 vs. 2, 1 vs. 3, 2 vs. 3 [P < .001]), and peak velocity (1.5T vs. 7T, sequence 1 vs. 3 [P > .001]). All parameters at all field strengths/with all sequences correlated moderately to strongly (r ≥ 0.5). CONCLUSION: Data from all sequences could be acquired and resulting images showed sufficient quality for further analysis. However, the variability of the measurements of peak velocity, flow volumes, and WSS was higher when comparing field strengths/sequences as the equivalence limits defined by the intraobserver assessments.

Assessing the Quality and Coherence of Network Meta-Analyses of Biologics in Plaque Psoriasis: What Does All This Evidence Synthesis Tell Us?

INTRODUCTION: A range of treatments are available for moderate-to-severe psoriasis; however, there remains a paucity of direct comparisons of these in head-to-head trials. Network meta-analyses (NMA) allow comparisons of these to support clinical decision making. This systematic literature review assesses the methodological quality of NMAs available for moderate-to-severe psoriasis and compares their methods and results. Their validity and applicability for current practice is also assessed. METHODS: A systematic review of published NMAs of at least two biologics for moderate-to-severe psoriasis was undertaken. Embase, MEDLINE, MEDLINE In-Process, and the Cochrane Library were last searched on 19 February 2020. The quality of NMAs was assessed using the International Society of Pharmacoeconomics and Outcomes Research (ISPOR) criteria. NMA methodology, funding, and results were compared and differences in results explored. RESULTS: Twenty-five analyses evaluating up to 19 different treatments at 8-24 weeks, and two analyses at 1 year, were included. Psoriasis Area Severity Index (PASI) response was assessed in 23, facilitating comparisons between NMAs. All NMAs met at least half of the ISPOR criteria. The major limitations were explaining the rationale for methodology, exploring effect modifiers, and consistency between direct and indirect estimates. The analyses differed in model type (Bayesian or frequentist), analysis of PASI response (binomial or multinomial), and analysis of different treatment doses (separate or pooled). PASI results were broadly similar, except for the Cochrane Collaboration NMA which provided lower estimates of treatment efficacy versus placebo. This analysis differed methodologically from others, including pooling data for different doses. CONCLUSIONS: Based on PASI 90 at induction, the majority of recent NMAs came to similar conclusions: interleukin (IL) 17 inhibitors (brodalumab, ixekizumab, secukinumab), IL-23 inhibitors (guselkumab and risankizumab) and infliximab were most efficacious, supporting the validity of NMAs in this clinical area. Decisions should be made using high-quality, up-to-date NMAs with assumptions relevant to clinical practice.

Non-contrast-enhanced MR-angiography (MRA) of lower extremity peripheral arterial disease at 3 tesla: Examination time and diagnostic performance of 2D quiescent-interval single-shot MRA vs. 3D fast spin-Echo MRA.

PURPOSE: Non-contrast enhanced MRA is a promising diagnostic alternative to contrast-enhanced (CE-) MRA or CT in patients with lower extremity peripheral arterial disease (PAD) but potentially associated with prolonged examination times and inferior diagnostic performance. We aimed to compare examination times and diagnostic performance of non-contrast enhanced quiescent-interval slice-selective (QISS)-MRA and fast-spin-echo (FSE)-MRA at 3.0 T. MATERIALS AND METHODS: Forty-five patients with PAD were recruited for this IRB approved prospective study. Subjects underwent lower extremity MRA with 1) QISS-MRA, 2) FSE-MRA, and 3) CE-MRA (continuous table movement MRA and time-resolved MRA of the calf), which served as the standard of reference. Scan times for each examination step and total examination times for each of the three techniques was determined. Image quality and degree of stenosis were rated by two readers on a 5-point Likert scale. Sensitivity, specificity and diagnostic accuracy for relevant (>50%) stenosis were calculated. RESULTS: Median total examination time was 27:02 min for QISS-MRA (IQR, 25:13-31:01 min), 28:37 min for FSE-MRA (IQR, 25:51-33:12 min), and 31:22 min for CE-MRA (IQR, 26:41-33:23 min). Acquisition time for QISS-MRA was significantly longer compared to FSE-MRA and CE-MRA (p ≤ 0.0001), while time for localizers, scouts and planning of the MRA sequence was significantly shorter for QISS-MRA compared to FSE-MRA and CE-MRA (p ≤ 0.0001). QISS-MRA had significantly better image quality compared to FSE-MRA with less segments classified as non-diagnostic (Reader 1: 3% vs. 35%; Reader 2: 3% vs. 50%, p ≤ 0.0001). Overall, QISS-MRA showed significantly better diagnostic performance than FSE-MRA (sensitivity, 85% vs. 54%; specificity, 90% vs. 47%, diagnostic accuracy, 89% vs. 48%; p ≤ 0.0001). CONCLUSION: Total examination time of QISS-MRA and FSE-MRA was comparable with a conventional CE-MRA protocol. QISS-MRA showed significantly higher diagnostic performance than FSE-MRA.

Comparability of compressed sensing-based gradient echo perfusion sequence SPARSE and conventional gradient echo sequence in assessment of myocardial ischemia.

PURPOSE: Stress perfusion imaging plays a major role in non-invasive detection of coronary artery disease. We compared a compressed sensing-based and a conventional gradient echo perfusion sequence with regard to image quality and diagnostic performance. METHOD: Patients sent for coronary angiography due to pathologic stress perfusion CMR were recruited. All patients underwent two adenosine stress CMR using conventional TurboFLASH and prototype SPARSE sequence as well as quantitative coronary angiography with fractional flow reserve (FFR) within 6 weeks. Coronary angiography was considered gold standard with FFR < 0.75 or visual stenosis >90 % for identification of myocardial ischemia. Diagnostic performance of perfusion imaging was assessed in basal, mid-ventricular and apical slices by quantification of myocardial perfusion reserve (MPR) analysis utilizing the signal upslope method and a deconvolution technique using the fermi function model. RESULTS: 23 patients with mean age of 69.6 ± 8.9 years were enrolled. 46 % were female. Image quality was similar in conventional TurboFLASH sequence and SPARSE sequence (2.9 ± 0.5 vs 3.1 ± 0.7, p = 0,06). SPARSE sequence showed higher contrast-to-noise ratio (52.1 ± 27.4 vs 40.5 ± 17.6, p < 0.01) and signal-to-noise ratio (15.6 ± 6.2 vs 13.2 ± 4.2, p < 0.01) than TurboFLASH sequence. Dark-rim artifacts occurred less often with SPARSE (9 % of segments) than with TurboFLASH (23 %). In visual assessment of perfusion defects, SPARSE sequence detected less false-positive perfusion defects (n = 1) than TurboFLASH sequence (n = 3). Quantitative perfusion analysis on segment basis showed equal detection of perfusion defects for TurboFLASH and SPARSE with both upslope MPR analysis (TurboFLASH 0.88 ± 0.18; SPARSE 0.77 ± 0.26; p = 0.06) and fermi function model (TurboFLASH 0.85 ± 0.24; SPARSE 0.76 ± 0.30; p = 0.13). CONCLUSIONS: Compressed sensing perfusion imaging using SPARSE sequence allows reliable detection of myocardial ischemia.

Safety and immunogenicity of the α-synuclein active immunotherapeutic PD01A in patients with Parkinson's disease: a randomised, single-blinded, phase 1 trial.

BACKGROUND: Robust evidence supports the role of α-synuclein pathology as a driver of neuronal dysfunction in Parkinson's disease. PD01A is a specific active immunotherapy with a short peptide formulation targeted against oligomeric α-synuclein. This phase 1 study assessed the safety and tolerability of the PD01A immunotherapeutic in patients with Parkinson's disease. METHODS: We did a first-in-human, randomised, phase 1 study of immunisations with PD01A, followed by three consecutive study extensions. Patients aged 45-65 years with a clinical diagnosis of Parkinson's disease (≤4 years since diagnosis and Hoehn and Yahr Stage 1 to 2), imaging results (dopamine transporter single photon emission CT and MRI) consistent with their Parkinson's disease diagnosis, and on stable doses of Parkinson's disease medications for at least 3 months were recruited at a single private clinic in Vienna, Austria. Patients were randomly assigned (1:1), using a computer-generated sequence with varying block size, to receive four subcutaneous immunisations with either 15 µg or 75 µg PD01A injected into the upper arms and followed up initially for 52 weeks, followed by a further 39 weeks' follow-up. Patients were then randomly assigned (1:1) again to receive the first booster immunisation at 15 µg or 75 µg and were followed up for 24 weeks. All patients received a second booster immunisation of 75 µg and were followed up for an additional 52 weeks. Patients were masked to dose allocation. Primary (safety) analyses included all treated patients. These four studies were registered with EU Clinical Trials Register, EudraCT numbers 2011-002650-31, 2013-001774-20, 2014-002489-54, and 2015-004854-16. FINDINGS: 32 patients were recruited between Feb 14, 2012, and Feb 6, 2013, and 24 were deemed eligible and randomly assigned to receive four PD01A priming immunisations. One patient had a diagnosis change to multiple system atrophy and was withdrawn and two patients withdrew consent during the studies. 21 (87%) of 24 patients received all six immunisations and completed 221-259 weeks in-study (two patients in the 15 µg dose group and one patient in the 75 µg dose group discontinued). All patients experienced at least one adverse event, but most of them were considered unrelated to study treatment (except for transient local injection site reactions, which affected all but one patient). Serial MRI assessments also ruled out inflammatory processes. Systemic treatment-related adverse events were fatigue (n=4), headache (n=3), myalgia (n=3), muscle rigidity (n=2), and tremor (n=2). The geometric group mean titre of antibodies against the immunising peptide PD01 increased from 1:46 at baseline to 1:3580 at week 12 in the 15 µg dose group, and from 1:76 to 1:2462 at week 12 in the 75 µg dose group. Antibody titres returned to baseline over 2 years, but could be rapidly reactivated after booster immunisation from week 116 onwards, reaching geometric group mean titres up to 1:20218. INTERPRETATION: Repeated administrations of PD01A were safe and well tolerated over an extended period. Specific active immunotherapy resulted in a substantial humoral immune response with target engagement. Phase 2 studies are needed to further assess the safety and efficacy of PD01A for the treatment of Parkinson's disease. FUNDING: AFFiRiS, Michael J Fox Foundation.

Comparison of 2 CT Contrast Media Injection Systems: Visual Air Identification and Injector Face Cleaning.

PURPOSE: To compare the MEDRAD Stellant and MEDRAD Stellant FLEX computed tomography contrast media injection systems in terms of radiologic technologists' ability to visually identify air in the syringes at various distances and under different lighting conditions, as well as the ease of cleaning contrast media spills on the injector faces. METHODS: Ten experienced radiologic technologists performed 104 tests (52 per injector) in normal light and in ambient light conditions. The tests were randomized for the radiologic technologists' distance from the injector at 2 ft (61 cm), 8 ft (244 cm), and 16 ft (488 cm). In addition, the authors tested the cleaning efficiency of the Stellant injector face with raised buttons and the Stellant FLEX injector face with buttons on a flush surface by applying a mixture of contrast media and invisible ultraviolet ink. Radiologic technologists followed 2 cleaning protocols: a quick clean (5 seconds) and a full clean (1 minute). Residual contrast mixture was measured. RESULTS: The Stellant FLEX injector had an overall higher rate of correct air identification than did the Stellant injector, 97.5% vs 86.9%, respectively (P < .001), with improvement seen at greater distances. The rates for the Stellant FLEX injector remained stable for all distances (99.4%-93.9%; P < .003). A similar result was seen with ambient lighting: The visibility of air in the Stellant FLEX injector remained stable (P < .001). During cleaning, the Stellant FLEX injector required less time to reach a greater level of cleanliness and showed less contrast mixture residue, especially after the quick clean procedure (16% and 59%, respectively; P < .001). DISCUSSION: Injector manufacturers provide various technologies to assist radiologic technologists in visualizing the presence of air in a syringe. The Stellant injector features clear syringes with FluiDots as an air identification technology. The Stellant FLEX injector incorporates an added feature called Beacon technology. This study's results are highly clinically relevant because unintentional iatrogenic air injection occurs in clinical practice and can, in rare cases, severely harm patients. CONCLUSION: Radiologic technologists showed an improved ability to identify air in the syringes in the Stellant FLEX system. In addition, radiologic technologists were confident about their identification, specifically at greater distances and in ambient lighting conditions. The Stellant FLEX injector face also enabled quicker and more efficient cleaning.

Magnetic Resonance Perfusion or Fractional Flow Reserve in Coronary Disease.

BACKGROUND: In patients with stable angina, two strategies are often used to guide revascularization: one involves myocardial-perfusion cardiovascular magnetic resonance imaging (MRI), and the other involves invasive angiography and measurement of fractional flow reserve (FFR). Whether a cardiovascular MRI-based strategy is noninferior to an FFR-based strategy with respect to major adverse cardiac events has not been established. METHODS: We performed an unblinded, multicenter, clinical-effectiveness trial by randomly assigning 918 patients with typical angina and either two or more cardiovascular risk factors or a positive exercise treadmill test to a cardiovascular MRI-based strategy or an FFR-based strategy. Revascularization was recommended for patients in the cardiovascular-MRI group with ischemia in at least 6% of the myocardium or in the FFR group with an FFR of 0.8 or less. The composite primary outcome was death, nonfatal myocardial infarction, or target-vessel revascularization within 1 year. The noninferiority margin was a risk difference of 6 percentage points. RESULTS: A total of 184 of 454 patients (40.5%) in the cardiovascular-MRI group and 213 of 464 patients (45.9%) in the FFR group met criteria to recommend revascularization (P = 0.11). Fewer patients in the cardiovascular-MRI group than in the FFR group underwent index revascularization (162 [35.7%] vs. 209 [45.0%], P = 0.005). The primary outcome occurred in 15 of 421 patients (3.6%) in the cardiovascular-MRI group and 16 of 430 patients (3.7%) in the FFR group (risk difference, -0.2 percentage points; 95% confidence interval, -2.7 to 2.4), findings that met the noninferiority threshold. The percentage of patients free from angina at 12 months did not differ significantly between the two groups (49.2% in the cardiovascular-MRI group and 43.8% in the FFR group, P = 0.21). CONCLUSIONS: Among patients with stable angina and risk factors for coronary artery disease, myocardial-perfusion cardiovascular MRI was associated with a lower incidence of coronary revascularization than FFR and was noninferior to FFR with respect to major adverse cardiac events. (Funded by the Guy's and St. Thomas' Biomedical Research Centre of the National Institute for Health Research and others; MR-INFORM ClinicalTrials.gov number, NCT01236807.).

Diagnostic Efficacy and Safety of Gadoxetate Disodium vs Gadobenate Dimeglumine in Patients With Known or Suspected Focal Liver Lesions: Results of a Clinical Phase III Study.

PURPOSE: The aim of this study is to evaluate the diagnostic efficacy and safety of gadoxetate disodium vs gadobenate dimeglumine in patients with known or suspected focal liver lesions. METHODS: This was a prospective, multicenter, double-blind, randomized, inter-individual Phase III study. The primary target-technical efficacy-was already published. Here, secondary efficacy parameters-sensitivity and specificity-and safety in specific patient populations are presented. Patients with suspected or known focal liver lesions scheduled for contrast-enhanced liver magnetic resonance imaging (MRI) were recruited and categorized in 4 a priori specified subgroups: (1) all patients, (2) patients with liver cancer (hepatocellular carcinoma [HCC]), (3) patients with cirrhosis, and (4) patients with HCC + cirrhosis. Dual multi-detector liver computed tomography (CT) served as standard of reference. RESULTS: A total of 295 patients were included. While the overall increase in sensitivity across all 4 patient groups was comparable for gadoxetate disodium (increase from pre- to post-contrast ranging from 6.2% to 9.9%) and gadobenate dimeglumine (ranging from -2.9% to 10.0%), significant differences were seen for some of the subgroups. There was a significantly higher increase in sensitivity for gadoxetate disodium in patients with HCC (7%) and HCC + cirrhosis (12.8%) in comparison with gadobenate dimeglumine. Specificity decreased for both agents: gadoxetate disodium by -2.8% to -6.3% and gadobenate dimeglumine by -3.3% to -8.7%. Gadoxetate showed a significantly lower loss of specificity in all subgroups. Safety was comparable in both groups. CONCLUSIONS: Gadoxetate disodium proved to be an effective liver-specific MRI contrast agent. Some distinct advantages over gadobenate dimeglumine were demonstrated in patients with HCC and patients with HCC + liver cirrhosis for sensitivity and specificity in liver lesion detection.

Detection of Sacroiliitis by Short-tau Inversion Recovery and T2-weighted Turbo Spin Echo Sequences: Results from the SIMACT Study.

OBJECTIVE: To compare proton density-weighted short-tau inversion recovery (PD-STIR) and T2-weighted fat-suppressed turbo spin echo (T2-FS) sequences for detecting osteitis lesions of the sacroiliac joints (SIJ) in patients with chronic low back pain (CLBP). METHODS: This prospective study included 110 patients with CLBP and suspected spondyloarthritis and 18 healthy controls. All 128 participants (age range: 19-57 yrs) underwent 3.0 Tesla magnetic resonance imaging (MRI) of the SIJ including PD-STIR and T2-FS. Two readers independently scored PD-STIR and T2-FS images for osteitis in separate sessions. Sum scores and signal-to-noise (SNR) and contrast-to-noise (CNR) ratios were calculated. Images were further analyzed as to whether they fulfilled the Assessment of SpondyloArthritis international Society (ASAS) criterion of a positive MRI (MRI+). Interreader agreement was calculated using intraclass correlation coefficients. RESULTS: Average osteitis sum scores were higher for T2-FS images (mean sum score of 4.10 in T2-FS vs 2.55 in PD-STIR, p = 0.017). Mean SNR was 16.54 for PD-STIR and 37.30 for T2-FS (p = 0.0289). Mean CNR was 4.14 for PD-STIR and 20.20 for T2-FS (p = 0.0212). For both readers, the ASAS MRI+ definition was more often fulfilled by T2-FS than by PD-STIR images, resulting in more patients being classified as having axial spondyloarthritis (axSpA): 68 patients using T2-FS versus 58 patients using PD-STIR. Interreader intraclass correlation coefficients were very good for both PD-STIR (0.91) and T2-FS (0.86). CONCLUSION: T2-FS sequences improve image quality and hence the detection of osteitis compared to the PD-STIR sequence. More patients were classified as axSpA based on a positive MRI by T2-FS.

Comparing the EQ-5D-5L utility index based on value sets of different countries: impact on the interpretation of clinical study results.

OBJECTIVE: To compare the country-specific value sets of the EQ-5D-5L utility index and to evaluate the impact on the interpretation of clinical study results. Six country value sets from Canada, England, Japan, Korea, Netherlands and Uruguay were obtained from literature. In addition, ten crosswalk value sets were downloaded from the EuroQol.org website. RESULTS: For each of the 3125 possible health states the difference between the country with the highest index and the country with the lowest index was calculated. The median difference was 0.417 across the health states. When analyzing multinational clinical studies, country-specific value sets should be used to evaluate treatment effects. Additional country-specific analyses are needed.

DCE-MR imaging of orbital lesions: diagnostic performance of the tumor flow residence time τ calculated by a multi-compartmental pharmacokinetic tumor model based on individual factors.

BACKGROUND: Differentiating benign from malignant orbital lesions by imaging and clinical presentation can be challenging. PURPOSE: To differentiate benign from malignant orbital masses using dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) based on tumor flow residence time τ calculated with the aid of a pharmacokinetic tumor model. MATERIAL AND METHODS: Sixty patients with orbital masses were investigated by 3-T MRI including dynamic sequences. The signal intensity-time curve after i.v. contrast medium administration within lesions was approximated by Gd-concentration profiles on the basis of model calculations where the tumor is embedded in a whole-body kinetic model. One output of the model was tumor flow residence time τ, defined as the ratio of the tumor volume and the tumor blood flow rate. Receiver operating characteristic (ROC) curves were used to analyze the diagnostic performance of τ. The results were compared with those of Ktrans, kep, ve, iAUC, and ADC. RESULTS: Thirty-one benign and 29 malignant orbital masses were identified (reference standard: histopathology, clinical characteristics). Mean τ was significantly longer for benign masses (94 ± 48 s) than for malignant masses (21 ± 19 s, P < 0.001). ROC analysis revealed the highest area under the curve (AUC = 0.94) for τ in orbital masses compared to standard methods. CONCLUSION: Tumor flow residence times τ of benign and malignant orbital masses are valuable in the diagnostic work-up of orbital tumors. Measures of diagnostic accuracy were superior for τ compared to ADC, Ktrans, ve, and iAUC.

On estimands and the analysis of adverse events in the presence of varying follow-up times within the benefit assessment of therapies.

The analysis of adverse events (AEs) is a key component in the assessment of a drug's safety profile. Inappropriate analysis methods may result in misleading conclusions about a therapy's safety and consequently its benefit-risk ratio. The statistical analysis of AEs is complicated by the fact that the follow-up times can vary between the patients included in a clinical trial. This paper takes as its focus the analysis of AE data in the presence of varying follow-up times within the benefit assessment of therapeutic interventions. Instead of approaching this issue directly and solely from an analysis point of view, we first discuss what should be estimated in the context of safety data, leading to the concept of estimands. Although the current discussion on estimands is mainly related to efficacy evaluation, the concept is applicable to safety endpoints as well. Within the framework of estimands, we present statistical methods for analysing AEs with the focus being on the time to the occurrence of the first AE of a specific type. We give recommendations which estimators should be used for the estimands described. Furthermore, we state practical implications of the analysis of AEs in clinical trials and give an overview of examples across different indications. We also provide a review of current practices of health technology assessment (HTA) agencies with respect to the evaluation of safety data. Finally, we describe problems with meta-analyses of AE data and sketch possible solutions.

Quantification of the left atrium applying cardiovascular magnetic resonance in clinical routine.

OBJECTIVES: In recent years the impact of the left atrium (LA) has become more evident in different cardiovascular pathologies. We aim to provide LA parameters in healthy volunteers for cardiovascular magnetic resonance (CMR) using a fast approach. DESIGN: We analyzed 203 healthy volunteers (mean age 44.6 years (y), range 19y-76y) at 1.5 and 3.0 Tesla (T) using steady-state free precession (SSFP) cine in routine long axis view. Left atrial enddiastolic volume (LA-EDV), endsystolic volume (LA-ESV), stroke volume (LA-SV) and ejection fraction (LA-EF) were quantified and indexed to body-surface-area (BSA). Dependency on age and sex was analyzed. RESULTS: 21 subjects had to be excluded. In the remaining, there was no significant difference between 1.5 T and 3.0 T. Absolut LA-EDV and LA-ESV were larger in men than in women (LA-EDV: male 70 ± 19 ml vs. female 61 ± 16 ml (p = .001); LA-ESV: male 24 ± 9 ml vs. female 21 ± 8 ml (p = .01)). These differences disappeared after indexing to BSA (LA-EDV/BSA: male 34 ± 10 ml/m2 vs. female 33 ± 9 ml/m2 (p = .65) and LA-ESV/BSA: male 12 ± 4 ml/m2 vs. female 11 ± 4 ml/m2 (p = .71)). LA-EDV/BSA decreased with older age. CONCLUSIONS: Reference values for LA size and function based on a fast approach are provided. LA size decreases with older age. Normalization to body size overcomes sex-dependency. Reports should be related to body size.