Pretreatment With Fragments of Substance-P or With Cholecystokinin Differentially Affects Recovery From Sub-Total Nigrostriatal 6-Hydroxydopamine Lesion

The neuropeptide substance P is known to have mnemogenic and reinforcing actions and can exert neurotrophic and regenerative effects in vitro as well as in vivo. Furthermore, our previous work in the rat showed that either pre- or post-lesion treatment with substance P can promote functional recovery in cases of partial nigrostriatal dopamine lesions. Other work has provided evidence that the effects of substance P might be differentially encoded by its C- and N-terminal fragments. The C-terminal fragment was found to be reinforcing, whereas the mnemogenic as well as neurotrophic properties have been ascribed to the N-terminal sequences. Given these relations, we asked here whether pre-lesion treatment with either a C- or an N-terminal fragment of substance P might differentially affect the behavioral and neurochemical outcome of nigrostriatal dopamine lesions. Therefore, either substance P1−7 or substance P5−11 (37 nmol/kg each) was administered intraperitoneally daily for eight consecutive days before unilateral 6-hydroxy-dopamine lesions of the substantia nigra. Control rats received prelesion treatment with vehicle. Furthermore, we investigated the effects of pre-treatment with Boc-cholecystokinin-4 (0.91 nmol/kg), as we had found an increase in dopamine metabolism in animals that were pre-treated with cholecystokinin-8 in a former study. In accordance with our previous work, drug treatment effects were observed when excluding animals with most severe dopamine lesions: In animals with partial lesions (residual neostriatal dopamine levels of more than 10%), lesion-dependent asymmetries in turning behavior were observed in animals that were pre-treated with vehicle-, substance P1−7 , or Boc-cholecysto-kinin–4,. whereas turning after pre-treatment with substance P5−11 was not significantly asymmetrical. Furthermore, the ipsi- and contra-lateral neostriatal dopamine levels did not differ significantly in this group. Moreover, pre treatment with substance P5−11 affected dopamine metabolism in the neostriatum and in the venral striatum, as indicated by increased ratios of dihydroxyphenyllic acid to dopamine. The data provide the first evidence that the promotive effects of substance-P treatment in the unilateral dopamine lesion model might be mediated by its C-terminal and might depend on actions on residual dopamine mechanisms

THU0366 SYSTEMATIC CORONARY RISK EVALUATION (SCORE) MISCLASSIFIES CARDIOVASCULAR RISK IN ANTISYNTHETASE SYNDROME: RESULTS OF THE PILOT MULTICENTRIC STUDY RI.CAR.D.A.

Background:Antisynthetase Syndrom (ASyS) is an autoimmune overlap disease characterized by antiaminoacyl-tRNA-synthetase (anti-ARS) antibodies and the classic triad of arthritis, myositis and interstitial lung disease (ILD) (1). Markers of cardiovascular (CV) or cerebrovascular (CVB) risk have never been examined in ASyS.Objectives:Aim of this study (RIsk of CARdiovascular Disease in ASyS: RI.CAR.D.A.) was to test the ability of an established traditional CV risk prediction score (Systematic Coronary Risk Evaluation-SCORE) and its EULAR modified version (mSCORE) to identify ASyS patients at high CV risk. Moreover, we sought to examine for the first time associations of CV surrogate markers with clinical and immunological ASyS parameters.Methods:SCORE/mSCORE and the gold standard marker of aortic stiffness (carotid-femoral pulse wave velocity-cfPWV) were examined in patients with ASyS and healthy controls in a multicenter setting (6 Rheumatology Centers). Moreover, sonography of the common- (CCA), internal- (ICA) and external- (ECA) carotid arteries was performed in subsets of both groups, evaluating carotid intima-media-thickness (cIMT), plaques and duplex-sonographic indices of CBV risk such as the resistance- (RI) and pulsatility-index (PI).Figure 1.Carotid Doppler surrogate markers of cardiovascular and cerebrovascular risk in controls and ASyS (case).cIMTCarotid intima media thickness;CAA(common-),ICA(internal),ECA(external) carotid artery;RIresistance index;PIpulsatility index. (all;p0.9 mm) (SCA) in85.7%of the patients respectively. ROC analyses showed similarly poor diagnostic performances of SCORE/mSCORE in comparison to cfPWV(>10 m/s) and SAC by areas under the curve (AUC) of0.56 (95%CI=0.39-0.73) and0.63 (95%CI=0.3-0.96),respectively. cfPWV and SCA were higher in ASyS patients compared to controls (padj=0.021andp=0.003, respectively). cfPWV and cIMT correlated in the patient group significantly with age (r=0.679; p<0.001 and r=0.664; p<0.001,respectively).Moreover, cfPWV correlated with BMI (padj=0.001) and diabetes(padj=0.043). ACC-RI and ACC-PI showed significant associations with a marker of myositis activity [creatine phosphokinase (CPK):r=0.629;p=0.012andr=0.574;p=0.032, respectively]. Finally, ACI-RI and ACI-PI values were higher in patients with ILD (both;p=0.039).Conclusion:This is the first report of higher aortic stiffness and SCA in ASyS patients compared to controls. Active myositis and presence of ILD were associated with higher CVB risk parameters. Furthermore, SCORE/mSCORE performed poorly in identifying patients at high CV risk and carotid arteriosclerosis compared to cfPWV and CS respectively. Thus, cfPWV and CS could improve CV and CBV screening in ASyS patients.References:[1]Cavagna L, et al. Clinical Spectrum Time Course in Anti Jo-1 Positive Antisynthetase Syndrome.Medicine2015;94:1144.Disclosure of Interests:None declare

Endovascular thrombectomy is cost-saving in patients with acute ischemic stroke with large infarct

ObjectiveEndovascular thrombectomy (EVT) is the standard of care for acute large vessel occlusion stroke. Recently, the ANGEL-ASPECT and SELECT 2 trials showed improved outcomes in patients with acute ischemic Stroke presenting with large infarcts. The cost-effectiveness of EVT for this subpopulation of stroke patients has only been calculated using data from the previously published RESCUE-Japan LIMIT trial. It is, therefore, limited in its generalizability to an international population. With this study we primarily simulated patient-level costs to analyze the economic potential of EVT for patients with large ischemic stroke from a public health payer perspective based on the recently published data and secondarily identified determinants of cost-effectiveness.MethodsCosts and outcome of patients treated with EVT or only with the best medical care based on the recent prospective clinical trials ANGEL-ASPECT, SELECT2 and RESCUE-Japan LIMIT. A A Markov model was developed using treamtment outcomes derived from the most recent available literature. Deterministic and probabilistic sensitivity analyses addressed uncertainty.ResultsEndovascular treatment resulted in an incremental gain of 1.32 QALYs per procedure with cost savings of $17,318 per patient. Lifetime costs resulted to be most sensitive to the costs of the endovascular procedure.ConclusionEVT is a cost-saving (i.e., dominant) strategy for patients presenting with large ischemic cores defined by inclusion criteria of the recently published ANGEL-ASPECT, SELECT2, and RESCUE-Japan LIMIT trials in comparison to best medical care in our simulation. Prospective data of individual patients need to be collected to validate these results

Primitive Simultaneous Optimization of Similarity Metrics for Image Registration

Even though simultaneous optimization of similarity metrics represents a standard procedure in the field of semantic segmentation, surprisingly, this does not hold true for image registration. To close this unexpected gap in the literature, we investigate in a complex multi-modal 3D setting whether simultaneous optimization of registration metrics, here implemented by means of primitive summation, can benefit image registration. We evaluate two challenging datasets containing collections of pre- to post-operative and pre- to intra-operative Magnetic Resonance Imaging (MRI) of glioma. Employing the proposed optimization we demonstrate improved registration accuracy in terms of Target Registration Error (TRE) on expert neuroradiologists' landmark annotations

Framing image registration as a landmark detection problem for better representation of clinical relevance

Nowadays, registration methods are typically evaluated based on sub-resolution tracking error differences. In an effort to reinfuse this evaluation process with clinical relevance, we propose to reframe image registration as a landmark detection problem. Ideally, landmark-specific detection thresholds are derived from an inter-rater analysis. To approximate this costly process, we propose to compute hit rate curves based on the distribution of errors of a sub-sample inter-rater analysis. Therefore, we suggest deriving thresholds from the error distribution using the formula: median + delta * median absolute deviation. The method promises differentiation of previously indistinguishable registration algorithms and further enables assessing the clinical significance in algorithm development

The Brain Tumor Sequence Registration Challenge: Establishing Correspondence between Pre-Operative and Follow-up MRI scans of diffuse glioma patients

Registration of longitudinal brain Magnetic Resonance Imaging (MRI) scans containing pathologies is challenging due to tissue appearance changes, and still an unsolved problem. This paper describes the first Brain Tumor Sequence Registration (BraTS-Reg) challenge, focusing on estimating correspondences between pre-operative and follow-up scans of the same patient diagnosed with a brain diffuse glioma. The BraTS-Reg challenge intends to establish a public benchmark environment for deformable registration algorithms. The associated dataset comprises de-identified multi-institutional multi-parametric MRI (mpMRI) data, curated for each scan's size and resolution, according to a common anatomical template. Clinical experts have generated extensive annotations of landmarks points within the scans, descriptive of distinct anatomical locations across the temporal domain. The training data along with these ground truth annotations will be released to participants to design and develop their registration algorithms, whereas the annotations for the validation and the testing data will be withheld by the organizers and used to evaluate the containerized algorithms of the participants. Each submitted algorithm will be quantitatively evaluated using several metrics, such as the Median Absolute Error (MAE), Robustness, and the Jacobian determinant

Clinical outcomes and safety of rituximab treatment for patients with systemic lupus erythematosus (SLE) - results from a nationwide cohort in Germany (GRAID)

ObjectiveThe objective of this article is to evaluate the safety and clinical outcome of rituximab treatment in systemic lupus erythematosus (SLE) patients refractory to standard of care therapy in a real-life setting in Germany. MethodsThe GRAID registry included patients with different autoimmune diseases who were given off-label treatment with rituximab. Data on safety and clinical response were collected retrospectively. In SLE patients, clinical parameters included tender and swollen joint counts, fatigue, myalgia, general wellbeing, Raynaud's and the SLEDAI index. Laboratory tests included dsDNA antibody titres, complement factors, hematologic parameters and proteinuria. Finally, the investigators rated their patients as non-, partial or complete responders based on clinical grounds. ResultsData from 85 SLE patients were collected, 69 female and 16 male, with a mean disease duration of 9.8 years. The mean follow-up period was 9.67.4 months, resulting in 66.8 patient years of observation. A complete response was reported in 37 patients (46.8%), partial response in 27 (34.2%), no response in 15 (19.0%). On average, major clinical as well as laboratory efficacy parameters improved substantially, with the SLEDAI decreasing significantly from 12.2 to 3.3 points. Concerning safety, one infusion reaction leading to discontinuation of treatment occurred. Infections were reported with a rate of 19.5 (including six severe infections) per 100 patient years. ConclusionWith the restrictions of a retrospective data collection, the results of this study confirm data of other registries, which suggest a favourable benefit-risk ratio of rituximab in patients with treatment-refractory SLE

Clinical outcomes and safety of rituximab treatment for patients with systemic lupus erythematosus (SLE) - results from a nationwide cohort in Germany (GRAID)

ObjectiveThe objective of this article is to evaluate the safety and clinical outcome of rituximab treatment in systemic lupus erythematosus (SLE) patients refractory to standard of care therapy in a real-life setting in Germany. MethodsThe GRAID registry included patients with different autoimmune diseases who were given off-label treatment with rituximab. Data on safety and clinical response were collected retrospectively. In SLE patients, clinical parameters included tender and swollen joint counts, fatigue, myalgia, general wellbeing, Raynaud's and the SLEDAI index. Laboratory tests included dsDNA antibody titres, complement factors, hematologic parameters and proteinuria. Finally, the investigators rated their patients as non-, partial or complete responders based on clinical grounds. ResultsData from 85 SLE patients were collected, 69 female and 16 male, with a mean disease duration of 9.8 years. The mean follow-up period was 9.67.4 months, resulting in 66.8 patient years of observation. A complete response was reported in 37 patients (46.8%), partial response in 27 (34.2%), no response in 15 (19.0%). On average, major clinical as well as laboratory efficacy parameters improved substantially, with the SLEDAI decreasing significantly from 12.2 to 3.3 points. Concerning safety, one infusion reaction leading to discontinuation of treatment occurred. Infections were reported with a rate of 19.5 (including six severe infections) per 100 patient years. ConclusionWith the restrictions of a retrospective data collection, the results of this study confirm data of other registries, which suggest a favourable benefit-risk ratio of rituximab in patients with treatment-refractory SLE

Yardstick Competition in German Municipalities

Does increasing transparency improve fiscal policy behavior of local governments? One way this could take place is via Yardstick Competition between incumbents of neighboring municipalities. This paper contributes to the literature by introducing a simple model which employs probabilistic voting to show the effect of Yardstick Competition on the amount of political rents diverted from the tax revenue. Since additional rents lower the probability of being reelected, the incumbent will reduce equilibrium rents if voters use information on fiscal performance in similar municipalities to evaluate the incumbent's quality. I test this hypothesis on a panel dataset of municipal budget and electoral data in the german state of Northrine-Westphalia. I show evidence for Yardstick Competition in the local business and property tax rates.Kann zunehmende Transparenz im kommunalen Budgetprozess die fiskalpolitische Disziplin der politischen Entscheidungsträger verbessern? In dieser Arbeit wird ein positiver Modellrahmen entwickelt, anhand dessen die Wirkungsweise von steigen - der Transparenz auf das Entscheidungsverhalten von Kommunalpolitikern durch den Yardstick Competition Effekt dargestellt werden kann. Politiker reduzieren die Veruntreuung finanzieller Mittel, wenn ihr Verhalten von den Wählern relativ zur Leistung von Politikern in benachbarten Kommunen bewertet wird. Unter Anwendung von Methoden der räumlichen Ökonometrie auf kommunale Haushalts- und Wahldaten der Jahre 1989 bis 2004 wird gezeigt, dass die räumliche Korrelation in den Gewerbe- und Grundsteuerhebesätzen in Nordrhein-Westfalen auf die Existenz von Yardstick Competition zurückzuführen ist