The use of embolic signal detection in multicenter trials to evaluate antiplatelet efficacy: signal analysis and quality control mechanisms in the CARESS (Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic carotid Stenosis) trial

<p><b>Background and Purpose:</b> The CARESS (Clopidogrel and Aspirin for Reduction of Emboli in Symptomatic carotid Stenosis) trial proved the effectiveness of the combination of clopidogrel and aspirin compared with aspirin alone in reducing presence and number of microembolic signals (MES) in patients with recently symptomatic carotid stenosis. The present study aimed at installing primary and secondary quality control measures in CARESS because MES evaluation relies on subjective judgment by human experts.</p> <p><b>Methods:</b> As primary quality control, centers participating in CARESS evaluated a reference digital audio tape (DAT) before the study containing both MES and artifacts. Interobserver agreement of classifying signals as MES was expressed as proportions of specific agreement of positive ratings (ps±values). For all DATs included in CARESS (n=300), online number of MES and off-line number of MES read by the central reader were compared using correlation coefficients. As secondary control, a sample of 16 of 300 DATs was cross-validated by another independent reader (post-trial validator).</p> <p><b>Results:</b> For the reference tape, the cumulative ps±value was 0.894 based on 12 of 14 observers. Two observers with very different results improved after a training procedure. Agreement between post-trial validator and central reader was ps+=0.805, indicating very good agreement. Correlation between online evaluation and off-line evaluation of DATs was very good overall (cumulative ρ=0.84; P<0.001).</p> <p><b>Conclusion:</b> Multicenter studies using MES as outcome parameter are feasible. However, primary and secondary quality control procedures are important.</p&gt

Interferon-beta-related tumefactive brain lesion in a Caucasian patient with neuromyelitis optica and clinical stabilization with tocilizumab

Background: Neuromyelitis optica (NMO) is a severely disabling inflammatory disorder of the central nervous system and is often misdiagnosed as multiple sclerosis (MS). There is increasing evidence that treatment options shown to be beneficial in MS, including interferon-β (IFN-β), are detrimental in NMO. Case presentation: We here report the first Caucasian patient with aquaporin 4 (AQP4) antibody (NMO-IgG)-seropositive NMO presenting with a tumefactive brain lesion on treatment with IFN-β. Disease started with relapsing optic neuritis and an episode of longitudinally extensive transverse myelitis (LETM) in the absence of any brain MRI lesions or cerebrospinal fluid-restricted oligoclonal bands. After initial misdiagnosis of multiple sclerosis (MS) the patient received subcutaneous IFN-β1b and, subsequently, subcutaneous IFN-β1a therapy for several years. Under this treatment, the patient showed persisting relapse activity and finally presented with a severe episode of subacute aphasia and right-sided hemiparesis due to a large T2 hyperintensive tumefactive lesion of the left brain hemisphere and a smaller T2 lesion on the right side. Despite rituximab therapy two further LETM episodes occurred, resulting in severe neurological deficits. Therapeutic blockade of the interleukin (IL)-6 signalling pathway by tocilizumab was initiated, followed by clinical and radiological stabilization. Conclusion: Our case (i) illustrates the relevance of correctly distinguishing NMO and MS since these disorders differ markedly in their responsiveness to immunomodulatory and -suppressive therapies; (ii) confirms and extends a previous report describing the development of tumefactive brain lesions under IFN-β therapy in two Asian NMO patients; and (iii) suggests tocilizumab as a promising therapeutic alternative in highly active NMO disease courses

Evaluación de los riegos de la Comunidad de Regantes V del Canal de las Bardenas

14 Pag., 2 Tabl., 1 Fig.[ES] En este artículo se presentan los resultados de las evaluaciones de riego que se han llevado a cabo dentro de la segunda fase del trabajo denominado “Mejora de la Gestión Integral del Agua de Riego en la Comunidad de Regantes V del Canal de Bardenas”. El 80 % de la superficie de esta comunidad está ocupado por suelos de plataformas residuales, mientras que el resto son suelos de aluvial. Para caracterizar la capacidad de retención de agua de los suelos (CRA) se realizó un muestro en el que se describieron 50 perfiles. Para determinar la infiltración de los suelos y los índices de calidad del riego por superficie se realizaron 50 evaluaciones de riego. Un adecuado manejo del agua a nivel de parcela y unas texturas francas-franco arenosas permiten alcanzar niveles de eficiencia medios en las parcelas de las plataformas (53 % de media), cuyos suelos se caracterizan por una baja CRA (60 mm de media). En aluviales la eficiencia llega hasta un 80 % de media, gracias a las elevadas capacidades de retención de agua de estos suelos (182 mm de media). Actualmente se está realizado un reaprovechamiento de las aguas de desagüe que posiblemente provoque que la eficiencia a nivel de comunidad sea mayor que la obtenida a nivel de parcela. Estos resultados permiten pensar que la modernización de los regadíos, mediante el cambio a un sistema de riego presurizado, tendría un fuerte impacto sobre la eficiencia en parcela, aunque el impacto sobre la eficiencia en la comunidad sería menor. La modernización tendría resultados muy beneficiosos social y económicamente para los agricultores, además de mejorar la calidad de las aguas de los ríos que atraviesan la comunidad.[EN] Results of the irrigation evaluations performed in the second phase of the project “Improvement of the Water Irrigation Integral Management in the Comunidad de Regantes V del Canal de Bardenas” are presented in this paper. An 80 % of the area of the Irrigation District is occupied by soils of residual platforms, and the rest of the soils are alluvial. A soil survey was performed for characterising the water holding capacity (WHC) of the soils, using 50 soil profiles. A total of 50 irrigation evaluations was performed for determining soil infiltration and the performance indexes of surface irrigation in the study area. An adequate water management in border irrigation and loam-sandy loam textures permit to attain 53 % application efficiency in platforms, whose soils are characterized by a low WHC (with an average of 60 mm). In alluvial soils the application efficiency is higher, with an average of 80 %, due to the high water holding capacity of these soils (an average of 182 mm). Currently, The district is enforcing a program for irrigation return flows reuse. This program surely results in an irrigation district efficiency substantially higher that the average application efficiency. With these results is possible to think that an irrigation modernization, through a change to a pressurized irrigation system will severely improve the application efficiency, but the effect on the irrigation district efficiency will only be moderate. However, this modernisation would have great social and economical benefits for farmers, and also, the water quality of rivers crossing the irrigation district will be improved.Este proyecto de investigación ha sido cofinanciado por la CICYT, por Fondos FEDER, por el CONSI+D y por la Comunidad de Regantes V de Bardenas.Peer reviewe

Clinical, paraclinical and serological findings in Susac syndrome: an international multicenter study

Background: Susac syndrome (SuS) is a rare disorder thought to be caused by autoimmune-mediated occlusions of microvessels in the brain, retina and inner ear leading to central nervous system (CNS) dysfunction, visual disturbances due to branch retinal artery occlusions (BRAO), and hearing deficits. Recently, a role for anti-endothelial cell antibodies (AECA) in SuS has been proposed. Objectives: To report the clinical and paraclinical findings in the largest single series of patients so far and to investigate the frequency, titers, and clinical relevance of AECA in SuS. Patients and methods: A total of 107 serum samples from 20 patients with definite SuS, 5 with abortive forms of SuS (all with BRAO), and 70 controls were tested for AECA by immunohistochemistry employing primate brain tissue sections. Results: IgG-AECA >1:100 were detected in 25% (5/20) of patients with definite SuS and in 4.3% (3/70) of the controls. Median titers were significantly higher in SuS (1:3200, range 1:100 to 1:17500) than in controls (1:100, range 1:10 to 1:320); IgG-AECA titers >1:320 were exclusively present in patients with SuS; three controls had very low titers (1:10). Follow-up samples (n = 4) from a seropositive SuS patient obtained over a period of 29 months remained positive at high titers. In all seropositive cases, AECA belonged to the complement-activating IgG1 subclass. All but one of the IgG-AECA-positive samples were positive also for IgA-AECA and 45% for IgM-AECA. SuS took a severe and relapsing course in most patients and was associated with bilateral visual and hearing impairment, a broad panel of neurological and neuropsychological symptoms, and brain atrophy in the majority of cases. Seropositive and seronegative patients did not differ with regard to any of the clinical or paraclinical parameters analyzed. Conclusions: SuS took a severe and protracted course in the present cohort, resulting in significant impairment. Our finding of high-titer IgG1 and IgM AECA in some patients suggest that humoral autoimmunity targeting the microvasculature may play a role in the pathogenesis of SuS, at least in a subset of patients. Further studies are warranted to define the exact target structures of AECA in SuS

Volume Estimation of the Thalamus Using Freesurfer and Stereology: Consistency between Methods

Freely available automated MR image analysis techniques are being increasingly used to investigate neuroanatomical abnormalities in patients with neurological disorders. It is important to assess the specificity and validity of automated measurements of structure volumes with respect to reliable manual methods that rely on human anatomical expertise. The thalamus is widely investigated in many neurological and neuropsychiatric disorders using MRI, but thalamic volumes are notoriously difficult to quantify given the poor between-tissue contrast at the thalamic gray-white matter interface. In the present study we investigated the reliability of automatically determined thalamic volume measurements obtained using FreeSurfer software with respect to a manual stereological technique on 3D T1-weighted MR images obtained from a 3 T MR system. Further to demonstrating impressive consistency between stereological and FreeSurfer volume estimates of the thalamus in healthy subjects and neurological patients, we demonstrate that the extent of agreeability between stereology and FreeSurfer is equal to the agreeability between two human anatomists estimating thalamic volume using stereological methods. Using patients with juvenile myoclonic epilepsy as a model for thalamic atrophy, we also show that both automated and manual methods provide very similar ratios of thalamic volume loss in patients. This work promotes the use of FreeSurfer for reliable estimation of global volume in healthy and diseased thalami.</p

An Automated Solution for Analyzing Supply Chain Performance

The world is becoming increasingly connected as technology progresses and globalization reaches more countries. This interconnection creates new challenges and new relationships for both people and businesses. Now, more than ever, businesses have to work together to satisfy the high demands of customers.In a world full of complex organizations that do business together, the supply chain has become the heartbeat of corporations. The interconnectedness of the organizations in the supply chain is critical to the success of all components of the supply chain. In order to gain an advantage in markets today, data needs to be used to determine where these relationships can be improved and how the supply chain can perform more efficiently or responsively. This senior project was dedicated to create an automated methodology to evaluate supply chain performance. Iterative development was utilized to progress the solution to the next stages after testing and data validation ensured accurate results. After thorough testing and ensuring data quality, much attention was paid to the user experience provided by the solution. The layout, interface, and user interaction were all considered and continually improved upon with a similar iterative development. Communication with the advisor and the client facilitated the development of the needs, desires, and improvements required to generate a useful output of data for a variety of users with as little need for training as possible. Once development and testing was complete, the final solution was presented to the client in order to be used in their operations and analyses. With the data and analyses presented by the solution, certain areas within the supply chain can be identified and improved upon to add value to the business. The methodology developed helped the client save time and money on their analyses, and enabled a wider range of users to engage in this type of analysis

direct comparison of M1-AQP4-DNA-transfected cells with leaky scanning versus M23-AQP4-DNA-transfected cells as antigenic substrate

Background Neuromyelitis optica (NMO, Devic syndrome) is associated with antibodies to aquaporin-4 (NMO-IgG/AQP4-Ab) in the majority of cases. NMO- IgG/AQP4-Ab seropositivity in patients with NMO and its spectrum disorders has important differential diagnostic, prognostic and therapeutic implications. So-called cell-based assays (CBA) are thought to provide the best AQP4-Ab detection rates. Objective To compare directly the AQP4-IgG detection rates of the currently most widely used commercial CBA, which employs cells transfected with a full-length (M1)-human AQP4 DNA in a fashion that allows leaky scanning (LS) and thus expression of M23-AQP4 in addition to M1-AQP, to that of a newly developed CBA from the same manufacturer employing cells transfected with human M23-AQP4-DNA. Methods Results from 368 serum samples that had been referred for routine AQP4-IgG determination and had been tested in parallel in the two assays were compared. Results Seventy-seven out of 368 samples (20.9%) were positive for NMO-IgG/AQP4-Ab in at least one assay. Of these, 73 (94.8%) were positive in both assays. A single sample (1.3%) was exclusively positive in the novel assay; three samples (3.9%) were unequivocally positive only in the ‘classic’ assay due to high background intensity in the novel assay. Both median fluorescence intensity and background intensity were higher in the new assay. Conclusions This large study did not reveal significant differences in AQP4-IgG detection rates between the ‘classic’ CBA and a new M23-DNA-based CBA. Importantly, our results largely re-affirm the validity of previous studies that had used the ‘classic’ AQP4-CBA to establish NMO-IgG/AQP4-Ab seropositivity rates in NMO and in a variety of NMO spectrum disorders

Early microstructural white matter changes in patients with HIV: A diffusion tensor imaging study

Background: Previous studies have reported white matter (WM) brain alterations in asymptomatic patients with human immunodeficiency virus (HIV).Methods: We compared diffusion tensor imaging (DTI) derived WM fractional anisotropy (FA) between HIV-patients with and without mild macroscopic brain lesions determined using standard magnetic resonance imaging (MRI). We furthermore investigated whether WM alterations co-occurred with neurocognitive deficits and depression. We performed structural MRI and DTI for 19 patients and 19 age-matched healthy controls. Regionally-specific WM integrity was investigated using voxel-based statistics of whole-brain FA maps and region-of-interest analysis. Each patient underwent laboratory and neuropsychological tests.Results: Structural MRI revealed no lesions in twelve (HIV-MRN) and unspecific mild macrostructural lesions in seven patients ( HIV-MRL). Both analyses revealed widespread FA-alterations in all patients. Patients with HIV-MRL had FA-alterations primarily adjacent to the observed lesions and, whilst reduced in extent, patients with HIV- MRN also exhibited FA-alterations in similar regions. Patients with evidence of depression showed FA-increase in the ventral tegmental area, pallidum and nucleus accumbens in both hemispheres, and patients with evidence of HIV- associated neurocognitive disorder showed widespread FA-reduction.Conclusion: These results show that patients with HIV-MRN have evidence of FA-alterations in similar regions that are lesioned in HIV-MRL patients, suggesting common neuropathological processes. Furthermore, they suggest a biological rather than a reactive origin of depression in HIV-patients.</p