Induction of Paralysis and Visual System Injury in Mice by T Cells Specific for Neuromyelitis Optica Autoantigen Aquaporin-4.

While it is recognized that aquaporin-4 (AQP4)-specific T cells and antibodies participate in the pathogenesis of neuromyelitis optica (NMO), a human central nervous system (CNS) autoimmune demyelinating disease, creation of an AQP4-targeted model with both clinical and histologic manifestations of CNS autoimmunity has proven challenging. Immunization of wild-type (WT) mice with AQP4 peptides elicited T cell proliferation, although those T cells could not transfer disease to naïve recipient mice. Recently, two novel AQP4 T cell epitopes, peptide (p) 135-153 and p201-220, were identified when studying immune responses to AQP4 in AQP4-deficient (AQP4-/-) mice, suggesting T cell reactivity to these epitopes is normally controlled by thymic negative selection. AQP4-/- Th17 polarized T cells primed to either p135-153 or p201-220 induced paralysis in recipient WT mice, that was associated with predominantly leptomeningeal inflammation of the spinal cord and optic nerves. Inflammation surrounding optic nerves and involvement of the inner retinal layers (IRL) were manifested by changes in serial optical coherence tomography (OCT). Here, we illustrate the approaches used to create this new in vivo model of AQP4-targeted CNS autoimmunity (ATCA), which can now be employed to study mechanisms that permit development of pathogenic AQP4-specific T cells and how they may cooperate with B cells in NMO pathogenesis

Instrumented splint for the diagnosis of bruxism

Bruxism is a health problem consisting in grinding or tightly clenching the upper and lower teeth. Both the grinding and sliding lead to wear of the teeth and produce a noise during the night that is sufficiently loud to disturb the sleep of anyone sharing the bedroom. The tension produced causes problems in the muscles, tissues and other structures surrounding the jaw, ear pain, headaches, lesions to the teeth and disorders in the jaw joints. For an early, rapid, effective and economical diagnosis of bruxism, we propose the use of instrumented splints to detect and record the intensity and duration of inter dental pressure episodes. This paper sets out the design, manufacture and testing of an instrumented splint for diagnosing the signs of bruxism. The system stands out for its use of piezoelectric polymeric sensors which, because of their reduced thickness, do not cause any alteration to the patient’s bite. It lets a quantitative assessment of intraoral pressure be made and bruxism behavior be diagnosed at an early stage, so as to being able to programme corrective actions before irreversible dental wear appears. The first “in vitro” simulations and “in vivo “trials performed served to demonstrate the feasibility of the system in accordance with the initial objectives

Monitoring retinal changes with optical coherence tomography predicts neuronal loss in experimental autoimmune encephalomyelitis.

BACKGROUND:Retinal optical coherence tomography (OCT) is a clinical and research tool in multiple sclerosis, where it has shown significant retinal nerve fiber (RNFL) and ganglion cell (RGC) layer thinning, while postmortem studies have reported RGC loss. Although retinal pathology in experimental autoimmune encephalomyelitis (EAE) has been described, comparative OCT studies among EAE models are scarce. Furthermore, the best practices for the implementation of OCT in the EAE lab, especially with afoveate animals like rodents, remain undefined. We aimed to describe the dynamics of retinal injury in different mouse EAE models and outline the optimal experimental conditions, scan protocols, and analysis methods, comparing these to histology to confirm the pathological underpinnings. METHODS:Using spectral-domain OCT, we analyzed the test-retest and the inter-rater reliability of volume, peripapillary, and combined horizontal and vertical line scans. We then monitored the thickness of the retinal layers in different EAE models: in wild-type (WT) C57Bl/6J mice immunized with myelin oligodendrocyte glycoprotein peptide (MOG35-55) or with bovine myelin basic protein (MBP), in TCR2D2 mice immunized with MOG35-55, and in SJL/J mice immunized with myelin proteolipid lipoprotein (PLP139-151). Strain-matched control mice were sham-immunized. RGC density was counted on retinal flatmounts at the end of each experiment. RESULTS:Volume scans centered on the optic disc showed the best reliability. Retinal changes during EAE were localized in the inner retinal layers (IRLs, the combination of the RNFL and the ganglion cell plus the inner plexiform layers). In WT, MOG35-55 EAE, progressive thinning of IRL started rapidly after EAE onset, with 1/3 of total loss occurring during the initial 2 months. IRL thinning was associated with the degree of RGC loss and the severity of EAE. Sham-immunized SJL/J mice showed progressive IRL atrophy, which was accentuated in PLP-immunized mice. MOG35-55-immunized TCR2D2 mice showed severe EAE and retinal thinning. MBP immunization led to very mild disease without significant retinopathy. CONCLUSIONS:Retinal neuroaxonal damage develops quickly during EAE. Changes in retinal thickness mirror neuronal loss and clinical severity. Monitoring of the IRL thickness after immunization against MOG35-55 in C57Bl/6J mice seems the most convenient model to study retinal neurodegeneration in EAE

A multi-stakeholder multicriteria decision analysis for the reimbursement of orphan drugs (FinMHU-MCDA study)

Background: Patient access to orphan medicinal products (OMPs) is limited and varies between countries, reimbursement decisions on OMPs are complex, and there is a need for more transparent processes to know which criteria should be considered to inform these decisions. This study aimed to determine the most relevant criteria for the reimbursement of OMPs in Spain, from a multi-stakeholder perspective, and using multicriteria decision analysis (MCDA). Methods: An MCDA was developed in 3 phases and included 28 stakeholders closely related to the field of rare diseases (6 physicians, 5 hospital pharmacists, 7 health economists, 4 patient representatives and 6 members from national and regional health authorities). Initially [phase A], a bibliographic review was conducted to identify the potential reimbursement criteria. Then, a reduced advisory board (8 members) proposed, selected, and defined the final list of criteria that could be relevant for reimbursement. A discrete choice experiment (DCE) [phase B] was developed to determine the relevance and relative importance weight of such criteria according to the stakeholders’ preferences by choosing between pairs of hypothetical financing scenarios. A multinomial logit model was fitted to analyze the DCE responses. Finally [phase C], the advisory board review the results using a deliberative process. Results: Thirteen criteria were selected, related to 4 dimensions: patient population, disease, treatment, and economic evaluation. Nine criteria were deemed relevant for decision-making and associated with a higher relative importance: Health-related quality of life (HRQL) (23.53%), treatment efficacy (14.64%), availability of treatment alternatives (13.51%), disease severity (12.62%), avoided costs (11.21%), age of target population (7.75%), safety (seriousness of adverse events) (4.72%), quality of evidence (3.82%) and size of target population (3.12%). The remaining criteria had a < 3% relative importance: economic burden of disease (2.50%), cost of treatment (1.73%), cost-effectiveness (0.83%) and safety (frequency of adverse events) (0.03%). Conclusion: The reimbursement of OMPs in Spain should be determined by its effect on patient’s HRQL, the extent of its therapeutic benefit from efficacy and the availability of other therapeutic options. Furthermore, the severity of the rare disease should also influence the decision along with the potential of the treatment to avoid associated costs

Planck early results. V. The low frequency instrument data processing

We describe the processing of data from the Low Frequency Instrument (LFI) used in production of the Planck Early Release Compact Source Catalogue (ERCSC). In particular, we discuss the steps involved in reducing the data from telemetry packets to cleaned, calibrated, time-ordered data (TOD) and frequency maps. Data are continuously calibrated using the modulation of the temperature of the cosmic microwave background radiation induced by the motion of the spacecraft. Noise properties are estimated from TOD from which the sky signal has been removed using a generalized least square map-making algorithm. Measured 1/f noise knee-frequencies range from ~100 mHz at 30 GHz to a few tens of mHz at 70GHz. A destriping code (Madam) is employed to combine radiometric data and pointing information into sky maps, minimizing the variance of correlated noise. Noise covariance matrices required to compute statistical uncertainties on LFI and Planck products are also produced. Main beams are estimated down to the ??10dB level using Jupiter transits, which are also used for geometrical calibration of the focal plane.Planck is too large a project to allow full acknowledgement of all contributions by individuals, institutions, industries, and funding agencies. The main entities involved in the mission operations are as follows. The European Space Agency operates the satellite via its Mission Operations Centre located at ESOC (Darmstadt, Germany) and coordinates scientific operations via the Planck Science Office located at ESAC (Madrid, Spain). Two Consortia, comprising around 50 scientific institutes within Europe, the USA, and Canada, and funded by agencies from the participating countries, developed the scientific instruments LFI and HFI, and continue to operate them via Instrument Operations Teams located in Trieste (Italy) and Orsay (France). The Consortia are also responsible for scientific processing of the acquired data. The Consortia are led by the Principal Investigators: J.L. Puget in France for HFI (funded principally by CNES and CNRS/INSU-IN2P3) and N. Mandolesi in Italy for LFI(funded principally via ASI). NASA US Planck Project, based at J.P.L. and involving scientists at many US institutions, contributes significantly to the efforts of these two Consortia. The author list for this paper has been selected by the Planck Science Team, and is composed of individuals from all of the above entities who have made multi-year contributions to the development of the mission. It does not pretend to be inclusive of all contributions. The Planck-LFI project is developed by an International Consortium lead by Italy and involving Canada, Finland, Germany, Norway, Spain, Switzerland, UK, USA. The Italian contribution to Planck is supported by the Italian Space Agency (ASI) and INAF. This work was supported by the Academy of Finland grants 121703 and 121962. We thank the DEISA Consortium (http://www.deisa.eu), co-funded through the EU FP6 project RI-031513 and the FP7 project RI-222919, for support within the DEISA Virtual Community Support Initiative. We thank CSC – IT Center for Science Ltd (Finland) for computational resources. We acknowledge financial support provided by the Spanish Ministerio de Ciencia e Innovaciõn through the Plan Nacional del Espacio y Plan Nacional de Astronomia y Astrofisica. We acknowledge The Max Planck Institute for Astrophysics Planck Analysis Centre (MPAC) is funded by the Space Agency of the German Aerospace Center (DLR) under grant 50OP0901 with resources of the German Federal Ministry of Economics and Technology, and by the Max Planck Society. This work has made use of the Planck satellite simulation package (Level-S), which is assembled by the Max Planck Institute for Astrophysics Planck Analysis Centre (MPAC) Reinecke et al. (2006). We acknowledge financial support provided by the National Energy Research Scientific Computing Center, which is supported by the Office of Science of the U.S. Department of Energy under Contract No. DE-AC02-05CH11231. Some of the results in this paper have been derived using the HEALPix package Górski et al. (2005). A description of the Planck Collaboration and a list of its members, indicating which technical or scientific activities they have been involved in, can be found at http://www.rssd.esa.int/index.php?project=PLANCK&page=Planck_Collaboration

APOSTEL 2.0 Recommendations for Reporting Quantitative Optical Coherence Tomography Studies.

OBJECTIVE To update the consensus recommendations for reporting of quantitative optical coherence tomography (OCT) study results, thus revising the previously published Advised Protocol for OCT Study Terminology and Elements (APOSTEL) recommendations. METHODS To identify studies reporting quantitative OCT results, we performed a PubMed search for the terms "quantitative" and "optical coherence tomography" from 2015 to 2017. Corresponding authors of the identified publications were invited to provide feedback on the initial APOSTEL recommendations via online surveys following the principle of a modified Delphi method. The results were evaluated and discussed by a panel of experts and changes to the initial recommendations were proposed. A final survey was recirculated among the corresponding authors to obtain a majority vote on the proposed changes. RESULTS A total of 116 authors participated in the surveys, resulting in 15 suggestions, of which 12 were finally accepted and incorporated into an updated 9-point checklist. We harmonized the nomenclature of the outer retinal layers, added the exact area of measurement to the description of volume scans, and suggested reporting device-specific features. We advised to address potential bias in manual segmentation or manual correction of segmentation errors. References to specific reporting guidelines and room light conditions were removed. The participants' consensus with the recommendations increased from 80% for the previous APOSTEL version to greater than 90%. CONCLUSIONS The modified Delphi method resulted in an expert-led guideline (evidence Class III; Grading of Recommendations, Assessment, Development and Evaluations [GRADE] criteria) concerning study protocol, acquisition device, acquisition settings, scanning protocol, funduscopic imaging, postacquisition data selection, postacquisition analysis, nomenclature and abbreviations, and statistical approach. It will be essential to update these recommendations to new research and practices regularly

Clonal chromosomal mosaicism and loss of chromosome Y in elderly men increase vulnerability for SARS-CoV-2

The pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, COVID-19) had an estimated overall case fatality ratio of 1.38% (pre-vaccination), being 53% higher in males and increasing exponentially with age. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, we found 133 cases (1.42%) with detectable clonal mosaicism for chromosome alterations (mCA) and 226 males (5.08%) with acquired loss of chromosome Y (LOY). Individuals with clonal mosaic events (mCA and/or LOY) showed a 54% increase in the risk of COVID-19 lethality. LOY is associated with transcriptomic biomarkers of immune dysfunction, pro-coagulation activity and cardiovascular risk. Interferon-induced genes involved in the initial immune response to SARS-CoV-2 are also down-regulated in LOY. Thus, mCA and LOY underlie at least part of the sex-biased severity and mortality of COVID-19 in aging patients. Given its potential therapeutic and prognostic relevance, evaluation of clonal mosaicism should be implemented as biomarker of COVID-19 severity in elderly people. Among 9578 individuals diagnosed with COVID-19 in the SCOURGE study, individuals with clonal mosaic events (clonal mosaicism for chromosome alterations and/or loss of chromosome Y) showed an increased risk of COVID-19 lethality

Adelante / Endavant

Séptimo desafío por la erradicación de la violencia contra las mujeres del Institut Universitari d’Estudis Feministes i de Gènere "Purificación Escribano" de la Universitat Jaume