Emplacement and associated sedimentary record of the Jurassic submarine salt allochthon of the Wurzeralm (Eastern Alps, Austria).

A fossil salt sheet emplaced in the Jurassic in submarine conditions is described in the Eastern Alps of Austria, providing unique insights into the emplacement of similar submarine structures and their potential control on depositional systems. The salt sheet is a plug-fed extrusion emplaced due to squeezing of a salt diapir under compression. The preserved mylonitic shear fabric in the evaporites indicates radial, south-directed emplacement of the salt sheet. Tectono-sedimentary relationships record the evolution of the salt structure, from initial diapiric growth, to salt sheet extrusion and posterior collapse. Syn-extrusion sediments record the variable bathymetry of the extruding salt sheet, with reefal carbonates building up on the crestal bulge while their deeper water equivalents accumulated on the extruding salt lobe. This is the first description of a salt allochthon still linked to its source diapir in the Eastern Alps.

Preventive interventions for children and adolescents of parents with mental illness: A systematic review.

BACKGROUND: Children of parents with mental disorders have a relatively high risk of developing a mental illness or behavioural disorder. OBJECTIVE: The aim of this systematic review was to evaluate the efficacy of preventive psychotherapeutic interventions in children of parents with mental illness. In particular, the development of mental illness and/or psychological symptomatology in this population was assessed. METHOD: This qualitative systematic review looked at interventions targeting children aged 4-18 years without a diagnosed mental disorder, alone or with their families, with a parent with a diagnosed mental disorder. The protocol was pre-registered in Open Science Framework. A total of 1255 references were retrieved from MEDLINE, PsychArticles, PsycINFO, Springer Link, Science Direct, Scopus and WOS databases, and 12 references from grey literature. This search was replicated by an external reviewer. RESULTS: Fifteen studies involving 1941 children and 1328 parents were included. Interventions were based on cognitive-behavioural and/or psychoeducational components, including six randomized controlled trials. Internalizing symptomatology was assessed in 80% of the studies, externalizing and prosocial behaviour in 47%, and coping style in 33%. Only two studies measured the future risk of developing a mental disorder (ORs of 2.37 and 6.6). There was variability in the format of the intervention (group; family) as well as in the type of intervention and its duration (from one session to 12 sessions). CONCLUSIONS: Interventions for children of parents with mental disorder were clinically and statistically significant, especially in preventing internalizing symptomatology at one-year follow-up, with effect sizes ranging from d = -0.28 to 0.57 (95% CI).

Autoimmunity and long-term safety and efficacy of alemtuzumab for multiple sclerosis: Benefit/risk following review of trial and post-marketing data.

Does preexisting or treatment-emergent autoimmunity increase the risk of subsequent autoimmune disease in individuals with relapsing-remitting multiple sclerosis (MS) after alemtuzumab? In the extended phase 2/3 trials, 34/96 (35.4%) patients with and 395/1120 (35.3%) without preexisting autoimmunity developed non-MS autoimmunity. Thyroid autoimmunity after alemtuzumab courses 1 or 2 did not increase subsequent non-thyroid autoimmune adverse events. Therefore, autoimmune disease before or after alemtuzumab treatment does not predict autoimmunity after further courses, so should not preclude adequate alemtuzumab dosing to control MS. Finally, post-marketing safety data contribute toward a full record of the alemtuzumab benefit/risk profile for the MS field.

A real-world evidence study of nabiximols in multiple sclerosis patients with resistant spasticity: Analysis in relation to the newly described 'spasticity-plus syndrome'.

BACKGROUND AND PURPOSE: Nabiximols is a therapeutic option for patients with multiple sclerosis (MS) spasticity whose symptoms are poorly controlled by conventional oral first-line medications. This study aimed to assess the relationship between changes in spasticity severity (measured on the 0-10 numeric rating scale [NRS]) and the presence of associated symptoms in patients treated with nabiximols, and to investigate the presence of the newly described 'spasticity-plus syndrome'. METHODS: We analyzed real-world data from the Italian Medicines Agency e-Registry on 1138 patients with MS spasticity who began treatment with nabiximols. Evaluation time points were baseline, 4 weeks, and 3, 6, 12 and 18 months after treatment start. RESULTS: Common symptoms associated with MS spasticity in this cohort were pain (38.4% at baseline), sleep disturbances (32.7%), and spasms/cramps (28.5%). Pain was frequently clustered with sleep disturbances (57.2% of pain cases) and spasms/cramps (43.9%). Approximately one-third of patients with data at all evaluation time points maintained treatment at 18 months. Nabiximols reduced the baseline mean spasticity 0-10 NRS score by 24.6% at Week 4, and by 33.9% at 18 months in treatment continuers. Nabiximols resolved a range of MS spasticity-associated symptoms at Week 4, and after 18 months in treatment continuers. CONCLUSION: This real-world analysis supports the concept of a spasticity-plus syndrome and suggests that nabiximols can favorably impact a range of spasticity-associated symptoms.

Hippocampal infarction: redefining transient global amnesia.

BACKGROUND AND AIMS: Transient global amnesia (TGA) is a clinical syndrome characterized by sudden anterograde amnesia not accompanied by other neurological symptoms. There is no consensus on the underlying pathophysiological mechanism. However, diffusion-weighted imaging (DWI) of the magnetic resonance imaging (MRI) has demonstrated hippocampal lesions in as many as 50% of cases. This paper describes a series of patients with TGA and hippocampal lesions. METHODS: This study assessed vascular risk factors in patients older than age 18 admitted to the Hospital Universitario San Ignacio, Bogota, Colombia, from May 2017 to June 2020 with a diagnosis of TGA and evidence of hippocampal ischemic lesion on 3 Tesla brain MRI. RESULTS: The authors identified 36 patients, 72.2% female, with mean age 62 years. Cardiovascular risk factors, most frequently high blood pressure, carotid disease, and dyslipidemia, were present in 75% of these patients. Hippocampal lesions were unilateral in 80% of cases, with median size 2.5 mm, most frequently located at the hippocampal body. Approximately 14% of patients also presented acute ischemic lesions in locations other than the hippocampus. CONCLUSIONS: TGA is a clinical entity previously considered to have undetermined etiology. The present study used brain MRI to identify a group of patients with hippocampal ischemic lesions, finding associated vascular risk factors in a high proportion of them.

Does infection predispose to thrombosis during long-term ventricular assist device support?

BACKGROUND: Infections and thrombotic events remain life-threatening complications in patients with ventricular assist devices (VAD). METHODS: We describe the relationship between both events in our cohort of patients (n = 220) supported with the HeartWare VAD (HVAD). This is a retrospective analysis of patients undergoing HVAD implantation between July 2009 and March 2019 at the Freeman Hospital, Newcastle upon Tyne, United Kingdom. RESULTS: Infection was the most common adverse event in HVAD patients, with 125 patients (56.8%) experiencing ≥ one infection (n = 168, 0.33 event per person year (EPPY)), followed by pump thrombosis (PT) in 61 patients (27.7%, 0.16 EPPY). VAD-specific infections were the largest group of infections. Of the 125 patients who had an infection, 66 (53%) had a thrombotic event. Both thrombotic events and infections were related to the duration of support, though there was only limited evidence that infections predispose to thrombosis. Those with higher than median levels of C-reactive protein during the infection were more likely to have an ischaemic stroke (IS) (34.5% vs 16.7%, p = .03), though not PT or a combined thrombotic event (CTE: first PT or IS). However, in multivariate analysis, there was no significant effect of infection predisposing to CTE. CONCLUSIONS: Infection and thrombotic events are significant adverse events related to the duration of support in patients receiving HVADs. Infections do not clearly predispose to thrombotic events.

How to Get Away with Gradients.

Biomolecular gradients are widely present in multiple biological processes. Historically they were reproduced in vitro by using micropipettes, Boyden and Zigmond chambers, or hydrogels. Despite the great utility of these setups in the study of gradient-related problems such as chemotaxis, they face limitations when trying to translate more complex in vivo-like scenarios to in vitro systems. In the last 20 years, the advances in manufacturing of micromechanical systems (MEMS) had opened the possibility of applying this technology to biology (BioMEMS). In particular, microfluidics has proven extremely efficient in setting-up biomolecular gradients which are stable, controllable, reproducible and at length scales that are relevant to cells. In this chapter, we give an overview of different methods to generate molecular gradients using microfluidics, then we discuss the different steps of the pipeline to fabricate a gradient generator microfluidic device, and at the end, we show an application example of the fabrication of a microfluidic device that can be used to generate a surface-bound biomolecular gradient.

Under-graduate nursing students working during the first outbreak of the COVID-19 pandemic: A qualitative study of psychosocial effects and coping strategies.

BACKGROUND: The first wave of the COVID-19 pandemic caused a shortage of health care staff, forcing the hiring of senior nursing students. AIMS: To describe the psychosocial impact and coping strategies used by nursing students during the first outbreak of the COVID-19 pandemic and to understand the coping strategies they employed. METHOD: A qualitative exploratory study was conducted, based on Sandelowski's proposal. Purposive sampling was carried out to recruit 18 students hired during the pandemic. The students were interviewed between 18 March and 15 June 2020. Semi-structured interviews were conducted using a digital platform. An inductive thematic analysis was performed. FINDINGS: The students lived alone and isolated during their contract to protect their cohabitants from possible contagion. The impact of working during the pandemic leads to experiences of stress, insomnia, nightmares and anxiety. Nursing students coped with the emotional burden through mental disconnection and the support of co-workers and family members. CONCLUSION: Psychological support and tutoring should be provided by health centres. In addition, in these special circumstances, universities should adapt the training provided.

Ethical challenges during the COVID-19 pandemic: Perspectives of nursing students.

BACKGROUND: The first wave of the COVID-19 pandemic caused a shortage of qualified nurses in Spain. As a result, the government authorized the hiring of senior students. OBJECTIVES: To explore the ethical dilemmas and ethical conflicts experienced by final-year nursing students who worked during the first outbreak of the COVID-19 pandemic in Spain. RESEARCH DESIGN: A qualitative exploratory study was conducted using purposive sampling. Semi-structured interviews were carried out using a question guide. Interviews took place via a private video chat room platform. A thematic, inductive analysis was performed of the information gathered. PARTICIPANTS AND RESEARCH CONTEXT: Eighteen nursing students were recruited from two universities of Madrid, aged between 18 and 65 years old, enrolled in the fourth year of nursing studies and who were hired under a relief contract for health professionals during the pandemic. ETHICAL CONSIDERATIONS: The present study was carried out in accordance with the Declaration of Helsinki, and the study was approved by the Local Ethics Committee of Universidad Rey Juan Carlos. RESULTS: Three specific themes emerged: (a) coping with patient triage, (b) difficulties in providing end-of-life care, and (c) coping with patient death. Nursing students participated in the process of patient selection for resource allocation and ICU bed occupancy. They were shown how to care for patients who were not admitted to the ICU, in their last moments and were faced with the difficulties of applying end-of-life care. Finally, the nursing students were confronted with the death of their patients, in overwhelming numbers and under adverse conditions. CONCLUSIONS: These findings can help shed light on the ethical dilemmas and ethical conflicts faced by novice nursing students, incorporated into the workforce during the COVID-19 pandemic. Moreover, it was described that students may normalize the death due to the exhaustion and overwhelmed routine.

The Dead with No Wake, Grieving with No Closure: Illness and Death in the Days of Coronavirus in Spain.

The pandemic caused by the spread of Covid-19 is giving rise to an exceptional social situation because of the great speed of propagation of the illness and the high level of mortality it has occasioned in a very short time. Moreover, the lockdown measures decreed in Spain prohibit the holding of wakes to avoid contagion, and limit funerals to three people plus the officiant. Thus, coronavirus is robbing people of the opportunity of a final farewell, stripping the dead of their dignity and worsening the grief of the living. This article investigates the situation and the social and cultural impact it has provoked. The method used takes the line of critical dialogue analysis (CDA) applied to information contained in the mass media, employing qualitative material from a related small-scale study. The results show that in countries like Spain where there is a strong Roman Catholic tradition the importance of these rituals is unquestionable. Although the country has become laicized over recent years, many traditions around death are still maintained. Hence, the impossibility of holding funerals is triggering a large number of social and personal conflicts. Furthermore, they indicate that lockdown, and the lack of rituals and of accompaniment constitute some of the most crucial stressors in the epidemic. Grief in solitude has become widespread and all the more fundamental in a society that values social support from close friends and family members. The conclusions show that the social distancing imposed by the epidemic is especially hard to bear when relatives are passing into death.

Validity of Hemodynamic Monitoring Using Inert Gas Rebreathing Method in Patients With Chronic Heart Failure and Those Implanted With a Left Ventricular Assist Device.

OBJECTIVE: The present study assessed agreement between resting cardiac output estimated by inert gas rebreathing (IGR) and thermodilution methods in patients with heart failure and those implanted with a left ventricular assist device (LVAD). METHODS AND RESULTS: Hemodynamic measurements were obtained in 42 patients, 22 with chronic heart failure and 20 with implanted continuous flow LVAD (34 males, aged 50 ± 11 years). Measurements were performed at rest using thermodilution and IGR methods. Cardiac output derived by thermodilution and IGR were not significantly different in LVAD (4.4 ± 0.9 L/min vs 4.7 ± 0.8 L/min, P = .27) or patients with heart failure (4.4 ± 1.4 L/min vs 4.5 ± 1.3 L/min, P = .75). There was a strong relationship between thermodilution and IGR cardiac index (r = 0.81, P = .001) and stroke volume index (r = 0.75, P = .001). Bland-Altman analysis showed acceptable limits of agreement for cardiac index derived by thermodilution and IGR, namely, the mean difference (lower and upper limits of agreement) for patients with heart failure -0.002 L/min/m2 (-0.65 to 0.66 L/min/m2), and -0.14 L/min/m2 (-0.78 to 0.49 L/min/m2) for patients with LVAD. CONCLUSIONS: IGR is a valid method for estimating cardiac output and should be used in clinical practice to complement the evaluation and management of chronic heart failure and patients with an LVAD.

Two-photon grayscale lithography for free-form micro-optical arrays.

Compared to standard rotationally symmetric macroscopic optical components, free-form micro-optical arrays (FMOAs), sometimes termed microstructured optical surfaces, offer greater design freedom and a smaller footprint. Hence, they are used in optical devices to deliver new functionalities, enhanced device performance, and/or a greater degree of miniaturization. But their more complex surface shape is a challenge for traditional manufacturing technologies, and this has triggered a substantial effort by research institutes and industry to develop alternative fabrication solutions. Two-photon polymerization (2PP) is a promising additive manufacturing technology to manufacture 3D optical (micro)structures. The manufacturing times involved are, however, often impractically long, especially for the excellent surface quality required for optical applications. Recently, Nanoscribe GmbH has reduced manufacturing times substantially with the introduction of so-called two-photon grayscale lithography (2GL). However, its acceleration potential and consequent impact on surface quality have, to the best of our knowledge, yet to be reported. A direct comparison between 2PP and 2GL indicates that, for the investigated FMOA, 2GL is around five times faster than 2PP and also delivers better surface quality. This study therefore confirms the potential of 2GL to manufacture complexly shaped FMOAs.

Surface topology and functionality of freeform microlens arrays.

Nonsymmetric (also known as freeform) optical components have attracted a great deal of academic and industrial attention due to the substantial benefits they have demonstrated in imaging and nonimaging optical systems. Additionally, freeform microlens arrays (FMLAs) are very promising with regard to the growing demand for device miniaturization and cost reduction. As a flip side, FMLAs entail specific challenges in design, manufacturing, and characterization. Here we report on the latter and present an innovative characterization strategy that makes it possible to assess the quality of FMLAs quickly and accurately. The precisely measured surface topology of FMLAs was accurately represented using nonuniform rational basis-spline (NURBS) and its optical response was predicted by means of ray-tracing simulations. We show that for reliably measured surface topology, the results are in excellent agreement with the experimental measurements. We also show that, compared to previous studies, illuminance levels displayed in a logarithmic scale are more adequate for low light levels and represent a closer match to nonlinear human visual perception. We believe that the method presented here will contribute to speeding up the FMLA manufacturing process, one of the current downsides of this promising technology.

Noninvasive Assessment of Cardiac Output in Advanced Heart Failure and Heart Transplant Candidates Using the Bioreactance Method.

OBJECTIVES: The aim of the present study was to assess the validity and trending ability of the bioreactance method in estimating cardiac output at rest and in response to stress in advanced heart failure patients and heart transplant candidates. DESIGN: This was a prospective single-center study. SETTING: This study was conducted at the heart transplant center at the Freeman Hospital, Newcastle upon Tyne, UK. PARTICIPANTS: Eighteen patients with advanced chronic heart failure due to reduced left ventricular ejection fraction (19 ± 7%), and peak oxygen consumption 12.3 ± 3.9 mL/kg/min. INTERVENTIONS: Participants underwent right heart catheterization using the Swan-Ganz catheter. MEASUREMENTS AND MAIN RESULTS: Cardiac output was measured simultaneously using thermodilution and bioreactance at rest and during active straight leg raise test to volitional exertion. There was no significant difference in cardiac index values obtained by the thermodilution and bioreactance methods (2.26 ± 0.59 v 2.38 ± 0.50 L/min, p > 0.05) at rest and peak straight leg raise test (2.92 ± 0.77 v 3.01 ± 0.66 L/min, p > 0.05). In response to active leg raise test, thermodilution cardiac output increased by 22% and bioreactance by 21%. There was also a strong relationship between cardiac outputs from both methods at rest (r = 0.88, p < 0.01) and peak straight leg raise test (r = 0.92, p < 0.01). Cartesian plot analysis showed good trending ability of bioreactance compared with thermodilution (concordance rate = 93%) CONCLUSIONS: `Cardiac output measured by the bioreactance method is comparable to that from the thermodilution method. Bioreactance method may be used in clinical practice to assess hemodynamics and improve management of advanced heart failure patients undergoing heart transplant assessment.

A Generative Method for Indoor Localization Using Wi-Fi Fingerprinting.

Indoor localization is an enabling technology for pervasive and mobile computing applications. Although different technologies have been proposed for indoor localization, Wi-Fi fingerprinting is one of the most used techniques due to the pervasiveness of Wi-Fi technology. Most Wi-Fi fingerprinting localization methods presented in the literature are discriminative methods. We present a generative method for indoor localization based on Wi-Fi fingerprinting. The Received Signal Strength Indicator received from a Wireless Access Point is modeled by a hidden Markov model. Unlike other algorithms, the use of a hidden Markov model allows ours to take advantage of the temporal autocorrelation present in the Wi-Fi signal. The algorithm estimates the user's location based on the hidden Markov model, which models the signal and the forward algorithm to determine the likelihood of a given time series of Received Signal Strength Indicators. The proposed method was compared with four other well-known Machine Learning algorithms through extensive experimentation with data collected in real scenarios. The proposed method obtained competitive results in most scenarios tested and was the best method in 17 of 60 experiments performed.

Targeted resequencing reveals rare variants enrichment in multiple sclerosis susceptibility genes.

Although genome-wide association studies have identified a number of common variants associated with multiple sclerosis (MS) susceptibility, little is known about the relevance of rare variants. Here, we aimed to explore the role of rare variants in 14 MS risk genes (FCRL1, RGS1, TIMMDC1, HHEX, CXCR5, LTBR, TSFM, GALC, TRAF3, STAT3, TNFSF14, IFI30, CD40, and CYP24A1) by targeted resequencing in an Iberian population of 524 MS cases and 546 healthy controls. Four rare variants-enriched regions within CYP24A1, FCRL1, RGS1, and TRAF3 were identified as significantly associated with MS. Functional studies revealed significantly decreased regulator of G protein signaling 1 (RGS1) gene expression levels in peripheral blood mononuclear cells from MS patients with RGS1 rare variants compared to noncarriers, whereas no significant differences in gene expression were observed for CYP24A1, FCRL1, and TRAF3 between rare variants carriers and noncarriers. Immunophenotyping showed significant decrease in RGS1 expression in peripheral blood B lymphocytes from MS patients with RGS1 rare variants relative to noncarriers. Lastly, peripheral blood mononuclear cell from MS patients carrying RGS1 rare variants showed significantly lower induction of RGS1 gene expression by interferon-ß compared to MS patients lacking RGS1 variants. The presence of rare variants in RGS1 reinforce the ideas of high genetic heterogeneity and a role of rare variants in MS pathogenesis.

Efficacy of alemtuzumab over 6 years in relapsing-remitting multiple sclerosis patients who relapsed between courses 1 and 2: Post hoc analysis of the CARE-MS studies.

BACKGROUND: Alemtuzumab is administered as two annual courses for relapsing-remitting multiple sclerosis (MS). Patients may relapse before completing the two-course regimen. OBJECTIVE: The objective was to evaluate 6-year outcomes in patients who relapsed between alemtuzumab Courses 1 and 2 (early relapsers). METHODS: Post hoc analysis of patients from the Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis (CARE-MS) studies who enrolled in the extension. RESULTS: Early relapsers (CARE-MS I: 15%; CARE-MS II: 24%) had more relapses in 1-2 years pre-alemtuzumab and higher mean baseline Expanded Disability Status Scale score than patients without relapse. Their annualized relapse rate declined from Year 1 (CARE-MS I: 1.3; CARE-MS II: 1.2) to Year 2 following Course 2 (0.3; 0.5) and remained low thereafter. Over 6 years, 60% remained free of 6-month confirmed disability worsening; 24% (CARE-MS I) and 34% (CARE-MS II) achieved 6-month confirmed disability improvement. During Year 6, 69% (CARE-MS I) and 68% (CARE-MS II) were free of magnetic resonance imaging (MRI) disease activity. Median percent yearly brain volume loss (Year 1: -0.67% (CARE-MS I); -0.47% (CARE-MS II)) declined after Course 2 (Year 6: -0.24%; -0.13%). CONCLUSION: Early relapsers' outcomes improved after completing the second alemtuzumab course. These findings support administering the approved two-course regimen to maximize clinical benefit. CLINICALTRIALS.GOV REGISTRATION NUMBERS: CARE-MS I, II, extension: NCT00530348, NCT00548405, NCT00930553.

Efficacy of alemtuzumab in relapsing-remitting MS patients who received additional courses after the initial two courses: Pooled analysis of the CARE-MS, extension, and TOPAZ studies.

BACKGROUND: Alemtuzumab is given as two annual courses. Patients with continued disease activity may receive as-needed additional courses. OBJECTIVE: To evaluate efficacy and safety of additional alemtuzumab courses in the CARE-MS (Comparison of Alemtuzumab and Rebif® Efficacy in Multiple Sclerosis) studies and their extensions. METHODS: Subgroups were based on the number of additional alemtuzumab courses received. Exclusion criteria: other disease-modifying therapy (DMT); <12-month follow-up after last alemtuzumab course. RESULTS: In the additional-courses groups, Courses 3 and 4 reduced annualized relapse rate (12 months before: 0.73 and 0.74, respectively; 12 months after: 0.07 and 0.08). For 36 months after Courses 3 and 4, 89% and 92% of patients were free of 6-month confirmed disability worsening, respectively, with 20% and 26% achieving 6-month confirmed disability improvement. Freedom from magnetic resonance imaging (MRI) disease activity increased after Courses 3 and 4 (12 months before: 43% and 53%, respectively; 12 months after: 73% and 74%). Safety was similar across groups; serious events occurred irrespective of the number of courses. CONCLUSION: Additional alemtuzumab courses significantly improved outcomes, without increased safety risks, in CARE-MS patients with continued disease activity after Course 2. How this compares to outcomes if treatment is switched to another DMT instead remains unknown.

Social value of a set of proposals for the ideal approach of multiple sclerosis within the Spanish National Health System: a social return on investment study.

BACKGROUND: Multiple Sclerosis (MS) is a chronic inflammatory, demyelinating and neurodegenerative disease that in many cases produces disability, having a high impact in patients' lives, reducing significantly their quality of life. The aim of this study was to agree on a set of proposals to improve the current management of MS within the Spanish National Health System (SNHS) and apply the Social Return on Investment (SROI) method to measure the potential social impact these proposals would create. METHODS: A Multidisciplinary Working Team of nine experts, with representation from the main stakeholders regarding MS, was set up to agree on a set of proposals to improve the management of MS. A forecast SROI analysis was carried out, with a one-year timeframe. Data sources included an expert consultation, a narrative literature review and a survey to 532 MS patients. We estimated the required investment of a hypothetical implementation, as well as the potential social value that it could create. We calculated outcomes in monetary units and we measured intangible outcomes through financial proxies. RESULTS: The proposed ideal approach revealed that there are still unmet needs related to MS that can be addressed within the SNHS. Investment would amount to 148 million € and social return to 272 million €, so each euro invested could yield almost €2 of social return. CONCLUSIONS: This study could guide health interventions, resulting in money savings for the SNHS and increases in patients' quality of life.

The presence and suppressive activity of myeloid-derived suppressor cells are potentiated after interferon-ß treatment in a murine model of multiple sclerosis.

Multiple sclerosis (MS) is an autoimmune demyelinating disease of the human central nervous system (CNS), mainly affecting young adults. Among the immunomodulatory disease modifying treatments approved up to date to treat MS, IFN-ß remains to be one of the most widely prescribed for the Relapsing-Remitting (RR) variant of the disease, although its mechanism of action is still partially understood. RR-MS variant is characterized by phases with increasing neurological symptoms (relapses) followed by periods of total or partial recovery (remissions), which implies the existence of immunomodulatory agents to promote the relapsing-to-remitting transition. Among these agents, it has been described the immunosuppressive role of a heterogeneous population of immature myeloid cells, namely the myeloid-derived suppressor cells (MDSCs) during the clinical course of the experimental autoimmune encephalomyelitis (EAE), the most used MS model to study RRMS. However, it is still unknown how the current MS disease modifying treatments, e.g. IFN- ß, affects to MDSCs number or activity. Our present results show that a single injection of IFN-ß at the onset of the clinical course reduces the severity of the EAE, enhancing the presence of MDSCs within the smaller demyelinated areas. Moreover, the single dose of IFN-ß promotes MDSC immunosuppressive activity both in vivo and in vitro, augmenting T cell apoptosis. Finally, we show that IFN-ß preserves MDSC immaturity, preventing their differentiation to mature and less suppressive myeloid cell subsets. Taking together, all these data add new insights into the mechanism of IFN-ß treatment in EAE and point to MDSCs as a putative endogenous mediator of its beneficial role in this animal model of MS.