Experimental Evaluation of Immediate Recanalization Effect and Recanalization Efficacy of a New Thrombus Retriever for Acute Stroke Treatment In Vivo

BACKGROUND AND PURPOSE: Currently, several new stent retriever devices for acute stroke treatment are under development and early clinical evaluation. Preclinical testing under standardized conditions is an important first step to evaluate the technical performance and potential of these devices. The aim of this study was to evaluate the immediate recanalization effect, recanalization efficacy, thrombus-device interaction, and safety of a new stent retriever intended for thrombectomy in patients with acute stroke. MATERIAL AND METHODS: The pREset thrombectomy device (4 × 20 mm) was evaluated in 16 vessel occlusions in an established swine model. Radiopaque thrombi (10-mm length) were used for visualization of thrombus-device interaction during application and retrieval. Flow-restoration effect immediately after deployment and after 5-minute embedding time before retrieval, recanalization rate after retrieval, thromboembolic events, and complications were assessed. High-resolution FPCT was performed to illustrate thrombus-device interaction during the embedding time. RESULTS: Immediate flow restoration was achieved in 75% of occlusions. An increase or stable percentage of recanalizations during embedding time before retrieval was seen in 56.3%; a decrease, in 12.5%; reocclusion of a previously recanalized vessel, in 18.8%; and no recanalization effect at all, in 12.5%. Complete recanalization (TICI 3) after retrieval was achieved in 93.8%; partial recanalization (TICI 2b), in 6.2%. No distal thromboembolic events were observed. High-resolution FPCT illustrated entrapment of the thrombus between the stent struts and compression against the contralateral vessel wall, leading to partial flow restoration. During retrieval, the thrombus was retained in a straight position within the stent struts. CONCLUSIONS: In this experimental study, the pREset thrombus retriever showed a high recanalization rate in vivo. High-resolution FPCT allows detailed illustration of the thrombus-device interaction during embedding time and is advocated as an add-on tool to the animal model used in this study.

Rotational atherectomy followed by drug-eluting stent implantation (Rota-DES): a rational approach for complex calcified coronary lesions

Rotational atherectomy has been regaining interest over the last couple of years after it almost has disappeared from most interventional catheterization laboratories for several years due to failure to prove its original concept of improving long term results of percutaneous coronary interventions (PCI) as was repeatedly shown in studies in the 1990s. Its revival coupled the introduction of drug-eluting stents (DES); these devices have led to treating much more complex lesions and high-risk patients by PCI. However, real-world experience suggested that off-label use of DES is associated with a higher rate of early and late stent thrombosis. Therefore, more attention is now being paid to the initial implantation technique of DES including aggressive lesion preparation to facilitate stent delivery and expansion. The limited studies with rot-ablation and DES showed promising results with no long term safety concerns. In these studies, a subtle observation was made suggesting that rot-ablation prior to DES implantation in such lesions may have an add-on effect on long term outcome compared to DES alone. An ongoing multicenter study is investigating such effect among complex calcified coronary lesions. Even if this additive benefit does not prove true, rot-ablation remains an efficient tool for preparing certain lesions to facilitate effective and safe DES implantation. Therefore, interventional training programs should focus on this difficult technique to bridge the gap of experience which resulted from neglecting it for several years. In this regard, dedicated courses at experienced sites as well as medical simulation may be appropriate.

Evidence-based diagnosis

Making an accurate diagnosis is essential to ensure that a patient receives appropriate treatment and correct information regarding their prognosis. Characteristics of diagnostic tests are quantified in test accuracy studies, but many such studies have methodological flaws. The HSRC evidence-based diagnosis programme has focused on methods for systematic reviews of test accuracy studies, and the wider context in which tests are ordered and interpreted. We carried out a range of projects relating to literature searching, quality assessment, meta-analysis, presentation of results, and interactions between doctors and patients during the diagnostic process. We have shown that systematic reviews of test accuracy studies should search a range of databases and that current diagnostic filters do not have sufficient accuracy to be used in test accuracy reviews. Summary quality scores should not be used in test accuracy reviews; the Quality Assessment of Studies of Diagnostic Accuracy included in Systematic Reviews (QUADAS) tool for assessing test accuracy studies is acceptable for quality assessment. We have shown that the hierarchical summary receiver operating characteristic (HSROC) and bivariate models for meta-analysis of test accuracy are statistically equivalent in many circumstances, and have developed an add-on module for the statistical software package Stata that enables these statistically rigorous models to be fitted by those without expert statistical knowledge. Three areas that would benefit from further research are literature searching, synthesis of results from individual patient data and presentation of results.

Non-invasive brain stimulation in neglect rehabilitation: an update

Here, we review the effects of non-invasive brain stimulation such as transcranial magnetic stimulation (TMS) or transcranial direct current stimulation (tDCS) in the rehabilitation of neglect. We found 12 studies including 172 patients (10 TMS studies and 2 tDCS studies) fulfilling our search criteria. Activity of daily living measures such as the Barthel Index or, more specifically for neglect, the Catherine Bergego Scale were the outcome measure in three studies. Five studies were randomized controlled trials with a follow-up time after intervention of up to 6 weeks. One TMS study fulfilled criteria for Class I and one for Class III evidence. The studies are heterogeneous concerning their methodology, outcome measures, and stimulation parameters making firm comparisons and conclusions difficult. Overall, there are however promising results for theta-burst stimulation, suggesting that TMS is a powerful add-on therapy in the rehabilitation of neglect patients.

Cost-effectiveness of ticagrelor and generic clopidogrel in patients with acute coronary syndrome in Switzerland

QUESTION UNDER STUDY The aim of this study was to evaluate the cost-effectiveness of ticagrelor and generic clopidogrel as add-on therapy to acetylsalicylic acid (ASA) in patients with acute coronary syndrome (ACS), from a Swiss perspective. METHODS Based on the PLATelet inhibition and patient Outcomes (PLATO) trial, one-year mean healthcare costs per patient treated with ticagrelor or generic clopidogrel were analysed from a payer perspective in 2011. A two-part decision-analytic model estimated treatment costs, quality-adjusted life years (QALYs), life years and the cost-effectiveness of ticagrelor and generic clopidogrel in patients with ACS up to a lifetime at a discount of 2.5% per annum. Sensitivity analyses were performed. RESULTS Over a patient's lifetime, treatment with ticagrelor generates an additional 0.1694 QALYs and 0.1999 life years at a cost of CHF 260 compared with generic clopidogrel. This results in an Incremental Cost Effectiveness Ratio (ICER) of CHF 1,536 per QALY and CHF 1,301 per life year gained. Ticagrelor dominated generic clopidogrel over the five-year and one-year periods with treatment generating cost savings of CHF 224 and 372 while gaining 0.0461 and 0.0051 QALYs and moreover 0.0517 and 0.0062 life years, respectively. Univariate sensitivity analyses confirmed the dominant position of ticagrelor in the first five years and probabilistic sensitivity analyses showed a high probability of cost-effectiveness over a lifetime. CONCLUSION During the first five years after ACS, treatment with ticagrelor dominates generic clopidogrel in Switzerland. Over a patient's lifetime, ticagrelor is highly cost-effective compared with generic clopidogrel, proven by ICERs significantly below commonly accepted willingness-to-pay thresholds.

A randomized, double-blind, placebo-controlled pilot study of naltrexone in outpatients with bipolar disorder and alcohol dependence.

BACKGROUND: Alcohol dependence is extremely common in patients with bipolar disorder and is associated with unfavorable outcomes including treatment nonadherence, violence, increased hospitalization, and decreased quality of life. While naltrexone is a standard treatment for alcohol dependence, no controlled trials have examined its use in patients with co-morbid bipolar disorder and alcohol dependence. In this pilot study, the efficacy of naltrexone in reducing alcohol use and on mood symptoms was assessed in bipolar disorder and alcohol dependence. METHODS: Fifty adult outpatients with bipolar I or II disorders and current alcohol dependence with active alcohol use were randomized to 12 weeks of naltrexone (50 mg/d) add-on therapy or placebo. Both groups received manual-driven cognitive behavioral therapy designed for patients with bipolar disorder and substance-use disorders. Drinking days and heavy drinking days, alcohol craving, liver enzymes, and manic and depressed mood symptoms were assessed. RESULTS: The 2 groups were similar in baseline and demographic characteristics. Naltrexone showed trends (p < 0.10) toward a greater decrease in drinking days (binary outcome), alcohol craving, and some liver enzyme levels than placebo. Side effects were similar in the 2 groups. Response to naltrexone was significantly related to medication adherence. CONCLUSIONS: Results suggest the potential value and acceptable tolerability of naltrexone for alcohol dependence in bipolar disorder patients. A larger trial is needed to establish efficacy.

Effects of Motive-Oriented Therapeutic Relationship in a Ten-Session General Psychiatric Treatment of Borderline Personality Disorder: A Randomized Controlled Trial

Background: Motive-oriented therapeutic relationship (MOTR) was postulated to be a particularly helpful therapeutic ingredient in the early treatment phase of patients with personality disorders, in particular with borderline personality disorder (BPD). The present randomized controlled study using an add-on design is the first study to test this assumption in a 10-session general psychiatric treatment with patients presenting with BPD on symptom reduction and therapeutic alliance. Methods: A total of 85 patients were randomized. They were either allocated to a manual-based short variant of the general psychiatric management (GPM) treatment (in 10 sessions) or to the same treatment where MOTR was deliberately added to the treatment. Treatment attrition and integrity analyses yielded satisfactory results. Results: The results of the intent-to-treat analyses suggested a global efficacy of MOTR, in the sense of an additional reduction of general problems, i.e. symptoms, interpersonal and social problems (F 1, 73 = 7.25, p < 0.05). However, they also showed that MOTR did not yield an additional reduction of specific borderline symptoms. It was also shown that a stronger therapeutic alliance, as assessed by the therapist, developed in MOTR treatments compared to GPM (Z 55 = 0.99, p < 0.04). Conclusions: These results suggest that adding MOTR to psychiatric and psychotherapeutic treatments of BPD is promising. Moreover, the findings shed additional light on the perspective of shortening treatments for patients presenting with BPD.

Validation of the DRAGON score in 12 stroke centers in anterior and posterior circulation

BACKGROUND AND PURPOSE The DRAGON score predicts functional outcome in the hyperacute phase of intravenous thrombolysis treatment of ischemic stroke patients. We aimed to validate the score in a large multicenter cohort in anterior and posterior circulation. METHODS Prospectively collected data of consecutive ischemic stroke patients who received intravenous thrombolysis in 12 stroke centers were merged (n=5471). We excluded patients lacking data necessary to calculate the score and patients with missing 3-month modified Rankin scale scores. The final cohort comprised 4519 eligible patients. We assessed the performance of the DRAGON score with area under the receiver operating characteristic curve in the whole cohort for both good (modified Rankin scale score, 0-2) and miserable (modified Rankin scale score, 5-6) outcomes. RESULTS Area under the receiver operating characteristic curve was 0.84 (0.82-0.85) for miserable outcome and 0.82 (0.80-0.83) for good outcome. Proportions of patients with good outcome were 96%, 93%, 78%, and 0% for 0 to 1, 2, 3, and 8 to 10 score points, respectively. Proportions of patients with miserable outcome were 0%, 2%, 4%, 89%, and 97% for 0 to 1, 2, 3, 8, and 9 to 10 points, respectively. When tested separately for anterior and posterior circulation, there was no difference in performance (P=0.55); areas under the receiver operating characteristic curve were 0.84 (0.83-0.86) and 0.82 (0.78-0.87), respectively. No sex-related difference in performance was observed (P=0.25). CONCLUSIONS The DRAGON score showed very good performance in the large merged cohort in both anterior and posterior circulation strokes. The DRAGON score provides rapid estimation of patient prognosis and supports clinical decision-making in the hyperacute phase of stroke care (eg, when invasive add-on strategies are considered).

Clinical and radiographic outcomes at 2 years and the effect of tocilizumab discontinuation following sustained remission in the second and third year of the ACT-RAY study

OBJECTIVE To assess the efficacy and safety of tocilizumab (TCZ) plus methotrexate/placebo (MTX/PBO) over 2 years and the course of disease activity in patients who discontinued TCZ due to sustained remission. METHODS ACT-RAY was a double-blind 3-year trial. Patients with active rheumatoid arthritis despite MTX were randomised to add TCZ to ongoing MTX (add-on strategy) or switch to TCZ plus PBO (switch strategy). Using a treat-to-target approach, open-label conventional synthetic disease-modifying antirheumatic drugs (csDMARDs), other than MTX, were added from week 24 if Disease Activity Score in 28 joints based on erythrocyte sedimentation rate (DAS28-ESR) >3.2. Between weeks 52 and 104, patients in sustained clinical remission (DAS28-ESR <2.6 at two consecutive visits 12 weeks apart) discontinued TCZ and were assessed every 4 weeks for 1 year. If sustained remission was maintained, added csDMARDs, then MTX/PBO, were discontinued. RESULTS Of the 556 randomised patients, 76% completed year 2. Of patients entering year 2, 50.4% discontinued TCZ after achieving sustained remission and 5.9% achieved drug-free remission. Most patients who discontinued TCZ (84.0%) had a subsequent flare, but responded well to TCZ reintroduction. Despite many patients temporarily stopping TCZ, radiographic progression was minimal, with differences favouring add-on treatment. Rates of serious adverse events and serious infections per 100 patient-years were 12.2 and 4.4 in add-on and 15.0 and 3.7 in switch patients. In patients with normal baseline values, alanine aminotransferase elevations >3×upper limit of normal were more frequent in add-on (14.3%) versus switch patients (5.4%). CONCLUSIONS Treat-to-target strategies could be successfully implemented with TCZ to achieve sustained remission, after which TCZ was stopped. Biologic-free remission was maintained for about 3 months, but most patients eventually flared. TCZ restart led to rapid improvement. TRIAL REGISTRATION NUMBER NCT00810199.

Alleviation of chronic venous leg ulcers with a hand-held dielectric barrier discharge plasma generator (PlasmaDerm(®) VU-2010): results of a monocentric, two-armed, open, prospective, randomized and controlled trial (NCT01415622).

BACKGROUND Cold atmospheric plasma (CAP, i.e. ionized air) is an innovating promising tool in reducing bacteria. OBJECTIVE We conducted the first clinical trial with the novel PlasmaDerm(®) VU-2010 device to assess safety and, as secondary endpoints, efficacy and applicability of 45 s/cm(2) cold atmospheric plasma as add-on therapy against chronic venous leg ulcers. METHODS From April 2011 to April 2012, 14 patients were randomized to receive standardized modern wound care (n = 7) or plasma in addition to standard care (n = 7) 3× per week for 8 weeks. The ulcer size was determined weekly (Visitrak(®) , photodocumentation). Bacterial load (bacterial swabs, contact agar plates) and pain during and between treatments (visual analogue scales) were assessed. Patients and doctors rated the applicability of plasma (questionnaires). RESULTS The plasma treatment was safe with 2 SAEs and 77 AEs approximately equally distributed among both groups (P = 0.77 and P = 1.0, Fisher's exact test). Two AEs probably related to plasma. Plasma treatment resulted in a significant reduction in lesional bacterial load (P = 0.04, Wilcoxon signed-rank test). A more than 50% ulcer size reduction was noted in 5/7 and 4/7 patients in the standard and plasma groups, respectively, and a greater size reduction occurred in the plasma group (plasma -5.3 cm(2) , standard: -3.4 cm(2) ) (non-significant, P = 0.42, log-rank test). The only ulcer that closed after 7 weeks received plasma. Patients in the plasma group quoted less pain compared to the control group. The plasma applicability was not rated inferior to standard wound care (P = 0.94, Wilcoxon-Mann-Whitney test). Physicians would recommend (P = 0.06, Wilcoxon-Mann-Whitney test) or repeat (P = 0.08, Wilcoxon-Mann-Whitney test) plasma treatment by trend. CONCLUSION Cold atmospheric plasma displays favourable antibacterial effects. We demonstrated that plasma treatment with the PlasmaDerm(®) VU-2010 device is safe and effective in patients with chronic venous leg ulcers. Thus, larger controlled trials and the development of devices with larger application surfaces are warranted.

Temporal change in prevalence and complications of uveitis associated with juvenile idiopathic arthritis:data from a cross-sectional analysis of a prospective nationwide study

OBJECTIVES To analyse the nationwide prevalence of uveitis in JIA and its complications over a whole decade. METHODS We conducted a prospective, observational and cross-sectional study including all JIA patients from a National Paediatric Rheumatological Database (NPRD) with a uveitis add-on module in Germany (2002-2013). Temporal changes in uveitis prevalence, related secondary complications and anti-inflammatory medication were evaluated. RESULTS A total of 60 centres including 18,555 JIA patients (mean 3,863 patients/year, SD=837) were documented in the NPRD between 2002 and 2013. The mean age of the patients was 11.4±4.6 years, their mean disease duration 4.4±3.7 years. Among them, 66.9% were female and 51.7% ANA positive. Patients' mean age at arthritis onset was 6.9±4.5 years. Treatment rates with synthetic and biological DMARDs increased during the observation period (sDMARD: 39.8% to 47.2%, bDMARD: 3.3% to 21.8%). Uveitis prevalence decreased significantly from 2002 to 2013 (13.0% to 11.6%, OR = 0.98, p=0.015). The prevalence of secondary uveitis complications also decreased significantly between 2002 and 2013 (33.6% to 23.9%, OR=0.94, p<0.001). Among the complications, the most common ones were posterior synechiae, cataract and band keratopathy. A significant increase in achieving uveitis inactivity was observed at 30.6% in 2002 and 65.3% in 2013 (OR=1.15, p<0.001). CONCLUSIONS Uveitis prevalence and complications significantly decreased between 2002 and 2013. This may be associated with a more frequent use of DMARDs.

Treatment of optic neuritis with erythropoietin (TONE): a randomised, double-blind, placebo-controlled trial-study protocol.

INTRODUCTION Optic neuritis leads to degeneration of retinal ganglion cells whose axons form the optic nerve. The standard treatment is a methylprednisolone pulse therapy. This treatment slightly shortens the time of recovery but does not prevent neurodegeneration and persistent visual impairment. In a phase II trial performed in preparation of this study, we have shown that erythropoietin protects global retinal nerve fibre layer thickness (RNFLT-G) in acute optic neuritis; however, the preparatory trial was not powered to show effects on visual function. METHODS AND ANALYSIS Treatment of Optic Neuritis with Erythropoietin (TONE) is a national, randomised, double-blind, placebo-controlled, multicentre trial with two parallel arms. The primary objective is to determine the efficacy of erythropoietin compared to placebo given add-on to methylprednisolone as assessed by measurements of RNFLT-G and low-contrast visual acuity in the affected eye 6 months after randomisation. Inclusion criteria are a first episode of optic neuritis with decreased visual acuity to ≤0.5 (decimal system) and an onset of symptoms within 10 days prior to inclusion. The most important exclusion criteria are history of optic neuritis or multiple sclerosis or any ocular disease (affected or non-affected eye), significant hyperopia, myopia or astigmatism, elevated blood pressure, thrombotic events or malignancy. After randomisation, patients either receive 33 000 international units human recombinant erythropoietin intravenously for 3 consecutive days or placebo (0.9% saline) administered intravenously. With an estimated power of 80%, the calculated sample size is 100 patients. The trial started in September 2014 with a planned recruitment period of 30 months. ETHICS AND DISSEMINATION TONE has been approved by the Central Ethics Commission in Freiburg (194/14) and the German Federal Institute for Drugs and Medical Devices (61-3910-4039831). It complies with the Declaration of Helsinki, local laws and ICH-GCP. TRIAL REGISTRATION NUMBER NCT01962571.

Superior outcomes of decompression with an interlaminar dynamic device versus decompression alone in patients with lumbar spinal stenosis and back pain: a cross registry study.

INTRODUCTION Surgical decompression for lumbar spinal stenosis (LSS) has been associated with poorer outcomes in patients with pronounced low back pain (LBP) as compared to patients with predominant leg pain. This cross registry study assessed potential benefits of the interlaminar coflex® device as an add-on to bony decompression alone. METHODS Patients with lumbar decompression plus coflex® (SWISSspine registry) were compared with decompressed controls (Spine Tango registry). Inclusion criteria were LSS and a preoperative back pain level of ≥5 points. 1:1 propensity score-based matching was performed. Outcome measures were back and leg pain relief, COMI score improvement, patient satisfaction, complication, and revision rates. RESULTS 50 matched pairs without residual significant differences but age were created. At the 7-9 months follow-up interval the coflex® group had higher back (p=0.014) and leg pain relief (p<0.001) and COMI score improvement (p=0.029) than the decompression group. Patient satisfaction was 90% in both groups. No revision was documented in the coflex® and one in the decompression group (2.0%). DISCUSSION In the short-term, lumbar decompression with coflex® compared with decompression alone in patients with LSS and pronounced LBP at baseline is a safe and effective treatment option that appears beneficial regarding clinical and functional outcomes. However, residual confounding of non-measured covariables may have partially influenced our findings. Also, despite careful inclusion and exclusion of cases the cross registry approach introduces a potential for selection bias that we could not totally control for and that makes additional studies necessary.

AUTOFLY-Aid: Flight Deck Automation Support with Dynamic 4D Trajectory Management for Responsive and Adaptive Airborne Collision Avoidance

AUTOFLY-Aid Project aims to develop and demonstrate novel automation support algorithms and tools to the flight crew for flight critical collision avoidance using “dynamic 4D trajectory management”. The automation support system is envisioned to improve the primary shortcomings of TCAS, and to aid the pilot through add-on avionics/head-up displays and reality augmentation devices in dynamically evolving collision avoidance scenarios. The main theoretical innovative and novel concepts to be developed by AUTOFLY-Aid project are a) design and development of the mathematical models of the full composite airspace picture from the flight deck’s perspective, as seen/measured/informed by the aircraft flying in SESAR 2020, b) design and development of a dynamic trajectory planning algorithm that can generate at real-time (on the order of seconds) flyable (i.e. dynamically and performance-wise feasible) alternative trajectories across the evolving stochastic composite airspace picture (which includes new conflicts, blunder risks, terrain and weather limitations) and c) development and testing of the Collision Avoidance Automation Support System on a Boeing 737 NG FNPT II Flight Simulator with synthetic vision and reality augmentation while providing the flight crew with quantified and visual understanding of collision risks in terms of time and directions and countermeasures.

Evaluación de los co-beneficios sobre el desarrollo sostenible y la reducción de la pobreza de proyectos de mitigación del cambio climático en Brasil

El cambio climático y los diferentes aspectos del concepto de “desarrollo” están intrínsecamente interconectados. Por un lado, el desarrollo económico de nuestras sociedades ha contribuido a un aumento insostenible de las emisiones de gases de efecto invernadero, las cuales están desestabilizando el sistema climático global, generando al mismo tiempo una distribución desigual de la capacidad de las personas para hacer frente a estos cambios. Por otro lado, en la actualidad existe un amplio consenso sobre que el cambio climático impacta directamente y de manera negativa sobre el denominando desarrollo sostenible. De igual manera, cada vez existe un mayor consenso de que el cambio climático va a desafiar sustancialmente nuestra capacidad de erradicar la pobreza a medio y largo plazo. Ante esta realidad, no cabe duda de que las estrategias de adaptación son esenciales para mantener el desarrollo. Es por esto que hasta el momento, los mayores esfuerzos realizados por unir las agendas globales de la lucha contra la pobreza y del cambio climático se han dado en el entorno de la adaptación al cambio climático. Sin embargo, cada vez son más los actores que defienden, desde distintos escenarios, que existen sinergias entre la mitigación de emisiones y la mejora de las condiciones de vida de las poblaciones más vulnerables, favoreciendo así un “desarrollo sostenible” sin disminuir los recursos financieros destinados a la adaptación. Para hacer efectivo este potencial, es imprescindible identificar diseños de estrategias de mitigación que incrementen los resultados de desarrollo, contribuyendo al desarrollo sostenible al mismo tiempo que a reducir la pobreza. En este contexto se sitúa el objetivo principal de esta investigación, consistente en analizar los co-beneficios locales, para el desarrollo sostenible y la reducción la pobreza, de proyectos de mitigación del cambio climático que se implementan en Brasil. Por co-beneficios se entienden, en el lenguaje de las discusiones internacionales de cambio climático, aquellos beneficios que van más allá de la reducción de emisiones de Gases de Efecto Invernadero (GEI) intrínsecas por definición a los proyectos de mitigación. Los proyectos de mitigación más relevantes hasta el momento bajo el paraguas de la Convención Marco de las Naciones Unidas para el Cambio Climático (CMNUCC), son los denominados Mecanismos de Desarrollo Limpio (MDL) del Protocolo de Kioto. Sin embargo, existen alternativas de proyectos de mitigación (tales como los denominados “estándares adicionales” a los MDL de los Mercados Voluntarios de Carbono y las Tecnologías Sociales), que también serán tenidos en cuenta en el marco de este estudio. La elección del tema se justifica por la relevancia del mismo en un momento histórico en el que se está decidiendo el futuro del régimen climático a partir del año 2020. Aunque en el momento de redactar este documento, todavía no se ha acordado la forma que tendrán los futuros instrumentos de mitigación, sí que se sabe que los co-beneficios de estos instrumentos serán tan importantes, o incluso más, que las reducciones de GEI que generan. Esto se debe, principalmente, a las presiones realizadas en las negociaciones climáticas por parte de los países menos desarrollados, para los cuales el mayor incentivo de formar parte de dichas negociaciones se basa principalmente en estos potenciales co-beneficios. Los resultados de la tesis se estructuran alrededor de tres preguntas de investigación: ¿cómo están contribuyendo los MDL implementados en Brasil a generar co-beneficios que fomenten el desarrollo sostenible y reduzcan la pobreza?; ¿existen proyectos de mitigación en Brasil que por tener compromisos más exigentes en cuanto a su contribución al desarrollo sostenible y/o la reducción de la pobreza que los MDL estén siendo más eficientes que estos en relación a los co-beneficios que generan?; y ¿qué características de los proyectos de mitigación pueden resultar críticas para potenciar sus co-beneficios en las comunidades en las que se implementan? Para dar respuesta a estas preguntas, se ha desarrollado durante cuatro años una labor de investigación estructurada en varias fases y en la que se combinan diversas metodologías, que abarcan desde el desarrollo de un modelo de análisis de cobeneficios, hasta la aplicación del mismo tanto a nivel documental sobre 194 documentos de diseño de proyecto (denominado análisis ex-ante), como a través de 20 casos de estudio (denominado análisis ex-post). Con la realización de esta investigación, se ha confirmado que los requisitos existentes hasta el momento para registrar un proyecto como MDL bajo la CMNUCC no favorecen sustancialmente la generación de co-beneficios locales para las comunidades en las que se implementan. Adicionalmente, se han identificado prácticas y factores, que vinculadas a las actividades intrínsecas de los proyectos de mitigación, son efectivas para incrementar sus co-beneficios. Estas prácticas y factores podrán ser tenidas en cuenta tanto para mejorar los requisitos de los actuales proyectos MDL, como para apoyar la definición de los nuevos instrumentos climáticos. ABSTRACT Climate change and development are inextricably linked. On the one hand, the economic development of our societies has contributed to the unsustainable increase of Green House Gases emissions, which are destabilizing the global climate system while fostering an unequal distribution of people´s ability to cope with these changes. On the other hand, there is now a consensus that climate change directly impacts the so-called sustainable development. Likely, there is a growing agreement that climate change will substantially threaten our capacity to eradicate poverty in the medium and long term. Given this reality, there is no doubt that adaptation strategies are essentials to keep development. This is why, to date, much of the focus on poverty in the context of climate change has been on adaptation However, without diverting resources from adaptation, there may exist the potential to synergize efforts to mitigate emissions, contribute to sustainable development and reduce poverty. To fulfil this potential, it is key identifying how mitigation strategies can also support sustainable development and reduce poverty. In this context, the main purpose of this investigation is to explore the co-benefits, for sustainable development and for poverty reduction, of climate change mitigation projects being implemented in Brazil. In recent years the term co-benefits, has been used by policy makers and academics to refer the potentially large and diverse range of collateral benefits that can be associated with climate change mitigation policies in addition to the direct avoided climate impact benefits. The most relevant mitigation projects developed during the last years under the United Nations Framework Convention on Climate Change (UNFCCC) are the so-called Clean Development Mechanisms (CDM) of the Kyoto Protocol. Thus, this research will analyse this official mechanism. However, there are alternatives to the mitigation projects (such as the "add-on standards" of the Voluntary Carbon Markets, and the Social Technologies) that will also be assessed as part of the research. The selection of this research theme is justified because its relevance in a historic moment in which proposals for a future climate regime after 2020 are being negotiated. Although at the moment of writing this document, there is not a common understanding on the shape of the new mitigation instruments, there is a great agreement about the importance of the co-benefits of such instruments, which may be even more important for the Least Developed Countries that their expected greenhouse gases emissions reductions. The results of the thesis are structured around three research questions: how are the CDM projects being implemented in Brazil generating local co-benefits that foster sustainable development and poverty reduction?; are other mitigation projects in Brazil that due to their more stringent sustainable development and/o poverty reduction criteria, any more successful at delivering co-benefits than regular CDM projects?; and what are the distinguishing characteristics of mitigation projects that are successful at delivering co-benefits? To answer these research questions, during four years it has been developed a research work structured in several phases and combining various methodologies. Those methodologies cover from the development of a co-benefits assessment model, to the application of such model both to a desktop analysis of 194 project design documents, and to 20 case studies using field data based on site visits to the project sites. With the completion of this research, it has been confirmed that current requirements to register a CDM project under the UNFCCC not substantially favour co-benefits at the local level. In addition, some practices and factors enablers of co-benefits have been identified. These characteristics may be taken into consideration to improve the current CDM and to support the definition of the new international market mechanisms for climate mitigation.