Showing papers by "University of Modena and Reggio Emilia published in 2013"

Retinoic acid and arsenic trioxide for acute promyelocytic leukemia

Abstract: Background All-trans retinoic acid (ATRA) with chemotherapy is the standard of care for acute promyelocytic leukemia (APL), resulting in cure rates exceeding 80%. Pilot studies of treatment with arsenic trioxide with or without ATRA have shown high efficacy and reduced hematologic toxicity. Methods

Mutations and prognosis in primary myelofibrosis

Abstract: Patient outcome in primary myelofibrosis (PMF) is significantly influenced by karyotype. We studied 879 PMF patients to determine the individual and combinatorial prognostic relevance of somatic mutations. Analysis was performed in 483 European patients and the seminal observations were validated in 396 Mayo Clinic patients. Samples from the European cohort, collected at time of diagnosis, were analyzed for mutations in ASXL1, SRSF2, EZH2, TET2, DNMT3A, CBL, IDH1, IDH2, MPL and JAK2. Of these, ASXL1, SRSF2 and EZH2 mutations inter-independently predicted shortened survival. However, only ASXL1 mutations (HR: 2.02; P<0.001) remained significant in the context of the International Prognostic Scoring System (IPSS). These observations were validated in the Mayo Clinic cohort where mutation and survival analyses were performed from time of referral. ASXL1, SRSF2 and EZH2 mutations were independently associated with poor survival, but only ASXL1 mutations held their prognostic relevance (HR: 1.4; P=0.04) independent of the Dynamic IPSS (DIPSS)-plus model, which incorporates cytogenetic risk. In the European cohort, leukemia-free survival was negatively affected by IDH1/2, SRSF2 and ASXL1 mutations and in the Mayo cohort by IDH1 and SRSF2 mutations. Mutational profiling for ASXL1, EZH2, SRSF2 and IDH identifies PMF patients who are at risk for premature death or leukemic transformation.

Structure and Mineralogy of Clay Minerals

Abstract: Phyllosilicates, and among them clay minerals, are of great interest not only for the scientific community but also for their potential applications in many novel and advanced areas. However, the correct application of these minerals requires a thorough knowledge of their crystal chemical properties. This chapter provides crystal chemical and structural details related to phyllosilicates and describes the fundamental features leading to their different behaviour in different natural or technical processes, as also detailed in other chapters of this book. Phyllosilicates, described in this chapter, are minerals of the (i) kaolin-serpentine group (e.g. kaolinite, dickite, nacrite, halloysite, hisingerite, lizardite, antigorite, chrysotile, amesite, carlosturanite, greenalite); (ii) talc and pyrophyllite group (e.g. pyrophyllite, ferripyrophyllite); (iii) mica group, with particular focus to illite; (iv) smectite group (e.g. montmorillonite, beidellite, nontronite, saponite, hectorite, sauconite); (v) vermiculite group; (vi) chlorite group; (vii) some 2:1 layer silicates involving a discontinuous octahedral sheet and a modulated tetrahedral sheet such as kalifersite, palygorskite and sepiolite; (viii) allophane and imogolite and (ix) mixed layer structures with particular focus on illite-smectite.

Antioxidant properties of potentially probiotic bacteria: in vitro and in vivo activities

Abstract: Thirty-four strains of lactic acid bacteria (seven Bifidobacterium, 11 Lactobacillus, six Lactococcus, and 10 Streptococcus thermophilus) were assayed in vitro for antioxidant activity against ascorbic and linolenic acid oxidation (TAA(AA) and TAA(LA)), trolox-equivalent antioxidant capacity (TEAC), intracellular glutathione (TGSH), and superoxide dismutase (SOD). Wide dispersion of each of TAA(AA), TAA(LA), TEAC, TGSH, and SOD occurred within bacterial groups, indicating that antioxidative properties are strain specific. The strains Bifidobacterium animalis subsp. lactis DSMZ 23032, Lactobacillus acidophilus DSMZ 23033, and Lactobacillus brevis DSMZ 23034 exhibited among the highest TAA(AA), TAA(LA), TEAC, and TGSH values within the lactobacilli and bifidobacteria. These strains were used to prepare a potentially antioxidative probiotic formulation, which was administered to rats at the dose of 10(7), 10(8), and 10(9) cfu/day for 18 days. The probiotic strains colonized the colon of the rats during the trial and promoted intestinal saccharolytic metabolism. The analysis of plasma antioxidant activity, reactive oxygen molecules level, and glutathione concentration, revealed that, when administered at doses of at least 10(8) cfu/day, the antioxidant mixture effectively reduced doxorubicin-induced oxidative stress. Probiotic strains which are capable to limit excessive amounts of reactive radicals in vivo may contribute to prevent and control several diseases associated with oxidative stress.

Deep-Level Characterization in GaN HEMTs-Part I: Advantages and Limitations of Drain Current Transient Measurements

Abstract: This paper critically investigates the advantages and limitations of the current-transient methods used for the study of the deep levels in GaN-based high-electron mobility transistors (HEMTs), by evaluating how the procedures adopted for measurement and data analysis can influence the results of the investigation. The article is divided in two parts within Part I. 1) We analyze how the choice of the measurement and analysis parameters (such as the voltage levels used to induce the trapping phenomena and monitor the current transients, the duration of the filling pulses, and the method used for the extrapolation of the time constants of the capture/emission processes) can influence the results of the drain current transient investigation and can provide information on the location of the trap levels responsible for current collapse. 2) We present a database of defects described in more than 60 papers on GaN technology, which can be used to extract information on the nature and origin of the trap levels responsible for current collapse in AlGaN/GaN HEMTs. Within Part II, we investigate how self-heating can modify the results of drain current transient measurements on the basis of combined experimental activity and device simulation.

Differential integrity of TALE nuclease genes following adenoviral and lentiviral vector gene transfer into human cells

Abstract: The array of genome editing strategies based on targeted double-stranded DNA break formation have recently been enriched through the introduction of transcription activator-like type III effector (TALE) nucleases (TALENs). To advance the testing of TALE-based approaches, it will be crucial to deliver these custom-designed proteins not only into transformed cell types but also into more relevant, chromosomally stable, primary cells. Viral vectors are among the most effective gene transfer vehicles. Here, we investigated the capacity of human immunodeficiency virus type 1- and adenovirus-based vectors to package and deliver functional TALEN genes into various human cell types. To this end, we attempted to assemble particles of these two vector classes, each encoding a monomer of a TALEN pair targeted to a bipartite sequence within the AAVS1 'safe harbor' locus. Vector DNA analyses revealed that adenoviral vectors transferred intact TALEN genes, whereas lentiviral vectors failed to do so, as shown by their heterogeneously sized proviruses in target cells. Importantly, adenoviral vector-mediated TALEN gene delivery resulted in site-specific double-stranded DNA break formation at the intended AAVS1 target site at similarly high levels in both transformed and non-transformed cells. In conclusion, we demonstrate that adenoviral, but not lentiviral, vectors constitute a valuable TALEN gene delivery platform.

People reidentification in surveillance and forensics: A survey

Abstract: The field of surveillance and forensics research is currently shifting focus and is now showing an ever increasing interest in the task of people reidentification. This is the task of assigning the same identifier to all instances of a particular individual captured in a series of images or videos, even after the occurrence of significant gaps over time or space. People reidentification can be a useful tool for people analysis in security as a data association method for long-term tracking in surveillance. However, current identification techniques being utilized present many difficulties and shortcomings. For instance, they rely solely on the exploitation of visual cues such as color, texture, and the object’s shape. Despite the many advances in this field, reidentification is still an open problem. This survey aims to tackle all the issues and challenging aspects of people reidentification while simultaneously describing the previously proposed solutions for the encountered problems. This begins with the first attempts of holistic descriptors and progresses to the more recently adopted 2D and 3D model-based approaches. The survey also includes an exhaustive treatise of all the aspects of people reidentification, including available datasets, evaluation metrics, and benchmarking.

Clinicopathologic Characteristics of Angioimmunoblastic T-Cell Lymphoma: Analysis of the International Peripheral T-Cell Lymphoma Project

Abstract: Purpose The International Peripheral T-Cell Lymphoma Project was undertaken to better understand the subtypes of T-cell and natural killer (NK) ‐cell lymphomas. Patients and Methods Angioimmunoblastic T-cell lymphoma (AITL) was diagnosed according to the 2001 WHO criteria by a central review process consisting of panels of expert hematopathologists. Clinical, pathologic, immunophenotyping, treatment, and survival data were correlated. Results Of 1,314 patients, 243 (18.5%) were diagnosed with AITL. At presentation, generalized lymphadenopathy was noted in 76% of patients, and 89% had stages III to IV disease. Skin rash was observed in 21% of patients. Hemolytic anemia and hypergammoglobulinemia occurred in 13% and 30% of patients, respectively. Five-year overall and failure-free survivals were 33% and 18%, respectively. At presentation, prognostic models were evaluated, including the standard International Prognostic Index, which comprised the following factors: age 60 years, stages III to IV disease, lactic dehydrogenase (LDH) normal, extranodal sites (ENSs) one, and performance status (PS) 2; the Prognostic Index for Peripheral T-Cell Lymphoma, comprising: age 60 years, PS 2, LDH normal, and bone marrow involvement; and the alternative Prognostic Index for AITL (PIAI), comprising: age 60 years, PS 2, ENSs one, B symptoms, and platelet count 150 10 9 /L. The simplified PIAI had a low-risk group (zero to one factors), with 5-year survival of 44%, and a high-risk group (two to five factors), with 5-year survival of 24% (P .0065). Conclusion AITL is a rare clinicopathologic entity characterized by an aggressive course and dismal outcome with current therapies. J Clin Oncol 31:240-246. © 2012 by American Society of Clinical Oncology

Review and meta-analysis of incidence and clinical predictors of anthracycline cardiotoxicity.

Abstract: The management of individual patients requiring anthracyclines remains challenging because uncertainty persists on predictors of cardiotoxicity. We aimed to perform a systematic review and meta-analysis on incidence and predictors of anthracycline chemotherapy in patients with cancer. Databases were searched for pertinent studies. Meta-analytic pooling with random-effects methods was performed for incidence estimates, while relying on descriptive statistics for prevalence and strength of association of predictors. From 16,054 retrieved citations, 18 studies reporting on 49,017 patients with cancer were included, with 22,815 treated with anthracyclines. After a median follow-up of 9 years, clinically overt cardiotoxicity occurred in 6% (95% confidence interval 3% to 9%), whereas subclinical cardiotoxicity developed in 18% (95% confidence interval 12% to 24%). Appraisal of independent risk factors of cardiotoxicity showed that cumulative anthracycline dose was most consistently reported as an accurate and robust predictor of cardiotoxicity, with an acceptable prognostic role also for chest radiotherapy, African-American ethnicity, very young or very old age, diabetes, hypertension, very high or very low body weight, or severe co-morbidities. In conclusion, despite ongoing refinements in chemotherapy regimens, anthracyclines still pose a significant risk of cardiotoxicity, especially in those requiring a high cumulative dose or chest radiotherapy.

Age refinement of the Messinian salinity crisis onset in the Mediterranean

Abstract: We propose a revised age calibration of the Messinian salinity crisis onset in the Mediterranean at 5.971 Ma based on the recognition of an extra gypsum cycle in the transitional interval of the Perales section (Sorbas basin, Spain) and the revision of the magnetostratigraphy of the Monticino section (Vena del Gesso basin, Italy). This age re-calibration allows to state more accurately that: (i) the interval encompassing the MSC-onset is continuous, thus ruling out any erosional feature or stratigraphic hiatus related to a major sea-level fall affecting the Mediterranean; (ii) the first gypsum was deposited during the summer insolation peak at 5.969 Ma associated with an eccentricity minimum and roughly coincident with glacial stage TG32; (iii) the MSC-onset was preconditioned by the tectonically-driven reduction of the hydrological exchanges with the Atlantic Ocean and finally triggered by glacial conditions in the northern hemisphere and by arid conditions in northern Africa.

Copy-move forgery detection and localization by means of robust clustering with J-Linkage

Abstract: Understanding if a digital image is authentic or not, is a key purpose of image forensics. There are several different tampering attacks but, surely, one of the most common and immediate one is copy-move. A recent and effective approach for detecting copy-move forgeries is to use local visual features such as SIFT. In this kind of methods, SIFT matching is often followed by a clustering procedure to group keypoints that are spatially close. Often, this procedure could be unsatisfactory, in particular in those cases in which the copied patch contains pixels that are spatially very distant among them, and when the pasted area is near to the original source. In such cases, a better estimation of the cloned area is necessary in order to obtain an accurate forgery localization. In this paper a novel approach is presented for copy-move forgery detection and localization based on the JLinkage algorithm, which performs a robust clustering in the space of the geometric transformation. Experimental results, carried out on different datasets, show that the proposed method outperforms other similar state-of-the-art techniques both in terms of copy-move forgery detection reliability and of precision in the manipulated patch localization.

Explaining Consumer Reactions to Corporate Social Responsibility: The Role of Gratitude and Altruistic Values

Abstract: Although a lot of research establishes consumer reactions to corporate social responsibility (CSR), little is known about the theoretical mechanisms for these reactions. We conduct a field experiment with adult consumers to test the hypothesis that the effects of perceived CSR on consumer reactions are mediated by felt gratitude and moderated by the magnitude of altruistic values held by consumers. Two classes of consumer reactions are considered: intentions to (1) say positive things about the company, and (2) participate in advocacy actions benefiting the company.

R-CVP Versus R-CHOP Versus R-FM for the Initial Treatment of Patients With Advanced-Stage Follicular Lymphoma: Results of the FOLL05 Trial Conducted by the Fondazione Italiana Linfomi

Abstract: Purpose Although rituximab (R) is commonly used for patients with advanced follicular lymphoma (FL) requiring treatment, the optimal associated chemotherapy regimen has yet to be clarified. Patients and Methods We conducted an open-label, multicenter, randomized trial among adult patients with previously untreated stages II to IV FL to compare efficacy of eight doses of R associated with eight cycles of cyclophosphamide, vincristine, and prednisone (CVP) or six cycles of cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) or six cycles of fludarabine and mitoxantrone (FM). The principal end point of the study was time to treatment failure (TTF). Results There were 534 patients enrolled onto the study. Overall response rates were 88%, 93%, and 91% for R-CVP, R-CHOP, and R-FM, respectively (P .247). After a median follow-up of 34 months, 3-year TTFs were 46%, 62%, and 59% for the respective treatment groups (R-CHOP v R-CVP, P .003; R-FM v R-CVP, P .006; R-FM v R-CHOP, P .763). Three-year progression-free survival (PFS) rates were 52%, 68%, and 63% (overall P .011), respectively, and 3-year overall survival was 95% for the whole series. R-FM resulted in higher rates of grade 3 to 4 neutropenia (64%) compared with R-CVP (28%) and R-CHOP (50%; P .001). Overall, 23 second malignancies were registered during follow-up: four in R-CVP, five in R-CHOP, and 14 in R-FM. Conclusion In this study, R-CHOP and R-FM were superior to R-CVP in terms of 3-year TTF and PFS. In addition, R-CHOP had a better risk-benefit ratio compared with R-FM. J Clin Oncol 31:1506-1513. © 2013 by American Society of Clinical Oncology

Prevalence and prognosis of unclassifiable interstitial lung disease

Abstract: The aim of this study was to determine the prevalence, characteristics and outcomes of patients with unclassifiable interstitial lung disease (ILD) and to develop a simple method of predicting disease behaviour. Unclassifiable ILD patients were identified from an ongoing longitudinal cohort. Unclassifiable ILD was diagnosed after a multidisciplinary review did not secure a specific ILD diagnosis. Clinical characteristics and outcomes were compared with idiopathic pulmonary fibrosis (IPF) and non-IPF ILDs. Independent predictors of mortality were determined using Cox proportional-hazards analysis to identify subgroups with distinct disease behaviour. Unclassifiable ILD was diagnosed in 10% of the ILD cohort (132 out of 1370 patients). The most common reason for being unclassifiable was missing histopathological assessment due to a high risk of surgical lung biopsy. Demographic and physiological features of unclassifiable ILD were intermediate between IPF and non-IPF disease controls. Unclassifiable ILD had longer survival rates when compared to IPF on adjusted analysis (hazard ratio 0.62, p = 0.04) and similar survival compared to non-IPF ILDs (hazard ratio 1.54, p = 0.12). Independent predictors of survival in unclassifiable ILD included diffusion capacity of the lung for carbon monoxide (p = 0.001) and a radiological fibrosis score (p = 0.02). Unclassifiable ILD represents approximately 10% of ILD cases and has a heterogeneous clinical course, which can be predicted using clinical and radiological variables.

Limited Preemptive Scheduling for Real-Time Systems. A Survey

Abstract: The question whether preemptive algorithms are better than nonpreemptive ones for scheduling a set of real-time tasks has been debated for a long time in the research community. In fact, especially under fixed priority systems, each approach has advantages and disadvantages, and no one dominates the other when both predictability and efficiency have to be taken into account in the system design. Recently, limited preemption models have been proposed as a viable alternative between the two extreme cases of fully preemptive and nonpreemptive scheduling. This paper presents a survey of the existing approaches for reducing preemptions and compares them under different metrics, providing both qualitative and quantitative performance evaluations.

Preterm birth and behaviour problems in infants and preschool-age children: a review of the recent literature.

Abstract: The behaviour problems of children born preterm at school age are well known, but there have been few studies on the behaviour problems of preterm-born infants during infancy and at preschool age. Fourteen cohort studies published in PubMed and PsycINFO between 2000 and 2012 were reviewed with a focus on the type, occurrence, comorbidity, stability, prediction, perinatal, social, and relational risk factors for behaviour problems of preterm-born children in infancy (0-2y) and at preschool age (3-5y). The relational risk factor was considered in an additional four papers. Very-preterm, very-low-birthweight, and moderately-preterm children, in both age groups, show more behaviour problems than term-born comparison children even after perinatal and social risk factors and cognitive performance have been controlled for. Poor social/interactive skills, poor behavioural and emotional self-regulation, emotional difficulties, and reduced attention are the most common behaviour problems. Behaviour problems in infancy are predictive of later behaviour problems and they should be included in follow-up programmes.

Acetic Acid Bacteria: Physiology and Carbon Sources Oxidation

Abstract: Acetic acid bacteria (AAB) are obligately aerobic bacteria within the family Acetobacteraceae, widespread in sugary, acidic and alcoholic niches. They are known for their ability to partially oxidise a variety of carbohydrates and to release the corresponding metabolites (aldehydes, ketones and organic acids) into the media. Since a long time they are used to perform specific oxidation reactions through processes called “oxidative fermentations”, especially in vinegar production. In the last decades physiology of AAB have been widely studied because of their role in food production, where they act as beneficial or spoiling organisms, and in biotechnological industry, where their oxidation machinery is exploited to produce a number of compounds such as l-ascorbic acid, dihydroxyacetone, gluconic acid and cellulose. The present review aims to provide an overview of AAB physiology focusing carbon sources oxidation and main products of their metabolism.

Age and organ damage correlate with poor survival in myeloma patients: meta-analysis of 1435 individual patient data from 4 randomized trials

Abstract: Thalidomide and bortezomib are extensively used to treat elderly myeloma patients. In these patients, treatment-related side effects are frequent and full drug doses difficult to tolerate. We retrospectively analyzed data from 1435 elderly patients enrolled in 4 European phase III trials including thalidomide and/or bortezomib. After a median follow up of 33 months (95%CI: 10–56 months), 513 of 1435 patients (36%) died; median overall survival was 50 months (95%CI: 46–60 months). The risk of death was increased in patients aged 75 years or over (HR 1.44, 95%CI: 1.20–1.72; P<0.001), in patients with renal failure (HR 2.02, 95%CI: 1.51–2.70; P<0.001), in those who experienced grade 3–4 infections, cardiac or gastrointestinal adverse events during treatment (HR 2.53, 95%CI: 1.75–3.64; P<0.001) and in those who required drug discontinuation due to adverse events (HR 1.67, 95%CI; 1.12–2.51; P=0.01). This increased risk was restricted to the first six months after occurrence of adverse events or drug discontinuation and declined over time. More intensive approaches, such as the combination of bortezomib-thalidomide, negatively affected outcome. Bortezomib-based combinations may overcome the negative impact of renal failure. Age 75 years or over or renal failure at presentation, occurrence of infections, cardiac or gastrointestinal adverse events negatively affected survival. A detailed geriatric assessment, organ evaluation and less intense individualized approaches are suggested in elderly unfit subjects.

Skin aging: In vivo microscopic assessment of epidermal and dermal changes by means of confocal microscopy

Abstract: Background Skin aging is thought to be a complex biological process that is traditionally classified as intrinsic and extrinsic aging. Several clinical score and instrumental devices have been applied to obtain a precise assessment of skin aging. Among them, confocal microscopy has emerged as a new technique capable of assessing cytoarchitectural changes with a nearly histopathologic resolution. Objective We sought to determine the microscopic skin changes occurring on the face in different age groups by means of confocal microscopy. Methods The skin of the cheek in 63 volunteers belonging to distinct age groups was analyzed by confocal microscopy. In 4 cases, routine histopathology was performed on site-matched surplus areas from routine excisions for obtaining a better comparison with confocal findings. Results Young skin was characterized by regular polygonal keratinocytes and thin reticulated collagen fibers. With aging, more irregularly shaped keratinocytes and areas with unevenly distributed pigmentation and increased compactness of collagen fibers were observed. In the elderly, thinning of the epidermis, marked keratinocyte alterations, and huddles of collagen and curled fibers, corresponding to elastosis, were present. A side-by-side correlation between confocal descriptors and histopathologic aspects has been provided in a few cases. Limitations Reticular dermal changes cannot be assessed because of the limited depth laser penetration. Conclusions Confocal microscopy was successfully applied to identify in vivo skin changes occurring in aged skin at both the epidermal and dermal levels at histopathologic resolution. This offers the possibility to test cosmetic product efficacy and to identify early signs of sun damage.

N-polar GaN epitaxy and high electron mobility transistors

Abstract: This paper reviews the progress of N-polar () GaN high frequency electronics that aims at addressing the device scaling challenges faced by GaN high electron mobility transistors (HEMTs) for radio-frequency and mixed-signal applications. Device quality (Al, In, Ga)N materials for N-polar heterostructures are developed using molecular beam epitaxy and metalorganic chemical vapor deposition. The principles of polarization engineering for designing N-polar HEMT structures will be outlined. The performance, scaling behavior and challenges of microwave power devices as well as highly-scaled depletion- and enhancement-mode devices employing advanced technologies including self-aligned processes, n+ (In,Ga)N ohmic contact regrowth and high aspect ratio T-gates will be discussed. Recent research results on integrating N-polar GaN with Si for prospective novel applications will also be summarized.

Immunomodulators and immunosuppressants for multiple sclerosis: a network meta‐analysis

Abstract: BACKGROUND: Different therapeutic strategies are available for treatment of multiple sclerosis (MS) including immunosuppressants, immunomodulators, and monoclonal antibodies. Their relative effectiveness in the prevention of relapse or disability progression is unclear due to the limited number of direct comparison trials. A summary of the results, including both direct and indirect comparisons of treatment effects, may help to clarify the above uncertainty. OBJECTIVES: To estimate the relative efficacy and acceptability of interferon s-1b (IFNs-1b) (Betaseron), interferon s-1a (IFNs-1a) (Rebif and Avonex), glatiramer acetate, natalizumab, mitoxantrone, methotrexate, cyclophosphamide, azathioprine, intravenous immunoglobulins, and long-term corticosteroids versus placebo or another active agent in participants with MS and to provide a ranking of the treatments according to their effectiveness and risk-benefit balance. SEARCH METHODS: We searched the Cochrane Database of Systematic Reviews, the Cochrane MS Group Trials Register, and the Food and Drug Administration (FDA) reports. The most recent search was run in February 2012. SELECTION CRITERIA: Randomized controlled trials (RCTs) that studied one of the 11 treatments for use in adults with MS and that reported our pre-specified efficacy outcomes were considered for inclusion. DATA COLLECTION AND ANALYSIS: Identifying search results and data extraction were performed independently by two authors. Data synthesis was performed by pairwise meta-analysis and network meta-analysis that was performed within a Bayesian framework. The body of evidence for outcomes within the pairwise meta-analysis was assessed according to GRADE, as very low, low, moderate, or high quality. MAIN RESULTS: Forty-four trials were included in this review, in which 17,401 participants had been randomised. Twenty-three trials included relapsing-remitting MS (RRMS) (9096 participants, 52%), 18 trials included progressive MS (7726, 44%), and three trials included both RRMS and progressive MS (579, 3%). The majority of the included trials were short-term studies, with the median duration being 24 months. The results originated mostly from 33 trials on IFNs, glatiramer acetate, and natalizumab that overall contributed outcome data for 9881 participants (66%).From the pairwise meta-analysis, there was high quality evidence that natalizumab and IFNs-1a (Rebif) were effective against recurrence of relapses in RRMS during the first 24 months of treatment compared to placebo (odds ratio (OR) 0.32, 95% confidence interval (CI) 0.24 to 0.43; OR 0.45, 95% CI 0.28 to 0.71, respectively); they were more effective than IFNs-1a (Avonex) (OR 0.28, 95% CI 0.22 to 0.36; OR 0.19, 95% CI 0.06 to 0.60, respectively). IFNs-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having clinical relapses compared to placebo (OR 0.55, 95% CI 0.31 to 0.99; OR 0.15, 95% CI 0.04 to 0.54, respectively) but the quality of evidence for these treatments was graded as moderate. From the network meta-analysis, the most effective drug appeared to be natalizumab (median OR versus placebo 0.29, 95% credible intervals (CrI) 0.17 to 0.51), followed by IFNs-1a (Rebif) (median OR versus placebo 0.44, 95% CrI 0.24 to 0.70), mitoxantrone (median OR versus placebo 0.43, 95% CrI 0.20 to 0.87), glatiramer acetate (median OR versus placebo 0.48, 95% CrI 0.38 to 0.75), IFNs-1b (Betaseron) (median OR versus placebo 0.48, 95% CrI 0.29 to 0.78). However, our confidence was moderate for direct comparison of mitoxantrone and IFNB-1b vs placebo and very low for direct comparison of glatiramer vs placebo. The relapse outcome for RRMS at three years' follow-up was not reported by any of the included trials.Disability progression was based on surrogate markers in the majority of included studies and was unavailable for RRMS beyond two to three years. The pairwise meta-analysis suggested, with moderate quality evidence, that natalizumab and IFNs-1a (Rebif) probably decreased the odds of the participants with RRMS having disability progression at two years' follow-up, with an absolute reduction of 14% and 10%, respectively, compared to placebo. Natalizumab and IFNs-1b (Betaseron) were significantly more effective (OR 0.62, 95% CI 0.49 to 0.78; OR 0.35, 95% CI 0.17 to 0.70, respectively) than IFNs-1a (Avonex) in reducing the number of the participants with RRMS who had progression at two years' follow-up, and confidence in this result was graded as moderate. From the network meta-analyses, mitoxantrone appeared to be the most effective agent in decreasing the odds of the participants with RRMS having progression at two years' follow-up, but our confidence was very low for direct comparison of mitoxantrone vs placebo. Both pairwise and network meta-analysis revealed that none of the individual agents included in this review were effective in preventing disability progression over two or three years in patients with progressive MS.There was not a dose-effect relationship for any of the included treatments with the exception of mitoxantrone. AUTHORS' CONCLUSIONS: Our review should provide some guidance to clinicians and patients. On the basis of high quality evidence, natalizumab and IFNs-1a (Rebif) are superior to all other treatments for preventing clinical relapses in RRMS in the short-term (24 months) compared to placebo. Moderate quality evidence supports a protective effect of natalizumab and IFNs-1a (Rebif) against disability progression in RRMS in the short-term compared to placebo. These treatments are associated with long-term serious adverse events and their benefit-risk balance might be unfavourable. IFNs-1b (Betaseron) and mitoxantrone probably decreased the odds of the participants with RRMS having relapses, compared with placebo (moderate quality of evidence). The benefit-risk balance with azathioprine is uncertain, however this agent might be effective in decreasing the odds of the participants with RRMS having relapses and disability progression over 24 to 36 months, compared with placebo. The lack of convincing efficacy data shows that IFNs-1a (Avonex), intravenous immunoglobulins, cyclophosphamide and long-term steroids have an unfavourable benefit-risk balance in RRMS. None of the included treatments are effective in decreasing disability progression in patients with progressive MS. It is important to consider that the clinical effects of all these treatments beyond two years are uncertain, a relevant point for a disease of 30 to 40 years duration. Direct head-to-head comparison(s) between natalizumab and IFNs-1a (Rebif) or between azathioprine and IFNs-1a (Rebif) should be top priority on the research agenda and follow-up of the trial cohorts should be mandatory.