MULTIPLE OUTCOME META-ANALYSES

Introduction Commonly, the main aim of a meta-analysis is to provide, when possible, a clear and definite evidence on, for example, the best treatment available for a disease. However, when multiple potentially correlated outcomes are of interest in evidence synthesis, they should be jointly analyzed, taking into account their correlation. Standard meta-analysis combines estimates of one parameter over several studies, but it is not appropriate when there is the necessity to consider multiple potentially correlated outcomes. Thus, the Multiple Outcome Meta-Analysis (MOMA) was thought as an extension of the standard meta-analysis in order to combine estimates of several related parameters. Methods In order to evaluate the feasibility, advantages and limitations of the MOMA compared to the standard meta-analysis, data on azathioprine use in multiple sclerosis treatment, in terms of number of patients with relapses, number of dropouts and number of patients with a disease progression over two years, were analyzed through the use of these two methods. Results Using a method proposed by Riley at al. in 2008 in the context of the MOMA, which showed to be a good method especially when the within-study correlations are not known, compared to the standard meta-analysis, different results were observed in terms of Odds Ratios (ORs), corresponding 95% Confidence Intervals (95% CIs), explained and residual variances, and between-studies correlations. In particular, considering the two outcomes of efficacy, in terms of number of patients with relapses, and of safety, in terms of number of dropouts, over two years, and comparing results obtained through the use of the MOMA with those derived from the standard meta-analysis, the ORs and the corresponding 95% CIs were similar, but the corresponding standard errors (SE) appeared to be very different. Accordingly, using the MOMA methods, SE reductions of 18% and 5% for the two outcomes were observed, respectively. Moreover, when the two outcomes representing two different efficacy measures in terms of number of patients with relapses and number of patients with a disease progression over two years were considered, a relapse risk reduction of over 20% (i.e., an OR of 0.50 from the MOMA vs 0.64 from the standard meta-analysis), and a progression risk reduction of almost 15% (i.e., a significant OR of 0.66 vs a non-significant OR of 0.77) were observed. In this second application, however, the small number of studies could have led to a very high between-studies correlation estimate, which is associated with unstable pooled estimates and SE. Thus, in this case the MOMA could not represent the better choice. Discussion Unless the variation observed was very large, or the number of studies in the meta-analysis was small, and when there is the necessity to combine estimates of several potentially correlated outcomes, the MOMA methods appear to produce appropriate pooled estimates, which show better statistical properties than those from the standard meta-analysis. Finally, how to combine the methods of the MOMA with those of the Multiple Treatment Meta-Analysis (MTMA), in order to jointly analyzed multiple outcomes and including both direct and indirect comparisons, was presented

Immunomodulators and immunosuppressants for relapsing-remitting multiple sclerosis: A network meta-analysis

This is the protocol for a review and there is no abstract. The objectives are as follows: We aim to compare the efficacy and acceptability of immunomodulators and immunosuppressants to treat participants with RRMS and to generate a clinically useful hierarchy of available immunotherapies according to their efficacy and acceptability

Antiplatelet drugs for secondary prevention in patients with ischemic stroke or transient ischemic attack: a systematic review and network meta-analysis

Background: Antiplatelet drugs may prevent recurrent ischemic events after ischemic stroke but their relative effectiveness and harms still need to be clarified. Within this network meta-analysis we aimed to summarize the current evidence for using antiplatelet drugs for secondary stroke prevention. Methods: We searched MEDLINE, EMBASE and CENTRAL up to September 2020. Randomized controlled trials (RCTs) assessing antiplatelet drugs for secondary stroke prevention were included. We did pairwise meta-analyses and network meta-analyses using random-effects models. Primary outcomes were all strokes (ischemic or hemorrhagic) and all-cause mortality. Results: The review included 57 RCTs, 50 (n = 165,533 participants) provided data for the meta-analyses. Compared to placebo/no treatment, moderate to high-confidence evidence indicated that cilostazol, clopidogrel, dipyridamole + aspirin, ticagrelor, ticlopidine, and aspirin ≤ 150 mg/day significantly reduced the risk of all strokes (odds ratios, ORs and absolute risk difference, ARD): cilostazol 0.51 (95 % confidence interval, CI, 0.37 to 0.71; 3.6 % fewer), clopidogrel 0.63 (95 % CI, 0.49 to 0.79; 2.7 % fewer), dipyridamole + aspirin 0.65 (95 % CI, 0.55 to 0.78; 2.5 % fewer), ticagrelor 0.68 (95 % CI, 0.50 to 0.93; 2.3 % fewer), ticlopidine 0.74 (95 % CI 0.59 to 0.93; 1.9 % fewer), aspirin ≤ 150 mg/day 0.79 (95 % CI, 0.66 to 0.95; 1.5 % fewer). Aspirin > 150 mg/day and the combinations clopidogrel/aspirin, ticagrelor/aspirin, also decrease all strokes but increase the risk of hemorrhagic events. Only aspirin > 150 mg/day significantly reduced all-cause mortality (OR 0.86, 95 % CI 0.76 to 0.97; ARD 0.9 %, 95 %CI 1.5–0.2 % fewer, moderate confidence). Compared to aspirin ≤ 150 mg/day, clopidogrel significantly reduced the risk of all strokes, cardiovascular events, and intracranial hemorrhage outcomes. Cilostazol also appeared to provide advantages but data are limited to the Asian population. Conclusions: Considering the benefits and harms ratio, cilostazol, clopidogrel, dipyridamole + aspirin, ticagrelor, ticlopidine, and aspirin ≤ 150 mg/day appear to be the best choices as antiplatelet drugs for secondary prevention of patients with ischemic stroke or TIA. Systematic review registration: PROSPERO CRD42020159896

No efficacy of transcranial direct current stimulation on chronic migraine with medication overuse : a double blind, randomised clinical trial

Background: Transcranial direct current stimulation was suggested to provide beneficial effects in chronic migraine, a condition often associated with medication overuse for which no long-term therapy is available. Methods: We conducted a randomised controlled trial to assess long-term efficacy of transcranial direct current stimulation. Adults diagnosed with chronic migraine and medication overuse were assigned to receive in a 1:1:1 ratio anodal, cathodal, or sham transcranial direct current stimulation daily for five consecutive days, along with standardised drug withdrawal protocol. Primary outcome was 50% reduction of days of headache per month at 12 months. Co-secondary outcomes were 50% reduction of days of headache per month at 6 months, reduction of analgesic intake per month, and change in disability and quality of life, catastrophising, depression, state and trait anxiety, dependence attitude and allodynia intensity. Patients were not allowed to take any migraine prophylaxis drug for the entire study period. Results: We randomly allocated 135 patients to anodal (44), cathodal (45), and sham (46) transcranial direct current stimulation. At 6 and 12 months, the percentage of reduction of days of headache and number of analgesics per month ranged between 48.5% and 64.7%, without differences between transcranial direct current stimulation (cathodal, anodal, or the results obtained from the two arms of treatment, anodal plus cathodal) and sham. Catastrophising attitude significantly reduced at 12 months in all groups. There was no difference for the other secondary outcomes. Conclusions: Transcranial direct current stimulation did not influence the short and long-term course of chronic migraine with medication overuse after acute drug withdrawal. Behavioral and educational measures and support for patients' pain management could provide long-term improvement and low relapse rate. Trial registration number NCT04228809

Deciphering the Large-Scale Environment of Radio Galaxies in the Local Universe II. A Statistical Analysis of Environmental Properties

In our previous analysis we investigated the large-scale environment of two samples of radio galaxies (RGs) in the local Universe (i.e. with redshifts z<0.15), classified as FR I and FR II on the basis of their radio morphology. The analysis was carried out using i) extremely homogeneous catalogs and ii) a new method, known as cosmological overdensity, to investigate their large-scale environments. We concluded that, independently by the shape of their radio extended structure, RGs inhabit galaxy-rich large-scale environments with similar characteristics and richness. In the present work, we first highlight additional advantages of our procedure, that does not suffer cosmological biases and/or artifacts, and then we carry out an additional statistical test to strengthen our previous results. We also investigate properties of RG environments using those of the cosmological neighbors. We find that large-scale environments of both FRIs and FRIIs are remarkably similar and independent on the properties of central RG. Finally, we highlight the importance of comparing radio sources in the same redshift bins to obtain a complete overview of their large-scale environments.Comment: 15 pages, 21 figures, 3 tables, ApJS in press (pre-proof version

Polarization and photometric observations of the gamma-ray blazar PG 1553+113

We present the results of an observational photo-polarimetry campaign of the blazar PG 1553+113 at optical wavelengths. The blazar was recently detected at very high energies (> 100 GeV) by the H.E.S.S and MAGIC gamma-ray Cherenkov telescopes. Our high-temporal resolution data show significant variations in the linear polarization percentage and position angle at inter-night time-scales, while at shorter (intra-night) time-scales both parameters varied less significantly, if at all. Changes in the polarization angle seem to be common in gamma-ray emitting blazars. Simultaneous differential photometry (through the B and R bands) shows no significant variability in the total optical flux. We provide B and R magnitudes, along with a finding chart, for a set of field stars suitable for differential photometry.Comment: 4 pages, 3 figures. To be published by Astronomy and Astrophysic

Treatment with disease-modifying drugs for people with a first clinical attack suggestive of multiple sclerosis

Background: The treatment of multiple sclerosis has changed over the last 20 years. The advent of disease-modifying drugs in the mid-1990s heralded a period of rapid progress in the understanding and management of multiple sclerosis. With the support of magnetic resonance imaging early diagnosis is possible, enabling treatment initiation at the time of the first clinical attack. As most of the disease-modifying drugs are associated with adverse events, patients and clinicians need to weigh the benefit and safety of the various early treatment options before taking informed decisions. Objectives: 1. to estimate the benefit and safety of disease-modifying drugs that have been evaluated in all studies (randomised or non-randomised) for the treatment of a first clinical attack suggestive of MS compared either with placebo or no treatment; 2. to assess the relative efficacy and safety of disease-modifying drugs according to their benefit and safety; 3. to estimate the benefit and safety of disease-modifying drugs that have been evaluated in all studies (randomised or non-randomised) for treatment started after a first attack ('early treatment') compared with treatment started after a second attack or at another later time point ('delayed treatment'). Search methods: We searched the Cochrane Multiple Sclerosis and Rare Diseases of the CNS Group Trials Register, MEDLINE, Embase, CINAHL, LILACS, clinicaltrials.gov, the WHO trials registry, and US Food and Drug Administration (FDA) reports, and searched for unpublished studies (until December 2016). Selection criteria: We included randomised and observational studies that evaluated one or more drugs as monotherapy in adult participants with a first clinical attack suggestive of MS. We considered evidence on alemtuzumab, azathioprine, cladribine, daclizumab, dimethyl fumarate, fingolimod, glatiramer acetate, immunoglobulins, interferon beta-1b, interferon beta-1a (Rebif®, Avonex®), laquinimod, mitoxantrone, natalizumab, ocrelizumab, pegylated interferon beta-1a, rituximab and teriflunomide. Data collection and analysis: Two teams of three authors each independently selected studies and extracted data. The primary outcomes were disability-worsening, relapses, occurrence of at least one serious adverse event (AE) and withdrawing from the study or discontinuing the drug because of AEs. Time to conversion to clinically definite MS (CDMS) defined by Poser diagnostic criteria, and probability to discontinue the treatment or dropout for any reason were recorded as secondary outcomes. We synthesized study data using random-effects meta-analyses and performed indirect comparisons between drugs. We calculated odds ratios (OR) and hazard ratios (HR) along with relative 95% confidence intervals (CI) for all outcomes. We estimated the absolute effects only for primary outcomes. We evaluated the credibility of the evidence using the GRADE system. Main results: We included 10 randomised trials, eight open-label extension studies (OLEs) and four cohort studies published between 2010 and 2016. The overall risk of bias was high and the reporting of AEs was scarce. The quality of the evidence associated with the results ranges from low to very low. Early treatment versus placebo during the first 24 months' follow-up There was a small, non-significant advantage of early treatment compared with placebo in disability-worsening (6.4% fewer (13.9 fewer to 3 more) participants with disability-worsening with interferon beta-1a (Rebif®) or teriflunomide) and in relapses (10% fewer (20.3 fewer to 2.8 more) participants with relapses with teriflunomide). Early treatment was associated with 1.6% fewer participants with at least one serious AE (3 fewer to 0.2 more). Participants on early treatment were on average 4.6% times (0.3 fewer to 15.4 more) more likely to withdraw from the study due to AEs. This result was mostly driven by studies on interferon beta 1-b, glatiramer acetate and cladribine that were associated with significantly more withdrawals for AEs. Early treatment decreased the hazard of conversion to CDMS (HR 0.53, 95% CI 0.47 to 0.60). Comparing active interventions during the first 24 months' follow-up Indirect comparison of interferon beta-1a (Rebif®) with teriflunomide did not show any difference on reducing disability-worsening (OR 0.84, 95% CI 0.43 to 1.66). We found no differences between the included drugs with respect to the hazard of conversion to CDMS. Interferon beta-1a (Rebif®) and teriflunomide were associated with fewer dropouts because of AEs compared with interferon beta-1b, cladribine and glatiramer acetate (ORs range between 0.03 and 0.29, with substantial uncertainty). Early versus delayed treatment We did not find evidence of differences between early and delayed treatments for disability-worsening at a maximum of five years' follow-up (3% fewer participants with early treatment (15 fewer to 11.1 more)). There was important variability across interventions; early treatment with interferon beta-1b considerably reduced the odds of participants with disability-worsening during three and five years' follow-up (OR 0.52, 95% CI 0.32 to 0.84 and OR 0.57, 95% CI 0.36 to 0.89). The early treatment group had 19.6% fewer participants with relapses (26.7 fewer to 12.7 fewer) compared to late treatment at a maximum of five years' follow-up and early treatment decreased the hazard of conversion to CDMS at any follow-up up to 10 years (i.e. over five years' follow-up HR 0.62, 95% CI 0.53 to 0.73). We did not draw any conclusions on long-term serious AEs or discontinuation due to AEs because of inadequacies in the available data both in the included OLEs and cohort studies. Authors' conclusions: Very low-quality evidence suggests a small and uncertain benefit with early treatment compared with placebo in reducing disability-worsening and relapses. The advantage of early treatment compared with delayed on disability-worsening was heterogeneous depending on the actual drug used and based on very low-quality evidence. Low-quality evidence suggests that the chances of relapse are less with early treatment compared with delayed. Early treatment reduced the hazard of conversion to CDMS compared either with placebo, no treatment or delayed treatment, both in short- and long-term follow-up. Low-quality evidence suggests that early treatment is associated with fewer participants with at least one serious AE compared with placebo. Very low-quality evidence suggests that, compared with placebo, early treatment leads to more withdrawals or treatment discontinuation due to AEs. Difference between drugs on short-term benefit and safety was uncertain because few studies and only indirect comparisons were available. Long-term safety of early treatment is uncertain because of inadequately reported or unavailable data

Treatment with disease modifying drugs for people with a first clinical attack suggestive of multiple sclerosis

This is the protocol for a review and there is no abstract. The objectives are as follows: To estimate the benefit and safety of all DMDs that have been evaluated in all studies (randomised and non-randomised) for early treatment. We will employ novel, high-quality methods for systematic reviews and network meta-analysis in collaboration with the Cochrane Multiple Interventions Group. To evaluate the quality of the evidence provided by existing studies. We will consider the credibility of included studies and other characteristics of the evidence base as we characterise conclusions pertaining to high, low or very low quality of evidence. We will undertake this review in accordance with the methods described by the template protocol published online and will use this template as we prepare the review

Investigating the large-scale environment of wide-angle tailed radio galaxies in the local Universe

We present a statistical analysis of the large-scale (up to 2 Mpc) environment of an homogeneous and complete sample, both in radio and optical selection, of wide-angle tailed radio galaxies (WATs) in the local Universe (i.e., with redshifts $z\lesssim$ 0.15). The analysis is carried out using the parameters obtained from cosmological neighbors within 2 Mpc of the target source. Results on WATs large-scale environments are then compared with that of Fanaroff-Riley type I (FR Is) and type II (FR IIs) radio galaxies, listed in two others homogeneous and complete catalogs, and selected with the same criterion adopted for the WATs catalog. We obtain indication that at low redshift WATs inhabit environments with a larger number of galaxies than that of FR Is and FR IIs. In the explored redshift range, the physical size of the galaxy group/cluster in which WATs reside appears to be almost constant with respect to FR Is and FR IIs, being around 1 Mpc. From the distribution of the concentration parameter, defined as the ratio between the number of cosmological neighbors lying within 500 kpc and within 1 Mpc, we conclude that WATs tend to inhabit the central region of the group/cluster in which they reside, in agreement with the general paradigm that WATs are the cluster BCG.Comment: 8 pages, 5 figures, 1 table. Accepted for publication on A&