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clinicaltrials.gov, the WHO trials registry, and US Food and Drug Administration (FDA) reports, and searched for unpublished studies (until December 2016).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

Challenges to promoting population-based cancer registration in Iran: A workshop report

In December 2011, the Cancer Research Centre of the Cancer Institute of Iran sponsored a 3-day workshop on "Cancer Registration Principle and Challenges in Iran", which convened cancer registry experts. The objectives of the workshop were: to introduce standard cancer registration, to review the policy and procedure of cancer registration in Iran, and to review the best practices in the cancer registries in Iran. Challenges to cancer registration were discussed and recommendations were developed. The workshop was evaluated by participants for better organization of subsequent workshops. The objective of publication of this report is that based on Cancer in 5 Continents, many low- or middle-income countries do not meet the criteria for a standard population-based cancer registry (PBCR); on the other hand cancer is the most important cause of mortality and the essential part of any cancer control program is the cancer registry. Therefore this report focuses on problems and challenges of PBCR and provides recommendations which might help other developing countries to decrease their PBCR defects

Dietary intake of xylose impacts the transcriptome and proteome of tissues involved in xylose metabolism in swine

Xylose is a primary component of arabinoxylan in swine diets. As arabinoxylan is a significant component of fiber, and fiber is generally rising in practical pig diets globally, the study of arabinoxylan and xylose is of increasing interest. However, the mechanisms by which free xylose may be absorbed and the pathways impacted by xylose have yet to be elucidated in pigs. The objective of this study was to determine the impact of xylose supplementation on gene expression and protein abundance in jejunum, kidney, liver, and muscle tissues which have previously been identified as possible sites of xylose absorption or metabolism. This study aimed to expand the preliminary understanding of dietary xylose metabolism and utilization in pigs. One study, replicated twice with 24 crossbred gilts, was used to assess two dietary treatments: a xylose-free (0%) control and 8% D-xylose. The impact of xylose on growth was monitored by measuring initial and final body weight, serum IGF-1, and liver glycogen concentrations. The rate and efficiency of weight gain were reduced on the xylose diet but not to a level that would occur if xylose was not used at all; the detection of xylose systemically further supports this conclusion. This study confirmed that pigs can utilize dietary xylose. To determine the impact of xylose on tissue metabolism, samples were collected from all four tissues for gene expression analysis by RNA-sequencing, and kidney and liver samples were subjected to proteomic analysis using 2D-DIGE and mass spectrometry. The majority of differentially expressed (DE) genes were identified in the kidney samples (n = 157), with a few identified in the jejunum (n = 16), liver (n = 1), and muscle (n = 20) samples. The DE genes in the kidney were mainly identified as being involved in lipid biosynthesis and fatty acid metabolism. Proteomic results corroborated these findings. Although the inclusion of xylose in a diet at practical levels is shown to impact energy metabolic processes, it has been confirmed that this five-carbon sugar can support levels of growth only slightly below those of glucose, a six-carbon sugar that is more commonly utilized as an energy source in pig diets

Intracranial hemorrhage in normotensive and hypertensive patients receiving streptokinase after decreasing elevated blood pressure

Background: Many patients with suspected acute myocardial infarction (AMI) and eligible for thrombolytic therapy may not be treated because of association between hemorrhagic complications especially intracranial hemorrhage (ICH), and severe hypertension (HTN) at presentation. Unfortunately, this leads to under use or delay in thrombolytic therapy. We assessed effect of decreasing elevated blood pressure before thrombolytic therapy in order to reduce the incidence of ICH without increasing mortality rate.
 Methods: This observational and analytical cohort study enrolled 293 patients (215males and 78 female) with STsegment elevation (AMI) that were hospitalized in emergency department of Noor hospital, Isfahan, Iran. Severe hypertension (blood pressure ≥180/110mmHg) was diagnosed in 132 patients. All of them received 1.5 million units streptokinase within one hour intravenously. In the hypertensive group, elevated blood pressure was lowered to less than180/110mmhg before thrombolysis and they were observed to detect development of symptomatic ICH and they underwent Brain CT scan, if required.
 Results: The incidence of total stroke, ICH and death were 1.4%, 0.7% and 4.8%, respectively. The incidence of death and ICH in patients with severe hypertension was less than control group (P value=0.13 and 0.59, respectively)
 Conclusion: Although we did not find any increase in ICH incidence in severe hypertensive patients treated be streptokinase due to AMI, but we recommend a multi-centric study with more cases and varied thrombolytic protocols.
 Key words: Acute myocardial infarction, Intracranial hemorrhage, Thrombolytic therap

Changes in the risk of reaching multiple sclerosis disability milestones in recent decades: A nationwide population-based cohort study in sweden

Importance: Clinicians' experience and findings from recent natural history studies suggest that multiple sclerosis (MS) may now be running a more slowly progressing course than before. Objective: To investigate whether the risk of reaching MS disability milestones has changed over the last decade in Sweden. Design, Setting, and Participants: A nationwide population-based retrospective cohort study. By April 2017, 12512 patients with available information on demographics, MS phenotype, and date of MS onset and diagnosis were registered in the Swedish MS Registry of which 7331 patients with at least 2 recorded Expanded Disability Status Scale scores (EDSS) and diagnosed between January 1995 and December 2010 were included. No further exclusion criteria were applied. Patients were followed up until December 2016 with a median duration follow-up of 8.5 (interquartile range, 4.7-13.8) years. Statistical analysis began in April 2017. Main Outcomes and Measures: Patients were followed up from MS onset date to the date of sustained EDSS 3.0, 4.0, and 6.0. To handle interval-censored observations, a Weibull model was fit, and the change in the risk of EDSS 3.0, 4.0, and 6.0 over calendar years was estimated and hazard ratios (HRs) with corresponding CIs were calculated. Results: Of 7331 patients, 5196 (70.9%) were women, and the mean (SD) age at diagnosis was 38.3 (11.7) years. Adjusting for sex, number of clinic visits, diagnostic delay, and onset age, a 3% decrease per calendar year of diagnosis for the risk of sustained EDSS 3.0 (HR, 0.97; 95% CI, 0.96-0.97), a 6% decrease for the risk of EDSS 4.0 (HR, 0.94; 95% CI, 0.93-0.95), and a 7% decrease for the risk of EDSS 6.0 (HR, 0.93; 95% CI, 0.91-0.94) among patients with relapsing-onset MS was found. The trends were not significant for patients with progressive-onset MS (EDSS 3.0: HR, 1.01; 95% CI, 0.98-1.03; EDSS 4.0: HR, 1.00; 95% CI, 0.98-1.02; EDSS 6.0: HR, 1.00; 95% CI, 0.98-1.02). Conclusions and Relevance: Risk of reaching major disability milestones has significantly decreased over the last decade in patients with relapsing-onset MS in Sweden. Several factors could potentially be responsible for this observation. However, given that no change was seen in disability accrual of patients with progressive-onset MS and the absence of efficacious treatment option in this group, increased use of more efficacious disease-modifying treatments could be a possible driver of this change

Evaluation of Ejection Fraction (Ef) and Ccsfc after Coronary Artery Bypass Graft (Cabg)

Introduction: Coronary artery bypass graft can Improve myocardial contractility and functional class in Ischemic heart disease. Materials & Methods: This study was done on 200 patient’s with CABG operation during 6 months. 142 patients were men and 56 patients were women with mean age 57.7 9.2 years (36-83). EF was measured by echocardiography before & 1 week after CABG, CCSFC evaluated before and 3 months after surgery by questioner. Data was analyzed statistically SPSS software. Results: Mean EF was 48.1 5.9 before surgery, and 48.3 8.5 after surgery. CCSFC was 2.9 0.9 before surgery and 1.10.3 after surgery (P Value = 0.0001). Conclusion: CABG can improve EF and reduce CCSFC in ischemic heart disease especially in patient’s with EF<35% and history of myocardial infarction

Smoking and worsening disability in multiple sclerosis: A meta-analysis

Objectives: Multiple sclerosis (MS) is a chronic demyelinating disorder affecting young adults. Environmental factors and lifestyle behaviors are pivotal in MS pathophysiology. Smoking has been considered as an important risk factor in MS. Various recent studies have been conducted to measure the role of smoking on worsening disability in patients with MS, thus we intended to systematically assess effect of smoking on evolution of disability in this study. Materials & methods: We queried MEDLINE, EMBASE and Cochrane Library with following keywords �Multiple Sclerosis, Smoking, Tobacco Use, Disability� on December 1st 2016. Original articles were included when smoking history was mentioned, disability was measured via expanded disability status scale (EDSS) or multiple sclerosis severity score (MSSS). Studies with insufficient outcome data, non-human, or in other languages than English were excluded. Results: Through literature review after duplicate removals, 268 articles were retrieved. A total of 56 articles were screened and 15 articles were assessed for eligibility, finally, eleven articles were included in this systematic review and meta-analysis. Ever smoking was significantly associated with increased EDSS (standardized mean difference (SMD) = 0.15, 95 CI = 0.01-0.28), but had no significant association with risk of reaching EDSS 4 (HR = 1.24, 95 CI = 0.89-1.72) or EDSS 6 (HR = 1.17, 95 CI = 0.88-1.57). Smoking had no effect on MSSS (SMD = 0.14, 95 CI = �0.04-0.32) or T2 lesion volume (SMD = 0.07, 95 CI = �0.08-0.22). Conclusions: This meta-analysis showed smoking increased EDSS, insignificant findings were possibly due to the small number of studies, significant differences in methodologies, and variations in reporting of disability outcomes. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Lt

Smoking and worsening disability in multiple sclerosis: A meta-analysis

Objectives: Multiple sclerosis (MS) is a chronic demyelinating disorder affecting young adults. Environmental factors and lifestyle behaviors are pivotal in MS pathophysiology. Smoking has been considered as an important risk factor in MS. Various recent studies have been conducted to measure the role of smoking on worsening disability in patients with MS, thus we intended to systematically assess effect of smoking on evolution of disability in this study. Materials & methods: We queried MEDLINE, EMBASE and Cochrane Library with following keywords �Multiple Sclerosis, Smoking, Tobacco Use, Disability� on December 1st 2016. Original articles were included when smoking history was mentioned, disability was measured via expanded disability status scale (EDSS) or multiple sclerosis severity score (MSSS). Studies with insufficient outcome data, non-human, or in other languages than English were excluded. Results: Through literature review after duplicate removals, 268 articles were retrieved. A total of 56 articles were screened and 15 articles were assessed for eligibility, finally, eleven articles were included in this systematic review and meta-analysis. Ever smoking was significantly associated with increased EDSS (standardized mean difference (SMD) = 0.15, 95 CI = 0.01-0.28), but had no significant association with risk of reaching EDSS 4 (HR = 1.24, 95 CI = 0.89-1.72) or EDSS 6 (HR = 1.17, 95 CI = 0.88-1.57). Smoking had no effect on MSSS (SMD = 0.14, 95 CI = �0.04-0.32) or T2 lesion volume (SMD = 0.07, 95 CI = �0.08-0.22). Conclusions: This meta-analysis showed smoking increased EDSS, insignificant findings were possibly due to the small number of studies, significant differences in methodologies, and variations in reporting of disability outcomes. © 2018 John Wiley & Sons A/S. Published by John Wiley & Sons Lt