A Systematic Review and Mixed Treatment Comparison of Pharmaceutical Interventions for Multiple Sclerosis.

BACKGROUND: Since 2010, 27 mixed-treatment comparisons (MTCs) of disease-modifying therapies (DMTs) for multiple sclerosis have been published. However, there has been continued evolution in the field of MTCs. Additionally, limitations in methodological approach and reporting transparency, even in the most recent publications, makes interpretation and comparison of existing studies difficult. OBJECTIVES: The objectives of this study are twofold: (1) to estimate the efficacy and safety of DMTs at European Commission-approved doses compared with placebo in adults with relapsing-remitting multiple sclerosis (RRMS) using MTC, and (2) to identify and address methodological challenges when performing MTC in RRMS, thereby creating a baseline for comparisons with future treatments. METHODS: Searches were completed in 14 databases, including MEDLINE, Embase, CENTRAL, CDSR and DARE, from inception to June 2018 to identify published or unpublished prospective, randomised controlled trials of all European Union-approved DMTs or DMTs expected to be approved in the near future in RRMS or rapidly-evolving severe RRMS. No language or date restrictions were applied. Studies were included in the MTC if they were judged to have sufficiently similar characteristics, based on the following: patient age; proportion of male participants; Expanded Disability Status Scale (EDSS) score; duration of disease; number of relapses prior to enrolment and proportion of previously treated patients. Background information from the included studies, as well as effect size and confidence intervals (where relevant) of defined outcomes were extracted. Reporting of the MTC was consistent with the International Society for Pharmacoeconomics and Outcomes Research (ISPOR) and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) network meta-analysis guidelines. RESULTS: In total, 33 studies were included in the MTC. Annualised relapse rate (ARR 28 trials) was significantly reduced in all treatments compared with placebo. Alemtuzumab had the highest probability (63%) of being the most effective treatment in terms of ARR compared with placebo (rate ratio [RR] 0.28, 95% credible interval [CrI] 0.21-0.38), followed by natalizumab (30% probability; RR 0.32, 95% CrI 0.23-0.43). The risk of 3- and 6-month confirmed disability progression (CDP3M, 13 trials; CDP6M, 14 trials) were similar; CDP6M was significantly reduced for alemtuzumab (hazard ratio [HR] 0.365; 95% CrI 0.165-0.725), ocrelizumab (HR 0.405, 95% CrI 0.188-0.853) and natalizumab (HR 0.459, 95% CrI 0.252-0.840) relative to placebo. There were no significant differences in the odds of serious adverse events (SAEs, 6 trials) between any treatment and placebo. The results of the MTC were limited by the lack of studies reporting direct comparisons between the included treatments and by heterogeneous reporting of key outcome data. CONCLUSIONS: Meta-analyses confirmed the benefit of all DMTs in terms of relapse rate compared with placebo with a comparable rate of SAEs for the DMTs that could be included in the network. The rigor and transparency of reporting in this study provide a benchmark for comparisons with future new agents.

Single-Port Versus Conventional Laparoscopic Cholecystectomy: Better Cosmesis at the Price of an Increased Incisional Hernia Rate?

Background: The incidence of trocar site hernia (TSH) in single-port laparoscopic cholecystectomy (SPC) is still a debated issue. Aim of this retrospective study was to compare the incidence of postoperative hernia and cosmetic results among patients undergoing SPC and multiport laparoscopic cholecystectomy (MPC) performed at a single institution. Methods: A series of 60 SPC and 60 MPC patients operated on between July 2016 and May 2018 were compared. Primary endpoint was to assess the incidence of TSH at long term. All the patients were admitted as outpatients for physical examination and scar measurement. Secondary endpoints were the cosmetic results assessed by a cosmesis score (CS) and the body image questionnaire (BIQ). Results: After a median 18-month follow-up (range: 6-29 months), a hernia in umbilical trocar site was detected in 4 (7.1%) SPC patients and 1 (2%) MPC patient, the difference not being statistically significant (P = .216). BIQ was almost equivalent in SPC and MPC groups (5.15 versus 5.27; P = .518), respectively. Statistically significant differences in favor of SPC were found in CS (22.3 versus 19.72; P = .001) and in total length of scars (1.2 cm versus 4 cm; P < .001). Conclusions: SPC technique has proved to be safe and effective in experienced hands. Superior cosmesis of SPC over MPC is confirmed, but close attention to fascial closure is a vital component of SPC, and surgeons performing single-site surgery need to be aware of this increased potential for hernia formation.

Expanded disability status scale progression assessment heterogeneity in multiple sclerosis according to geographical areas.

Using placebo data from 3 randomized multiple sclerosis (MS) trials with uniform inclusion criteria, we investigated heterogeneity of Expanded Disability Status Scale (EDSS) progression by geographical areas. Our analysis revealed a significantly lower EDSS progression in Eastern European countries (10.8%) compared with Western Europe (13.1%) or the USA/Canada (21.4%, p < 0.001); EDSS improvement behaved the same way. This heterogeneity is not explained by differences of baseline variables. No differences were detected on more easily quantifiable measures, the Timed 25-Foot Walk or the Multiple Sclerosis Functional Composite. At a time when disease progression represents the target for future interventions in MS, establishment of more quantitative and objective outcomes remains a key priority of MS research. Ann Neurol 2018;84:621-625.

Quantitative assessment of finger motor performance: Normative data.

BACKGROUND: Finger opposition movements are the basis of many daily living activities and are essential in general for manipulating objects; an engineered glove quantitatively assessing motor performance during sequences of finger opposition movements has been shown to be useful to provide reliable measures of finger motor impairment, even subtle, in subjects affected by neurological diseases. However, the obtained behavioral parameters lack published reference values. OBJECTIVE: To determine mean values for different motor behavioral parameters describing the strategy adopted by healthy people in performing repeated sequences of finger opposition movements, examining associations with gender and age. METHODS: Normative values for finger motor performance parameters were obtained on a sample of 255 healthy volunteers executing sequences of finger-to-thumb opposition movements, stratified by gender and over a wide range of ages. Touch duration, inter-tapping interval, movement rate, correct sequences (%), movements in advance compared with a metronome (%) and inter-hand interval were assessed. RESULTS: Increasing age resulted in decreased movement speed, advance movements with respect to a cue, correctness of sequences, and bimanual coordination. No significant performance differences were found between male and female subjects except for the duration of the finger touch, the interval between two successive touches and their ratio. CONCLUSIONS: We report age- and gender-specific normal mean values and ranges for different parameters objectively describing the performance of finger opposition movement sequences, which may serve as useful references for clinicians to identify possible deficits in subjects affected by diseases altering fine hand motor skills.

Reporting treatment outcomes in observational data: A fine balance.

Analyses of observational data have been gaining momentum in the evaluation of ever increasing spectrum of disease modifying therapies for multiple sclerosis. While high cost-effectiveness and generalisability represent their main advantages, these studies are also burdened with high risk of bias that may lead to erroneous conclusions. In this viewpoint, we highlight the key role of rigorous and transparent statistical methodology in the studies of observational data and encourage its thorough editorial scrutiny.

Brain health: time matters in multiple sclerosis.

INTRODUCTION: We present international consensus recommendations for improving diagnosis, management and treatment access in multiple sclerosis (MS). Our vision is that these will be used widely among those committed to creating a better future for people with MS and their families. METHODS: Structured discussions and literature searches conducted in 2015 examined the personal and economic impact of MS, current practice in diagnosis, treatment and management, definitions of disease activity and barriers to accessing disease-modifying therapies (DMTs). RESULTS: Delays often occur before a person with symptoms suggestive of MS sees a neurologist. Campaigns to raise awareness of MS are needed, as are initiatives to improve access to MS healthcare professionals and services. We recommend a clear treatment goal: to maximize neurological reserve, cognitive function and physical function by reducing disease activity. Treatment should start early, with DMT and lifestyle measures. All parameters that predict relapses and disability progression should be included in the definition of disease activity and monitored regularly when practical. On suboptimal control of disease activity, switching to a DMT with a different mechanism of action should be considered. A shared decision-making process that embodies dialogue and considers all appropriate DMTs should be implemented. Monitoring data should be recorded formally in registries to generate real-world evidence. In many jurisdictions, access to DMTs is limited. To improve treatment access the relevant bodies should consider all costs to all parties when conducting economic evaluations and encourage the continuing investigation, development and use of cost-effective therapeutic strategies and alternative financing models. CONCLUSIONS: The consensus findings of an international author group recommend a therapeutic strategy based on proactive monitoring and shared decision-making in MS. Early diagnosis and improved treatment access are also key components.

Breast density assessment using a 3T MRI system: comparison among different sequences.

PURPOSE: To compare MRI sequences for breast density measurements on a 3T MRI system using IDEAL (Iterative Decomposition of water and fat with Echo Asymmetry and Least squares estimation) as possible physiology-like reference. MATERIALS AND METHODS: MRI examination was performed in 48 consecutive patients (mean age 41, years; range, 35-67 years) on a 3.0T scanner and 46 were included. All (fertile) women, were examined between days 5 and 15 of their menstrual cycle. MRI protocol included: T1-turbo spin-echo (T1-tSE), T2-turbo spin-echo (T2-tSE), VIBRANT (Volume Imaging for Breast Assessment) before and after injection of contrast media and IDEAL. Breast density was calculated with semi-automated software. Statistical analysis was performed with non-parametric tests. RESULTS: Mean percentage of breast density calculated in each sequence was: T1-tSE = 56%; T2-tSE  = 52%; IDEAL FatOnly  = 55%; IDEAL WaterOnly  = 53%, VIBRANT = 55%. Significant differences were observed between T2-tSE and both T1-tSE (p<0.001), VIBRANT sequences (p = 0.009), T1-tSE and both IDEAL WaterOnly (p = 0.007) and IDEAL FatOnly (p = 0.047). Breast density percentage showed a positive linear correlation among different sequences: r ≥ 0.93. CONCLUSIONS: Differences exist between MRI sequences used to assess breast density percentage. T1-weighted sequences values were similar to IDEAL sequences.

Quantitative assessment of finger motor impairment in multiple sclerosis.

OBJECTIVE: To address the disability impact on fine hand motor functions in patients with Multiple Sclerosis (MS) by quantitatively measuring finger opposition movements, with the aim of providing a new "score" integrating current methods for disability assessment. METHODS: 40 MS patients (Expanded Disability Status Scale (EDSS): 0-7) and 80 healthy controls (HC) performed a repetitive finger-to-thumb opposition sequence with their dominant hand at spontaneous and maximal velocity, and uni- and bi-manually metronome-paced. A sensor-engineered glove was used to measure finger motor performance. Twenty-seven HC were tested twice, one month apart, to assess test-retest reliability. RESULTS: The motor parameters showed a good reproducibility in HC and demonstrated significantly worse performance in MS patients with respect to HC. A multivariate model revealed that rate of movement in the spontaneous velocity condition and inter-hand interval (IHI), indicating bimanual coordination, contributed independently to differentiate the two groups. A finger motor impairment score based on these two parameters was able to discriminate HC from MS patients with very low EDSS scores (p<0.001): a significant difference was already evident for patients with EDSS = 0. Further, in the MS group, some motor performance parameters correlated with the clinical scores. In particular, significant correlations were found between IHI and EDSS (r = 0.56; p<0.0001), MS Functional Composite (r = -0.40; p = 0.01), Paced Auditory Serial Addition (r = -0.38; p = 0.02). No motor performance parameter correlated with Timed 25-Foot Walk. CONCLUSIONS: A simple, quantitative, objective method measuring finger motor performance could be used to define a score discriminating healthy controls and MS patients, even with very low disability. This sensitivity might be of crucial importance for monitoring the disease course and the treatment effects in early MS patients, when changes in the EDSS are small or absent.

Early neurodevelopmental assessment in Duchenne muscular dystrophy.

The aim of this study was to assess neurodevelopmental profile in young boys affected by Duchenne muscular dystrophy and to establish the correlation between neurodevelopmental findings, and the type and site of mutations. A structured neurodevelopmental assessment (Griffiths Scale of Mental Development) was performed in 81 DMD boys before the age of four years (range: 7-47 months). The mean total DQ was 87 (SD 15.3). Borderline DQ (between 70 and 84) was found in 32% and DQ below 70 in 12.3% of the patients. Children with mutations upstream or in exon 44 had higher DQ than those with mutations downstream exon 44 which are associated with involvement of dystrophin isoforms expressed at high levels in brain. The difference was significant for total and individual subscale DQ with the exception of the locomotor subscale. Items, such as ability to run fast, or getting up from the floor consistently failed in all children, irrespective of the age or of the site of mutation. Our results help to understand the possible different mechanisms underlying the various aspects of neurodevelopmental delay, suggesting that the involvement of brain dystrophin isoforms may cause a delay in the maturation of coordination and dexterity.

Use of Magnetic Resonance Imaging as Well as Clinical Disease Activity in the Clinical Classification of Multiple Sclerosis and Assessment of Its Course: A Report from an International CMSC Consensus Conference, March 5-7, 2010.

It has recently been suggested that the Lublin-Reingold clinical classification of multiple sclerosis (MS) be modified to include the use of magnetic resonance imaging (MRI). An international consensus conference sponsored by the Consortium of Multiple Sclerosis Centers (CMSC) was held from March 5 to 7, 2010, to review the available evidence on the need for such modification of the Lublin-Reingold criteria and whether the addition of MRI or other biomarkers might lead to a better understanding of MS pathophysiology and disease course over time. The conference participants concluded that evidence of new MRI gadolinium-enhancing (Gd+) T1-weighted lesions and unequivocally new or enlarging T2-weighted lesions (subclinical activity, subclinical relapses) should be added to the clinical classification of MS in distinguishing relapsing inflammatory from progressive forms of the disease. The consensus was that these changes to the classification system would provide more rigorous definitions and categorization of MS course, leading to better insights as to the evolution and treatment of MS.

Sexual behaviour in Ligurian (Northern Italy) adolescents and young people: suggestions for HPV vaccination policies.

Human papillomavirus is a common sexually transmitted virus, and persistent infection with high-risk types is the necessary factor for cervical cancer. We investigated sexual behaviour and the age of the first sexual intercourse among young people (14-24 years) in Liguria (Northern Italy) in order to provide information that might orient the country's future vaccination policy. The Italian Authorities offer free vaccination to 12-year-old females, however a better prevention of HPV would to be implemented by introducing the vaccine to new cohorts of females after the first year of the vaccination campaign. Our survey was carried out from 1st May 2006 to 31st December 2007 and involved 3474 volunteers. We administered a written questionnaire to students (14-24 years) and workers (20-24 years). The median age+/-MAD of the sexual debut was 15+/-1 for both females and males in students group and 16+/-1 for both males and females in workers group. This study provides evidence that many Ligurian adolescents have their first sexual experience at a very early age, and often without protection against sexually transmitted diseases. Furthermore, a large percentage of all age-groups are sexually active and have multiple partners. The aim of this study was to identify those cohorts of females to whom vaccination should be offered free of charge. To this end, we calculated the percentage of infections that could be avoided by vaccination in each age-class: the younger the subjects, the higher the number of preventable infections. Our findings suggest that current HPV vaccination should be implemented by introducing new cohorts, especially young girls (14-16 years).

Assessment of disease activity in acromegaly by means of a single blood sample: comparison of the 120th minute postglucose value with spontaneous GH secretion and with the IGF system.

OBJECTIVE: It has been suggested that the threshold of 1 micro g/l of GH nadir after glucose load for definition of controlled acromegalic disease proposed in the 2000 consensus statement should be lowered to 0.30. We evaluated these two cut-off values in comparison with IGF-I, ALS and IGFBP-3 in a group of acromegalic patients. With the aim of simplifying the follow-up protocol in these patients we also tested if one single sample taken after glucose load could replace the nadir value. DESIGN AND MEASUREMENTS: GH secretion was evaluated by oral glucose tolerance test (OGTT), and by studying spontaneous secretion (GH day curve) with sampling at hourly intervals from 08.00 to 18.00 h; from the day curve, mean (MGHDC) and minimum (TRGH) values were considered. IGF-I, ALS, and IGFBP-3 were measured in the basal state at the first testing. patients Fifty acromegalic patients (26-83 years, 31 females, 19 males) in various phases of disease activity. Forty-two patients had previously undergone pituitary surgery (10 also radiotherapy), 23 were treated with SMS analogues and three with dopamine agonist drugs. RESULTS: The nadir GH value after glucose load correlated most significantly with the 120th-minute sample (R = 0.95). Comparison of the postglucose 120th minute at the two cut-off values with IGF-I, IGFBP-3 and ALS showed higher concordance of postglucose level at 0.3 with IGF-I, while concordance was similar for the two cut-off values with ALS and IGFBP-3. When the 120th minute postglucose GH value is lower than 1 micro g/l and IGF-I is within 2SD for age nearly all other parameters are normal. IGF-I correlated more with ALS (R = 0.78) than with IGFBP-3 (R = 0.50) and the latter was less concordant with GH secretion parameters than the previous two. CONCLUSIONS: A sample taken at the 120th minute after glucose load, together with IGF-I and/or ALS evaluation can give sufficient information for a routine assessment of disease activity, both in the diagnosis and in the follow-up to treatment. If GH is lower than 1 micro g/l and IGF-I/ALS are normal, then the patient can be classified as 'nonactive' or 'controlled'; a pathological IGF-I and/or ALS value is a sign of disease activity irrespective of the GH values, while normal IGF-I/ALS with an elevated GH requires further assessment.