Background:
It is unclear whether drugs approved for the treatment of progressive multiple sclerosis (PMS) are effective in disability progression only because of their effect on the inflammatory ...component of the disease.
Objective:
This meta-analysis aimed to evaluate whether the benefits of PMS treatments are mediated by its effect on the active component of the disease.
Methods:
We conducted a systematic search to identify randomised, double-blind, placebo-controlled trials evaluating the efficacy of disease-modifying therapies on disability progression for primary or secondary PMS. The primary endpoint of the analysis was disability progression based on the expanded disability status scale. A subgroup meta-analysis evaluated the effects of treatment according to disease activity at baseline.
Results:
Twelve trials (a total of 8659 PMS cases) were selected. Analysis of the included trials demonstrated that treatment benefit appears to be mainly confined to the group with active disease (hazard ratio (HR) = 0.67; 95% confidence interval (CI): 0.58–0.79) as compared to the group with inactive disease (HR = 0.90; 95% CI: 0.79–1.02, interaction test: p = 0.005).
Conclusions:
This study showed that the benefit of treating patients with PMS was mostly confined to those with the more active disease. Drugs targeting specific pathological processes leading to disability progression remain necessary.
Background:
Randomized clinical trials (RCTs) in progressive multiple sclerosis (MS) often revealed non-significant treatment effects on disability progression.
Objectives:
To investigate whether the ...failure to detect a significant benefit from treatment may be motivated by a delay in treatment effect, possibly related to baseline characteristics.
Methods:
We re-analyzed data from two RCTs testing interferon-beta and glatiramer-acetate versus placebo in progressive MS with no significant effect on EDSS progression. We first designed a time-dependent Cox model with no treatment effect up to time = t0, and constant hazard ratio (HR) after time = t0. We selected the best-fitting t0 from 0 (standard Cox model) to 2.5 years. Furthermore, we modeled the delay as a function of baseline EDSS and fitted the resulting Cox model to the merged dataset.
Results:
The time-dependent Cox model revealed a significant benefit of treatment delayed by t0 = 2.5 years for the SPECTRIMS study (HR = 0.65 (0.43–0.98), p = 0.041), and delayed by t0 = 2 years for the PROMISE study (HR = 0.65, (0.42–0.99), p = 0.044). In the merged dataset, the HR for the EDSS-dependent delayed effect was 0.68 (0.56, 0.82), p < 0.001.
Conclusion:
The assumption of a delayed treatment effect improved the fit to the data of the two examined RCTs, uncovering a significant, although shifted, benefit of treatment.
Objective:
To assess whether the age at which multiple sclerosis (MS) patients reach Expanded Disability Status Scale (EDSS) milestones changed as long as new drugs for the treatment of MS became ...available.
Methods:
We evaluated the long-term impact of therapies on disability progression assessing whether there is a detectable delay in the age at which patients reached EDSS milestones in more recent years. We used data collected over more than 30 years in the Center of Brescia, Italy. We compared the age at EDSS = 6 among patients diagnosed with relapsing-remitting MS in different time periods, adjusting for age at diagnosis and median interval among EDSS visits, by a multivariate Cox model.
Results:
A total of 1324 MS patients were included. Patients diagnosed in more recent periods reached EDSS = 6 at an older age: the rate at which patients reached EDSS = 6 in those diagnosed in 1991–1995 was similar to those diagnosed in 1980–1990 (hazard ratio (HR) = 1.09, p = 0.68) and to those diagnosed in 1996–2000 (HR = 0.85, p = 0.44), it was reduced by 37% in patients diagnosed in 2001–2005 (HR = 0.63, p = 0.05), by 46% in patients diagnosed in 2006–2010 (HR = 0.54, p < 0.02).
Conclusion:
A clear modification of MS course is observed after 2000; among other causes, this can be associated to the changes in the treatment patterns experienced in those years.
Background:
Brain magnetic resonance imaging (MRI) is the most effective surveillance tool for the detection of asymptomatic progressive multifocal leukoencephalopathy (PML). However, the optimal ...frequency for routine MRI surveillance is under-investigated.
Objective:
To understand whether, upon their first MRI appearance, PML lesions present a difference in volume when comparing patients who frequently underwent MRI surveillance (3/4 months) with those who were assessed at longer intervals (6/12 months) and to understand the impact of the volume of lesions on clinical outcome.
Methods:
The data of patients included in the Italian PML cohort were retrospectively analysed. Patients who had all the pre-diagnostic MRI scans available (n = 37) were included. The volume of PML lesion was calculated by manually outlining the PML lesion.
Results:
Compared with patients who underwent MRI examination at least every 4 months, patients who were assessed less frequently had a lesion of significantly higher volume (median: 2567 (883–3583) vs. 664 mm3 (392–963) p = 0.006) and suffered a higher rate of disability (median: 2.25 expanded disability status scale points (–2.5 to 8) vs. 0.5 (–1 to 2.5) p = 0.004).
Conclusion:
The positive clinical outcome of patients undergoing frequent MRI surveillance and the small volume of the PML lesion upon first appearance justify a frequent surveillance using MRI in patients at high risk of PML.
Objectives
The aim of this study was to evaluate the capability of sequences acquired on a 7-T MRI scanner, within times and anatomical coverage appropriate for clinical studies, to identify cortical ...lesions (CLs) in patients with Multiple Sclerosis (MS). Furthermore, we aimed to confirm the clinical significance of CL, testing the correlations between gray matter (GM) lesions and clinical scores.
Methods
A 7-T MRI protocol included 3D-T1-weighted and T2*-weighted sequences. Images were evaluated independently by three readers of different experience, and the number of CLs was recorded. Between-rater concordance was assessed calculating the intraclass correlation coefficient (ICC). Lin’s concordance correlation coefficient was used to compare CL detection between sequences, while partial correlations and multivariable regression models were used to study the relationship between CL and clinical data.
Results
Forty MS patients (M/F, 17/23; 44.7 ± 12.6 years) were enrolled in this study, and CLs were identified in 35/40 subjects (87.5%). CL detection rate on 3D-T1-weighted images was significantly correlated with the detection rate on T2*-weighted images (
r
= 0.99;
p
< 0.001), with high concordance between readers (ICC ≥ 0.995). CLs were significantly correlated with both motor and cognitive scores (all with
p
≤ 0.04).
Conclusions
CL can be identified over the whole brain at 7-T in MS using a 3D-T1-weighted volume, acquired in a clinically feasible time and with comparable performance to that achievable using the T2*-weighted sequence. Based on the central role of CL in the development of clinical disability, we suggest that 3D-T1-weighted volume may play a role in the evaluation of CL in MS undergoing MRI on ultra-high-field scanners.
Key Points
• Cortical lesions can be identified in a clinically feasible time with a 7-T protocol, which includes a 3D-T1-weighted volume.
• Cortical lesions correlated significantly with both motor and cognitive disability in MS patients.
• Given their correlation with clinical disability, evaluation of a cortical lesion on a 7-T clinical protocol could help in the management of MS patients.
ABSTRACT
Introduction
We prospectively compared ultrasound (US) and MRI in patients with common fibular neuropathy.
Methods
Forty adult patients with clinical suspicion of common fibular neuropathy ...and 40 healthy controls underwent both US and MRI. US and MRI datasets were randomized for prospective reading.
Results
The overall sensitivity of US and MRI for diagnosing fibular neuropathy was 90% (95% confidence interval CI, 79.7%‐97.3%) and 87.5% (95% CI, 71.55%‐93.1%), respectively. The overall specificity of US and MRI was 92% (95% CI, 77.45%‐96.1%) and 85% (95% CI, 73.3%‐94.4%), respectively. The overall sensitivity and specificity of US combined with MRI were 94% (95% CI, 0.80%‐0.99%) and 84% (95% CI, 0.70%‐0.91%), respectively. Overall intra‐ and inter‐observer agreements among 3 readers were 0.76% (95% CI, 0.62%‐0.85%) and 0.74% (95% CI, 0.65%‐0.81%).
Conclusions
US diagnostic accuracy for common fibular neuropathy was slightly higher than that of MRI. Muscle Nerve 55: 849–857, 2017
Purpose
To combine peripheral blood indices and clinical factors in a prognostic score for metastatic castration-resistant prostate cancer (mCRPC) patients treated with radium-223 dichloride (
223
...RaRaCl
2
).
Patients and methods
Baseline neutrophil-to-lymphocyte ratio (NLR), derived NLR (donor), lymphocyte-to-monocyte ratio (LMR), platelet-to-lymphocyte ratio (PLR), systemic inflammation index (SII), Eastern Cooperative Oncology Group performance status (ECOG PS), Gleason score (GS) group, number of bone metastases, prostate-specific antigen (PSA), alkaline phosphatase (ALP), line of therapy, previous chemotherapy, and the presence of lymphadenopathies were collected from seven Italian centers between 2013 and 2020. Lab and clinical data were assessed in correlation with the overall survival (OS). Inflammatory indices were then included separately in the multivariable analyses with the prognostic clinical factors. The model with the highest discriminative ability (c-index) was chosen to develop the BIO-Ra score.
Results
Five hundred and nineteen mCRPC patients (median OS: 19.9 months) were enrolled. Higher NLR, dNLR, PLR, and SII and lower LMR predicted worse OS (all with a
p
< 0.001). The multivariable model including NLR, ECOG PS, number of bone metastases, ALP, and PSA (c-index: 0.724) was chosen to develop the BIO-Ra score. Using the Schneeweiss scoring system, the BIO-Ra score identified three prognostic groups (36%, 27.3%, and 36.6% patients, respectively) with distinct median OS (31, 26.6, and 9.6 months, respectively; hazard ratio: 1.62,
p
= 0.008 for group 2 vs. 1 and 5.77,
p
< 0.001 for group 3 vs. 1).
Conclusions
The BIO-Ra score represents an easy and widely applicable tool for the prognostic stratification of mCRPC patients treated with
223
RaRaCl
2
with no additional costs.
The question of whether influenza vaccine effectiveness (VE) wanes over the winter season is still open and some contradictory findings have been reported. This study investigated the possible ...decline in protection provided by the available influenza vaccines.
An individual-level pooled analysis of six test-negative case-control studies conducted in Italy between the 2018/2019 and 2022/2023 seasons was performed. Multivariable logistic regression analyses were performed to estimate weekly change in the odds of testing positive for influenza 14 days after vaccination.
Of 6490 patients included, 1633 tested positive for influenza. Each week that had elapsed since vaccination was associated with an increase in the odds of testing positive for any influenza (4.9%; 95% CI: 2.0-8.0%) and for A(H3N2) (6.5%; 95% CI: 2.9-10.3%). This decline in VE was, however, significant only in children and older adults. A similar increase in the odds of testing positive was seen when the dataset was restricted to vaccinees only. Conversely, VE waning was less evident for A(H1N1)pdm09 or B strains.
Significant waning of VE, especially against influenza A(H3N2), may be one of the factors associated with suboptimal end-of-season VE. Next-generation vaccines should provide more durable protection against A(H3N2).
To measure the vertical occlusal forces transmitted through crowns made of different restorative materials onto simulated peri-implant bone.
The study was conducted using a masticatory robot that is ...able to reproduce the mandibular movements and forces exerted during mastication. During robot mastication, the forces transmitted onto the simulated peri-implant bone were recorded using nine different restorative materials for the simulated single crown: zirconia, two glass-ceramics, a gold alloy, three composite resins, and two acrylic resins. Three identical sample crowns for each material were used. Each crown was placed under 100 masticatory cycles, occluding with the flat upper surface of the robot to evaluate the vertical forces transmitted. Two-way analysis of variance was used. Alpha was set at .05.
The statistical evaluation of the force peaks recorded on the vertical z-axis showed mean values of 641.8 N for zirconia; 484.5 N and 344.5 N, respectively, for the two glass-ceramics; 344.8 N for gold alloy; 293.6 N, 236 N, and 187.4 N, respectively, for the three composite resins; and 39.3 N and 28.3 N, respectively, for the two acrylic resins. Significant differences were found between materials (P < .0001), except for the comparison between gold alloy and one of the glass-ceramics.
Composite and above all acrylic resin crowns were more able to absorb shock from occlusal forces than crowns made of zirconia, ceramic material, or gold alloy.
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.
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.
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.
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.
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.
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