Unexpected Low Rate of Amyloid-ß Pathology in Multiple Sclerosis Patients.

The life expectancy of people with multiple sclerosis (MS) has increased, yet we have noted that development of a typical Alzheimer disease dementia syndrome is uncommon. We hypothesized that Alzheimer disease pathology is uncommon in MS patients. In 100 MS patients, the rate of amyloid-ß plasma biomarker positivity was approximately half the rate in 300 non-MS controls matched on age, sex, apolipoprotein E proteotype, and cognitive status. Interestingly, most MS patients who did have amyloid-ß pathology had features atypical for MS at diagnosis. These results support that MS is associated with reduced Alzheimer disease risk, and suggest new avenues of research. ANN NEUROL 2024.

Cognitive rehabilitation effects on grey matter volume and Go-NoGo activity in progressive multiple sclerosis: results from the CogEx trial.

BACKGROUND: Research on cognitive rehabilitation (CR) and aerobic exercise (EX) to improve cognition in progressive multiple sclerosis (PMS) remains limited. CogEx trial investigated the effectiveness of CR and EX in PMS: here, we present MRI substudy volumetric and task-related functional MRI (fMRI) findings. METHODS: Participants were randomised to: 'CR plus EX', 'CR plus sham EX (EX-S)', 'EX plus sham CR (CR-S)' and 'CR-S plus EX-S' and attended 12-week intervention. All subjects performed physical/cognitive assessments at baseline, week 12 and 6 months post intervention (month 9). All MRI substudy participants underwent volumetric MRI and fMRI (Go-NoGo task). RESULTS: 104 PMS enrolled at four sites participated in the CogEx MRI substudy; 84 (81%) had valid volumetric MRI and valid fMRI. Week 12/month 9 cognitive performances did not differ among interventions; however, 25-62% of the patients showed Symbol Digit Modalities Test improvements. Normalised cortical grey matter volume (NcGMV) changes at week 12 versus baseline were heterogeneous among interventions (p=0.05); this was mainly driven by increased NcGMV in 'CR plus EX-S' (p=0.02). Groups performing CR (ie, 'CR plus EX' and 'CR plus EX-S') exhibited increased NcGMV over time, especially in the frontal (p=0.01), parietal (p=0.04) and temporal (p=0.04) lobes, while those performing CR-S exhibited NcGMV decrease (p=0.008). In CR groups, increased NcGMV (r=0.36, p=0.01) at week 12 versus baseline correlated with increased California Verbal Learning Test (CVLT)-II scores. 'CR plus EX-S' patients exhibited Go-NoGo activity increase (p<0.05, corrected) at week 12 versus baseline in bilateral insula. CONCLUSIONS: In PMS, CR modulated grey matter (GM) volume and insular activity. The association of GM and CVLT-II changes suggests GM plasticity contributes to cognitive improvements. TRIAL REGISTRATION NUMBER: NCT03679468.

Introducing a core dataset for real-world data in multiple sclerosis registries and cohorts: Recommendations from a global task force.

BACKGROUND: As of September 2022, there was no globally recommended set of core data elements for use in multiple sclerosis (MS) healthcare and research. As a result, data harmonisation across observational data sources and scientific collaboration is limited. OBJECTIVES: To define and agree upon a core dataset for real-world data (RWD) in MS from observational registries and cohorts. METHODS: A three-phase process approach was conducted combining a landscaping exercise with dedicated discussions within a global multi-stakeholder task force consisting of 20 experts in the field of MS and its RWD to define the Core Dataset. RESULTS: A core dataset for MS consisting of 44 variables in eight categories was translated into a data dictionary that has been published and disseminated for emerging and existing registries and cohorts to use. Categories include variables on demographics and comorbidities (patient-specific data), disease history, disease status, relapses, magnetic resonance imaging (MRI) and treatment data (disease-specific data). CONCLUSION: The MS Data Alliance Core Dataset guides emerging registries in their dataset definitions and speeds up and supports harmonisation across registries and initiatives. The straight-forward, time-efficient process using a dedicated global multi-stakeholder task force has proven to be effective to define a concise core dataset.

Randomized controlled trial of intravenous immunoglobulin for autoimmune postural orthostatic tachycardia syndrome (iSTAND).

OBJECTIVE: This study assesses response to intravenous immunoglobulin (IVIG) in presumed autoimmune postural orthostatic tachycardia syndrome (POTS). BACKGROUND: POTS may be associated with autoimmune disorders, serum autoantibodies, or recent infection. Uncontrolled case studies suggest that IVIG is beneficial for treating autoimmune POTS. No previous randomized controlled trials have been conducted. METHODS: This single-site randomized controlled trial compared IVIG with intravenous albumin infusions. Albumin comparator ensured blinding and control for effects of volume expansion. Eligible patients with POTS had COMPASS-31 total weighted score ≥ 40 and met predetermined criteria suggesting autoimmunity. Over 12 weeks, participants received eight infusions (0.4 gm/kg each). Four infusions were given weekly followed by four infusions every other week. Primary outcome measure was improvement in COMPASS-31 2 weeks after final infusion. RESULTS: A total of 50 participants consented; 30 met inclusion criteria and received study drug (16 IVIG and 14 albumin; 29 female). Group baseline characteristics were well matched; 27 participants completed treatment protocol. Change in COMPASS-31 did not differ between groups (median change [IQR]; IVIG: -5.5 [-23.3, 2.5] versus albumin: -10.6 [-14.1, -4.7]; p-value = 0.629). The IVIG group had a higher response rate (46.7% versus 38.5%), but this was not statistically significant. Adverse events were common but usually mild and did not differ between treatment groups. CONCLUSIONS: This small randomized controlled trial of IVIG in POTS found no statistical difference in response compared with albumin infusion. Both groups showed improvement possibly related to volume expansion or other effects obscuring group differences. These findings inform development of future immunomodulatory clinical trials in POTS.

Social Cognitive Theory Variables as Correlates of Physical Activity Behavior Among Hispanics With Multiple Sclerosis.

OBJECTIVE: To examine the association between social cognitive theory (SCT) variables and physical activity (PA) behavior in Hispanic adults with multiple sclerosis (MS). DESIGN: Observational, survey study. SETTING: General community. PARTICIPANTS: Inclusion criteria: (a) age 18 years or older, (b) self-identify as Hispanic or Latino, (c) diagnosis of MS, and (d) English or Spanish as primary language. Two hundred forty-three individuals opened the survey, 24 individuals did not meet inclusion criteria, and 66 individuals were excluded due to not completing any of the SCT variable measures (N=153). INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURE(S): PA was measured using the Godin Leisure Time Exercise Questionnaire (GLTEQ) total and Health Contribution Scores (HCS). SCT variables included standard measures of exercise self-efficacy, planning, goal setting, outcome expectations, social support, and functional impairment. RESULTS: The final sample included 153 participants with a mean (SD) age of 43 (11) years, 78% identified as women, 57% were employed, and 63% had a college degree or higher. The mean (SD) MS disease duration was 11 (9) years, 74% of participants reported relapsing remitting MS, and median (interquartile range) Patient Determined Disease Steps (PDDS) score was 3.0 (3.0). Significant correlations were observed between all SCT variables and both GLTEQ total and GLTEQ HCS scores (P<.001). Forward stepwise regression with Akaike's Information Criterion (AICC) identified PDDS, age, exercise planning, exercise self-efficacy, and exercise goal setting as the most appropriate covariates and SCT variables to include in a multivariable model examining independent contributions on GLTEQ HCS scores. The multivariable, linear regression analysis indicated that PDDS (Standardized B=-.280, P<.001), exercise planning (Standardized B=.214, P<.05), and exercise self-efficacy (Standardized B=.183, P<.05) explained 42.4% of variance in GLTEQ HCS scores. CONCLUSIONS: This study provides a contribution to the literature by identifying SCT variables that correlate with PA behavior among Hispanics with MS that may guide the creation of culturally appropriate PA programs.

Assessing everyday functional activity in cognitively impaired people with multiple sclerosis: The use of Actual RealityTM.

BACKGROUND: There is considerable evidence that persons with multiple sclerosis (PwMS) who experience cognitive impairments (CIs) are at risk of having significant limitations in activities of daily living (ADLs). However, ADL assessment often consists of proxies or self-report of ADLs. This study examined whether the performance of instrumental ADLs (I-ADL) is impaired in PwMS with and without CI. METHODS: Participants included 72 PwMS and 48 matched healthy controls (HCs). PwMS were divided into MS-CI (n = 25) and MS-not-impaired (n = 47) groups based on the Brief International Cognitive Assessment for Multiple Sclerosis (BICAMS) scores. All participants performed the Actual RealityTM (AR) test, measuring I-ADL using authentic websites. RESULTS: The MS-CI performed significantly worse on AR compared with HC and MS-not-impaired. In addition, the MS-not-impaired performed significantly worse than HC on AR. AR differentiates well between PwMS with and without CI. CONCLUSIONS: While CI in MS results in significant limitations in the performance of I-ADL, PwMS who do not show evidence of CI can have limitations in I-ADL. AR assessment is a valid and reliable tool sensitive to CI. It should be used in addition to traditional cognitive assessments to detect early functional deterioration through the course of MS.

Improving the efficiency of clinical trials in multiple sclerosis.

BACKGROUND: Phase 3 clinical trials for disease-modifying therapies in relapsing-remitting multiple sclerosis (RRMS) have utilized a limited number of conventional designs with a high degree of success. However, these designs limit the types of questions that can be addressed, and the time and cost required. Moreover, trials involving people with progressive multiple sclerosis (MS) have been less successful. OBJECTIVE: The objective of this paper is to discuss complex innovative trial designs, intermediate and composite outcomes and to improve the efficiency of trial design in MS and broaden questions that can be addressed, particularly as applied to progressive MS. METHODS: We held an international workshop with experts in clinical trial design. RESULTS: Recommendations include increasing the use of complex innovative designs, developing biomarkers to enrich progressive MS trial populations, prioritize intermediate outcomes for further development that target therapeutic mechanisms of action other than peripherally mediated inflammation, investigate acceptability to people with MS of data linkage for studying long-term outcomes of clinical trials, use Bayesian designs to potentially reduce sample sizes required for pediatric trials, and provide sustained funding for platform trials and registries that can support pragmatic trials. CONCLUSION: Novel trial designs and further development of intermediate outcomes may improve clinical trial efficiency in MS and address novel therapeutic questions.

Racial disparities in skin tone representation of dermatomyositis rashes: a systematic review.

OBJECTIVE: This systemic review assesses skin tone representation in images of DM rashes in medical education literature. METHODS: A review was performed of 59 dermatology, 11 neurology, 10 neuromuscular, 7 rheumatology and 6 internal medicine textbooks published between 2011 and 2021 and 3 online image databases (UpToDate, VisualDx and DermNet NZ) that were available through an online medical school library. After extracting images, images with poor lighting or unclear rashes were removed. Authors graded skin tone independently on the Massey and Martin Skin Colour Scale (MMSCS) from 1 (very light) to 10 (very dark). The median score was taken for a final score, grouped within MMSCS 1-2, 3-4, 5-7 or 8-10. Inter-rater reliability was assessed using Kendall's coefficient of concordance (W). RESULTS: Six hundred and twenty-one images were extracted after reviewing 93 textbooks and 3 online databases. Of the 561 images analysed, 73.1% of images represented MMSCS 1-2, followed by 3-4 (13.4%), 5-7 (11.8%) and 8-10 (1.8%). Inter-rater reliability was high (W = 0.835). Of the images in MMSCS 5-10, 59.2% were in online databases and 80.6% of textbook images were in dermatology books. CONCLUSIONS: Patients with lighter skin tones were represented in a higher number of DM-related educational materials compared with patients with darker skin tones. Our findings add to current research implicating that darker skin tones are under-represented in cutaneous educational materials, specifically for DM. This leads to the inability to properly characterize skin involvement in DM and may lead to inappropriate exclusion from clinical trials due to erroneous skin scoring.

Quality Control of Magnetic Resonance Elastography Using Percent Measurable Liver Volume Estimation.

BACKGROUND: Although studies have described factors associated with failed magnetic resonance elastography (MRE), little is known about what factors influence usable elastography data. PURPOSE: To identify factors that have a negative impact on percent measurable liver volume (pMLV), defined as the proportion of usable liver elastography data relative to the volume of imaged liver in patients undergoing MRE. STUDY TYPE: Retrospective. SUBJECTS: A total of 264 patients (n = 132 males, n = 132 females; mean age = 57 years) with suspected or known chronic liver disease underwent MRE paired with a liver protocol MRI. FIELD STRENGTH/SEQUENCE: MRE was performed on a single 1.5 T scanner using a two-dimensional gradient-recalled echo phase-contrast sequence with a passive acoustic driver overlying the right hemiliver. ASSESSMENT: Stiffness maps (usable data at 95% confidence) and liver contours on magnitude images of the MRE acquisition were manually traced and used to assess mean stiffness and pMLV. Hepatic fat fraction and R2 * values were also calculated. The distance from the acoustic wave generator on the skin surface to the liver edge was measured. Two radiologists performed the MR analyses with 50 overlapping cases for inter-reader analysis. STATISTICAL TESTS: Linear regression was performed to identify factors significantly associated with pMLV. Intraclass correlation was performed for inter-reader reliability. RESULTS: pMLV was 31% ± 20% (range 0%-86%). Complete MRE failure (i.e. pMLV = 0%) occurred in 10 patients (4%). Multivariate linear regression identified higher hepatic fat fraction, R2 *, BMI, and driver-to-liver surface distance; male sex; and lower mean liver stiffness was significantly independently associated with lower pMLV. Intraclass correlation for pMLV was 0.96, suggestive of excellent reliability. DATA CONCLUSION: Higher fat fraction, R2 *, BMI, driver-to-liver surface distance, male sex, and lower mean liver stiffness were associated with lower pMLV. Optimization of image acquisition parameters and driver placement may improve MRE quality, and pMLV likely serves as a diagnostic utility quality control metric. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY STAGE: 2.

The relationship between processing speed and verbal and non-verbal new learning and memory in progressive multiple sclerosis.

OBJECTIVE: Processing speed (PS) deficits are the most common cognitive deficits in multiple sclerosis (MS), followed by learning and memory deficits, and are often an early cognitive problem. It has been argued that impaired PS is a primary consequence of MS, which in turn decreases learning. The current analysis examined the association between PS and learning in a large cohort of individuals with progressive MS. METHODS: Baseline data from a randomized clinical trial on rehabilitation taking place at 11 centers across North America and Europe were analyzed. Participants included 275 individuals with clinically definite progressive MS (primary, secondary) consented into the trial. RESULTS: Symbol Digit Modalities Test (SDMT) significantly correlated with California Verbal Learning Test-II (CVLT-II) (r = 0.21, p = 0.0003) and Brief Visuospatial Memory Test-Revised (BVMT-R) (r = 0.516, p < 0.0001). Receiver operating characteristic (ROC) analysis of the SDMT z score to distinguish between impaired and non-impaired CVLT-II performance demonstrated an area under the curve (AUC) of 0.61 (95% confidence interval (CI): 0.55-0.68) and a threshold of -1.62. ROC analysis between SDMT and BVMT-R resulted in an AUC of 0.77 (95% CI: 0.71-0.83) and threshold of -1.75 for the SDMT z score to predict impaired BVMT-R. CONCLUSION: Results indicate little ability beyond chance to predict CVLT-II from SDMT (61%), albeit statistically significant. In contrast, there was a 77% chance that the model could distinguish between impaired and non-impaired BVMT-R. Several potential explanations are discussed.

Cardiorespiratory fitness and free-living physical activity are not associated with cognition in persons with progressive multiple sclerosis: Baseline analyses from the CogEx study.

BACKGROUND: Aerobic exercise training (physical activity for improving cardiorespiratory fitness) represents a promising approach for managing cognitive impairment in multiple sclerosis (MS). However, there is limited evidence that levels of physical activity and fitness are associated with cognition in progressive MS. OBJECTIVE: We examined associations among cardiorespiratory fitness, moderate-to-vigorous physical activity (MVPA), and cognitive performance in a large, international progressive MS sample. METHODS: Two hundred forty European and North American persons with progressive MS underwent cardiorespiratory fitness measurement on a recumbent stepper, wore an ActiGraph GT3X + accelerometer for 7 days for measuring MVPA, and underwent the Brief International Cognitive Assessment in MS. RESULTS: Cardiorespiratory fitness was not significantly correlated with Symbol Digit Modalities Test (SDMT; r = -0.01; r = -0.04), California Verbal Learning Test-II (CVLT-II; r = 0.05; r = 0.05), or Brief Visuospatial Memory Test-Revised (BVMT-R; r = -0.14; r = -0.14) z-scores controlling for age, sex, and education. MVPA and SDMT (r = 0.05), CVLT-II (r = -0.07), and BVMT-R (r = 0.01) z-scores were not significantly correlated. CONCLUSION: Cardiorespiratory fitness and MVPA were not associated with cognition in this large progressive MS sample, yet these outcomes represent critical manipulation checks for documenting the success of the CogEx trial. This highlights the importance of examining other exercise-related mechanisms-of-action for improving cognition in progressive MS.

Predictors of Clinical Outcomes of Pharmacomechanical Catheter-Directed Thrombolysis for Acute Iliofemoral Deep Vein Thrombosis: Analysis of a Multicenter Randomized Trial.

PURPOSE: To identify the baseline patient characteristics that predict who will benefit from pharmacomechanical catheter-directed thrombolysis (PCDT) of acute iliofemoral deep vein thrombosis (DVT). MATERIALS AND METHODS: In the Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis (ATTRACT) multicenter randomized trial, 381 patients with acute iliofemoral DVT underwent PCDT and anticoagulation or anticoagulation alone. The correlations between baseline factors and venous clinical outcomes were evaluated over 24 months using post hoc regression analyses. Interaction terms were examined to evaluate for differential effects by treatment arm. RESULTS: Patients with clinically severe DVT (higher baseline Villalta score) experienced greater effects of PCDT in improving 24-month venous outcomes, including moderate or severe postthrombotic syndrome (PTS) (odds ratios [ORs] and 95% confidence intervals [CIs] per unit increase in the baseline Villalta scores were as follows: for PCDT, OR, 1.08 [95% CI, 1.01-1.15]; for control, OR, 1.20 [95% CI, 1.12-1.29]; Pinteraction = .03), PTS severity (between-arm differences in the Villalta [Pinteraction = .004] and Venous Clinical Severity Scale [VCSS] [Pinteraction = .002)] scores), and quality of life (between-arm difference in the Venous Insufficiency Epidemiological and Economic Study Quality of Life score; Pinteraction = .025). Patients with previous DVT had greater effects of PCDT on 24-month PTS severity than those in patients without previous DVT (mean [95% CI] between-arm difference in the Villalta score, 4.2 [1.56-6.84] vs 0.9 [-0.44 to 2.26], Pinteraction = .03; mean [95% CI] between-arm difference in the VCSS score, 2.6 [0.94-4.21] vs 0.3 [-0.58 to 1.14], Pinteraction = .02). The effects of PCDT on some but not all outcomes were greater in patients presenting with left-sided DVT (Villalta PTS severity, Pinteraction = .04; venous ulcer, Pinteraction = .0499) or a noncompressible popliteal vein (PTS, Pinteraction = .02). The effects of PCDT did not vary by sex, race, ethnicity, body mass index, symptom duration, hypertension, diabetes, or hypercholesterolemia. CONCLUSIONS: In patients with acute iliofemoral DVT, greater presenting clinical severity (higher baseline Villalta score) and a history of previous DVT predict enhanced benefits from PCDT.

Chemokine Receptor 2-targeted Molecular Imaging in Pulmonary Fibrosis. A Clinical Trial.

Rationale: Idiopathic pulmonary fibrosis (IPF) is a progressive inflammatory lung disease without effective molecular markers of disease activity or treatment responses. Monocyte and interstitial macrophages that express the C-C motif CCR2 (chemokine receptor 2) are active in IPF and central to fibrosis.Objectives: To phenotype patients with IPF for potential targeted therapy, we developed 64Cu-DOTA-ECL1i, a radiotracer to noninvasively track CCR2+ monocytes and macrophages using positron emission tomography (PET).Methods: CCR2+ cells were investigated in mice with bleomycin- or radiation-induced fibrosis and in human subjects with IPF. The CCR2+ cell populations were localized relative to fibrotic regions in lung tissue and characterized using immunolocalization, single-cell mass cytometry, and Ccr2 RNA in situ hybridization and then correlated with parallel quantitation of lung uptake by 64Cu-DOTA-ECL1i PET.Measurements and Main Results: Mouse models established that increased 64Cu-DOTA-ECL1i PET uptake in the lung correlates with CCR2+ cell infiltration associated with fibrosis (n = 72). As therapeutic models, the inhibition of fibrosis by IL-1ß blockade (n = 19) or antifibrotic pirfenidone (n = 18) reduced CCR2+ macrophage accumulation and uptake of the radiotracer in mouse lungs. In lung tissues from patients with IPF, CCR2+ cells concentrated in perifibrotic regions and correlated with radiotracer localization (n = 21). Human imaging revealed little lung uptake in healthy volunteers (n = 7), whereas subjects with IPF (n = 4) exhibited intensive signals in fibrotic zones.Conclusions: These findings support a role for imaging CCR2+ cells within the fibrogenic niche in IPF to provide a molecular target for personalized therapy and monitoring.Clinical trial registered with www.clinicaltrials.gov (NCT03492762).

Diagnostic Performance of LI-RADS Version 2018 for Evaluation of Pediatric Hepatocellular Carcinoma.

Background The Liver Imaging Reporting and Data System (LI-RADS) has standardized the evaluation of adult but not pediatric hepatocellular carcinoma (HCC). Purpose To evaluate the performance of LI-RADS version 2018 for diagnosis of pediatric HCC. Materials and Methods This multi-institution retrospective study evaluated all available dynamic CT and/or MRI scans of pediatric (≤18 years) HCC from five institutions between July 2009 and April 2019. The control group included an equal number of other enhancing hepatic lesions. Blinded to final diagnosis, three radiologists independently applied LI-RADS version 2018 criteria. The reference standard was pathologic examination or more than 1 year follow-up. Sensitivity and specificity of LI-RADS were computed using a dichotomous classification of LR-1, LR-2, or LR-3 versus LR-4, LR-5, LR-TIV (tumor in vein), or LR-M (probably or definitely malignant but not HCC-specific) for predicting hepatic malignancy in the entire cohort and in patients at risk for HCC. Results The cohort consisted of 116 children: 58 with HCC (mean age, 12 years ± 5; 31 girls) and 58 with other enhancing hepatic masses (mean age, 12 years ± 5; 42 girls). Frequencies of major criteria in classic HCC for the three readers were as follows: nonrim arterial phase hyperenhancement, 49%-62% (19-24 of 39 patients); nonperipheral "washout," 36%-59% (14-23 of 39 patients); and enhancing "capsule," 28%-38% (11-15 of 39 patients). For the full cohort, the sensitivity of LR-4, LR-5, LR-TIV, or LR-M for malignancy among the three readers ranged from 85% (95% CI: 76, 94) to 88% (95% CI: 80, 96); specificity of LR-1, LR-2, or LR-3 for benignity ranged from 54% (95% CI: 40, 68) to 70% (95% CI: 57, 83). In the at-risk subgroup, sensitivity ranged from 58% (95% CI: 36, 80) to 68% (95% CI: 48, 89); specificity ranged from 56% (95% CI: 37, 74) to 63% (95% CI: 45, 81). All lesions categorized as LR-TIV (n = 10-13) were HCCs. Conclusion Liver Imaging Reporting and Data System version 2018 had moderate sensitivity but low specificity for the diagnosis of pediatric hepatocellular carcinoma (HCC), which had low frequencies of the major criteria used for adult HCC diagnosis. © RSNA, 2021 See also the editorial by Paltiel in this issue.

Adverse event profile differences between rituximab and ocrelizumab: Findings from the FDA Adverse Event Reporting Database.

BACKGROUND: Rituximab and ocrelizumab are anti-CD20 monoclonal antibodies that have shown a marked reduction in multiple sclerosis (MS) inflammatory activity. However, their real-world safety profile has not been adequately compared. OBJECTIVE: To investigate the adverse event (AE) profile of rituximab and ocrelizumab reported to the Food and Drug Administration Adverse Event Reporting System (FAERS) database. METHODS: The FAERS database was filtered by indication (MS) and drug (rituximab or ocrelizumab). Disproportionality analyses including but not limited to reporting odds ratio (ROR) were conducted to identify drug-AE associations. A signal was detected if the lower limit of the 95% confidence interval of ROR (ROR025) exceeded 1. RESULTS: There were 623 and 7948 reports for rituximab and ocrelizumab, respectively. The most frequent AEs with rituximab and ocrelizumab were infusion-related reaction (4.82%) and urinary tract infection (10.52%), respectively. The strongest drug-AE association for rituximab and ocrelizumab were ear pruritus (ROR025: 47.53) and oral herpes (ROR025: 38.99), respectively. Ocrelizumab was associated with an almost two times higher frequency of infections than rituximab (21.93% vs 11.05%, respectively). CONCLUSION: This study revealed differences in reporting AEs between rituximab and ocrelizumab. Infections were reported more frequently with ocrelizumab. Although speculative, a potentially different or more extensive B-cell depletion by ocrelizumab might explain these findings. Additional pharmacovigilance studies need to be performed to better characterize differences in the AE profile in B-cell-depleting therapies.

New applications for independent activities of daily living in measuring disability in multiple sclerosis.

BACKGROUND: Disability outcome measures in multiple sclerosis (MS) focus heavily on ambulation; however, limitations in performing everyday activities encompass another type of disability. OBJECTIVES: The aim of this study was to examine the ability of instrumental activities of daily living (IADL) scale to discriminate between different levels of disability and to predict disability progression. METHODS: The North American Research Committee on Multiple Sclerosis (NARCOMS) registry fall 2006 semi-annual survey asked participants to complete the RAND-12, Performance Scales, Patient Determined Disease Steps (PDDS), and IADL questionnaires. We modeled the trajectory of disability change, using the PDDS, over 12 years. Analyses used linear and repeated measures regression methods. RESULTS: Of respondents (n = 9931), 9559 (96%) completed the PDDS and IADL scale. Respondents were mostly female (76%), Caucasian (92%), and 52.3 (10.5) years old with moderate disability (median PDDS 4 (early cane)). Mean (SD) IADL total score was 20.5 (3.7). Discriminant ability of the IADL scale was higher than other measures considered at higher levels of disability. Adjusted longitudinal models showed that needing greater assistance on IADLs was independently predictive of trajectories of greater disability change. CONCLUSION: IADL scale had a greater ability to discriminate between higher disability levels than RAND-12 domains. The IADL scale may provide a useful and clinically relevant tool to measure disability in progressive MS populations.

Comparative responsiveness of the health utilities index and the RAND-12 for multiple sclerosis.

BACKGROUND: Outcome measures need to be valid and have good test-retest reliability and responsiveness. We compared the responsiveness of the RAND-12 and the Health Utilities Index-mark III (HUI3) in persons with multiple sclerosis (MS). METHODS: In Spring 2018 and 2019, North American Research Committee on Multiple Sclerosis (NARCOMS) registry participants completed the HUI3, the RAND-12, and reported disability (Patient Determined Disease Steps (PDDS)) and employment status (full-time, part-time, and no). We used changes in PDDS and employment status as anchors. We assessed responsiveness using effect size, standardized response mean, and the responsiveness index. We used relative efficiency (RE) to compare the responsiveness of the health-related quality of life (HRQOL) scores, adjusting for sociodemographic factors. RESULTS: We included 4769 participants in the analysis. They had a mean (standard deviation (SD)) age of 60.9 (10.1) years, and 3826 participants (80.2%) were women. RE was highest for the HUI3 for changes in in disability status (HUI3: 1.0, Physical Component Score-12 (PCS-12): 0.80, and Mental Component Score-12 (MCS-12): 0.41) and for changes in employment status (HUI3: 1.0, PCS-12: 0.70, and MCS-12: 0.17). CONCLUSION: The HUI3 was more responsive to changes in disability and employment status than the PCS-12 or MCS-12. Given the HUI3's other strong psychometric properties, it may be the preferred generic measure of HRQOL in MS.

Mendelian randomization provides no evidence for a causal role in the bidirectional relationship between depression and multiple sclerosis.

BACKGROUND: Major depressive disorder (MDD) is common in multiple sclerosis (MS) and its incidence rises before MS diagnosis. However, the causality and direction of this association remain unclear. OBJECTIVE: The objective is to investigate the bidirectional relationship between MS and MDD using Mendelian randomization (MR). METHODS: We selected genetic instruments associated with risk of MDD (n = 660,937 cases; 1,453,489 controls) and MS (n = 47,429 cases; 68,374 controls). Using two-sample MR, we examined putative causal effects in either direction, with sensitivity analyses to assess pleiotropy. Also, we adjusted for body mass index (BMI) in multivariable MR. RESULTS: We found no effect of genetic liability to MDD on the odds of MS (OR = 1.07/doubling in odds, 95% CI = 0.90-1.28). Similarly, our findings did not support a causal effect of genetic liability to MS on MDD (OR = 1.00/doubling in odds, 95% CI = 0.99-1.01). Despite heterogeneity, sensitivity analyses indicated that bias from pleiotropy was unlikely. Conversely, genetic predisposition toward higher BMI increased the odds of MS (OR = 1.34/SD increase, 95% CI = 1.09-1.65) and MDD (OR = 1.08, 95% CI = 1.01-1.15). CONCLUSION: This study does not support a causal association between MDD genetic liability and MS susceptibility, and vice versa. Genetic evidence suggesting commonality of obesity to both conditions may partly explain the increased incidence of depression pre-MS diagnosis.

Clinical Outcomes of a Pharmacomechanical Catheter-Directed Venous Thrombolysis Strategy that Included Rheolytic Thrombectomy in a Multicenter Randomized Trial.

PURPOSE: To describe the clinical outcomes of a pharmacomechanical catheter-directed venous thrombolysis (PCDT) strategy that included AngioJet rheolytic thrombectomy. METHODS: In the Acute Venous Thrombosis: Thrombus Removal with Adjunctive Catheter-Directed Thrombolysis multicenter randomized trial, physicians at 33 sites designated AngioJet as their preferred device for PCDT. In these sites, 364 patients with acute proximal lower-extremity deep vein thrombosis (DVT) were randomized to a strategy of PCDT that incorporated either AngioJet along with anticoagulation or anticoagulation alone. Relief from presenting DVT symptoms was evaluated over 30 days of follow-up. Postthrombotic syndrome (PTS), quality of life (QOL), recurrent venous thromboembolism (VTE), and safety were evaluated over 24 months of follow-up. RESULTS: Within 30 days, AngioJet-PCDT led to a greater improvement in leg swelling (mean difference calf circumference 0.55 cm, P = .009), venous QOL (mean difference 6.5 Venous Insufficiency Epidemiologic and Economic Study [VEINES]-QOL points, P = .0073), and venous symptoms (mean difference 5.6 VEINES-symptoms points, P = .0134) than control, with differences most apparent in iliofemoral DVT. AngioJet-PCDT reduced PTS at 6 months (24% with AngioJet-PCDT vs 40% with control, P = .003) but did not influence PTS or QOL between 12 and 24 months. Major bleeding, pulmonary embolism, renal failure, and bradycardia were infrequent with AngioJet-PCDT (<2% each), but 24-month VTE recurrence may have been more frequent (13.9% with AngioJet-PCDT vs 6.8% with control, P = .03) CONCLUSIONS: In patients with acute proximal DVT, a treatment strategy that included first-line AngioJet-PCDT was reasonably safe and led to an improved symptom status and venous QOL at 1 month and reduced PTS at 6 months compared with anticoagulation alone. However, AngioJet-PCDT did not influence PTS or the QOL beyond 6 months and may have increased recurrent VTE.

The impact of adjunctive tomosynthesis on screening mammography outcomes in two widely diverse radiology practices.

To determine the effect of adjunctive digital breast tomosynthesis screening on dissimilar mammography practices. We compared the outcomes of breast cancer screening with digital mammography versus digital mammography combined with tomosynthesis in two independent breast imaging practices from June 1, 2015, to May 31, 2016. Institution one was a hospital-based academic practice of breast imaging specialists and institution two was a community-based practice with academic affiliation served by general radiologists. Screening mammography was linked to subsequent diagnostic imaging and pathology. Subject characteristics and performance metrics were compared via t test for continuous variables and the chi-square test for categorical variables. A two-sided z test was performed to test modality differences for assessment and pathology subtype. Of the 54 638 women, 54% (n = 29 295) were from institution one and 55% (n = 30 013) underwent digital mammography alone. Women undergoing mammography with tomosynthesis were older (60.8 years vs 56.9 years, P < .001) and had slightly less dense breast composition (P = .001). Performance metrics varied substantially between institutions. At both institutions the biopsy rate, positive predictive value of screening (PPV1 ), and invasive cancer detection rate increased significantly with adjunctive tomosynthesis. At institution one, the biopsy rate increased from 1.4% to 1.9%, the PPV1 from 6.0% to 8.2%, and the invasive cancer detection rate from 3.4 to 4.9/1000 women screened. At institution two, the respective increases were from 0.7% to 1.0%, 5.5% to 11.0%, and 2.3% to 4.1/1000. Tomosynthesis recalled asymmetry less and mass more and resulted in fewer BI-RADS 1 and 2 assessments than screening with mammography alone. Adjunctive tomosynthesis appears to have a consistent impact on breast cancer screening performance metrics despite marked variation in breast imaging practice. Combined tomosynthesis screening has a significantly higher PPV1 , leads to a greater number of biopsies, and detects more invasive cancer than screening with digital mammography.