Search

Seed dispersal is crucial for ecosystem persistence, especially in fragmented landscapes, such as those common in Europe. Ongoing defaunation might compromise effective seed dispersal, but the conservation status of pairwise interactions remains unknown. With a literature review, we reconstructed the first European-wide seed dispersal network and evaluated the conservation status of interactions by assessing each interacting partner's IUCN (International Union for Conservation of Nature) conservation status and population trends. We found that a third of the disperser species and interactions face potential extinction and that 30% of the plant species have most of their dispersers threatened or declining. Our study reveals a developing seed dispersal crisis in Europe and highlights large knowledge gaps regarding the dispersers and conservation status of zoochorous plants, urging further scrutiny and action to conserve the seed dispersal service.

Background: Patients with multiple sclerosis (PwMS) have an increased risk of infections., Objectives: To characterize incidence, clinical characteristics, outcomes and risk factors of infections, and serious infections (SIs) in ocrelizumab (OCR)-treated PwMS., Design: Post-hoc analysis of pooled data from 6155 patients in 13 clinical trials., Methods: Descriptive analyses of clinical characteristics and outcomes were reported over ⩽14 years. A Poisson Generalized Estimating Equation model was constructed to examine risk factors in a subgroup of patients with longer exposure to OCR ( n  = 2092)., Results: Over a median (max) treatment period of 3.7 (13.9) years, 420/6155 patients (6.8%) experienced 583 SIs, excluding coronavirus disease 2019. Incidence rates in relapsing multiple sclerosis (RMS; 1.50 per 100 patient years [95% confidence interval (CI): 1.34-1.68]) and progressive multiple sclerosis (PMS; 3.70 [95% CI: 3.27-4.17]) remained stable over this period. Lower respiratory tract, urinary tract, abdominal and gastrointestinal, and skin infections were the most commonly reported SIs. Most SIs (~90%) resolved, and treatment with OCR was continued in >80% of cases. The presence of 1 or ⩾2 comorbidities (rate ratio = 1.66, 2.73, respectively), recent relapse activity (2.06), and Expanded Disability Status Scale (EDSS) score ⩾6.0 (2.02) were significant risk factors for SIs in patients with RMS treated over a median (max) period of 8.3 (11.2) years. In patients with primary PMS treated over a median (max) period of 7.1 (11.8) years, an EDSS score ⩾6.0 was associated with the greatest risk of SIs, a 4-fold increase (rate ratio, 4.31), followed by abnormal immunoglobulin (Ig)M levels (1.89), the presence of ⩾2 comorbidities (1.80), and having overweight/obesity (1.46). Time on OCR and abnormal IgG levels were not significantly associated with an increased SI risk., Conclusion: Continuous long-term treatment with OCR is associated with a manageable infection risk profile. Optimal disease control and addressing modifiable risk factors may reduce the risk of infections., (© The Author(s), 2024.)

Background: Clinical trials comparing the efficacy of ocrelizumab (OCR) with other disease-modifying therapies (DMTs) other than interferon (IFN) β-1a in relapsing multiple sclerosis (RMS) are lacking., Objectives: To compare the treatment effect of OCR vs six DMTs' (IFN β-1a, glatiramer acetate, fingolimod, dimethyl fumarate, teriflunomide, natalizumab) treatment pathways used in clinical practice by combining clinical trial and real-world data., Methods: Patient-level data from OPERA trials and open-label extension phase, and from the German NeuroTransData (NTD) MS registry, were used to build 1:1 propensity score-matched (PSM) cohorts controlling for seven baseline covariates, including brain imaging activity. Efficacy outcomes were time to first relapse and time to 24-week confirmed disability progression over 5.5 years of follow-up. Intention-to-treat analysis using all outcome data irrespective of treatment switch was applied., Results: The analyses included 611 OPERA patients and 7141 NTD patients. We built 12 paired-matched cohorts (six for each outcome, two for each DMT) to compare efficacy of OCR in OPERA with each DMT treatment pathway in NTD. Post-matching, baseline covariates and PS were well balanced (standardized mean difference <.2 for all cohorts). Over 5.5 years, patients treated with OCR showed a statistically significant reduction in the risk of relapse (hazard ratios [HRs] .30 to .54) and disability progression (HRs .51 to .67) compared with all index therapies and their treatment switching pathways in NTD. Treatment switch and/or discontinuation occurred frequently in NTD cohorts., Conclusion: OCR demonstrates superiority in controlling relapses and disability progression in RMS compared with real-world treatment pathways over a 5.5-year period. These analyses suggest that high-efficacy DMTs and high treatment persistence are critical to achieve greatest clinical benefit in RMS., Registration: OPERA I (NCT01247324), OPERA II (NCT01412333)., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: F. Hoffmann-La Roche Ltd., Basel, Switzerland, provided financial support for the study and publication of this manuscript. Writing and editorial support was provided by Articulate Science, UK. E Muros-Le Rouzic is an employee of and shareholder in F. Hoffmann-La Roche Ltd. Y Heer was an employee of PricewaterhouseCoopers and contracted to perform statistical projects for NeuroTransData at the time of this analysis. S Yiu is an employee of Roche Products Ltd. V Tozzi is an employee of PricewaterhouseCoopers and contracted to perform statistical projects for NeuroTransData at the time of this analysis. S Braune has received honoraria from Kassenärztliche Vereinigung Bayerns and health maintenance organizations for patient care; and from Biogen, Merck, NeuroTransData, Novartis, and Roche for consulting, project management, clinical studies, and lectures; he also received honoraria and expense compensation as a board member of NeuroTransData. P van Hövell was an employee of PricewaterhouseCoopers and contracted to perform statistical projects for NeuroTransData at the time of this analysis. A Bergmann has received consultancy fees from advisory board, speaker, and other activities for NeuroTransData; project management and clinical studies for and travel expenses from Novartis and Servier. C Bernasconi is a consultant for F. Hoffmann-La Roche Ltd. F Model was an employee of and shareholder in F. Hoffmann-La Roche Ltd. at the time of this analysis and is now an employee of Denali Therapeutics. L Craveiro is an employee of and shareholder in F. Hoffmann-La Roche Ltd., (© The Author(s) 2024.)

Background: Multiple sclerosis (MS) paramagnetic rim lesions (PRLs) are markers of chronic active biology and exhibit complex iron and myelin changes that may complicate quantification when using conventional MRI approaches., Purpose: To conduct a multiparametric MRI analysis of PRLs., Study Type: Retrospective/longitudinal., Subjects: Ninety-five progressive MS subjects with at least one persistent PRL who were enrolled in the CONSONANCE trial., Field Strength/sequence: 3-T/Susceptibility-weighted, T1-weighted, T2-weighted, and fluid-attenuated inversion recovery., Assessment: Acute/chronic PRLs and non-PRLs were measured at screening, 24, 48, and 96 weeks using quantitative magnetic susceptibility (QS), R2*, and standardized T1w/T2w ratio (sT1w/T2w). PRL analyses were performed for whole lesion, core, and rim. The correlations between PRL core and rim sT1w/T2w, QS, and R2* were assessed., Statistical Tests: Linear mixed models. A P-value <0.05 was considered significant., Results: There was a significant decrease in sT1w/T2w (-0.24 ± -5.3 × 10 -3 ) and R2* (-3.6 ± 2.2 Hz) but a significant increase in QS (+21 ± 1.3 ppb) using whole-lesion analysis of chronic PRLs compared to non-PRLs at screening. Tissue damage accumulated at the 96-week time point was more evident in acute/chronic PRLs compared to acute/chronic non-PRLs (ΔsT1w/T2w = -0.21/-0.24 ± 0.033/0.0053; ΔR2* = -4.4/-3.6 ± 1.4/2.2 Hz). New, acute PRL sT1w/T2w significantly increased in lesion core (+4.3 × 10 -3  ± 1.2 × 10 -4 ) and rim (+5.6 × 10 -3  ± 1.2 × 10 -4 ) 24 weeks post lesion inception, suggestive of partial recovery. Chronic PRLs, contrastingly, showed significant decreases in sT1w/T2w over the initial 24 weeks for both core (-2.1 × 10 -4  ± 2.0 × 10 -5 ) and rim (-2.4 × 10 -4  ± 2.0 × 10 -5 ), indicative of irreversible tissue damage. Significant positive correlations between PRL core and rim sT1w/T2w (R 2  = 0.53), R2* (R 2  = 0.69) and QS (R 2  = 0.52) were observed., Data Conclusion: Multiparametric assessment of PRLs has the potential to be a valuable tool for assessing complex iron and myelin changes in chronic active PRLs of progressive MS patients., Level of Evidence: 2 TECHNICAL EFFICACY: Stage 3., (© 2024 The Author(s). Journal of Magnetic Resonance Imaging published by Wiley Periodicals LLC on behalf of International Society for Magnetic Resonance in Medicine.)

Species phenology - the timing of key life events - is being altered by ongoing climate changes with yet underappreciated consequences for ecosystem stability. While flowering is generally occurring earlier, we know much less about other key processes such as the time of fruit ripening, largely due to the lack of comprehensive long-term datasets. Here we provide information on the exact date and site where seeds of 4,462 taxa were collected for the Index Seminum (seed exchange catalogue) of the Botanic Garden of the University of Coimbra, between 1926 and 2013. Seeds were collected from spontaneous and cultivated individuals across Portugal, including both native and introduced taxa. The database consists of 127,747 curated records with information on the species, or infraspecific taxa (including authority), and the day and site where seeds were collected. All records are georeferenced and provided with a confidence interval for the collection site. Taxonomy was first curated manually by in-house botanists and then harmonized according to the GBIF backbone taxonomy., (© 2024. The Author(s).)

Background: The Expanded Disability Status Scale (EDSS) quantifies disability and measures disease progression in multiple sclerosis (MS), however is not available in administrative claims databases., Objectives: To develop a claims-based algorithm for deriving EDSS and validate it against a clinical dataset capturing true EDSS values from medical records., Methods: We built a unique linked dataset combining claims data from the German AOK PLUS sickness fund and medical records from the Multiple Sclerosis Management System 3D (MSDS 3D ). Data were deterministically linked based on insurance numbers. We used 69 MS-related diagnostic indicators recorded with ICD-10-GM codes within 3 months before and after recorded true EDSS measures to estimate a claims-based EDSS proxy (pEDSS). Predictive performance of the pEDSS was assessed as an eight-fold (EDSS 1.0-7.0, ≥8.0), three-fold (EDSS 1.0-3.0, 4.0-5.0, ≥6.0), and binary classifier (EDSS <6.0, ≥6.0). For each classifier, predictive performance measures were determined, and overall performance was summarized using a macro F1-score. Finally, we implemented the algorithm to determine pEDSS among an overall cohort of patients with MS in AOK PLUS, who were alive and insured 12 months prior to and after index diagnosis., Results: We recruited 100 people with MS insured by AOK PLUS who had ≥1 EDSS measure in MSDS 3D between 01/10/2015 and 30/06/2019 (620 measurements overall). Patients had a mean rescaled EDSS of 3.2 and pEDSS of 3.0. The pEDSS deviated from the true EDSS by 1.2 points, resulting in a mean squared error of prediction of 2.6. For the eight-fold classifier, the macro F1-score of 0.25 indicated low overall predictive performance. Broader severity groupings were better performing, with the three-fold and binary classifiers for severe disability achieving a F1-score of 0.68 and 0.84, respectively. In the overall AOK PLUS cohort (3,756 patients, 71.9% female, mean 51.9 years), older patients, patients with progressive forms of MS and those with higher comorbidity burden showed higher pEDSS., Conclusion: Generally, EDSS was underestimated by the algorithm as mild-to-moderate symptoms were poorly captured in claims across all functional systems. While the proxy-based approach using claims data may not allow for granular description of MS disability, broader severity groupings show good predictive performance., Competing Interests: EM-L and LC were employees of F. Hoffmann La Roche Ltd. MG and TW were employees of IPAM. EZ was an employee of Cytel Inc. AD has received personal compensation and travel grants from Biogen, Celgene, Janssen, Roche and Sanofi for speaker activity. TZ has received consulting fees, grants, and research support from various pharmaceutical companies e.g., Almirall, Bayer, Biogen, Genzyme, Merck, Novartis, Roche, Sanofi, and Teva. TW has received honoraria from several pharmaceutical/consultancy firms e.g. Novo Nordisk, Roche, Abbvie, Merck, GSK, BMS, Bayer, and Boehringer Ingelheim. The remaining author declares that the research was conducted in the absence of any commercial or financial relationships that can be construed as a potential conflict of interest. The authors declare that this study received funding from F. Hoffmann La Roche Ltd. The funder had the following involvement in the study: conception of the study, design, interpretation of the results and writing and revision of the manuscript., (Copyright © 2023 Muros-Le Rouzic, Ghiani, Zhuleku, Dillenseger, Maywald, Wilke, Ziemssen and Craveiro.)

Background: Gait and balance impairments are often present in people with multiple sclerosis (PwMS) and have a significant impact on quality of life and independence. Gold-standard quantitative tools for assessing gait and balance such as motion capture systems and force plates usually require complex technical setups. Wearable sensors, including those integrated into smartphones, offer a more frequent, convenient, and minimally burdensome assessment of functional disability in a home environment. We developed a novel smartphone sensor-based application (Floodlight) that is being used in multiple research and clinical contexts, but a complete validation of this technology is still lacking., Methods: This protocol describes an observational study designed to evaluate the analytical and clinical validity of Floodlight gait and balance tests. Approximately 100 PwMS and 35 healthy controls will perform multiple gait and balance tasks in both laboratory-based and real-world environments in order to explore the following properties: (a) concurrent validity of the Floodlight gait and balance tests against gold-standard assessments; (b) reliability of Floodlight digital measures derived under different controlled gait and balance conditions, and different on-body sensor locations; (c) ecological validity of the tests; and (d) construct validity compared with clinician- and patient-reported assessments., Conclusions: The Floodlight GaitLab study (ISRCTN15993728) represents a critical step in the technical validation of Floodlight technology to measure gait and balance in PwMS, and will also allow the development of new test designs and algorithms., Competing Interests: The author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MDR is a contractor for F. Hoffmann-La Roche Ltd. MZ is an employee of and shareholder in F. Hoffmann-La Roche Ltd. TAB was an employee of Roche Netherlands B.V. during her contribution to this work and is now an employee of a Dutch nonprofit organization. She is a shareholder in F. Hoffmann-La Roche Ltd. LA is a consultant for F. Hoffmann-La Roche Ltd via Capgemini Engineering. DS is a consultant for F. Hoffmann-La Roche Ltd via Capgemini Engineering. GGC is an employee of the University of Plymouth, which received research funding from F. Hoffman-La Roche Ltd. LB is an employee of the University of Plymouth, which received research funding for this study from F. Hoffmann-La Roche Ltd. FD was an employee of F. Hoffmann-La Roche Ltd during his contribution to this work, and is now an employee of Novartis International AG. FD is a shareholder in F. Hoffmann-La Roche Ltd and Novartis International AG. RH has received indirect funding from F. Hoffmann-La Roche Ltd via a University of Plymouth Enterprise Ltd contract. JF is an employee of the University of Plymouth, which received research funding for this study from F. Hoffmann-La Roche Ltd. JH or affiliated institutions have received either consulting fees, honoraria, support to attend meetings, clinical service support, or research support from Acorda, Bayer Schering Pharma, Biogen Idec., Brickell Biotech, F. Hoffmann-La Roche Ltd, Global Blood Therapeutics, Sanofi Genzyme, Merck Serono, Novartis, Oxford Health Policy Forum, Teva, and Vantia. JM is an employee of the University of Plymouth, which received research funding for this study from F. Hoffmann-La Roche Ltd. LC is an employee of and shareholder in F. Hoffmann-La Roche Ltd., (© The Author(s) 2023.)

Single-cell transcriptomics allows characterization of cerebrospinal fluid (CSF) cells at an unprecedented level. Here, we report a robust cryopreservation protocol adapted for the characterization of fragile CSF cells by single-cell RNA sequencing (RNA-seq) in moderate- to large-scale studies. Fresh CSF was collected from twenty-one participants at two independent sites. Each CSF sample was split into two fractions: one was processed fresh, while the second was cryopreserved for months and profiled after thawing. B and T cell receptor sequencing was also performed. Our comparison of fresh and cryopreserved data from the same individuals demonstrates highly efficient recovery of all known CSF cell types. We find no significant difference in cell type proportions and cellular transcriptomes between fresh and cryopreserved cells. Results were comparable at both sites and with different single-cell sequencing chemistries. Cryopreservation did not affect recovery of T and B cell clonotype diversity. Our CSF cell cryopreservation protocol provides an important alternative to fresh processing of fragile CSF cells., Competing Interests: D.M., D.C., C.R., L.C., and J.B. are full-time employees of F. Hoffmann-La Roche. D.M. was employed by F. Hoffmann-La Roche when the study was completed and the manuscript submitted. D.M. moved to Biogen while the manuscript was under review., (© 2023 The Authors.)

Background: Research suggests that serious infections (SIs), comorbidities, and advanced disability represent key drivers of early death in people with Multiple Sclerosis (pwMS). Nevertheless, further research is warranted to better characterize and quantify the risk of SI among pwMS compared to the general population., Methods: Our study consisted of a retrospective analysis of claims data provided by a German statutory health insurance fund, AOK PLUS, covering 3.4 million individuals in Saxony and Thuringia from 01/01/2015-31/12/2019. A propensity score (PS) matching method was used to compare the incidence of SIs among people with and without MS. PwMS were required to have ≥1 inpatient or ≥2 confirmed outpatient diagnoses of MS (ICD-10 G35) from a neurologist from 01/01/2016-31/12/2018, while people from the general population could not have any inpatient/outpatient codes for MS during the entire study period. The index date was defined as the first observed MS diagnosis or, in the case of the non-MS cohort, a randomly assigned date within the inclusion period. For both cohorts a PS was assigned, corresponding with their probabilistic likelihood of having MS based on observable factors including patient characteristics, comorbidities, medication use and other variables. People with and without MS were matched using a 1:1 nearest neighbor strategy. An exhaustive list of ICD-10 codes was created in association with 11 main SI categories. SIs were those recorded as the main diagnosis during an inpatient stay. ICD-10 codes from the 11 main categories were sorted into smaller classification units, used to distinguish between infections. A 60-day threshold for measuring new cases was defined to account for the potential risk of re-infection. Patients were observed until the end of the study period (31/12/2019) or death. Cumulative incidence, incidence rates (IRs) and IR ratios (IRRs) were reported during follow-up and at 1-, 2- and 3-years post-index., Results: A total of 4250 and 2,098,626 patients were included in the unmatched cohorts of people with and without MS. Ultimately, one match was identified for all 4,250 pwMS, corresponding with a final population of 8,500 patients. On average, patients were 52.0/52.2 years in the matched MS/non-MS cohorts; the gender breakdown was 72% female. Overall, IRs of SIs per 100 patient years (PY) were higher in pwMS than in those without MS (1 year: 7.6 vs. 4.3; 2 years: 7.1 vs. 3.8; 3 years: 6.9 vs. 3.9). During follow-up, the most common infection types in pwMS were of a bacterial/parasitic origin (2.3 per 100 PY), followed by respiratory (2.0) and genitourinary (1.9) infections. Respiratory infections were most common in patients without MS (1.5 per 100 PY). Differences in the IRs of SIs were statistically significant (p<0.01) at each measurement window, with IRRs ranging from 1.7-1.9. PwMS had a higher risk of hospitalized genitourinary infections (IRR: 3.3-3.8) and bacterial/parasitic infections (2.0-2.3)., Conclusions: The incidence of SIs is much higher in pwMS, than comparators from the general population in Germany. Differences in hospitalized infection rates were largely driven by higher levels of bacterial/parasitic and genitourinary infections in the MS population., Competing Interests: Declaration of Interest Statement R.K. and F.H. are employees of Cytel Inc. TW is an employee of IPAM e.V. and has received honoraria from several pharmaceutical/consultancy companies (Novo Nordisk, Abbvie, Merck, GSK, BMS, LEO Pharma, Astra Zeneca, Bayer, Boehringer Ingelheim, Pharmerit). UM works for a statutory insurance fund (AOK PLUS), which provided the data used in this study. CC is an employee of F. Hoffmann-La Roche Ltd. EMLR and LC are employees and shareholders of F. Hoffmann-La Roche Ltd., (Copyright © 2023. Published by Elsevier B.V.)

Background: A study was undertaken to evaluate remote monitoring via smartphone sensor-based tests in people with multiple sclerosis (PwMS). This analysis aimed to explore regional neural correlates of digital measures derived from these tests., Methods: In a 24-week, non-randomized, interventional, feasibility study (NCT02952911), sensor-based tests on the Floodlight Proof-of-Concept app were used to assess cognition (smartphone-based electronic Symbol Digit Modalities Test), upper extremity function (Draw a Shape Test, Pinching Test), and gait and balance (Static Balance Test, Two-Minute Walk Test, U-Turn Test). In this post-hoc analysis, digital measures and standard clinical measures (e.g., Nine-Hole Peg Test [9HPT]) were correlated against regional structural magnetic resonance imaging outcomes. Seventy-six PwMS aged 18-55 years with an Expanded Disability Status Scale score of 0.0-5.5 were enrolled from two different sites (USA and Spain). Sixty-two PwMS were included in this analysis., Results: Worse performance on digital and clinical measures was associated with smaller regional brain volumes and larger ventricular volumes. Whereas digital and clinical measures had many neural correlates in common (e.g., putamen, globus pallidus, caudate nucleus, lateral occipital cortex), some were observed only for digital measures. For example, Draw a Shape Test and Pinching Test measures, but not 9HPT score, correlated with volume of the hippocampus (r = 0.37 [drawing accuracy over time on the Draw a Shape Test]/ - 0.45 [touching asynchrony on the Pinching Test]), thalamus (r = 0.38/ - 0.41), and pons (r = 0.35/ - 0.35)., Conclusions: Multiple neural correlates were identified for the digital measures in a cohort of people with early MS. Digital measures showed associations with brain regions that clinical measures were unable to demonstrate, thus providing potential novel information on functional ability compared with standard clinical assessments., (© 2022. The Author(s).)

Background: People with multiple sclerosis (pwMS) have a higher risk of serious infection (i.e., infection-related hospitalizations) than people without MS. Few studies have explored the risk of serious infections by MS phenotype in a real-world setting. This retrospective study compared the incidence of serious infections among people with relapse remitting MS (RRMS), primary progressive MS (PPMS), and secondary progressive MS (SPMS)., Methods: Adult pwMS were selected from a German claims database, based on one inpatient or two outpatient diagnoses of MS (ICD-10 G35) by a neurologist from 01/01/2016 to 12/31/2018. Three cohorts (RRMS, PPMS, SPMS) were identified based on codes for MS subtypes included in the German Modification of the ICD-10 system. A fourth cohort of unspecified MS patients combined those with conflicting MS subtype diagnoses and multiple unspecified codes for MS. Serious infections were defined as hospitalizations for which infections were selected as the primary inpatient diagnosis. Infections were identified from a basket of ICD-10 codes distributed across 11 main categories, according to possible pathogen (e.g., other bacterial diseases [A30-A49]) or anatomical location (e.g., urinary tract infection [N39.0]). Multiple infections were counted if an interval of at least 60 days was recorded between episodes. Serious infections were counted from index (i.e., first recorded MS code) until the end of the study period or death. Incidence rates (IRs) were reported per 100 patient years (PY)., Results: A total of 4,250 pwMS (RRMS: 2,307, PPMS: 282, SPMS: 558, unspecified MS: 1,135) were included; 32 patients progressed from RRMS to SPMS during the follow-up period. Mean (SD) age at baseline was 46.6 (13.6), 61.9 (12.4), and 62.5 (11.8) years in patients with RRMS, PPMS, and SPMS, respectively. Most pwMS were female (RRMS 74.8%, PPMS 62.1%, SPMS 67.4%). Progressive pwMS were more likely to have at least 1 comorbidity (PPMS 87.2%, SPMS 87.5%) compared to those with relapsing MS (61.9%). Most RRMS patients received disease-modifying therapy during follow-up (82.1%), while less than half of progressive MS patients did (PPMS 23.8%, SPMS 31.4%). Over a mean (SD) follow-up period of 3.5 (0.8) years, the IR of serious infections per 100 PY was higher in progressive MS cohorts (PPMS 13.5 [11.3-16.1], SPMS 13.6 [12.0-15.3]) than in the RRMS group (3.4 [3.0-3.7]). Yearly IRs remained stable over time in each cohort. Where anatomical location was specified, respiratory (2.0 per 100 PY) and genitourinary (1.9 per 100 PY) infections were most common. Across all subtypes, higher rates of serious infections were observed in men and older patients., Conclusion: Progressive MS, older age and male sex are associated with an increased risk of serious infections. Overall, respiratory and genitourinary infections were the most commonly reported serious infections., Competing Interests: Declaration of Competing Interest R.K., F.H. and J.K. are employees of Cytel Inc. T.W. is an employee of IPAM e.V. and has received honoraria from several pharmaceutical/consultancy companies (Novo Nordisk, Abbvie, Merck, GSK, BMS, LEO Pharma, Astra Zeneca, Bayer, Boehringer Ingelheim, Pharmerit). U.M. works for a statutory insurance fund (AOK PLUS), which provided the data used in this study. E.M.L.R. is an employee of F. Hoffmann-La Roche Ltd. C.C. and L.C. are employees and shareholders of F. Hoffmann-La Roche Ltd., (Copyright © 2022. Published by Elsevier B.V.)

Background: During the first year of life, B-cell level is a valuable indicator of whether external factors, such as exposure to B-cell-depleting therapies, have an adverse impact on immune system development. However, there are no standard reference ranges of B-cell levels in healthy infants by age., Objective: Our aim was to estimate the normal range of B-cell levels in infants, by age, during the first year of life by pooling data from published studies., Methods: Studies reporting B-cell levels measured by using flow cytometry and CD19 markers in healthy infants were identified via a systematic literature review. Quality and feasibility assessments determined suitability for inclusion in meta-analyses by age group and/or continuous age. Means and normal ranges (2.5th-97.5th percentile) were estimated for absolute and percentage B-cell levels. Sensitivity analyses assessed the impact of various assumptions., Results: Of the 37 relevant studies identified, 28 were included in at least 1 meta-analysis. The means and normal ranges of B-cell levels were found to be 707 cells/μL in cord blood (range 123-2324 cells/μL), 508 cells/μL in infants aged 0 to 1 month (range 132-1369 cells/μL), 1493 cells/μL in infants aged 1 to 6 months (range 416-3877 cells/μL), and 1474 cells/μL in infants older than 6 months (range 416-3805 cells/μL). The continuous age model showed that B-cell levels peaked at week 26. Trends were similar for the percentage B-cell estimates and in sensitivity analyses., Conclusion: These meta-analyses provide the first normal reference ranges for B-cell levels in infants, by week of age, during the first year of life., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Most disease-modifying therapies (DMTs) approved for the treatment of multiple sclerosis (MS) are not recommended during pregnancy, and discouraged while breastfeeding. However, discontinuation of some DMTs before pregnancy can leave women vulnerable to MS relapses. Although available data on ocrelizumab suggest no increased risk in terms of pregnancy or neonatal outcomes, it is unknown whether ocrelizumab transfers across the placenta or is absorbed through breastmilk; and if so, whether infant B cell development, immune responses or growth and development are affected. This manuscript describes two studies designed to address these uncertainties., Methods/design: MINORE and SOPRANINO are multicentre open-label studies. MINORE, which addresses placental transfer, will recruit 44 women with MS or clinically isolated syndrome (CIS) exposed to ocrelizumab between 6 months before the last menstrual period (LMP) to the end of the first trimester. It will evaluate pharmacodynamic effects of potential in utero exposure through the proportion of infants with B cell numbers below lower limit of normal (LLN) at week 6 of life (primary endpoint); as well as through vaccine-induced antibody responses (reflecting B cell function) during the first year of life. Placental transfer will be assessed through measurement of ocrelizumab concentrations in paired samples at delivery (maternal blood as well as umbilical cord blood), and infant serum at week 6 of life. SOPRANINO, which evaluates breastmilk transfer, will recruit 20 women with MS or CIS who resume or initiate ocrelizumab treatment while breastfeeding. The effect of potential exposure through breastmilk will be assessed through the proportion of infants with B cell levels below LLN at 30 days after the mother's first post-partum ocrelizumab infusion (co-primary endpoint). Infant exposure via breastmilk will be assessed through ocrelizumab average daily infant dose in breastmilk over 60 days after the same infusion (co-primary endpoint). Vaccine-induced responses will be measured as in MINORE. Both studies will also measure infant growth and development over the first year of life and safety outcomes in both mothers and infants. All analyses will be descriptive, under an estimand framework., Discussion: Both studies are designed to mimic real-world clinical practice. Treatment decisions for ocrelizumab are independent from study participation; as such, these studies will recruit women who decide, along with their physicians, to continue their pregnancies despite potential in utero exposure (for MINORE); or to breastfeed while under ocrelizumab treatment (for SOPRANINO). MINORE is the first prospective study to measure placental transfer of any DMT in MS, and to perform comprehensive assessments in infants and mothers. Results may inform the optimal contraception period for women treated with ocrelizumab who are planning a pregnancy. Similarly, SOPRANINO is the first prospective study to measure pharmacodynamic effects of ocrelizumab in breastfed infants in addition to pharmacokinetic parameters in breastmilk. SOPRANINO may establish whether breastfeeding is safe for infants whose mothers received treatment with ocrelizumab., Conclusion: By collecting detailed pharmacokinetic, pharmacodynamic and safety information, MINORE and SOPRANINO will contribute to understanding the risk/benefit of ocrelizumab in pregnant and lactating women with MS., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background and Purpose: Reaching Expanded Disability Status Scale (EDSS) ≥7.0 represents the requirement for a wheelchair. Here we (i) assess the effect of ocrelizumab on time to EDSS ≥7.0 over the ORATORIO (NCT01194570) double-blind and extended controlled periods (DBP+ECP), (ii) quantify likely long-term benefits by extrapolating results, and (iii) assess the plausibility of extrapolations using an independent real-world cohort (MSBase registry; ACTRN12605000455662)., Methods: Post hoc analyses assessing time to 24-week confirmed EDSS ≥7.0 in two cohorts of patients with primary progressive multiple sclerosis (baseline EDSS 3.0-6.5) were investigated in ORATORIO and MSBase., Results: In the ORATORIO DBP+ECP, ocrelizumab reduced the risk of 24-week confirmed EDSS ≥7.0 (hazard ratio = 0.54, 95% confidence interval [CI]: 0.31-0.92; p = 0.022). Extrapolated median time to 24-week confirmed EDSS ≥7.0 was 12.1 and 19.2 years for placebo and ocrelizumab, respectively (7.1-year delay [95% CI: -4.3 to 18.4]). In MSBase, the median time to 24-week confirmed EDSS ≥7.0 was 12.4 years., Conclusions: Compared with placebo, ocrelizumab significantly delayed time to 24-week confirmed wheelchair requirement in ORATORIO. The plausibility of the extrapolated median time to reach this milestone in the placebo group was supported by observed real-world data from MSBase. Extrapolated benefits for ocrelizumab over placebo could represent a truly meaningful delay in loss of ambulation and independence., (© 2021 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Background and Objectives: To report safety of ocrelizumab (OCR) up to 7 years in patients with relapsing multiple sclerosis (RMS) and primary progressive multiple sclerosis (PPMS) enrolled in clinical trials or treated in real-world postmarketing settings., Methods: Safety analyses are based on integrated clinical and laboratory data for all patients who received OCR in 11 clinical trials, including the controlled treatment and open-label extension (OLE) periods of the phase 2 and 3 trials, plus the phase 3b trials VELOCE, CHORDS, CASTING, OBOE, ENSEMBLE, CONSONANCE, and LIBERTO. For selected adverse events (AEs), additional postmarketing data were used. Incidence rates of serious infections (SIs) and malignancies were contextualized using multiple epidemiologic sources., Results: At data cutoff (January 2020), 5,680 patients with multiple sclerosis (MS) received OCR (18,218 patient-years [PY] of exposure) in clinical trials. Rates per 100 PY (95% confidence interval) of AEs (248; 246-251), serious AEs (7.3; 7.0-7.7), infusion-related reactions (25.9; 25.1-26.6), and infections (76.2; 74.9-77.4) were similar to those within the controlled treatment period of the phase 3 trials. Rates of the most common serious AEs, including SIs (2.01; 1.81-2.23) and malignancies (0.46; 0.37-0.57), were consistent with the ranges reported in epidemiologic data., Discussion: Continuous administration of OCR for up to 7 years in clinical trials, as well as its broader use for more than 3 years in the real-world setting, are associated with a favorable and manageable safety profile, without emerging safety concerns, in a heterogeneous MS population., Classification of Evidence: This analysis provides Class III evidence that long-term, continuous treatment with OCR has a consistent and favorable safety profile in patients with RMS and PPMS. This study is rated Class III because of the use of OLE data and historical controls., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Background: There are limited data on the impact of coronavirus disease 2019 (COVID-19) caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) on people with multiple sclerosis (MS)., Objective: To better understand SARS-CoV-2 infection in ocrelizumab-treated people with MS., Methods: Internal Roche/Genentech data sources: Cases of COVID-19 from ongoing Roche/Genentech clinical trials and from post-marketing use of ocrelizumab until July 31, 2020 were identified and assessed using descriptive statistics. External real-world data (RWD) source: An MS COVID-19 cohort and an ocrelizumab-treated MS COVID-19 cohort were identified and assessed from the OPTUM Ⓡ de-identified COVID-19 electronic health record (EHR) database., Results: Roche/Genentech clinical trial data: There were 51 (1.3%) suspected or confirmed cases of COVID-19 identified from 4,000 patients ongoing in 10 Roche/Genentech clinical trials. Of these, 26 (51%) were confirmed COVID-19 and 25 (49%) were suspected COVID-19. Sixteen (31.4%) patients were hospitalized. COVID-19 severity was mild to moderate in most patients (35, 68.6%). Ten (19.6%) patients had severe disease and there were three (5.9%) fatal cases. Most patients (43, 84.3%) recovered or were recovering. There was no association apparent between duration of exposure to ocrelizumab and COVID-19. Among COVID-19 patients with previous serum immunoglobulin status (27/51, 52.9%), all (27/27, 100%) had IgG levels within the normal range. Roche/Genentech post-marketing safety database data: There were 307 post-marketing cases of COVID-19 in the Roche/Genentech global safety database. Of these, 263 (85.7%) were confirmed and 44 (14.3%) were suspected COVID-19. 100 (32.6%) patients were hospitalized. COVID-19 was asymptomatic, mild or moderate in 143 (46.6%) patients, severe in 52 (16.9%) patients, and critical in 15 (4.9%) patients. There were 17 (5.5%) fatal cases. Information on severity was not reported in 80 (26.1%) cases. Most patients (211, 68.7%) recovered or were recovering at the time of the report. External RWD data source: As of July 13, 2020, the OPTUM Ⓡ database included EHRs for almost 1.2 million patients with suspected COVID-19, 130,500 of whom met the criteria for confirmed/clinically diagnosed COVID-19. A total of 357 patients with MS with confirmed COVID-19 were identified. Forty-eight (13.4%) were treated with ocrelizumab, of whom 12 (25.0%) were hospitalized and one died (2.1%). Similar rates of hospitalization, invasive ventilation, and death were observed in the ocrelizumab-treated and non-ocrelizumab-treated MS cohorts. Across the Roche/Genentech and RWD sources assessed, age, male sex, and the presence of comorbidities such as hypertension were associated with a more severe disease course of COVID-19. There was a higher number of comorbidities present in hospitalized versus non-hospitalized patients., Conclusions: This assessment provides evidence that COVID-19 in ocrelizumab-treated people with MS is predominantly mild to moderate in severity with most patients not requiring hospitalization; in line with data reported from the general population and MS datasets. Risk factors known to be associated with severe COVID-19 outcomes in the general population also appear to influence COVID-19 severity in ocrelizumab-treated people with MS. Case fatality rates for ocrelizumab-treated people with MS were within published ranges for the general population and other MS cohorts., (Copyright © 2020. Published by Elsevier B.V.)

We mapped the cytokine response to hematopoietic stem cell transplantation (HSCT) by assaying 51 cytokines and chemokines each week for 100 days in 51 children receiving allogeneic (n = 44) or autologous HSCT (n = 7). Assay values were reported as mean fluorescence intensity (MFI). Log transformation converted MFI to clinically relevant measures (ie, pg/mL). We searched for potential markers of transplant complications by using mixed treatment by subject analysis of variance. Global cytokine secretion in HSCT recipients was significantly lower than in concurrent control patients (n = 11). Coincident with the nadir in WBC count, the concentration of many cytokines declined further by the second and third week. All analytes (except monokine induced by gamma interferon [MIG]) subsequently rebounded by week 4 (coincident with engraftment and recovery of WBC count) but often still remained well below control levels. Concurrent with the collective nadir of multiple cytokines, monocyte chemoattractant protein 1 (MCP-1), growth-regulated oncogene alpha (GRO-a), and leptin surged during weeks 2 to 4. High levels of leptin persisted throughout the 100 post-transplant days. Also during weeks 2 to 4, hepatocyte growth factor (HGF) and IL-6 surged in children with complications but not in those without complications. The peak in HGF was more pronounced in veno-occlusive disease (VOD). HGF and IL-6 secretion rose at least 2 weeks before the clinical diagnosis of VOD or graft-versus-host disease (GVHD). From week 4 onward in all groups, the MFI of the cytokine resistin increased to 5 to 15 times above concurrent control. HGF has now emerged in 3 or more biomarker discovery efforts for GVHD (and in our population for VOD as well). HGF (with or without IL-6) should be investigated as a potential predictive biomarker of VOD or GVHD. Alternatively, the hyperinflammatory "signature" provided by a multicytokine assay may be predictive., (Copyright © 2014 American Society for Blood and Marrow Transplantation. Published by Elsevier Inc. All rights reserved.)