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Multiple sclerosis has been established as an inflammatory disease of the central nervous system. Many aspects of the pathophysiology are still unknown and it is presently unclear how different treatments affect the immunopathology of multiple sclerosis. In this study, we explored cytokines discriminating between individuals with multiple sclerosis and healthy controls and then how these cytokines were affected by treatment intervention with autologous haematopoietic stem cell transplantation or intrathecal rituximab. CSF from individuals with multiple sclerosis and healthy controls were analysed with a proximity extension assay to simultaneously determine the level of 92 cytokines and other inflammation-related proteins. In total, CSF from 158 multiple sclerosis patients and 53 healthy controls were analysed. Sixty-four patients with relapsing-remitting multiple sclerosis and 27 with progressive multiple sclerosis took part in a cross-sectional study and underwent lumbar puncture on a single occasion. Forty-five patients with relapsing-remitting multiple sclerosis were treated with autologous haematopoietic stem cell transplantation and underwent lumbar puncture at baseline and then at follow-up visits made at 1-, 2- and 5 years. Twenty-two patients with progressive multiple sclerosis were treated with intrathecal rituximab and followed with lumbar punctures at baseline and then at follow-up visits made at 3-, 6- and 12 months. Of the 92 studied cytokines, 16 were found to be altered in multiple sclerosis and 11 were decreased after treatment with autologous haematopoietic stem cell transplantation. None of the studied cytokines was affected by treatment with intrathecal rituximab for progressive multiple sclerosis. Some proteins were highly associated with each other. Therefore, a cluster analysis was made and then the highest-ranked protein from the four highest-ranked clusters was used for the subsequent analyses. CCL3, IL-12B, CXCL10 and IL-8 discriminated between multiple sclerosis patients and controls, but only IL-12B differed between patients with relapsing-remitting and progressive multiple sclerosis. The CSF concentrations of CCL3, IL-12B and CXCL10 were decreased after autologous haematopoietic stem cell transplantation, whereas IL-8 appeared to be unaffected by this intervention. High concentrations of IL-8 were associated with worse outcome in both treatment groups. Overall, the results suggest a profound effect of autologous haematopoietic stem cell transplantation on the inflammatory milieu of the CSF in multiple sclerosis., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Introduction: Transcatheter aortic valve implantation (TAVI) is associated with a high incidence of new silent brain infarcts (SBIs) on postprocedural neuroimaging. A venous blood sample reflecting neuronal damage following TAVI could help identify patients with potential SBIs. We aimed to investigate if a biochemical marker of neuronal injury, neurofilament light chain (NFL), is elevated after TAVI., Methods: In this observational study, NFL was measured in plasma from 31 patients before and after TAVI. Multivariable regression analysis was performed to investigate any effect of clinical- and procedure-related factors on differences in NFL levels before and after TAVI., Results: Samples were collected 41 (14-81) days before and 44 (35-59) days after TAVI, median (interquartile range). Median age was 81 (77-84) years, and 35% were female. No patient had any overt procedure-related neurological complications. The geometric mean (95% confidence interval) of the NFL concentration was 30 (25-36) pg/mL before TAVI and 48 (39-61) pg/mL, after TAVI, p <0.001. None of the included variables in the multiple linear regression model were statistically significantly associated with the difference in levels before and after TAVI., Conclusions: NFL levels in plasma were higher after TAVI as compared with levels before, with a mean increase of 60% (18 pg/mL). Further studies including neuroimaging and cognitive outcomes are needed to understand the potential value of measuring NFL in relation to TAVI., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Autologous hematopoietic stem cell transplantation (aHSCT) has seen increased use for relapsing-remitting multiple sclerosis (RRMS) in recent years. It is considered one of the most effective treatments for RRMS and has been associated with improvement in disability and prolonged remission. This suggests that the tissue-injuring disease process may have been altered by aHSCT. To assess whether this hypothesis is correct, we performed a study of three commonly used cerebrospinal fluid biomarkers of tissue damage., Methods: In this single center study, 63 patients treated with aHSCT at Uppsala University Hospital between January 1st 2012 and January 31st 2019 were screened for participation. A control group consisting of volunteers without neurologic disease were included as a reference. Cerebrospinal fluid concentrations of neurofilament light (NFL), myelin basic protein (MBP) and glial acidic fibrillary protein (GFAp) were determined using ELISA and a multiplex proteomics platform from Meso Scale Discovery., Results: Forty-three patients with a mean age of 31 and a median follow-up time of 3.9 years were included. Their median baseline expanded disability status scale (EDSS) score was 3.5 and the annualized relapse rate in the year preceding aHSCT was 1.6. At baseline the proportion of patients with values above the upper limit of normal was 67% for NFL, 63% for MBP and 16% for GFAp. At 5-year follow-up, the proportion of patients with values above the upper limit of normal was 12% for NFL, 12% for MBP and 25% for GFAp. The mean concentration of NFL decreased from 920 pg/mL at baseline to 270 pg/mL at 5-year follow-up (p < 0.001); MBP decreased from 1500 to 680 pg/mL (p < 0.001); whereas the mean concentration of GFAp was unchanged., Conclusion: In a majority of patients, biomarkers of demyelination and axonal damage reached normal values within five years from treatment with aHSCT., Competing Interests: Declaration of Competing Interest None., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Objectives: Epilepsy is associated with advanced multiple sclerosis (MS). We aimed to investigate whether the incidence of epilepsy in MS has been affected by the introduction of disease-modifying treatments (DMT) for MS., Materials and Methods: This retrospective study included 14,557 patients from the Swedish MS register with MS onset between 1991 and 2018. Incident diagnoses of epilepsy or any seizure were identified through cross-linkage with the National Patient Register. Next, yearly prevalence of epilepsy as well as 5- and 10 years incidence of epilepsy or any seizure for consecutive years of MS onset were estimated, the latter with Kaplan-Meier analysis. Cox regression was used to adjust the association between the year of MS onset and incidence of epilepsy for baseline variables., Results: Prevalence of epilepsy in the MS cohort increased from 0.34% in 1991 to 2.54% in 2018 (yearly odds: 1.26 [1.22, 1.29]). The 5 years incidence rate of epilepsy, ranging from 0.4% (95% CI 0.008-0.79%) to 1.3% (95% CI 0.71-1.89%), and the 10 years incidence rate of epilepsy, ranging from 1.1% (95% CI 0.31-1.88%) to 2.6% (95% CI 1.22-3.97%) showed no significant trends (p = .147 and p = .418, respectively). Similarly, no significant trends were found for the incidences of any seizure. The incidence trends of epilepsy remained not significant after adjusting for sex, MS onset type (relapsing or progressive onset), or age at MS onset., Conclusions: Our findings do not support the hypothesis that the introduction of novel DMT for MS has reduced the incidence of epilepsy among MS patients., (© 2022 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

Background: Bronchial hyperresponsiveness (BHR) and asthma are frequently present in children with food allergy. We assessed BHR in children receiving oral immunotherapy (OIT) for persistent egg or peanut allergy and examined whether OIT affects asthma control., Methods: Methacholine challenge testing was performed in 89 children with persistent egg or peanut allergy diagnosed by double-blind, placebo-controlled food challenge and 80 control children without food allergy. Of the 89 food-allergic children, 50 started OIT for egg allergy and 39 for peanut allergy. Sensitization to aeroallergens was evaluated by skin prick testing. Forty of the 89 children with regular controller treatment for asthma underwent methacholine challenge testing and 34 measurement of exhaled nitric oxide (FeNO) at baseline and after 6-12 months of OIT., Results: Methacholine challenge testing revealed significant BHR in 29/50 children (58%) with egg allergy, 15/39 children (38%) with peanut allergy, and 6/80 controls (7.5%). The mean cumulative dose of methacholine causing a 20% fall in FEV1 differed significantly between the egg and peanut-allergic versus the control children (1009 μg, 1104 μg, and 2068 μg, respectively, p  < 0.001). Egg or peanut OIT did not affect lung function, the degree of BHR or FeNO levels in children with asthma and had no adverse effect on asthma control. Lung function or BHR did not associate with the OIT outcome., Conclusion: BHR was significantly more frequent in children with persistent egg or peanut allergy than in children without food allergy. Oral immunotherapy did not increase BHR and was safe for children on regular asthma medication., Competing Interests: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported., (© 2022 The Authors. Clinical and Translational Allergy published by John Wiley & Sons Ltd on behalf of European Academy of Allergy and Clinical Immunology.)

Background: There is a great deal of psychological pressure on medical students, which results in depression, addiction, and suicide. Resilience plays a significant role in coping with psychological distress. The study aimed to determine the resilience level of medical students in Kolkata and factors related to it., Materials and Methods: A cross-sectional study was conducted among undergraduate students of a medical college in the eastern part of India during October 2020. Resilience was assessed using the validated "Adult Resilience Measure-R." Data were collected on Google Forms and analyzed using SPSS (version 16.0). Logistic regression analysis was performed to find factors associated with low resilience., Results: The study revealed that one-fourth (25.2%) of the participants had low-level resilience. Nearly half (44.9%) of them perceived their mental health status as having worsened during the lockdown. Students who did not enjoy staying at home during the lockdown and who spent <10 h of their time with their family members had higher odds of low resilience. In multivariable analysis, not enjoying staying at home during the lockdown remained the only significant predictor of low resilience., Conclusion: Students should spend more time with their parents and family members and learn coping skills. Appropriate resilience training programs have to be integrated into the medical curriculum to help in coping with future challenges., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Family and Community Medicine.)

Objective: To estimate risks for all-cause mortality and for severe COVID-19 in multiple sclerosis patients and across relapsing-remitting multiple sclerosis patients exposed to disease-modifying therapies., Methods: We conducted a Swedish nationwide population-based multi-register linkage cohort study and followed all multiple sclerosis patients (n = 17,692 in March 2020), individually age-, sex-, and region-matched to five population-based controls (n = 86,176 in March 2020) during March 2020-June 2021. We compared annual all-cause mortality within and across cohorts, and assessed incidence rates and relative risks for hospitalization, intensive care admission, and death due to COVID-19 in relation to disease-modifying therapy use, using Cox regression., Results: Absolute all-cause mortality among multiple sclerosis patients was higher from March to December 2020 than in previous years, but relative risks versus the population-based controls were similar to preceding years. Incidence rates of hospitalization, intensive care admission, and death due to COVID-19 remained in line with those for all-cause hospitalization, intensive care admission, and mortality. Among relapsing-remitting patients on rituximab, trends for differences in risk of hospitalization due to COVID-19 remained in the demographics-, socioeconomic status-, comorbidity-, and multiple sclerosis severity-adjusted model., Interpretation: Risks of severe COVID-19-related outcomes were increased among multiple sclerosis patients as a whole compared to population controls, but risk increases were also seen for non-COVID-19 hospitalization, intensive care admission, and mortality, and did not significantly differ during the pandemic compared to pre-pandemic years. The risk conveyed by disease-modifying therapies was smaller than previously assumed, likely as a consequence of the possibility to better control for confounders., (© 2022 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Background: Autologous haematopoietic stem cell transplantation (AHSCT) is a highly effective treatment for multiple sclerosis (MS). The impact of previous long-lasting disease-modifying treatments (DMT) for safety and efficacy of AHSCT is unknown., Objective: To explore whether previous DMTs with long-lasting effects on the immune system (anti-CD20 therapy, alemtuzumab and cladribine) affect treatment-related complications, long-term outcome and risk of new MS disease activity in patients treated with AHSCT., Methods: Retrospective observational study of 104 relapsing remitting patients with MS treated by AHSCT in Sweden and Norway from 2011 to 2021, grouped according to the last DMT used ≤6 months prior to AHSCT. The primary outcomes were early AHSCT-related complications (mortality, neutropenic fever and hospitalisation length), long-term complications (secondary autoimmunity) and proportion of patients with No Evidence of Disease Activity (NEDA-3 status): no new relapses, no MRI activity and no disease progression during the follow-up., Results: The mean follow-up time was 39.5 months (range 1-95). Neutropenic fever was a common AHSCT-related complication affecting 69 (66%) patients. There was no treatment-related mortality. During the follow-up period, 20 patients (19%) were diagnosed with autoimmunity. Occurrence of neutropenic fever, hospitalisation length or secondary autoimmunity did not vary dependent on the last DMT used prior to AHSCT. A total of 84 patients (81%) achieved NEDA-3 status, including all patients (100%) using rituximab, alemtuzumab or cladribine before AHSCT., Conclusion: This study provides level 4 evidence that AHSCT in patients previously treated with alemtuzumab, cladribine or rituximab is safe and efficacious., Competing Interests: Competing interests: SASK has received unrestricted grants from Novartis and Biogen Idec. LB has received speaker honoraria from Novartis. ØT has received speaker honoraria from and served on scientific advisory boards for Biogen, Sanofi-Aventis, Merck and Novartis., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: Multimorbidity is considered as a priority for global health research. It is defined as the coexistence of two or more chronic health conditions in an individual. It is increasingly being recognized as a major concern for primary care physicians due to its huge impact on individual, family, and societal level., Aim: The aim of this study was to find the quantum of gender-related inequalities and determinants of multimorbidity among the elderly people in a rural part of West Bengal., Materials and Methods: This is a cross-sectional study carried out among 246 elderly people (60 years and above) in a community setting from Oct 2017 to Sep 2018. Logistic regression analysis was done to find out the predictors of multimorbidity. Data were analyzed using the SPSS software (version 16.0. Chicago, SPSS Inc.)., Results: Approximately 82% of the study subjects were suffering from multi-morbidity with a significant difference between males (80.9%) and females (88.5%). In binary logistics, people of both the genders aged >70 years, who had less than primary level education, had more than three children, whose source of income was from their children (sons/daughters), were dependent on others for daily routine were at high risk of being multimorbid; whereas depression was a significant predictor of multimorbidity in females and not in males. In multivariable analysis, age remained the only significant predictor for both the gender and for females; depression remained significant after adjusting with significant variables in binary logistics., Conclusion: Morbidity screening at each visit, individual as well as family counseling and lifestyle modifications help to cope with the rising burden of multimorbidity at the primary care level. More insight into the epidemiology of multi-morbidity is necessary to take steps to prevent it, lower its burden and align health-care services as per needs., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Family Medicine and Primary Care.)

Background: B-cell depleting therapies are highly efficacious in relapsing-remitting multiple sclerosis but one such therapy, rituximab, is not approved for multiple sclerosis and no phase 3 trial data are available. We therefore examined the safety and efficacy of rituximab compared with dimethyl fumarate in patients with relapsing-remitting multiple sclerosis to obtain data that might allow inclusion of rituximab in treatment guidelines., Methods: RIFUND-MS was a multicentre, rater-blinded, active-comparator, phase 3, randomised controlled trial done at 17 Swedish university and community hospitals. Key inclusion criteria for participants were: age 18-50 years; relapsing-remitting multiple sclerosis or clinically isolated syndrome according to prevailing McDonald criteria; 10 years or less since diagnosis; untreated or only exposed to interferons or glatiramer acetate; and with clinical or neuroradiological disease activity in the past year. Patients were automatically randomly assigned (1:1) by the treating physician using a randomisation module in the Swedish multiple sclerosis registry, without stratification, to oral dimethyl fumarate 240 mg twice daily or to intravenous rituximab 1000 mg followed by 500 mg every 6 months. Relapse evaluation, Expanded Disability Status Scale rating, and assessment of MRI scans were done by examining physicians and radiologists masked to treatment allocation. The primary outcome was the proportion of patients with at least one relapse (defined as subacute onset of new or worsening neurological symptoms compatible with multiple sclerosis with a duration of more than 24 h and preceded by at least 30 days of clinical stability), assessed in an intention-to-treat analysis using log-binomial regression with robust standard errors. This trial is registered at ClinicalTrials.gov, NCT02746744., Findings: Between July 1, 2016, and Dec 18, 2018, 322 patients were screened for eligibility, 200 of whom were randomly assigned to a treatment group (100 assigned to rituximab and 100 assigned to dimethyl fumarate). The last patient completed 24-month follow-up on April 21, 2021. 98 patients in the rituximab group and 97 patients in the dimethyl fumarate group were eligible for the primary outcome analysis. Three (3%) patients in the rituximab group and 16 (16%) patients in the dimethyl fumarate group had a protocol-defined relapse during the trial, corresponding to a risk ratio of 0·19 (95% CI 0·06-0·62; p=0·0060). Infusion reactions (105 events [40·9 per 100 patient-years]) in the rituximab group and gastrointestinal reactions (65 events [47·4 per 100 patient-years]) and flush (65 events [47·4 per 100 patient-years]) in the dimethyl fumarate group were the most prevalent adverse events. There were no safety concerns., Interpretation: RIFUND-MS provides evidence that rituximab given as 1000 mg followed by 500 mg every 6 months is superior to dimethyl fumarate in preventing relapses over 24 months in patients with early relapsing-remitting multiple sclerosis. Health economic and long-term safety studies of rituximab in patients with multiple sclerosis are needed., Funding: Swedish Research Council., Competing Interests: Declaration of interests AS has served on the data safety monitoring board of GeNeuro. JS has received institutional consultancy fees from Mabion SA. MA has received compensation for lectures or advisory boards from Biogen, Novartis, and Genzyme. JM has received honoraria for advisory boards from Sanofi Genzyme and Merck and lecture honoraria from Merck. FP has received research grants from Janssen, Merck, and UCB, and fees for serving on data monitoring committees in clinical trials with Chugai, Lundbeck, and Roche. JL has received travel support or lecture honoraria from Biogen, Novartis, Merck, Roche, Axelion, Sanofi, and BMS; has served on scientific advisory boards for Almirall, Biogen, Novartis, Merck, Roche, BMS, and Sanofi; serves on the editorial board of the Acta Neurologica Scandinavica; and has received unconditional research grants from Biogen and Novartis. All other authors declare no competing interests., (Copyright © 2022 Elsevier Ltd. All rights reserved.)

Background Atrial fibrillation (AF) is associated with stroke and MRI features of cerebral tissue damage but its impact on levels of serum neurofilament light chain (sNFL), an established biochemical marker of neuroaxonal damage, is unknown. Methods and Results In this observational study, sNFL was analyzed in 280 patients with AF and 280 controls without AF matched for age, sex, and diabetes status within the STABILITY (Stabilization of Atherosclerotic Plaque by Initiation of Darapladib Therapy) trial. None of the patients had a history of previous stroke or transient ischemic attack. Patients with a diagnosis of AF were divided into two groups based on if they were in AF rhythm at the time of blood sampling (AF ECG+, n=74), or not (AF ECG-, n=206). Multiple linear regression analysis was performed to adjust for clinical risk factors. In patients with AF, the levels of sNFL were 15% (AF ECG+) and 10% (AF ECG-) higher than in the control group after adjustment for clinical risk factors, P =0.047 and 0.04, respectively. There was no association between anticoagulation treatment and sNFL levels. Conclusions sNFL was elevated in patients with AF compared with matched controls without AF. Ongoing AF rhythm was associated with even higher levels of sNFL than in patients with a diagnosis of AF but currently not in AF rhythm. Anticoagulation treatment did not affect sNFL levels. Trial Registration ClinicalTrials.gov NCT00799903.

Context: Household food insecurity (HFI) is considered one of the main risk factors of undernutrition. However, the evidence is not conclusive in our study settings. This study aimed to examine the association between HFI and nutritional status., Materials and Methods: It was a community-based cross-sectional observational study among children of age <5 years and their mothers ( n = 257) conducted in a slum of Kolkata, West Bengal, carried out from March to May 2019. Data were analyzed using the Statistical Package for the Social Sciences software (version 16.0. Chicago, SPSS Inc.). Logistic regression analysis was performed to find out the association., Results: The current study found that 72.4% of participants living in food-insecure households and the proportion of underweight, wasting, and stunting among the under-five children found to be 29.9%, 17.8%, and 27.2%, respectively. Bivariate analysis showed wasting and stunting associated with HFI, whereas in multivariable regression, only stunting remained significant., Conclusion and Implications: Food insecurity (FI) remains a predictor of chronic undernutrition (wasting and stunting) highlighting the need for multisectoral strategies and policies to combat FI and multiple forms of malnutrition which will lay the foundation for sustainable and inclusive growth., Competing Interests: There are no conflicts of interest., (Copyright: © 2022 Journal of Family Medicine and Primary Care.)

Glial fibrillary acidic protein (GFAP), myelin basic protein (MBP), neurofilament light chain (NFL), tau and ubiquitin carboxy-terminal hydrolase L1 (UCHL1) are five neuroglial proteins that are used as CSF or blood biomarkers of tissue damage in the nervous system. There is incomplete knowledge of how the concentration of these proteins differs between anatomical regions in the CNS as previous studies have focused on gene expression or non-quantitative protein analyses, limiting the interpretability of these biomarkers. The purpose of this study was to create a map of the tissue content of these proteins in different regions of the CNS. The concentrations of the investigated proteins were determined with ELISA in post mortem tissue homogenates from 17 selected anatomical regions in the CNS from ten deceased donors aged 24 to 50 years. When appropriate, the protein concentrations were adjusted for post-mortem interval. In total, 168 tissue samples were analysed. There was a substantial variation in the concentrations of GFAP, MBP, NFL, tau and UCHL1 between different CNS regions. Highly myelinated areas of the CNS had tenfold higher MBP concentration than cerebral cortex, whereas tau showed an inverse pattern. GFAP, NFL and tau displayed an anteroposterior gradient in cerebral white matter. The cerebellum had low concentrations of all the investigated proteins. In conclusion, the tissue concentrations of GFAP, MBP, NFL, tau and UCHL1 were determined throughout the CNS. This information can be used as a reference when interpreting circulating levels of these biomarkers in relation to the extent and localisation of CNS-damaging processes., (© 2022. The Author(s).)

Importance: B-cell-depleting monoclonal antibodies are widely used for treatment of multiple sclerosis but are associated with an impaired response to vaccines., Objective: To identify factors associated with a favorable vaccine response to tozinameran., Design, Setting, and Participants: This prospective cohort study was conducted in a specialized multiple sclerosis clinic at a university hospital from January 21 to December 1, 2021. Of 75 patients evaluated for participation who received a diagnosis of multiple sclerosis with planned or ongoing treatment with rituximab, 69 were included in the study, and data from 67 were analyzed., Exposures: Sex, age, number of previous rituximab infusions, accumulated dose of rituximab, previous COVID-19 infection, time since last rituximab treatment, CD19+ B-cell count before vaccination, CD4+ T-cell count, and CD8+ T-cell count were considered potential factors associated with the main outcome., Main Outcomes and Measures: Serological vaccine responses were measured by quantitation of anti-spike immunoglobulin G (IgG) antibodies, anti-receptor-binding domain (RBD) IgG antibodies, and their neutralizing capacities. Cellular responses to spike protein-derived SARS-CoV-2 peptide pools were assessed by counting interferon gamma spot-forming units in a FluoroSpot assay., Results: Among 60 patients with ongoing rituximab treatment (49 women [82%]; mean (SD) age, 43 [10] years), the median (range) disease duration was 9 (1-29) years, and the median (range) dose of rituximab was 2750 (500-10 000) mg during a median (range) time of 2.8 (0.5-8.3) years. The median (range) follow-up from the first vaccination dose was 7.3 (4.3-10.0) months. Vaccine responses were determined before vaccination with tozinameran and 6 weeks after vaccination. By using established cutoff values for anti-spike IgG (264 binding antibody units/mL) and anti-RBD IgG (506 binding antibody units/mL), the proportion of patients with a positive response increased with the number of B cells, which was the only factor associated with these outcomes. A cutoff for the B-cell count of at least 40/μL was associated with an optimal serological response. At this cutoff, 26 of 29 patients (90%) had positive test results for anti-spike IgG and 21 of 29 patients (72%) for anti-RBD IgG, and 27 of 29 patients (93%) developed antibodies with greater than 90% inhibition of angiotensin-converting enzyme 2. No factor associated with the cellular response was identified. Depending on the peptide pool, 21 of 25 patients (84%) to 22 of 25 patients (88%) developed a T-cell response with interferon gamma production at the B-cell count cutoff of at least 40/μL., Conclusions and Relevance: This cohort study found that for an optimal vaccine response from tozinameran, rituximab-treated patients with multiple sclerosis may be vaccinated as soon as possible, with rituximab treatment delayed until B-cell counts have reached at least 40/μL. An additional vaccination with tozinameran should be considered at that point.

Untargeted lipidomics using liquid chromatography high-resolution mass spectrometry (LC-HRMS) was performed using polarity switching, and in positive and negative polarity separately on the same set of serum samples, and the performances of the methods were evaluated. Polarity switching causes an increase in the cycle time of the HRMS measurements (1.18 s/cycle vs 0.27 s/cycle), resulting in fewer data points across chromatographic peaks. The coefficient of variation (CV) was on average lower for the added isotopically labelled standards in pooled samples (QC) and patient samples using separate polarities (QC = 5.6%, samples = 12.5%) compared to polarity switching (QC = 8.5%, samples = 13.4%), but the difference was not statistically significant. For the endogenous features measured in the QCs polarity switching resulted in on average significantly higher CVs (3.80 (p = 4.25e-30) and 3.3 percentage points (p = 6.84e-40), for positive and negative modes, respectively) however still acceptable for an untargeted method (mean CVs of 17.9% and 12.2% in positive and negative modes respectively). A slightly larger number of endogenous features were detected using the separate polarities, but the large majority of features (>95%) were detected with both methodologies. The overlap of features detected in both positive and negative polarities was low (4.1%) demonstrating the importance of using both polarities for untargeted lipidomics. When investigating the effects of a treatment on multiple sclerosis patients it was found that both methodologies gave highly similar biological results, further confirming the applicability of polarity switching., (Copyright © 2022 The Authors. Published by Elsevier B.V. All rights reserved.)

Background: Cellular immune memory responses post coronavirus disease 2019 (COVID-19) have been difficult to assess due to the risks of contaminating the immune response readout with memory responses stemming from previous exposure to endemic coronaviruses. The work herein presents a large-scale long-term follow-up study investigating the correlation between symptomology and cellular immune responses four to five months post seroconversion based on a unique severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-specific peptide pool that contains no overlapping peptides with endemic human coronaviruses., Methods: Peptide stimulated memory T cell responses were assessed with dual interferon-gamma (IFNγ) and interleukin (IL)-2 Fluorospot. Serological analyses were performed using a multiplex antigen bead array., Results: Our work demonstrates that long-term SARS-CoV-2-specific memory T cell responses feature dual IFNγ and IL-2 responses, whereas cross-reactive memory T cell responses primarily generate IFNγ in response to SARS-CoV-2 peptide stimulation. T cell responses correlated to long-term humoral immune responses. Disease severity as well as specific COVID-19 symptoms correlated with the magnitude of the SARS-CoV-2-specific memory T cell response four to five months post seroconversion., Conclusion: Using a large cohort and a SARS-CoV-2-specific peptide pool we were able to substantiate that initial disease severity and symptoms correlate with the magnitude of the SARS-CoV-2-specific memory T cell responses., (© 2022 The Authors. Immunity, Inflammation and Disease published by John Wiley & Sons Ltd.)

Ecosystem engineers affect other organisms by creating, maintaining or modifying habitats, potentially supporting species of conservation concern. However, it is important to consider these interactions alongside non-engineering trophic pathways. We investigated the relative importance of trophic and non-trophic effects of an ecosystem engineer, red deer, on a locally rare moth, the transparent burnet (Zygaena purpuralis). This species requires specific microhabitat conditions, including the foodplant, thyme, and bare soil for egg-laying. The relative importance of grazing (i.e., trophic effect of modifying microhabitat) and trampling (i.e., non-trophic effect of exposing bare soil) by red deer on transparent burnet abundance is unknown. We tested for these effects using a novel method of placing pheromone-baited funnel traps in the field. Imago abundance throughout the flight season was related to plant composition, diversity and structure at various scales around each trap. Indirect effects of red deer activity were accounted for by testing red deer pellet and trail presence against imago abundance. Imago abundance was positively associated with thyme and plant diversity, whilst negatively associated with velvet grass and heather species cover. The presence of red deer pellets and trails were positively associated with imago abundance. The use of these sites by red deer aids the transparent burnet population via appropriate levels of grazing and the provision of a key habitat condition, bare soil, in the form of deer trails. This study shows that understanding how both trophic and non-trophic interactions affect the abundance of a species provides valuable insights regarding conservation objectives., (© 2022. The Author(s).)

Over the past decades, hematopoietic stem cell transplantation (HSCT) has been evolving as specific treatment for patients with severe and refractory autoimmune diseases (ADs), where mechanistic studies have provided evidence for a profound immune renewal facilitating the observed beneficial responses. The intestinal microbiome plays an important role in host physiology including shaping the immune repertoire. The relationships between intestinal microbiota composition and outcomes after HSCT for hematologic diseases have been identified, particularly for predicting the mortality from infectious and non-infectious causes. Furthermore, therapeutic manipulations of the gut microbiota, such as fecal microbiota transplant (FMT), have emerged as promising therapeutic approaches for restoring the functional and anatomical integrity of the intestinal microbiota post-transplantation. Although changes in the intestinal microbiome have been linked to various ADs, studies investigating the effect of intestinal dysbiosis on HSCT outcomes for ADs are scarce and require further attention. Herein, we describe some of the landmark microbiome studies in HSCT recipients and patients with chronic ADs, and discuss the challenges and opportunities of microbiome research for diagnostic and therapeutic purposes in the context of HSCT for ADs., Competing Interests: AS reports research grants from Roche-Genentech, Abbvie, GSK, Scipher Medicine, Alimentiv, Inc, Boehringer Ingelheim and Origo Biopharma; consulting fees from Genentech, GSK, Pfizer, HotSpot Therapeutics, Surrozen, Alimentiv, Origo Biopharma and Morphic Therapeutic. FM reports lecture honoraria from Therakos/Mallinckrodt, Janssen, Biocodex, Sanofi, JAZZ pharmaceuticals and Astellas, all outside the submitted work. MM reports grants and lecture honoraria from Janssen, Sanofi, and JAZZ pharmaceuticals, lecture honoraria from Celgene, Amgen, BMS, Takeda, and Pfizer, consultancy honoraria from MaaT Pharma and grants from Roche, all outside the submitted work. JS declares honoraria for speaking at educational events supported by Jazz, Mallinckrodt, Gilead, Janssen, and Actelion, advisory board participation for Medac, and IDMC membership for a Kiadis Pharma supported clinical trial, none of which are directly related to this review. PM discloses travel support and speaker honoraria from unrestricted educational activities organized by Novartis, Bayer HealthCare, Bayer Pharma, Biogen Idec, Merck-Serono and Sanofi Aventis; and consulting to Magenta Therapeutics and Jasper Therapeutics. RG discloses honoraria for speaking from educational events supported by Biotest, Pfizer, and Magenta. TA received financial support from Amgen, Janssen, Neovii and Mallinckrodt. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Alexander, Snowden, Burman, Chang, Del Papa, Farge, Lindsay, Malard, Muraro, Nitti, Salas, Sharrack, Mohty and Greco.)

Chronic diseases affecting the central nervous system (CNS) like Alzheimer's or Parkinson's disease typically develop with advanced chronological age. Yet, aging at the metabolic level has been explored only sporadically in humans using biofluids in close proximity to the CNS such as the cerebrospinal fluid (CSF). We have used an untargeted liquid chromatography high-resolution mass spectrometry (LC-HRMS) based metabolomics approach to measure the levels of metabolites in the CSF of non-neurological control subjects in the age of 20 up to 74. Using a random forest-based feature selection strategy, we extracted 69 features that were strongly related to age (p age  < 0.001, r age  = 0.762, R 2 Boruta age  = 0.764). Combining an in-house library of known substances with in silico chemical classification and functional semantic annotation we successfully assigned putative annotations to 59 out of the 69 CSF metabolites. We found alterations in metabolites related to the Cytochrome P450 system, perturbations in the tryptophan and kynurenine pathways, metabolites associated with cellular energy (NAD+, ADP), mitochondrial and ribosomal metabolisms, neurological dysfunction, and an increase of adverse microbial metabolites. Taken together our results point at a key role for metabolites found in CSF related to the Cytochrome P450 system as most often associated with metabolic aging., (© 2021. The Author(s).)

Background: Cases of COVID-19 infection have increased sharply in Europe since August 2020, and the WHO recommend the use of respirators in situations where keeping distance is not possible. The purpose of this study was to evaluate the impact of the use of respirators on infection cases and viral deaths in European countries., Methods: COVID-19 cases and related deaths in 29 countries relative to population were searched through the WHO database on 15.10.2020. Recent 14-day cases in relation to the population were retrieved from the European Center for Disease Prevention and Control's website, covering the period from 1 to 14 October 2020. Information related to the use of respirators was retrieved from the IHME database of the University of Washington at time point, 1.6.2020., Results: The proportion of people using of respirators at 1.6.2020 correlate negatively to the reported cases of disease (Rs = -0.528) and to deaths (Rs = -0.553). No significant correlation was found for recent cases or mortality. Countries with at least 60% respirator use did not differ from other countries., Conclusion: Long-term use of respirators appears to reduce disease incidence and death in the population., Competing Interests: Conflict of interest statement The authors declare no conflict of interest., (©2021 Pacini Editore SRL, Pisa, Italy.)

Background: Separating individuals with viral-induced wheezing from those with asthma is challenging, and there are no guidelines for children under 6 years of age. Impulse oscillometry, however, is feasible in 4-year-old children., Objective: To explore the use of impulse oscillometry in diagnosing and monitoring asthma in young children and evaluating treatment response to inhaled corticosteroid (ICS)., Methods: A total of 42 children (median age 5.3 years, range 4.0-7.9 years) with physician-diagnosed asthma and lability in oscillometry were followed for 6 months after initiation of ICS treatment. All children performed the 6-minute free-running test and impulse oscillometry at 3 time points. After the baseline, they attended a second visit when they had achieved good asthma control and a third visit approximately 60 days after the second visit. A positive ICS response was defined as having greater than 19 points in asthma control test and no hyperreactivity on the third visit., Results: In total, 38 of 42 children responded to ICS treatment. Exercise-induced increases of resistance at 5 Hz decreased after ICS treatment (61% vs 18% vs 13.5%, P < .001), and running distance during the 6-minute test was lengthened (800 m vs 850 m vs 850 m, P = .001). Significant improvements in childhood asthma control scores occurred between the baseline and subsequent visits (21 vs 24 vs 24, P < .001) and acute physicians' visits for respiratory symptoms (1, (0-6) vs 0, (0-2), P = .001). Similar profiles were observed in children without aeroallergen sensitization and among those under 5 years of age., Conclusion: Impulse oscillometry is a useful tool in diagnosing asthma and monitoring lung function in young children., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: Neuropathy is a common complication of kidney disease that lacks proven disease-modifying treatments. Hemodiafiltration improves clearance of uremic toxins and is associated with better nerve function than hemodialysis. We aimed to determine whether hemodiafiltration reduces the progression of neuropathy in people receiving hemodialysis., Design, Setting, Participants, & Measurements: The Filtration in the Neuropathy of End-Stage Kidney Disease Symptom Evolution (FINESSE) study was an open-label, blinded end point assessment, controlled trial that randomized maintenance hemodialysis recipients to hemodiafiltration or high-flux hemodialysis for 48 months or until death or cessation of dialysis at four study centers. The primary outcome was the mean change in the yearly modified total neuropathy score from baseline, with time points weighted equally., Results: A total of 124 participants were randomized and followed for a mean of 41 months. At baseline, neuropathy was present in 91 (73%) participants (modified total neuropathy score greater than or equal to two), and 38 (31%) had moderate to severe neuropathy (modified total neuropathy score 9-28). Convection volume in the hemodiafiltration arm was a median of 24.7 (interquartile range, 22.4-26.5) L. The mean modified total neuropathy score (SEM) worsened by 1.7 (0.4)/28 and 1.2 (0.4)/28 in the hemodiafiltration and hemodialysis groups, respectively, with a mean difference of 0.5 (95% confidence interval, -0.7 to 1.7; P =0.37). There was no difference in survival (hazard ratio, 1.24; 95% confidence interval, 0.61 to 2.51; log rank P =0.55) or any of the prespecified adverse events. There was no difference between groups in the number of participants who suffered an adverse event adjusted by follow-up time (relative risk, 1.05; 95% confidence interval, 0.83 to 1.32; P =0.68)., Conclusions: Neuropathy is still a common complication of kidney disease without disease-altering therapy. Hemodiafiltration did not affect neuropathy progression compared with hemodialysis., Clinical Trial Registry Name and Registration Number: Filtration in the Neuropathy of End-Stage Kidney Disease Symptom Evolution (FINESSE), ACTRN12609000615280., (Copyright © 2021 by the American Society of Nephrology.)

Cerebral blood flow (CBF) can be measured with dynamic positron emission tomography (PET) of 15 O-labeled water by using tracer kinetic modelling. However, for quantification of regional CBF, an arterial input function (AIF), obtained from arterial blood sampling, is required. In this work we evaluated a novel, non-invasive approach for input function prediction based on machine learning (MLIF), against AIF for CBF PET measurements in human subjects.Twenty-five subjects underwent two 10 min dynamic 15 O-water brain PET scans with continuous arterial blood sampling, before (baseline) and following acetazolamide medication. Three different image-derived time-activity curves were automatically segmented from the carotid arteries and used as input into a Gaussian process-based AIF prediction model, considering both baseline and acetazolamide scans as training data. The MLIF approach was evaluated by comparing AIF and MLIF curves, as well as whole-brain grey matter CBF values estimated by kinetic modelling derived with either AIF or MLIF.The results showed that AIF and MLIF curves were similar and that corresponding CBF values were highly correlated and successfully differentiated before and after acetazolamide medication. In conclusion, our non-invasive MLIF method shows potential to replace the AIF obtained from blood sampling for CBF measurements using 15 O-water PET and kinetic modelling.

Ocrelizumab and siponimod have a scientifically proven effect in progressive MS and decrease the risk of disability in the short-term. The primary endpoints in the pivotal trials of ocrelizumab and siponimod were reported as a hazard ratio of 3-month confirmed disability progression, which was reported to be 0.76-0.79. Based on this, both drugs were subsequently licensed for use in patients with progressive multiple sclerosis. Hazard ratios are not easily communicated to patients and therefore the alternative endpoint average postponement of disability was calculated with data from the pivotal trials. After two years of treatment, the average postponement of disability was 16 days per year with ocrelizumab and 19 days with siponimod. Over time, the average postponement of disability reached a plateau, when further treatment added little value. Taken together, these data suggest that these interventions have a short-lived and limited clinical effect in patients with progressive MS., (Copyright © 2021 Elsevier B.V. All rights reserved.)

Purpose: Epilepsy in multiple sclerosis (MS) is rare, and longitudinal clinical studies evaluating treatment with antiseizure medications (ASMs) are difficult to conduct. We instead designed a nationwide register study to estimate retention rates of ASMs prescribed as initial monotherapy for epilepsy in MS and investigated factors influencing their retention., Methods: multiple sclerosis patients with a first prescription of ASM for epilepsy were identified by cross-referencing the Swedish MS register with comprehensive national registers. One and five-year retention rates of ASMs were estimated using Kaplan-Meier analysis. Cox proportional regression was employed to estimate hazard ratios (HR) of discontinuation for different ASMs as well as for baseline predictors., Results: One hundred and twenty-nine MS patients were included. The most commonly prescribed ASMs were: carbamazepine (n = 38, 29.5%), lamotrigine (n = 33, 25.6%) and levetiracetam (n = 19, 14.7%). One-year retention rates (95% CI) were: lamotrigine 87.5% [76, 98.9], carbamazepine 60.5% [45, 76], levetiracetam 60.2% [37.2, 83.2], valproate 51.3% [23, 79.6] and phenytoin 44.4% [11.8, 77]. Fiveyear retention rates (95% CI) were: lamotrigine 74.4% [57.3, 91.5], carbamazepine 52.2% [34.9, 69.4], valproate 51.3% [23.1, 79.5] and phenytoin 14.8% [0, 40.9]. With carbamazepine as reference, lamotrigine was the only ASM that displayed a lower hazard of discontinuation, HR 0.41 [0.17, 0.99]. We could not identify any baseline factors that influenced the risk of discontinuation., Conclusion: Lamotrigine displayed the lowest risk of discontinuation when prescribed as initial monotherapy for epilepsy in MS. Newer ASMs generally compared well to older ones, at least suggesting non-inferiority., Competing Interests: Declaration of Competing Interest J. Zelano reports consultancy fee from the Swedish medical products agency, the National Board of Health and Welfare and speaker honoraria from UCB and Eisai for non-branded educational events. As an employee of Sahlgrenska university hospital (no personal compensation) he is/has been investigator in clinical trials sponsored by GW pharma, Bial, SK life science, and UCB. The other authors have no disclosures to report., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Autologous haematopoietic stem cell transplantation (AHSCT) is an effective treatment for patients with multiple sclerosis (MS) who have highly active disease, despite the use of standard disease-modifying therapies (DMTs). However, the optimal time for offering AHSCT to patients with 'aggressive' MS is yet to be established., Objectives: The objective was to explore the safety and efficacy of AHSCT as a first-line DMT in patients with 'aggressive' MS., Methods: All patients with 'aggressive' MS who received AHSCT as a first-line DMT in five European and North American centres were retrospectively evaluated., Results: Twenty patients were identified. The median interval between diagnosis and AHSCT was 5 (1-20) months. All had multiple poor prognostic markers with a median pre-transplant Expanded Disability Status Scale (EDSS) score of 5.0 (1.5-9.5). After a median follow-up of 30 (12-118) months, the median EDSS score improved to 2.0 (0-6.5, p  < 0.0001). No patient had further relapses. Three had residual magnetic resonance imaging (MRI) disease activities in the first 6 months post-transplant, but no further new or enhancing lesions were observed in subsequent scans., Conclusion: AHSCT is safe and effective as a first-line DMT in inducing rapid and sustained remission in patients with 'aggressive' MS.

Background: Anemia and poor menstrual hygiene practices have a considerable impact on all aspects of an adolescent girl's life. There is a dire need for evidence on the burden and its association to provide actionable preventive measures., Objective: The objective of this study is to explore the magnitude and association between poor Menstrual Hygiene Management (MHM) practices and anemia., Materials and Methods: A cross-sectional study conducted among 393 adolescent girls of the urban slum of Bhopal (June 2017-July 2018). Hemoglobin (Hb) was determined by a portable Hb meter (HemoCue). Logistic regression analysis was done to find out if there is any association between poor MHM practices and anemia., Results: The present study found the prevalence of anemia as 38.7% among which 65.1%, 31.5%, and 3.2% were suffering from mild, moderate, and severe forms of anemia, respectively, and 87.3% were practicing poor MHM. Logistic regression found that the MHM, bleeding during menstruation, religion, educational status, and nutritional status of adolescents were significant factors associated with anemia., Conclusion: The study concluded that there is a significant association between poor MHM and anemia. Concerted convergent actions focusing on the provision of awareness regarding MHM and sanitary facilities to maintain proper menstrual hygiene are needed to reduce the burden of anemia., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Indian Journal of Community Medicine.)

Secondary autoimmune diseases (2ndADs), most frequently autoimmune cytopenias (AICs), were first described after allogeneic hematopoietic stem cell transplantation (HSCT) undertaken for malignant and hematological indications, occurred at a prevalence of ~5-6.5%, and were attributed to allogeneic immune imbalances in the context of graft versus host disease, viral infections, and chronic immunosuppression. Subsequently, 2ndADs were reported to complicate roughly 2-14% of autologous HSCTs performed for an autoimmune disease. Alemtuzumab in the conditioning regimen has been identified as a risk for development of 2ndADs after either allogeneic or autologous HSCT and is consistent with the high rates of 2ndADs when using alemtuzumab as monotherapy. Due to the significant consequences but variable incidence, depending on conditioning regimen, of 2ndADs and similarity in known immune reconstitution kinetics after autologous HSCT for autoimmune diseases and after alemtuzumab monotherapy, we propose that an imbalance between B and T lineage regeneration early after HSCT may underlie the pathogenesis of 2ndADs.

Coronavirus disease-19 (COVID-19), caused by Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), represents one of the biggest challenges of 21st century, threatening public health around the globe. Increasing age and presence of co-morbidities are reported risk factors for severe disease and mortality, along with autoimmune diseases (ADs) and immunosuppressive treatments such as haematopoietic stem cell transplantation (HSCT), which are also associated with adverse outcomes. We review the impact of the pandemic on specific groups of patients with neurological, rheumatological, and gastroenterological indications, along with the challenges delivering HSCT in adult and pediatric populations. Moving forward, we developed consensus-based guidelines and recommendations for best practice and quality of patient care in order to support clinicians, scientists, and their multidisciplinary teams, as well as patients and their carers. These guidelines aim to support national and international organizations related to autoimmune diseases and local clinical teams delivering HSCT. Areas of unmet need and future research questions are also highlighted. The waves of the COVID-19 pandemic are predicted to be followed by an "endemic" phase and therefore an ongoing risk within a "new normality". These recommendations reflect currently available evidence, coupled with expert opinion, and will be revised according to necessary modifications in practice.

Objective: To identify serum proteins associated with MS and affected by interferon beta treatment., Methods: Plasma samples from 29 untreated relapsing-remitting MS patients and 15 healthy controls were investigated with a multiplexed panel containing 92 proteins related to inflammation. Follow-up samples were available from 13 patients at 1 and 3 months after initiation of treatment with interferon beta-1a., Results: Ten proteins were differentially expressed in MS patients. Five of these were altered by treatment with IFN-β 1a: uPA, CX3CL1, CCL2, TRAIL and IL18., Conclusion: CCL2 and TRAIL were confirmed to be modulated with interferon beta treatment in MS. As novel findings, we now report that uPA and CX3CL1 were differentially expressed in MS and increased after IFN-beta-1a treatment. Conflicting results have been reported on how interferon beta affects IL-18., (© 2021 The Authors. Acta Neurologica Scandinavica published by John Wiley & Sons Ltd.)

Objective: To assess safety outcomes for the induction therapies alemtuzumab and autologous hematopoietic stem cell transplantation (AHSCT) compared to noninduction disease-modifying therapies., Methods: We performed a population-based cohort study linking the Swedish Multiple Sclerosis Register to national health care registers. Alemtuzumab, AHSCT, and a matched reference group of noninduction therapies (natalizumab, dimethyl fumarate, rituximab, fingolimod) were included if started between 2008 and 2017. Main outcomes were death, thyroid disease, nonthyroid autoimmune disease, and infection., Results: We identified 132 alemtuzumab-treated and 139 AHSCT-treated (68% high-dose cyclophosphamide and anti-thymocyte globulin [ATG], 32% BCNU, etoposide, cytosine-arabinoside, and melphalan/ATG) patients, together with 2,486 matched patients treated with noninduction therapies. Four patients in the alemtuzumab group died (incidence rate [IR] per 1,000 person-years 8.6, 95% confidence interval [CI] 2.3-22.0) compared to 1 patient in the AHSCT group (IR 1.7, 95% CI 0.0-9.6), and the mortality rate in the reference group was 0.7 (95% CI 0.3-1.3). Thyroid disease was most frequent in the alemtuzumab group (IR 109, 95% CI 75-154) but also occurred more often for AHSCT (IR 34, 95% CI 18-56) compared to the reference (IR 5.3 95% CI 3.9-7.1). The incidence of nonthyroid autoimmune disease was similar in all groups. IR for infection diagnosed ≥6 months from therapy initiation was 53 (95% CI 30-87) for alemtuzumab, 108 (95% CI 75-150) for AHSCT, and 51 (95% CI 46-57) for the reference., Conclusion: We confirmed a high incidence of thyroid disease in alemtuzumab- and, to a smaller extent, AHSCT-treated patients and found a higher incidence of infection for AHSCT compared to both alemtuzumab and noninduction therapies. The incidence of nonthyroid autoimmune disease was low for both therapies., Classification of Evidence: This study provides Class III evidence of an increased risk of thyroid disease with alemtuzumab and an increased risk of infection with AHSCT treatment., (Copyright © 2021 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Purpose: The purpose of this study is to find out the pattern and factors associated with self-care practices among diabetic patients as self-care was considered imperative for the control of disease and enhancement of patient's quality of life., Methods: This is a cross-sectional clinic-based observational study conducted among the type 2 diabetes mellitus patients who came for follow up to the outpatient department of a tertiary hospital of Kolkata from September to December 2019. Self-care practice assessed using questions adapted from the "Summary Diabetes Self-Care Activities Questionnaire" by face-to-face interview. Logistic regression used to find out the predictors of self-care practice., Results: Self-care practice was unsatisfactory among 67.5% of the patients. Near half (56%) of the patients had mild to moderate distress and about 18% were severely distressed. Self-care practice was significantly associated with the educational level, family history, presence of hypertension, advice given regarding self-care activities, and diabetes distress levels of the participants., Conclusions: Primary care physicians should be encouraged to give practical aspects of self-care practices and counseling regarding diabetes distress. To perform self-care practices adequate, support from the family level and community level is imperative., Competing Interests: There are no conflicts of interest., (Copyright: © 2021 Journal of Family Medicine and Primary Care.)

To increase our understanding of age-related diseases affecting the central nervous system (CNS) it is important to understand the molecular processes of biological ageing. Metabolomics of cerebrospinal fluid (CSF) is a promising methodology to increase our understanding of naturally occurring processes of ageing of the brain and CNS that could be reflected in CSF. In the present study the CSF metabolomes of healthy subjects aged 30-74 years ( n = 23) were studied using liquid chromatography high-resolution mass spectrometry (LC-HRMS), and investigated in relation to age. Ten metabolites were identified with high confidence as significantly associated with ageing, eight with increasing levels with ageing: isoleucine, acetylcarnitine, pipecolate, methionine, glutarylcarnitine, 5-hydroxytryptophan, ketoleucine, and hippurate; and two decreasing with ageing: methylthioadenosine and 3-methyladenine. To our knowledge, this is the first time the CSF metabolomes of healthy subjects are assessed in relation to ageing. The present study contributes to the field of ageing metabolomics by presenting a number of metabolites present in CSF with potential relevance for ageing and the results motivate further studies.

Multiple sclerosis (MS) is a neurodegenerative disease associated with inflammatory demyelination and astroglial activation, with neuronal and axonal damage as the leading factors of disability. We aimed to perform a meta-analysis to determine changes in CSF levels of neuronal and glial biomarkers, including neurofilament light chain (NFL), total tau (t-tau), chitinase-3-like protein 1 (CHI3L1), glial fibrillary acidic protein (GFAP), and S100B in various groups of MS (MS versus controls, clinically isolated syndrome (CIS) versus controls, CIS versus MS, relapsing-remitting MS (RRMS) versus progressive MS (PMS), and MS in relapse versus remission. According to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses, we included 64 articles in the meta-analysis, including 4071 subjects. For investigation of sources of heterogeneity, subgroup analysis, meta-regression, and sensitivity analysis were conducted. Meta-analyses were performed for comparisons including at least three individual datasets. NFL, GFAP, t-tau, CHI3L1, and S100B were higher in MS and NFL, t-tau, and CHI3L1 were also elevated in CIS patients than controls. CHI3L1 was the only marker with higher levels in MS than CIS. GFAP levels were higher in PMS versus RRMS, and NFL, t-tau, and CHI3L1 did not differ between different subtypes. Only levels of NFL were higher in patients in relapse than remission. Meta-regression showed influence of sex and disease severity on NFL and t-tau levels, respectively and disease duration on both. Added to the role of these biomarkers in determining prognosis and treatment response, to conclude, they may serve in diagnosis of MS and distinguishing different subtypes., (© 2021 Walter de Gruyter GmbH, Berlin/Boston.)

Inhaled corticosteroid treatment improves expiratory variability index in steroid-naïve asthmatic children aged 4-7 years https://bit.ly/3n4vBT3., Competing Interests: Conflict of interest: V-P. Seppä holds patents relating to impedance pneumography (IP) and is an employee of Revenio Group, which commercialises IP technology. The other authors declare no conflicts of interest., (Copyright ©The authors 2022.)

Objective: Identifying molecular changes that contribute to the onset and progression of Huntington's disease (HD) is of importance for the development and evaluation of potential therapies., Methods: We conducted an unbiased mass-spectrometry proteomic analysis on the cerebrospinal fluid of 12 manifest HD patients (ManHD), 13 pre-manifest (preHD), and 38 controls. A biologically plausible and significant possible biomarker was validated in samples from a separate cohort of patients and controls consisting of 23 ManHD patients and 23 controls., Results: In ManHD compared to preHD, 10 proteins were downregulated and 43 upregulated. Decreased levels of proenkephalin (PENK) and transthyretin were closely linked to HD symptom severity, whereas levels of 15 upregulated proteins were associated with symptom severity. The decreased PENK levels were replicated in the separate cohort where absolute quantitation was performed., Conclusions: We hypothesize that declining PENK levels reflect the degeneration of medium spiny neurons (MSNs) that produce PENK and that assays for PENK may serve as a surrogate marker for the state of MSNs in HD. © 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society., (© 2020 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.)

Objectives: To evaluate the effect of intrathecally (IT) delivered rituximab as a therapeutic intervention for progressive multiple sclerosis (PMS) during a 3-year follow-up period., Methods: Participants of a 1-year open-label phase 1b study of IT delivered rituximab to patients with PMS were offered extended treatment with follow-up for an additional 2 years. During the extension phase, treatment with 25 mg rituximab was administered every 6 months via a subcutaneous Ommaya reservoir connected to the right frontal horn with a ventricular catheter., Results: Mild to moderate vertigo and nausea occurred in 4 out of 14 participants as temporary adverse events associated with IT rituximab infusion. During the entire 3-year period, two cases of low-virulent bacterial meningitis occurred, which were successfully treated. Walking speed deteriorated significantly during the study., Conclusions: IT administration of rituximab via a ventricular catheter was well tolerated. Considering the meningitis cases, the risk of infection was not negligible. The continued loss of walking speed indicates that IT rituximab was not able to stop disease progression., Classification of Evidence: This study provides class IV evidence that intraventricularly administered rituximab in progressive MS is associated with a risk for bacterial meningitis and does not halt disease progression., Eu Clinical Trial Register: EudraCT; 2008-002626-11 and 2012-000721-53.

Objective: To compare outcomes after treatment with autologous haematopoietic stem cell transplantation (AHSCT) and alemtuzumab (ALZ) in patients with relapsing-remitting multiple sclerosis., Methods: Patients treated with AHSCT (n=69) received a conditioning regimen of cyclophosphamide (200 mg/kg) and rabbit anti-thymocyte globulinerG (6.0 mg/kg). Patients treated with ALZ (n=75) received a dose of 60 mg over 5 days, a repeated dose of 36 mg over 3 days after 1 year and then as needed. Follow-up visits with assessment of the expanded disability status scale score, adverse events and MR investigations were made at least yearly., Results: The Kaplan-Meier estimates of the primary outcome measure 'no evidence of disease activity' was 88% for AHSCT and 37% for ALZ at 3 years, p<0.0001. The secondary endpoint of annualised relapse rate was 0.04 for AHSCT and 0.1 for ALZ, p=0.03. At last follow-up, the proportions of patients who improved, were stable or worsened were 57%/41%/1% (AHSCT) and 45%/43%/12% (ALZ), p=0.06 Adverse events grade three or higher were present in 48/69 patients treated with AHSCT and 0/75 treated with ALZ in the first 100 days after treatment initiation. The most common long-term adverse event was thyroid disease with Kaplan-Meier estimates at 3 years of 21% for AHSCT and 46% for ALZ, p=0.005., Conclusions: In this observational cohort study, treatment with AHSCT was associated with a higher likelihood of maintaining 'no evidence of disease activity'. Adverse events were more frequent with AHSCT in the first 100 days, but thereafter more common in patients treated with ALZ., Competing Interests: Competing interests: AM-L has received compensation for lectures and/or service on advisory boards Roche, Sanofi, Merck Serono, Biogen and Teva. LN has received lecture honoraria from Biogen and Novartis and served on advisory boards for Merck. CM has received compensation for lectures, service on advisory boards and/or travel expenses from Sanofi-Genzyme, Merck, Novartis and Roche. MA has received compensation for lectures and/or service on advisory boards from Biogen, Genzyme, and Novartis. JL has received travel support and/or lecture honoraria from Biogen, Novartis, Merck, Alexion, Roche and SanofiGenzyme; has served on scientific advisory boards for Biogen, Novartis, Merck, Roche, BSM and SanofiGenzyme; serves on the editorial board of the Acta Neurologica Scandinavica; has received unconditional research grants from Biogen, and Novartis., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Exhaled nitric oxide (FeNO) measurements and eucapnic voluntary hyperventilation (EVH) tests have been used as diagnostic tools for asthma. Data on the impact of hyperventilation on the level of FeNO are limited., Aim: We aimed to evaluate whether EVH tests affect the level of FeNO in children aged 10-16 years., Methods: A total of 234 children aged 10-16 years had a 6-min EVH test performed. In total, FeNO values for 153 of 234 children were measured before the test and within 15 min after the test. According to a baseline FeNO level of 20 ppb, children were divided into two groups: those with low values (FeNO < 20 ppb) and those with high values (FeNO ≥ 20 ppb)., Results: The median age of the children was 13.4 years (interquartile range 12.3-15.3 years); 58% were boys and 42% were girls. Of these children, 51% were sensitized to aeroallergens. In 101 of 153 children (66%), the FeNO values decreased after the EVH test. In children with low and high baseline levels, the median level of FeNO decreased after the EVH test: 10.5 ppb before versus 9.5 ppb after (p < .011), and 31.0 ppb before versus 28.0 ppb after (p < .011), respectively. The decrease in FeNO after EVH test was not associated with induced bronchoconstriction expressed as a change in FEV1 (R s  = .19)., Conclusions: The EVH test decreases FeNO levels. Therefore, FeNO should be measured before an EVH test is performed., (© 2020 Scandinavian Society of Clinical Physiology and Nuclear Medicine. Published by John Wiley & Sons Ltd.)

Autologous haematopoietic stem cell transplantation (AHSCT) is increasingly used to treat people with multiple sclerosis (MS). Supported by an evolving evidence base, AHSCT can suppress active inflammation in the central nervous system and induce long-term changes in immune cell populations, thereby stabilizing, and, in some cases, reversing disability in carefully selected MS patients. However, AHSCT is an intensive chemotherapy-based procedure associated with intrinsic risks, including profound cytopenia, infection, and organ toxicity, accompanied by an on-going degree of immuno-compromise and general deconditioning, which can be associated with a transient increase in functional impairment in the early stages after transplantation. Although international guidelines and recommendations have been published for clinical and technical aspects of AHSCT in MS, there has been no detailed appraisal of the rehabilitation needed following treatment nor any specific guidelines as to how this is best delivered by hospital and community-based therapists and wider multidisciplinary teams in order to maximize functional recovery and quality of life. These expert consensus guidelines aim to address this unmet need by summarizing the evidence-base for AHSCT in MS and providing recommendations for current rehabilitation practice along with identifying areas for future research and development., Competing Interests: FR and HH work for Hobbs Rehabilitation, JS declares honoraria for speaking at educational meetings from Sanofi, Jazz, Janssen, Gilead, and Mallinckrodt, BV declares honoraria for speaking at educational meetings and consultancy from Janssen, Takeda, and Amgen. PM reports travel support and speaker honoraria from unrestricted educational activities organized by Novartis, Bayer HealthCare, Bayer Pharma, Biogen Idec, Merck-Serono, and Sanofi Aventis. He also discloses consulting to Magenta Therapeutics and Jasper Therapeutics. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The reviewer EP declared a shared affiliation, with no collaboration, with two of the authors RS and CB to the handling Editor. The Handling Editor declared a past co-authorship with one of the authors GM., (Copyright © 2020 Roberts, Hobbs, Jessop, Bozzolini, Burman, Greco, Ismail, Kazmi, Kirgizov, Mancardi, Mawson, Muraro, Puyade, Saccardi, Withers, Verhoeven, Sharrack and Snowden.)

Background: Oligoclonal bands (OCB) are widely believed to be stable over time and rarely affected by disease-modifying treatment in MS. It is presently unknown how intrathecal immunoglobulin production and other cerebrospinal fluid (CSF) biomarkers are impacted by a highly efficacious procedure such as autologous haematopoietic stem cell transplantation (aHSCT)., Objective: To describe the evolution of intrathecal immunoglobulin and neurofilament light (NFL) over time in MS patients treated with aHSCT., Methods: In this retrospective study, available data from previously made CSF investigations in 46 patients treated with aHSCT were analysed., Results: After a median follow-up time of 745 days, immunoglobulin G (IgG) OCB remained detectable in 74% of patients, the proportion of patients with a pathological IgG index went down from 70% to 46%, and the proportion of patients with a pathological NFL went down from 72% to 24%. In patients with follow-up time >1500 days, IgG OCB were detectable in 50% of patients, 14% had a pathological IgG index and none a pathological NFL., Conclusions: Intrathecal immunoglobulin production and NFL were lower after treatment with aHSCT, decreased over time and were normalised in a significant portion of patients. This challenges the notion that OCB are unaffected by therapeutic intervention in MS.

Background: Population-based real-world evidence studies of the effectiveness and tolerability of dimethyl fumarate in relation to common treatment alternatives are still limited., Objective: To evaluate the clinical effectiveness and tolerability of dimethyl fumarate (DMF) as the initial and secondary treatment for relapsing-remitting multiple sclerosis (RRMS) patients compared with common treatment alternatives in Sweden., Methods: We conducted a nationwide retrospective observational cohort study of all RRMS patients identified through the Swedish MS registry initiating DMF ( n  = 641) or interferons/glatiramer acetate (IFN/GA; n  = 555) as the initial therapy, or DMF ( n  = 703) or fingolimod (FGL; n  = 194) after switch from IFN/GA between 1 January 2014 and 31 December 2016., Results: The discontinuation rate was lower with DMF as the initial treatment than IFN/GA (adjusted hazard rate (HR): 0.46, 95% confidence interval (CI): 0.37-0.58, p  < 0.001), but higher than FGL as the secondary treatment (HR: 1.51, CI: 1.08-2.09, p  < 0.05). Annualized relapse rate (ARR) was lower with DMF compared to IFN/GA (0.04, CI: 0.03-0.06 vs 0.10, CI: 0.07-0.13; p  < 0.05), but not FGL (0.03, CI: 0.02-0.05 vs 0.02, CI: 0.01-0.04; p  = 0.41). Finally, time to first relapse (TTFR) was longer with DMF as the initial, but not secondary, therapy ( p  < 0.05 and p  = 0.20, respectively)., Conclusion: Our findings indicate that DMF performs better than IFN/GA as the initial treatment for RRMS. Compared to FGL, DMF displayed a lower tolerability, but largely similar effectiveness outcomes.

Background: Elder abuse is an important public health problem hidden from public view in spite of its detrimental effect on physical and mental health. In the last three decades, there is responsiveness toward abuse of children and spouses worldwide but even today abuse and neglect of aged people seem to be the matter of least concern. This study aims to reveal the magnitude of elder abuse and its predictors., Methods: This is a cross-sectional study carried out in a community setting among elderly people (60 years and older) from October 2015 to September 2017 in a rural area of West Bengal, eastern part of India. Elder abuse was elicited by questions adapted from the Actual Abuse Tool. Data were analysed using SPSS (version 16.0). Logistic regression analysis was performed to reveal the factors associated with elder abuse., Results: The study found that 25.6% of the respondents had experienced abuse, psychological abuse being the commonest type. Disability was the most common perceived risk for abuse. Univariate logistic regression showed higher age (70 years and older), female gender, who were Scheduled caste, living in a nuclear family, having more than three children, financially and functionally dependent, who was suffering from depression and multimorbidity had increased odds of being abused. In multivariable logistic regression, people aged above 70 years, living in a nuclear family and dependent for instrumental activities of daily living remained significant predictors of abuse., Conclusion: Around one in four of the respondents was abused in a 1 year duration which implies the urgent need for action. Routine screening for elder abuse at ground level and abuse prevention campaigns can be an important measure to alleviate this hidden problem. Also, there is a need to explore culturally specific forms of elder abuse to provide an age-friendly environment., (© 2020 Japanese Psychogeriatric Society.)

Background and Aim: The eucapnic voluntary hyperventilation (EVH) testing is a diagnostic tool for diagnostics of exercise-induced bronchoconstriction; while the testing has become more common among children, data on the test's feasibility among children remain limited. Our aim was to investigate EVH testing feasibility among children, diagnostic testing cut-off values, and which factors affect testing outcomes., Methods: We recruited 134 patients aged 10-16 years with a history of exercise-induced dyspnoea and 100 healthy control children to undergo 6-min EVH testing. Testing feasibility was assessed by the children's ability to achieve ≥70% of the target minute ventilation of 30 times forced expiratory volume in 1 s (FEV1). Bronchoconstriction was assessed as a minimum of 8%, 10%, 12%, 15% or 20% fall in FEV1. Patient characteristics were correlated with EVH outcomes., Results: Overall, 98% of the children reached ≥70%, 88% reached ≥80%, 79% reached ≥90% and 62% reached ≥100% of target ventilation in EVH testing; of children with a history of exercise-induced dyspnoea, the decline percentages were as follows: 24% (≥8% fall), 17% (≥10% fall), 10% (≥12% fall), 6% (≥15% fall) and 5% (≥20% fall) in FEV1, compared to 11%, 4%, 3%, 1% and 0% among the healthy controls, respectively. Healthy controls and boys performed testing at higher ventilation rates (p < .05)., Conclusion: Eucapnic voluntary hyperventilation testing is feasible among children aged 10-16 years and has diagnostic value in evaluating exercise-induced dyspnoea among children. A minimum 10% fall in FEV1 is a good diagnostic cut-off value. Disease status appears to be important covariates., (© 2020 The Authors. Clinical Physiology and Functional Imaging published by John Wiley & Sons Ltd on behalf of Scandinavian Society of Clinical Physiology and Nuclear Medicine.)

Background: The relationship between proteins in different CNS extracellular compartments is unknown. In this study the levels of selected proteins in three compartments in people with progressive multiple sclerosis (PMS) were compared., Methods: During an open label, phase 1b study on intraventricular administration of rituximab for PMS, samples were collected from the interstitial space (ISS) of the brain through microdialysis. Samples were also obtained from ventricular and lumbar cerebrospinal fluid (CSF). These samples were analyzed with a multiplexed proximity extension assay, measuring the levels of 180 proteins split equally between two panels, detecting proteins associated with immunology and neurology, respectively., Results: Considerable differences in concentrations were observed between the three analyzed compartments. Compared to ventricular CSF, ISS fluid contained statistically significant higher levels of 25 proteins (84% immunology panel and 16% neurology panel). Ventricular CSF contained significantly higher levels of 54 proteins (31% immunology panel and 69% neurology panel) compared to ISS fluid, and 17 proteins (76% immunology panel and 24% neurology panel) compared to lumbar CSF. Lumbar CSF showed significantly higher levels of 115 proteins (32% immunology panel and 68% neurology panel) compared to ventricular CSF. The three compartments displayed poor correlation with a median Spearman's rho of -0.1 (IQR 0.4) between ISS and ventricular CSF and 0.3 (IQR 0.4) between ventricular and lumbar CSF., Conclusion: A substantial heterogeneity in the protein levels of samples obtained from different CNS compartments was seen. Therefore, data obtained from analysis of lumbar CSF should be interpreted with caution when making conclusions about pathophysiological processes in brain tissue.

The foot-and-mouth disease is an ever-present hazard to the livestock industry due to the huge economic consequences following an outbreak that necessitates culling of possibly infected animals in vast numbers. The disease is highly contagious and previous epizootics have shown that it spreads by many routes. One such route is airborne transmission, which has been investigated in this study by means of a detailed multilevel model that includes all scales of an outbreak. Local spread within an infected farm is described by a stochastic compartment model while the spread between farms is quantified by atmospheric dispersion simulations using a network representation of the set of farms. The model was applied to the Swedish livestock industry and the risk for an epizootic outbreak in Sweden was estimated using the basic reproduction number of each individual livestock-holding farm as the endpoint metric. The study was based on comprehensive official data sets for both the current livestock holdings and regional meteorological conditions. Three species of farm animals are susceptible to the disease and are present in large numbers: cattle, pigs and sheep. These species are all included in this study using their individual responses and consequences to the disease. It was concluded that some parts of southern Sweden are indeed preconditioned to harbor an airborne epizootic, while the sparse farm population of the north renders such events unlikely to occur there. The distribution of the basic reproduction number spans over several orders of magnitudes with low risk of disease spread from the majority of the farms while some farms may act as very strong disease transmitters. The results may serve as basic data in the planning of the national preparedness for this type of events., Competing Interests: The authors have declared that no competing interests exist.

Objective: Novel, highly effective disease-modifying therapies have revolutionized multiple sclerosis (MS) care. However, evidence from large comparative studies on important safety outcomes, such as cancer, is still lacking., Methods: In this nationwide register-based cohort study, we linked data from the Swedish MS register to the Swedish Cancer Register and other national health care and census registers. We included 4,187 first-ever initiations of rituximab, 1,620 of fingolimod, and 1,670 of natalizumab in 6,136 MS patients matched for age, sex, and location to 37,801 non-MS general population subjects. Primary outcome was time to first invasive cancer., Results: We identified 78 invasive cancers among treated patients: rituximab 33 (incidence rate [IR] per 10,000 person-years = 34.4, 95% confidence interval [CI] = 23.7-48.3), fingolimod 28 (IR = 44.0, 95% CI = 29.2-63.5), and natalizumab 17 (IR = 26.0, 95% CI = 15.1-41.6). The general population IR was 31.0 (95% CI = 27.8-34.4). Adjusting for baseline characteristics, we found no difference in risk of invasive cancer between rituximab, natalizumab, and the general population but a possibly higher risk with fingolimod compared to the general population (hazard ratio [HR] = 1.53, 95% CI = 0.98-2.38) and rituximab (HR = 1.68, 95% CI = 1.00-2.84)., Interpretation: In this first large comparative study of 3 highly effective MS disease-modifying therapies, no increased risk of invasive cancer was seen with rituximab and natalizumab, compared to the general population. However, there was a borderline-significant increased risk with fingolimod, compared to both the general population and rituximab. It was not possible to attribute this increased risk to any specific type of cancer, and further studies are warranted to validate these findings. ANN NEUROL 2020;87:688-699., (© 2020 The Authors. Annals of Neurology published by Wiley Periodicals, Inc. on behalf of American Neurological Association.)