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Metastasis occurs frequently after resection of pancreatic cancer (PaC). In this study, we hypothesized that multi-parametric analysis of pre-metastatic liver biopsies would classify patients according to their metastatic risk, timing and organ site. Liver biopsies obtained during pancreatectomy from 49 patients with localized PaC and 19 control patients with non-cancerous pancreatic lesions were analyzed, combining metabolomic, tissue and single-cell transcriptomics and multiplex imaging approaches. Patients were followed prospectively (median 3 years) and classified into four recurrence groups; early (<6 months after resection) or late (>6 months after resection) liver metastasis (LiM); extrahepatic metastasis (EHM); and disease-free survivors (no evidence of disease (NED)). Overall, PaC livers exhibited signs of augmented inflammation compared to controls. Enrichment of neutrophil extracellular traps (NETs), Ki-67 upregulation and decreased liver creatine significantly distinguished those with future metastasis from NED. Patients with future LiM were characterized by scant T cell lobular infiltration, less steatosis and higher levels of citrullinated H3 compared to patients who developed EHM, who had overexpression of interferon target genes (MX1 and NR1D1) and an increase of CD11B + natural killer (NK) cells. Upregulation of sortilin-1 and prominent NETs, together with the lack of T cells and a reduction in CD11B + NK cells, differentiated patients with early-onset LiM from those with late-onset LiM. Liver profiles of NED closely resembled those of controls. Using the above parameters, a machine-learning-based model was developed that successfully predicted the metastatic outcome at the time of surgery with 78% accuracy. Therefore, multi-parametric profiling of liver biopsies at the time of PaC diagnosis may determine metastatic risk and organotropism and guide clinical stratification for optimal treatment selection., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.)

There is growing evidence suggesting that immunological mechanisms play a significant role in the development of psychiatric symptoms in certain patient subgroups. However, the relationship between clinical red flags for suspected autoimmune psychiatric disease and signs of central nervous system (CNS) pathology (e.g., routine cerebrospinal fluid (CSF) alterations, CNS damage markers, neurophysiological or neuroimaging findings) has received limited attention. Here, we aimed to describe the prevalence and distribution of potential CNS pathologies in psychiatric patients in relation to clinical red flags for autoimmune psychiatric disease and psychiatric symptoms. CSF routine findings and CNS damage markers; neurofilament light chain protein (NfL), glial fibrillary acidic protein (GFAP) and total Tau (t-Tau), in CSF from 127 patients with psychiatric disease preselected for suspected immunological involvement were related to recently proposed clinical red flags, psychiatric features, and MRI and EEG findings. Twenty-one percent had abnormal routine CSF findings and 27% had elevated levels of CNS damage markers. Six percent had anti-neuronal antibodies in serum and 2% had these antibodies in the CSF. Sixty-six percent of patients examined with MRI (n = 88) had alterations, mostly atrophy or nonspecific white matter lesions. Twenty-seven percent of patients with EEG recordings (n = 70) had abnormal findings. Elevated NfL levels were associated with comorbid autoimmunity and affective dysregulation symptoms. Elevated t-Tau was associated with catatonia and higher ratings of agitation/hyperactivity. Elevated GFAP was associated with acute onset, atypical presentation, infectious prodrome, tics, depressive/anxiety symptom ratings and overall greater psychiatric symptom burden. In conclusion, preselection based on suspected autoimmune psychiatric disease identifies a population with a high prevalence of CSF alterations suggesting CNS pathology. Future studies should examine the value of these markers in predicting treatment responses., (© 2024. The Author(s).)

Background: Biomarkers reflecting brain injury are not routinely used in risk assessment of stroke in atrial fibrillation (AF). Neurofilament light chain (NFL) is a novel biomarker released into blood after cerebral insults. We investigated the association between plasma concentrations of NFL, other biomarkers, and risk of stroke and death in patients with AF not receiving oral anticoagulation., Methods: For this observational study, baseline plasma samples were available from 3077 patients with AF randomized to aspirin in ACTIVE A (Atrial Fibrillation Clopidogrel Trial With Irbesartan for Prevention of Vascular Events; 2003 to 2008) and AVERROES (Apixaban Versus Acetylsalicylic Acid [ASA] to Prevent Stroke in Atrial Fibrillation Patients Who Have Failed or Are Unsuitable for Vitamin K Antagonist Treatment; 2007 to 2009). Median follow-up was 1.5 years. NFL was analyzed with a Single Molecule Array (Simoa). Associations with outcomes (total stroke or systemic embolism, ischemic stroke, cardiovascular death, and all-cause death) were explored with Cox regression models., Results: In the combined cohort, the median NFL level was 16.9 ng/L (interquartile range, 11.1-26.5 ng/L), the median age was 71 years, 58% were men, and 13% had a history of previous stroke. NFL was associated with older age, higher creatinine, lower body mass index, previous stroke, female sex, and diabetes but not cardiac rhythm. Higher NFL was associated with a higher risk of stroke or systemic embolism (n=206) independently of clinical characteristics (hazard ratio, 1.27 [95% CI, 1.10-1.46] per doubling of NFL) and other biomarkers (hazard ratio, 1.18 [95% CI, 1.01-1.37]) and including in patients without previous stroke (hazard ratio, 1.23 [95% CI, 1.02-1.48]). NFL was also independently associated with cardiovascular (n=219) and all-cause (n=311) death. The C index for stroke using only NFL was 0.642, on par with the currently used clinical risk scores. Addition of information on NFL improved discrimination in a model also including clinical information, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and high-sensitivity cardiac troponin T, yielding a C index of 0.727., Conclusions: NFL reflects overt and covert episodes of cerebral ischemia and improves risk assessment of stroke and death in patients with AF without oral anticoagulation, including in patients without previous stroke. The combination of NFL with information on age, history of stroke, and other biomarkers should be explored as a future avenue for stroke risk assessments in patients with AF.

Background: Natalizumab was not shown to modify disability in progressive multiple sclerosis (MS). This matched observational study compared the effectiveness of autologous haematopoietic stem cell transplantation (AHSCT) with natalizumab in progressive MS., Methods: Patients with primary/secondary progressive MS from seven AHSCT MS centres and the MSBase registry, treated with AHSCT or natalizumab, were matched on a propensity score derived from sex, age, Expanded Disability Status Scale (EDSS), number of relapses 12/24 months before baseline, time from MS onset, the most effective prior therapy and country. The pairwise-censored groups were compared on hazards of 6-month confirmed EDSS worsening and improvement, relapses and annualised relapse rates (ARRs), using Andersen-Gill proportional hazards models and conditional negative binomial model., Results: 39 patients treated with AHSCT (37 with secondary progressive MS, mean age 37 years, EDSS 5.7, 28% with recent disability progression, ARR 0.54 during the preceding year) were matched with 65 patients treated with natalizumab. The study found no evidence for difference in hazards of confirmed EDSS worsening (HR 1.49, 95% CI 0.70 to 3.14) and improvement (HR 1.50, 95% CI 0.22 to 10.29) between AHSCT and natalizumab over up to 4 years. The relapse activity was also similar while treated with AHSCT and natalizumab (ARR: mean±SD 0.08±0.28 vs 0.08±0.25; HR 1.05, 95% CI 0.39 to 2.82). In the AHSCT group, 3 patients experienced febrile neutropenia during mobilisation, 9 patients experienced serum sickness, 6 patients required intensive care unit admission and 36 patients experienced complications after discharge. No treatment-related deaths were reported., Conclusion: This study does not support the use of AHSCT to control disability in progressive MS with advanced disability and low relapse activity., Competing Interests: Competing interests: TK served on scientific advisory boards for MS International Federation and WHO, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck and Biogen; steering committee for Brain Atrophy Initiative by Sanofi Genzyme; received conference travel support and/or speaker honoraria from WebMD Global, Eisai, Novartis, Biogen, Roche, Sanofi-Genzyme, Teva, BioCSL and Merck; and received research or educational event support from Biogen, Novartis, Genzyme, Roche, Celgene and Merck. SS has nothing to disclose. IR served on scientific advisory boards/steering committees for Novartis and Merck; and received conference travel support and/or speaker honoraria from Roche, Novartis, Biogen, Teva, Sanofi-Genzyme and Merck. JM served on scientific advisory board for Roche; and received conference travel support and/or speaker honoraria from Novartis, Biogen, Roche and Merck. IS received compensation for an educational activity from Biogen. BW has nothing to disclose. MSF has nothing to disclose. HA has nothing to disclose. EKH received honoraria/research support from Biogen, Merck Serono, Novartis, Roche and Teva; and has been supported by the Czech Ministry of Education–project Cooperatio LF1, research area Neuroscience and the project National Institute for Neurological Research (Programme EXCELES, ID project no LX22NPO5107)–funded by the European Union-Next Generation EU. EK has nothing to disclose. MT received honoraria from Janssen, Gilead Sciences, Bristol-Myers Squibb, Takeda, Amgen, AbbVie, Roche, MorphoSys and Novartis; served as an advisor to Takeda, Bristol-Myers Squibb, Incyte, AbbVie, Amgen, Roche, Gilead Sciences, Janssen, MorphoSys and Novartis; and received conference travel support from Gilead Sciences, Takeda, Bristol-Myers Squibb, Roche, Janssen and AbbVie. TK has nothing to disclose. JB has nothing to disclose. RM received compensation for travelling, conference fees and consulting fees from Merck, Teva, Sanofi Genzyme, Biogen Idec, Novartis, Roche, BMS and Celgene. OT received speaker honoraria from and served on scientific advisory boards for Biogen, Sanofi-Aventis, Teva, Merck and Novartis. LB received speaker honoraria from Novartis, and consultant fees from Viatris. AKL did not declare any disclosures. BS has nothing to disclose. JS declares honoraria for educational events from Jazz, Gilead and Janssen; for advisory board membership from Medac and Vertex; and for trial IDMC membership from Kiadis Pharma., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: To assess comparative effectiveness, safety, and tolerability of off-label rituximab, compared with frequently used therapies approved for multiple sclerosis (MS)., Methods: A Swedish cohort study of persons with relapsing-remitting MS, age 18 to 75 years at inclusion and with a first therapy start or a first therapy switch between 2011 and 2018. Low-dose rituximab was compared with MS-approved therapies. Primary outcomes were proportions with 12 months confirmed disability worsening and change in MS Impact Scale-29 (MSIS-29) scores, respectively. Secondary endpoints included relapses, therapy discontinuation, and serious adverse events. Analyses used an intention-to-treat approach and were adjusted for demographics, MS features, and health characteristics., Results: We included 2,449 participants as first therapy start and 2,463 as first therapy switch. Proportions with disability worsening at 3 years were 9.1% for rituximab as first therapy and 5.1% after therapy switch, with no differences to MS-approved comparators. Worsening on rituximab was mostly independent of relapses. MSIS-29 with rituximab at 3 years improved by 1.3/8.4 points (physical/psychological) for first disease-modifying therapy (DMT) and 0.4/3.6 for DMT switch, and was mostly similar across therapies. Rituximab had lower relapse rates and higher therapy persistence in both groups. The rate of hospital-treated infections was higher with rituximab after a therapy switch, but not as a first therapy., Interpretation: This population-based real-world cohort study found low rates of disability progression, mostly independent of relapses, and without significant differences between rituximab and MS-approved comparators. Rituximab led to lower rates of inflammatory activity and higher treatment persistence, but was associated with an increased rate of serious infections. ANN NEUROL 2024., (© 2024 The Author(s). Annals of Neurology published by Wiley Periodicals LLC on behalf of American Neurological Association.)

Soluble CD27 (sCD27) is a potential biomarker for diseases involving immune dysfunction. As there is currently little data on cerebrospinal fluid (CSF) sCD27 concentrations in the general population we measured CSF and plasma concentrations in 486 patients (age range 18-92 years, 57% male) undergoing spinal anesthesia for elective surgery. Across the complete cohort the median [range] sCD27 concentrations were 163 [<50 to 7474] pg/mL in CSF and 4624 [1830 to >400,000] pg/mL in plasma. Plasma sCD27, age and Qalb were the factors most strongly associated with CSF sCD27 levels. Reference sCD27 concentration intervals (central 95% of values) in a sub-group without the indication of neuropsychiatric, inflammatory or systemic disease (158 patients) were <50 pg/mL - 419 pg/mL for CSF and 2344-36422 pg/mL for plasma. These data provide preliminary reference ranges that could inform future studies of the validity of sCD27 as a biomarker for neuro- and systemic inflammatory disorders., Competing Interests: The authors declare no competing interests., (© 2024 The Authors. Published by Elsevier Inc.)

Objective: This study aimed to explore the clinical characteristics and temporal disease course of patients with autoimmune encephalitis (AE) and paraneoplastic neurological syndrome (PNS) in Sweden., Methods: Thirty-seven antibody-positive AE and PNS cases were identified in the Healthcare region Mid Sweden between 2015 and 2019. Clinical data were collected through a retrospective review of electronic health records. Patients were divided into three subgroups based on antibody type: neuronal surface antibodies (NSAbs), onconeural antibodies, and anti-GAD65 antibodies., Results: Nineteen patients had NSAbs, 11 onconeural antibodies, and seven anti-GAD65 antibodies. Anti-LGI1 and anti-NMDAR were the most frequently detected NSAbs, with anti-NMDAR cases having an older-than-expected age distribution (median age 40, range 17-72). Only 11 of 32 (30%) of patients had findings suggesting encephalitis on initial MRI, but 28 of 31 (90%) had pathological findings on initial cerebrospinal fluid analysis. All patients but one had abnormal EEG findings. Median time to immunotherapy was comparable among the three subgroups, whereas patients with anti-LGI1, anti-CASPR2, and anti-IgLON5 had an eightfold longer time to immunotherapy than anti-NMDAR and anti-GABA-B (p = .0016). There was a seasonal variation in onset for patients with non-tumor-related NSAbs and anti-GAD65 antibodies, with most patients (72%) falling ill in spring or summer., Conclusion: Swedish patients with AE and PNS had similar clinical characteristics as previously described cohorts from other geographical regions except for anti-NMDAR encephalitis, with older onset than expected. The onset of non-tumor-related AE occurred predominantly in the warm seasons, and AE with a more insidious onset was associated with delayed treatment initiation., (© 2024 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Mitochondrial DNA (mtDNA) is a pro-inflammatory damage-associated molecular pattern molecule and could be an early indicator for inflammation and disease activity in MS. Autologous hematopoietic stem cell transplantation (aHSCT) is a potent treatment for MS, but its impact on mtDNA levels in cerebrospinal fluid (CSF) remains unexplored., Objectives: To verify elevated CSF mtDNA concentrations in MS patients and assess the impact of aHSCT on mtDNA concentrations., Methods: Multiplex droplet digital PCR (ddPCR) was used to quantify mtDNA and nuclear DNA in 182 CSF samples. These samples were collected from 48 MS patients, both pre- and post-aHSCT, over annual follow-ups, and from 32 healthy controls., Results: CSF ccf-mtDNA levels were higher in patients with MS, correlated to multiple clinical and analytical factors and were normalized after intervention with aHSCT. Differences before aHSCT were observed with regard to MRI-lesions, prior treatment and number of relapses in the last year prior to aHSCT., Conclusion: Our findings demonstrate elevated CSF mtDNA levels in MS patients, which correlate with disease activity and normalize following aHSCT. These results position mtDNA as a potential biomarker for monitoring inflammatory activity and response to treatment in MS., Competing Interests: Declaration of competing interest The authors have no disclosures to report., (Copyright © 2024. Published by Elsevier B.V.)

Background: While a few case-control studies indicated a possible correlation of IgG N-glycosylation patterns with pancreatitis, their restricted sample sizes and methodologies prevented conclusive insights into causality or distinguishing traits across pancreatitis types., Method: We conducted a two-sample Mendelian Randomization (MR) analysis to investigate the causal relationship between 77 IgG N-glycosylation traits and various types of pancreatitis, including acute pancreatitis (AP), chronic pancreatitis (CP), alcohol acute pancreatitis (AAP), and alcohol chronic pancreatitis (ACP). This analysis utilized summary-level data from genome-wide association studies (GWAS), employing methods such as IVW, MR-Egger, and weighted median. To ensure the robustness of our findings, several sensitivity analyses, including Cochran's Q statistic, leave-one-out, MR-Egger intercept, and MR-PRESSO global test were conducted., Result: Our study uncovered the causal relationship between specific IgG N-glycosylation traits and various types of pancreatitis. Notably, an increase in genetically predicted IGP7 levels was associated with a decreased risk of developing AP. For CP, our data suggested a protective effect associated with higher levels of both IGP7 and IGP31, contrasting with increased levels of IGP27 and IGP65, which were linked to a heightened risk. Moreover, in the case of AAP, elevated IGP31 levels were causatively associated with a lower incidence, while higher IGP26 levels correlated with an increased risk for ACP., Conclusion: This study establishes causal relationship between specific IgG N-glycosylation patterns and varying risks of different pancreatitis forms, underscoring their potential as predictive biomarkers. These findings necessitate further exploration into the underlying mechanisms, promising to inform more personalized diagnostic and therapeutic strategies in pancreatitis management., Competing Interests: The 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 © 2024 Chen, Li, Lu, Lv, Ye, Huang, Meng, Long, Burman, Mo and Fan.)

Background: Gender-based violence (GBV) is a global public health concern. India's socio-cultural and regional diversity poses challenges for obtaining accurate and comprehensive indicators of gender-based violence. This study aimed to explore the prevalence and predictors of GBV among adolescents. This was a community-based cross-sectional study conducted among adolescents aged 10 to 19 years in six districts of Madhya Pradesh, the central part of India, from December 2017 to 2019., Methods and Material: GBV was assessed using a validated questionnaire adapted from a nationwide survey. Data were analyzed using SPSS (version 16.0). Logistic regression analysis was performed to identify factors associated with GBV., Results: The study revealed that 10.4% of adolescents were victims of GBV. The multi-variable logistic regression showed that girls were at higher risk (odds ratio = 5.7) of facing GBV. Other significant factors associated with GBV included older adolescents (15-19 years old), those belonging to scheduled caste/tribal areas, those whose mothers were literate, those who had a boyfriend/girlfriend, and those who justified wife beating., Conclusion: GBV is a serious public health problem among adolescents, with one in every 10 adolescents experiencing GBV. It is essential to instil awareness of gender-equal norms from early childhood and within households. Implementing violence prevention policies and strategies in educational and work institutions, as well as at the community level, is crucial., Competing Interests: There are no conflicts of interest., (Copyright: © 2024 Indian Journal of Community Medicine.)

Objective: To investigate the effect of autologous hematopoietic stem cell transplantation (AHSCT) on functional aspects of the nervous system assessed by visual (VEP), somatosensory (SEP), and motor (MEP) evoked potentials in patients with relapsing-remitting multiple sclerosis., Background: Several studies have demonstrated the efficacy of AHSCT on inflammatory activity and disability progression in patients with multiple sclerosis. However, the impact of AHSCT on evoked potentials has not been evaluated before., Methods: Twelve AHSCT-treated patients from Uppsala University Hospital were consecutively recruited. Evoked potentials (EP) were collected at baseline and two follow-up visits, 3 and 12 months post-AHSCT. We calculated a composite EP score for each participant and compared it between different time points., Results: The median total EP score decreased from 5 at baseline, to 2.5 at 12 months post-ASHCT (p = 0.008). A significant improvement in tibial SEP (tSEP) latencies was observed (42.7 vs 41.5 ms, p < 0.001), with a similar trend for MEP latencies 12 months post-ASHCT. No significant changes in median SEP or VEP latencies were observed., Conclusions: Treatment with AHSCT was associated with improved transmission in some central nervous system pathways in multiple sclerosis patients., Competing Interests: Declaration of competing interest The authors declare that there is no conflict of interest., (Copyright © 2024. Published by Elsevier B.V.)

Autoimmune diseases (ADs) are characterized by loss of immune tolerance, high chronicity, with substantial morbidity and mortality, despite conventional immunosuppression (IS) or targeted disease modifying therapies (DMTs), which usually require repeated administration. Recently, novel cellular therapies (CT), including mesenchymal stromal cells (MSC), Chimeric Antigen Receptors T cells (CART) and regulatory T cells (Tregs), have been successfully adopted in ADs. An international expert panel of the European Society for Blood and Marrow Transplantation and the International Society for the Cell and Gene Therapy, reviewed all available evidence, based on the current literature and expert practices, on use of MSC, CART and Tregs, in AD patients with rheumatological, neurological, and gastroenterological indications. Expert-based consensus and recommendations for best practice and quality of patient care were developed to support clinicians, scientists, and their multidisciplinary teams, as well as patients and care providers and will be regularly updated., Competing Interests: RG discloses speaking honoraria from Biotest, Pfizer, Medac, Neovii and Magenta. TA received study support from Amgen, Janssen and honoraria from Neovii, GSK, Astra-Zeneca, Abbvie. FM received honoraria & travel support from BMS, Janssen, Gilead, Miltenyi, Novartis, Astra-Zeneca, Biontech, received research support from Gilead, and discloses advisory board from Biontech. JAS discloses consultancy for Vertex, Medac and Jazz, and advisory board from Kiadis. PA discloses study support by NIHR, payment for expert testimony by Pinsent Mason and Bugge Valentin and consulting to Cellerys AG. RS discloses speaking honoraria from Novartis and Gilead. CCL received travel support for attending meeting by Gilead and discloses consultancy for Nektar Therapeutics and Gilead. FSG received study support from Novartis and Gilead, speaking honoraria from Astra-Zeneca and travel support from Abbvie, Gilead and Pierre-Fabre. FO discloses speaking honoraria from Takeda, Medac, Kyowa Kirin, Menarini-Stemline, and travel support from Medac, Jazz and Janssen. JOL received study support from Abbvie, Gilead, Takeda, consultancy & honoraria from AbbVie, BMS, Celgene, Celtrion, Engytix, Ferring, Galapagos, Gilead, GSK, Janssen, Lilly, MSD, Pfizer, Shire, Takeda, travel support by Abbvie, Takeda, Celltrion. AM received study support from Kyverna, Miltenyi and honoraria from Miltenyi, and participated to advisory board from Century Therapeutics. RC discloses speaking honoraria from GSK, AstraZeneca, Werfen, Rubió, Eli-Lilly, Pfizer. IYA discloses speaking honoraria from Kite, Novartis and BMS. None of the mentioned conflicts of interest were related to financing of the content of this manuscript. The remaining authors have nothing to declare., (© 2024 The Author(s).)

Background: Autologous haematopoietic stem cell transplantation (AHSCT) is increasingly used as a treatment for aggressive multiple sclerosis (MS) and has the potential to induce long-term remission and resolution of disease activity. Despite the extensive research on treatment outcome after AHSCT, the experience of living with MS after AHSCT has not been previously described in the scientific literature. The aim of this study was to explore long-term lived experience of people with MS treated with AHSCT., Methods and Findings: To exclude selection bias, all persons treated with AHSCT for MS at Uppsala University Hospital, Sweden, between 2004 and 2007 (n = 10), were asked to participate in the study, and all accepted. Open-ended interviews were conducted, digitally recorded, transcribed verbatim, and then subjected to qualitative content analysis with an inductive approach. Five main themes emerged from the interviews: (I) being diagnosed with MS-an unpredictable existence; (II) a new treatment-a possibility for a new life; (III) AHSCT-a transition; (IV) reclaiming life; and (V) a bright future accompanied by insecurity. AHSCT was described by the participants in terms of a second chance and an opportunity for a new life. The treatment became a transition from a state of illness to a state of health, enabling a previous profound uncertainty to wane and normality to be restored. Although participants of different age and sex were included, the main limitation of this study is the relatively small number of participants. Also, the inclusion of persons from one centre alone could restrict transferability of the results., Conclusions: The results give a first insight into lived experience following a highly effective induction treatment for MS, and the experience of not having MS anymore. Underpinned by previously described outcome following AHSCT, the results of this study challenge the current view on MS as a chronic disease with no possible cure., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2024 Tolf et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: A growing evidence base supports the use of autologous haematopoietic stem cell transplantation (aHSCT) for treatment of relapsing-remitting multiple sclerosis (RRMS), but it has not yet been integrated into most national clinical guidelines. The objective of this study was to assess efficacy and safety when aHSCT is implemented in routine healthcare., Methods: We assessed 231 patients and the final analysis included 174 RRMS patients who were treated with aHSCT in Sweden before 1 January 2020. Efficacy was evaluated by performing a retrospective analysis of prospectively collected data from the Swedish MS registry. Procedure-related safety was assessed by analysing data from electronic patient records covering a period of 100 days following aHSCT., Results: With a median follow-up time of 5.5 (IQR: 3.4-7.5) years, the Kaplan-Meier estimate for no evidence of disease activity was 73% (95% CI 66% to 81%) at 5 years and 65% (95% CI 57% to 75%) at 10 years. Out of the 149 patients with baseline disability, 80 (54%) improved, 55 (37%) were stable and 14 (9%) deteriorated. The mean number of adverse events per patient was 1.7 (±SD: 1.5) for grade 3 events and 0.06 (±SD: 0.3) for grade 4 events. Febrile neutropenia was the most common adverse event, affecting 68% of patients. There was no treatment-related mortality., Conclusions: Treatment with aHSCT for RRMS is associated with freedom from disease activity in a majority of patients, with acceptable adverse events. This procedure should be considered a standard of care for patients with highly active RRMS., Competing Interests: Competing interests: EI has received speakers fee from Merck and honoraria from advisory boards for Sanofi-Aventis, Biogen and Merck. FP previously received research grants from Merck KGaA, Janssen and UCB outside this study. FP has received payment for expert testimony from Novartis. FP has participated in Data Monitoring Committee for clinical trials from Chugai, Lundbeck and Roche. JM has received lecture honorarium from Merck. NL has received honoraria from Sanofi. All other individual authors declare that there is no conflict of interest., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: We analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (NCT03193866), a Swedish nationwide observational study in relapsing-remitting multiple sclerosis (RRMS), to identify trajectories of processing speed and physical disability after disease-modulating therapy (DMT) start., Methods: Using a group-modelling approach, we assessed trajectories of processing speed with oral Symbol Digit Modalities Test (SDMT) and physical disability with Expanded Disability Status Scale, from first DMT start among 1645 patients with RRMS followed during 2011-2022. We investigated predictors of trajectories using group membership as a multinomial outcome and calculated conditional probabilities linking membership across the trajectories., Results: We identified 5 stable trajectories of processing speed: low SDMT scores (mean starting values=29.9; 5.4% of population), low/medium (44.3; 25.3%), medium (52.6; 37.9%), medium/high (63.1; 25.8%) and high (72.4; 5.6%). We identified 3 physical disability trajectories: no disability/stable (0.8; 26.8%), minimal disability/stable (1.6; 58.1%) and moderate disability (3.2; 15.1%), which increased to severe disability. Older patients starting interferons were more likely than younger patients starting rituximab to be on low processing speed trajectories. Older patients starting teriflunomide, with more than one comorbidity, and a history of pain treatment were more likely to belong to the moderate/severe physical disability trajectory, relative to the no disability one. There was a strong association between processing speed and physical disability trajectories., Conclusions: In this cohort of actively treated RRMS, patients' processing speed remained stable over the years following DMT start, whereas patients with moderate physical disability deteriorated in physical function. Nevertheless, there was a strong link between processing speed and disability after DMT start., Competing Interests: Competing interests: AF-H has received unrestricted funding from Biogen Idec, Pfizer, Orion Pharma and Celltrion, speaking honoraria from Merck and consulting fee from Roche and AstraZeneca. KF has received honoraria for serving on advisory boards for Biogen and Merck KGaA, and speaker’s fees from Biogen, Novartis and Merck KGaA. JH has received honoraria for serving on advisory boards for Biogen, Celgene, Sanofi-Genzyme, Merck KGaA, Novartis and Sandoz, and speaker’s fees from Biogen, Novartis, Merck, KGaA, Teva and Sanofi-Genzyme, and he has served as PI for projects, or received unrestricted research support from, Biogen, Celgene, Merck KGaA, Novartis, Roche and Sanofi-Genzyme. AML-G receives grant support and awards from the Patient Centered Outcomes Research Institute and the National MS Society; she currently serves as a voting member on the California Technology Assessment Forum, a core program of the Institute for Clinical and Economic Review (ICER); she has received sponsored and reimbursed travel from ICER and the National Institutes of Health. PN has received travel support from Bayer Schering Pharma, Merck Serono, Biogen and Genzyme a Sanofi Company, honoraria for lectures and advisory boards from Merck Serono and Genzyme a Sanofi Company, advisory boards for Novartis and Roche, lectures for Biogen and has received unrestricted grants from Biogen. JL has received travel support and/or lecture honoraria from Biogen, Novartis, Merck, Alexion, BMS, Celgene, Janssen and Sanofi Genzyme; has served on scientific advisory boards for Almirall, Teva, Biogen, Novartis, Merck, Roche, Sanofi Genzyme and BMS; serves on the editorial board of the Acta Neurologica Scandinavica; and has received unconditional research grants from Biogen and Novartis, and financial support from Sanofi for an investigator-initiated study. JS has received consultancy fees paid to the institution by Mabion S.A. FP has received research grants from Janssen, Merck KGaA and UCB, and fees for serving as Chair of DMC in clinical trials with Chugai, Lundbeck and Roche, and preparation of witness statement for Novartis. TO has received compensation for advisory boards/lectures and unrestricted MS research grants from Biogen, Merck, Novartis and Sanofi., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY. Published by BMJ.)

The global unmet need for kidney replacement therapy means that millions of people die every year as they cannot afford treatment. Peritoneal dialysis (PD) offers comparable survival to haemodialysis and is often more affordable, but one barrier to increasing access is that conventional manufacturing and distribution of PD fluid is costly. Here we report the results from a pilot proof-of-principal study demonstrating for the first time that the Ellen Medical Devices Point-of-Care system can be used by patients to produce sterile PD fluid at the point-of-care. With further development, this low-cost system could offer a solution to the many millions of people around the world who currently cannot afford treatment for kidney failure., Competing Interests: Declaration of conflicting interestThe authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: BT, JB, VG, AB, NK and JK are employees of Ellen Medical Devices on secondment from the George Institute for Global Health. BT, VG, VP, MJ, MG and JK are employees or hold appointments at the George Institute for Global Health which is the majority owner of Ellen Medical Devices. These relationships are considered to be synergies rather than conflicts. SD receives research funding from Baxter HealthCare, lecture fees from Baxter and Fresenius Medical Care, Advisory Board Fees from Ellen Medical and is president of EuroPD. MJ is responsible for research projects that have received funding from Amgen, Baxter, CSL, Dimerix, Eli Lilly, Gambro and MSD; has received fees for Advisory, Steering Committee and/or Scientific Presentations from Akebia, Amgen, Astra Zeneca, Baxter, Bayer, Boehringer Ingelheim, Cesas Linx, Chinook, CSL, Janssen, Medscape, MSD, Roche and Vifor; with any consultancy, honoraria or travel support paid to her institution.

Neuromyelitis optica (NMO), which is also referred to as Devic's disease, was originally considered an aggressive subtype of multiple sclerosis (MS) presenting as optic neuritis and/or extensive transverse myelitis in which 50% of patients become blind or in a wheelchair within 5 years of onset. Subsequently, NMO was categorized as one of a spectrum of inflammatory and demyelinating autoimmune disorders that are distinct from multiple sclerosis and termed neuromyelitis optica spectrum disorder (NMOSD). NMOSD differs from multiple sclerosis by its clinical course, presentation, magnetic resonance imaging findings, clinical presentation, serum biomarker prognosis, and response to treatment. More recently, NMOSD has been subdivided according to auto-antibody status as aquaporin 4 (AQP4) seropositive NMO, myelin oligodendrocyte glycoprotein (MOG) antibody-associated disease (MOGAD), and seronegative NMOSD. The only treatment to date that has resulted in treatment-free remissions, now lasting for more than 5-10 years with posttreatment disappearance of anti-AQP4 antibodies, is hematopoietic stem cell transplantation (HSCT) using either an allogeneic (matched sibling or unrelated) donor with a reduced toxicity conditioning regimen or an autologous stem cell source using a nonmyeloablative conditioning regimen of plasmapheresis (PLEX), cyclophosphamide (Cytoxan®), rabbit antithymocyte (ATG), and rituximab (Rituxan®). Post-HSCT long-term resolution of disease activity and disappearance of AQP4 antibodies is consistent with HSCT-induced immune tolerance., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Autologous hematopoietic stem cell transplantation (aHSCT) may be effective in carefully selected pediatric patients with multiple sclerosis (MS), neuromyelitis optica (NMO), and chronic inflammatory demyelinating polyneuropathy (CIDP). aHSCT for pediatric MS (same as for adults) is performed to eradicate inflammatory autoreactive cells with lympho-ablative regimens and restore immune tolerance. Its therapeutic effect in MS relies on various mechanisms: (1) the immunosuppressive conditioning regimen prior to aHSCT was able to eradicate the autoreactive cells and (2) the regeneration/renewal of the immune system to reset the aberrant immune response against self-antigens. The aHSCT procedure includes the following different steps, as described in this chapter: patient selection through careful pretransplant screening, "wash-out" period from previous treatments, mobilization of hematopoietic stem cells (HSC), conditioning regimen, HSC infusion, and posttransplant monitoring for early and late complications. Moreover, specific aspects of pediatric population undergoing aHSCT are described. According to the available evidence, aHSCT appears to be safe in pediatric MS, obtaining disease control for a prolonged time after the procedure. A reasonable approach in this setting includes the application of less toxic treatments while reserving aHSCT procedure for patients with severe/refractory forms of the disease. The EBMT considers MS, NMO, and CIDP in pediatric patients within the category of the clinical option (CO), where candidates for aHSCT can be selected on the basis of careful consideration of individual case history in the multidisciplinary setting., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Autologous hematopoietic stem cell transplantation (HSCT) is associated with 5-year treatment-free remissions in approximately 80% of patients with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) who failed or were dependent on intravenous immunoglobulin and or plasmapheresis. Autologous HSCT was associated with significant improvement in strength, independent ambulation, quality of life, nerve conduction velocity, and compound muscle action potential amplitude. The results of HSCT are dependent on proper patient selection, i.e., the right diagnosis and the right stage of the disease. An important caveat is that a significant number of patients with a CIDP diagnostic label are found upon further workup have a peripheral neuropathy of another etiology. Patients undergoing HSCT for CIDP should be reevaluated before HSCT to confirm the diagnosis and those who fail HSCT should be reevaluated for a diagnosis other than CIDP., (Copyright © 2024 Elsevier B.V. All rights are reserved, including those for text and data mining, AI training, and similar technologies.)

Background COVID-19 has affected the physical and mental health of people globally, and vaccination is seen as a crucial tool in controlling the pandemic. However, the readiness to vaccinate children remains a concern, particularly in India. Aim The study aimed to investigate the association between the psychological impact of COVID-19 and willingness to vaccinate their children among attendees of the COVID-19 vaccination clinic at Nil Ratan Sircar Medical College, Kolkata. Method The study used an observational, cross-sectional design and collected data from 356 participants between August and September 2022. The COVID-19 Perceived Stress Scale-10 was used to assess participants' psychological impact, and willingness to vaccinate was determined using a survey. Results Approximately 64% (n=227) and 71% (n=253) of the participants exhibited a high level of perceived stress and willingness to vaccinate their children. The vaccine acceptance was significantly associated with perceived stress level and other factors such as family type, presence of chronic illness, and history of acquaintances suffering from COVID-19. Conclusion The study highlights the importance of addressing parental stress and anxiety to enhance vaccination rates among children. To achieve this, population-level awareness of vaccine safety measures and benefits should be raised to alleviate stress and increase vaccine uptake., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Burman et al.)

Background: Neuroinflammatory processes have been suggested to play a role in the pathophysiology of neurodegenerative diseases and post-hemorrhagic hydrocephalus, but have rarely been investigated in patients with idiopathic normal pressure hydrocephalus (iNPH). The aim of this study was to investigate whether levels of inflammatory proteins in CSF are different in iNPH compared to healthy controls and patients with selected neurodegenerative disorders, and whether any of these markers can aid in the differential diagnosis of iNPH., Methods: Lumbar CSF was collected from 172 patients from a single center and represented iNPH (n = 74), Alzheimer's disease (AD) (n = 21), mild cognitive impairment (MCI) due to AD (n = 21), stable MCI (n = 22), frontotemporal dementia (n = 13), and healthy controls (HC) (n = 21). Levels of 92 inflammatory proteins were analyzed using a proximity extension assay. As a first step, differences between iNPH and HC were investigated, and proteins that differed between iNPH and HC were then compared with those from the other groups. The linear regressions were adjusted for age, sex, and plate number., Results: Three proteins showed higher (MCP-1, p = 0.0013; CCL4, p = 0.0008; CCL11, p = 0.0022) and one lower (PD-L1, p = 0.0051) levels in patients with iNPH compared to HC. MCP-1 was then found to be higher in iNPH than in all other groups. CCL4 was higher in iNPH than in all other groups, except in MCI due to AD. PD-L1 was lower in iNPH compared to all other groups, except in stable MCI. Levels of CCL11 did not differ between iNPH and the differential diagnoses. In a model based on the four proteins mentioned above, the mean area under the receiver operating characteristic curve used to discriminate between iNPH and the other disorders was 0.91., Conclusions: The inflammatory cytokines MCP-1 and CCL4 are present at higher-and PD-L1 at lower-levels in iNPH than in the other investigated diagnoses. These three selected cytokines may have diagnostic potential in the work-up of patients with iNPH., (© 2023. BioMed Central Ltd., part of Springer Nature.)

p53 mutation is common and highly related to radiotherapy resistance in rectal cancer. APR-246, as a small molecule, can restore the tumor-suppressor function to mutant p53. As there is currently no existing study on combining APR-246 with radiation in rectal cancer, our objective was to investigate whether APR-246 could enhance the sensitivity of colorectal cancer cells, regardless of their p53 status, to radiation treatment. The combination treatment had synergistic effects on HCT116p53-R248W/- (p53Mut) cells, followed by HCT116p53+/+ [wild-type p53 (p53WT)] cells, and exhibited an additive effect on HCT116p53-/- (p53Null) cells through inhibiting proliferation, enhancing reactive oxygen species, and apoptosis. The results were confirmed in zebrafish xenografts. Mechanistically, p53Mut and p53WT cells shared more activated pathways and differentially expressed genes following the combination treatment, compared with p53Null cells, although the combination treatment regulated individual pathways in the different cell lines. APR-246 mediated radiosensitization effects through p53-dependent and -independent ways. The results may provide evidence for a clinical trial of the combination in patients with rectal cancer., (©2023 The Authors; Published by the American Association for Cancer Research.)

Background: The common inflammatory disease multiple sclerosis (MS) is a disease of the central nervous system. For more than 25 years autologous hematopoietic stem cell transplantation (AHSCT) has been used to treat MS. It has been shown to be highly effective in suppressing inflammatory activity in relapsing-remitting MS (RRMS) patients. This treatment is thought to lead to an immune system reset, inducing a new, more tolerant system; however, the precise mechanism behind the treatment effect in MS patients is unknown. In this study, the effect of AHSCT on the metabolome and lipidome in peripheral blood from RRMS patients was investigated., Methods: Peripheral blood samples were collected from 16 patients with RRMS at ten-time points over the five months course of AHSCT and 16 MS patients not treated with AHSCT. Metabolomics and lipidomics analysis were performed using liquid-chromatography high-resolution mass spectrometry. Mixed linear models, differential expression analysis, and cluster analysis were used to identify differentially expressed features and groups of features that could be of interest. Finally, in-house and in-silico libraries were used for feature identification, and enrichment analysis was performed., Results: Differential expression analysis found 657 features in the lipidomics dataset and 34 in the metabolomics dataset to be differentially expressed throughout AHSCT. The administration of cyclophosphamide during mobilization and conditioning was associated with decreased concentrations in glycerophosphoinositol species. Thymoglobuline administration was associated with an increase in ceramide and glycerophosphoethanolamine species. After the conditioning regimen, a decrease in glycerosphingoidlipids concentration was observed, and following hematopoietic stem cell reinfusion glycerophosphocholine concentrations decreased for a short period of time. Ceramide concentrations were strongly associated with leukocyte levels during the procedure. The ceramides Cer(d19:1/14:0) and Cer(d20:1/12:0) were found to be increased (P < .05) in concentration at the three-month follow-up compared to baseline. C16 ceramide, Cer(D18:2/16:0), and CerPE(d16:2(4E,6E)/22:0) were found to be significantly increased in concentration after AHSCT compared to prior to treatment as well as compared to newly diagnosed RRMS patients., Conclusion: AHSCT had a larger impact on the lipids in peripheral blood compared to metabolites. The variation in lipid concentration reflects the transient changes in the peripheral blood milieu during the treatment, rather than the changes in the immune system that are assumed to be the cause of clinical improvement within RRMS patients treated with AHSCT. Ceramide concentrations were affected by AHSCT and associated with leukocyte counts and were altered three months after treatment, suggesting a long-lasting effect., (© 2023. The Author(s).)

Importance: Autologous hematopoietic stem cell transplant (AHSCT) is available for treatment of highly active multiple sclerosis (MS)., Objective: To compare the effectiveness of AHSCT vs fingolimod, natalizumab, and ocrelizumab in relapsing-remitting MS by emulating pairwise trials., Design, Setting, and Participants: This comparative treatment effectiveness study included 6 specialist MS centers with AHSCT programs and international MSBase registry between 2006 and 2021. The study included patients with relapsing-remitting MS treated with AHSCT, fingolimod, natalizumab, or ocrelizumab with 2 or more years study follow-up including 2 or more disability assessments. Patients were matched on a propensity score derived from clinical and demographic characteristics., Exposure: AHSCT vs fingolimod, natalizumab, or ocrelizumab., Main Outcomes: Pairwise-censored groups were compared on annualized relapse rates (ARR) and freedom from relapses and 6-month confirmed Expanded Disability Status Scale (EDSS) score worsening and improvement., Results: Of 4915 individuals, 167 were treated with AHSCT; 2558, fingolimod; 1490, natalizumab; and 700, ocrelizumab. The prematch AHSCT cohort was younger and with greater disability than the fingolimod, natalizumab, and ocrelizumab cohorts; the matched groups were closely aligned. The proportion of women ranged from 65% to 70%, and the mean (SD) age ranged from 35.3 (9.4) to 37.1 (10.6) years. The mean (SD) disease duration ranged from 7.9 (5.6) to 8.7 (5.4) years, EDSS score ranged from 3.5 (1.6) to 3.9 (1.9), and frequency of relapses ranged from 0.77 (0.94) to 0.86 (0.89) in the preceding year. Compared with the fingolimod group (769 [30.0%]), AHSCT (144 [86.2%]) was associated with fewer relapses (ARR: mean [SD], 0.09 [0.30] vs 0.20 [0.44]), similar risk of disability worsening (hazard ratio [HR], 1.70; 95% CI, 0.91-3.17), and higher chance of disability improvement (HR, 2.70; 95% CI, 1.71-4.26) over 5 years. Compared with natalizumab (730 [49.0%]), AHSCT (146 [87.4%]) was associated with marginally lower ARR (mean [SD], 0.08 [0.31] vs 0.10 [0.34]), similar risk of disability worsening (HR, 1.06; 95% CI, 0.54-2.09), and higher chance of disability improvement (HR, 2.68; 95% CI, 1.72-4.18) over 5 years. AHSCT (110 [65.9%]) and ocrelizumab (343 [49.0%]) were associated with similar ARR (mean [SD], 0.09 [0.34] vs 0.06 [0.32]), disability worsening (HR, 1.77; 95% CI, 0.61-5.08), and disability improvement (HR, 1.37; 95% CI, 0.66-2.82) over 3 years. AHSCT-related mortality occurred in 1 of 159 patients (0.6%)., Conclusion: In this study, the association of AHSCT with preventing relapses and facilitating recovery from disability was considerably superior to fingolimod and marginally superior to natalizumab. This study did not find evidence for difference in the effectiveness of AHSCT and ocrelizumab over a shorter available follow-up time.

Background and Objectives: In the past decade, autologous hematopoietic stem cell transplantation (AHSCT) has emerged as a treatment for relapsing-remitting multiple sclerosis (RRMS). How this procedure affects biomarkers of B- and T-cell activation is currently unknown. The objective of this study was to investigate CXCL13 and sCD27 concentrations in CSF before and after AHSCT., Methods: This prospective cohort study was conducted at a specialized MS clinic in a university hospital. Patients with a diagnosis of RRMS, treated with AHSCT between January 1, 2011, and December 31, 2018, were evaluated for participation. Patients were included if CSF samples from baseline plus at least 1 follow-up were available on June 30, 2020. A control group of volunteers without neurologic disease was included as a reference. CSF concentrations of CXCL13 and sCD27 were measured with ELISA., Results: The study comprised 29 women and 16 men with RRMS, aged 19-46 years at baseline, and 15 women and 17 men, aged 18-48 years, in the control group. At baseline, patients had higher CXCL13 and sCD27 concentrations than controls, with a median (IQR) of 4 (4-19) vs 4 (4-4) pg/mL ( p < 0.0001) for CXCL13 and 352 (118-530) vs 63 (63-63) pg/mL ( p < 0.0001) for sCD27. After AHSCT, the CSF concentrations of CXCL13 were considerably lower at the first follow-up at 1 year than at baseline, with a median (IQR) of 4 (4-4) vs 4 (4-19) pg/mL ( p < 0.0001), and then stable throughout follow-up. The CSF concentrations of sCD27 were also lower at 1 year than at baseline, with a median (IQR) of 143 (63-269) vs 354 (114-536) pg/mL ( p < 0.0001). Thereafter, sCD27 concentrations continued to decrease and were lower at 2 years than at 1 year, with a median (IQR) of 120 (63-231) vs 183 (63-290) pg/mL ( p = 0.017)., Discussion: After AHSCT for RRMS, CSF concentrations of CXCL13 were rapidly normalized, whereas sCD27 decreased gradually over the course of 2 years. Thereafter, the concentrations remained stable throughout follow-up, indicating that AHSCT induced long-lasting biological changes., (Copyright © 2023 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Academy of Neurology.)

Multiple sclerosis is a highly complex and heterogeneous disease. At the onset it often presents as a clinically isolated syndrome. Thereafter relapses are followed by periods of remissions, but eventually, most patients develop secondary progressive multiple sclerosis. It is widely accepted that autoantibodies are important to the pathogenesis of multiple sclerosis, but hitherto it has been difficult to identify the target of such autoantibodies. As an alternative strategy, cell-based methods of detecting autoantibodies have been developed. The objective of this study was to explore differences in the binding of antibodies from sera and CSF of multiple sclerosis patients and controls to oligodendroglial and neuronal cell-lines, related to antibody type, immunoglobulin (IgG/IgM), matrix (serum/CSF) and disease course. The oligodendroglial and neuronal cell-lines were expanded in tissue culture flasks and transferred to 96-well plates at a concentration of 50 000 cells/well followed by fixation and blocking with bovine serum albumin. Sera and CSF samples, from healthy controls and multiple sclerosis patients, were incubated with the fixed cells. Epitope binding of immunoglobulins (IgG and IgM) in sera and CSF was detected using biotinylated anti-human IgM and IgG followed by avidin conjugated to horseradish peroxidase. Horseradish peroxidase activity was detected with 3,3',5,5'-tetramethylbenzidine substrate. Serum from 76 patients and 30 controls as well as CSF from 62 patients and 32 controls were investigated in the study. The binding was similar between clinically isolated syndrome patients and controls, whereas the largest differences were observed between secondary progressive multiple sclerosis patients and controls. Antibodies from multiple sclerosis patients (all disease course combined) bound more to all investigated cell-lines, irrespectively of matrix type, but binding of immunoglobulin G from CSF to human oligodendroglioma cell-line discriminated best between multiple sclerosis patients and controls with a sensitivity of 93% and a specificity of 96%. The cell-based enzyme linked immunosorbent assay (ELISA) was able to discriminate between multiple sclerosis patients and controls with a high degree of accuracy. The disease course was the major determinant for the antibody binding., Competing Interests: The authors report no conflict of interest., (© The Author(s) 2023. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Progressive multiple sclerosis (PMS) is currently diagnosed retrospectively. Here, we work toward a set of biomarkers that could assist in early diagnosis of PMS. A selection of cerebrospinal fluid metabolites (n = 15) was shown to differentiate between PMS and its preceding phenotype in an independent cohort (AUC = 0.93). Complementing the classifier with conformal prediction showed that highly confident predictions could be made, and that three out of eight patients developing PMS within three years of sample collection were predicted as PMS at that time point. Finally, this methodology was applied to PMS patients as part of a clinical trial for intrathecal treatment with rituximab. The methodology showed that 68% of the patients decreased their similarity to the PMS phenotype one year after treatment. In conclusion, the inclusion of confidence predictors contributes with more information compared to traditional machine learning, and this information is relevant for disease monitoring., Competing Interests: The authors declare no competing interests., (© 2023 The Authors.)

Autologous hematopoietic stem cell transplantation (AHSCT) has been approved for multiple sclerosis (MS) in many European countries. A large proportion of patients are women of child-bearing age. For them, AHSCT may have negative consequences for reproductive health, since the ovaries are particularly susceptible to alkylating agents. Anti-Müllerian hormone (AMH) reflects the ovarian reserve and has been suggested as a potential biomarker of fertility in women. The aim of this study was to investigate AMH levels in relation to age and reproductive potential in MS patients treated with AHSCT. The study cohort comprised 38 female patients, aged 20-44 years, who underwent AHSCT for MS using a cyclophosphamide (200 mg/kg)/rabbit-anti-thymocyte globulin (6 mg/kg) conditioning regimen between 2013-2020. Clinal follow-up visits were made 3 months after AHSCT and then yearly. AMH was analysed in blood samples. The median age at transplantation was 28 years (interquartile range, IQR 25-33). The median AMH concentration was 23 pmol/l at baseline (IQR 6.0-30), 0.5 pmol/l at 3 months (IQR 0-1.5) and 1.1 pmol/l at 2 years (IQR 0-2.9). A multiple linear regression model was used to determine if age and/or AHSCT influenced AMH values; both significantly did (age, -0.21 per year, p = 0.018; AHSCT -19, p <0.0001). Seven women became pregnant, six spontaneously and one both spontaneously and with IVF. One patient underwent an abortion, all other pregnancies led to live births. Six of the women became pregnant despite low or very low post-AHSCT serum concentrations of AMH, suggesting that low serum AMH concentrations do not necessarily reflect impaired fertility in patients treated with high-dose cyclophosphamide., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Zafeiri et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Background: Quantitative positron emission tomography (PET) scans of the brain typically require arterial blood sampling but this is complicated and logistically challenging. One solution to remove the need for arterial blood sampling is the use of image-derived input functions (IDIFs). Obtaining accurate IDIFs, however, has proved to be challenging, mainly due to the limited resolution of PET. Here, we employ penalised reconstruction alongside iterative thresholding methods and simple partial volume correction methods to produce IDIFs from a single PET scan, and subsequently, compare these to blood-sampled input curves (BSIFs) as ground truth. Retrospectively we used data from sixteen subjects with two dynamic 15 O-labelled water PET scans and continuous arterial blood sampling: one baseline scan and another post-administration of acetazolamide., Results: IDIFs and BSIFs agreed well in terms of the area under the curve of input curves when comparing peaks, tails and peak-to-tail ratios with R 2 values of 0.95, 0.70 and 0.76, respectively. Grey matter cerebral blood flow (CBF) values showed good agreement with an average difference between the BSIF and IDIF CBF values of 2% ± and a coefficient of variation (CoV) of 7.3%., Conclusion: Our results show promising results that a robust IDIF can be produced for dynamic 15 O-water PET scans using only the dynamic PET scan images with no need for a corresponding MRI or complex analytical techniques and thereby making routine clinical use of quantitative CBF measurements with 15 O-water feasible., (© 2023. The Author(s).)

Background: Fatigue is a debilitating symptom of multiple sclerosis (MS), but its relation to sociodemographic and disease-related characteristics has not been investigated in larger studies. The objectives of this study were to evaluate predictors of self-reported fatigue in a Swedish nationwide register-based MS cohort., Methods: Using a repeated cross-sectional design, we included 2,165 persons with relapsing- remitting and secondary progressive MS with one or multiple Fatigue Scale for Motor and Cognitive Functions (FSMC) scores, which was modelled using multivariable linear regressions for multiple predictors., Results: Only associations to expanded disability status scale (EDSS) and Symbol Digit Modalities Test (SDMT) were considered clinically meaningful among MS-associated characteristics in our main model; compared to mild disability (EDSS 0-2.5), those with severe disability (EDSS ≥6) scored 17.6 (95% CI 13.1-22.2) FSMC points higher, while the difference was 10.7 (95% CI 8.0-13.4) points for the highest and lowest quartiles of SDMT. Differences between highest and lowest quartiles of health-related quality of life (HRQoL) instruments were even greater and considered clinically meaningful; EuroQoL Visual Analogue Scale (EQ-VAS) 31.9 (95% CI 29.9-33.8), Multiple Sclerosis Impact Scale (MSIS-29) psychological component 35.6 (95% CI 33.8-37.4) and MSIS-29 physical component 45.5 (95% CI 43.7-47.4)., Conclusion: Higher self-reported fatigue is associated with higher disability level and worse cognitive processing speed, while associations to other MS-associated characteristics including MS type, line of disease modifying therapy (DMT), MS duration, relapse and new cerebral lesions are weak. Furthermore, we found a strong correlation between high fatigue rating and lower ratings on health-related quality of life instruments., Competing Interests: Declaration of Competing Interest Simon Englund declare that there is no conflict of interest; Marie Kierkegaard has received honoraria for lectures from Sanofi, Genzyme Roche and Novartis; Joachim Burman declare that there is no conflict of interest; Katharina Fink has received lecture honoraria from Biogen and Merck, has served on scientific advisory boards for Biogen, Roche, Merck and Alexion, has received a research grant from Amicus; Anna Fogdell-Hahn has received unrestricted funding from Biogen Idec, Pfizer, Orion Pharma and Celltrion, speaking honoraria from Merck, and consulting fee from Roche; Martin Gunnarsson declare that there is no conflict of interest; Jan Hillert has received honoraria for serving on advisory boards for Biogen, Celgene, Sanofi-Genzyme, Merck KGaA, Novartis and Sandoz and speaker's fees from Biogen, Novartis, Merck KGaA, Teva and Sanofi-Genzyme. He has served as P.I. for projects, or received unrestricted research support from, Biogen, Celgene, Merck KGaA, Novartis, Roche and Sanofi-Genzyme. His MS research was funded by the Swedish Research Council and the Swedish Brain foundation; Annette Langer-Gould receives grant support and awards from the Patient Centered Outcomes Research Institute and the National MS Society; she currently serves as a voting member on the California Technology Assessment Forum, a core program of the Institute for Clinical and Economic Review (ICER). She has received sponsored and reimbursed travel from ICER and the National Institutes of Health; Jan Lycke has received travel support and/or lecture honoraria from Biogen, BMS, Novartis, Sanofi, Roche and Alexion, has served on scientific advisory boards for Biogen, BMS, Novartis, Sanofi, Roche and Alexion, serves on the editorial board of the Acta Neurologica Scandinavica, and has received unconditional research grants from Biogen and Novartis. Petra Nilsson has received travel support from Bayer Schering Pharma, Merck Serono, Biogen and Genzyme a Sanofi Company, honoraria for lectures and advisory boards from Merck Serono and Genzyme a Sanofi Company, advisory boards for Novartis and Roche, lectures for Biogen and has received unrestricted grants from Biogen. Jonatan Salzer has received institutional fees from Mabion S.A. for serving as a consultant in a clinical trial. Anders Svenningsson declare that there is no conflict of interest; Johan Mellergård has received honoraria for Advisory boards for Sanofi Genzyme and Merck and lecture honoraria from Merck; Tomas Olsson has received honoraria for lectures/advisory boards, and unrestricted MS research grants from Biogen, Novartis, Sanofi, Merck and Roche; Elisa Longinetti declare that there is no conflict of interest; Thomas Frisell declare that there is no conflict of interest; Fredrik Piehl has received research grants from Janssen, Merck KGaA and UCB, and fees for serving on DMC in clinical trials with Chugai, Lundbeck and Roche, and preparation of expert witness statement for Novartis. There is no commercial entity relevant for potential conflicts., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

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 &lt;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.)