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Multiple sclerosis (MS) is an autoimmune disease of the central nervous system (CNS) that results in significant neurodegeneration in the majority of those affected and is a common cause of chronic neurological disability in young adults1,2. Here, to provide insight into the potential mechanisms involved in progression, we conducted a genome-wide association study of the age-related MS severity score in 12,584 cases and replicated our findings in a further 9,805 cases. We identified a significant association with rs10191329 in the DYSF-ZNF638 locus, the risk allele of which is associated with a shortening in the median time to requiring a walking aid of a median of 3.7 years in homozygous carriers and with increased brainstem and cortical pathology in brain tissue. We also identified suggestive association with rs149097173 in the DNM3-PIGC locus and significant heritability enrichment in CNS tissues. Mendelian randomization analyses suggested a potential protective role for higher educational attainment. In contrast to immune-driven susceptibility3, these findings suggest a key role for CNS resilience and potentially neurocognitive reserve in determining outcome in MS.

Background: A challenge to implementation is management of the adaptation-fidelity dilemma or the balance between adopting an intervention with fidelity while assuring fit when transferred between contexts. A prior meta-analysis found that adapted interventions produce larger effects than novel and adopted interventions. This study attempts to replicate and expand previous findings. Methods: Meta-analysis was used to compare effects across a whole-population of Swedish outcome studies. Main and subcategories are explored. Results: The 523 studies included adapted (22%), adopted (33%), and novel (45%) interventions. The largest effect was found for adapted followed by novel and adopted interventions. Interventions in the mental health setting showed the highest effects, followed by somatic healthcare and social services. Conclusions: These results replicate and expand earlier findings. Results were stable across settings with the exception of social services. Consistent with a growing body of evidence results suggest that context is important when transferring interventions across settings.

QC 20221215

QC 20221215

QC 20221212

QC 20221212

Introduction: Dimethyl fumarate (DMF) is an oral therapy for relapsing-remitting multiple sclerosis (RRMS). DMF is included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE). Objectives/Aims: To assess the effectiveness and safety of DMF with focus on patients treated at least 72 months. Methods: Descriptive data of Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - 5 Dimensions Test (EQ-5D), Visual Analog Scale (VAS), Adverse Events (AEs) and Serious AEs (SAEs) is obtained from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and drug survival using the Kaplan-Meier curve. Results: 2565 DMF-treated patients were included between March 2014 and March 2022 with an overall drug survival rate of 38.7% and a mean treatment duration of 37 months. The main reasons for discontinuation were AEs (47%) and lack of effect (30%). 199 AEs were reported of which 63 were serious. For both serious and non-serious AEs reported, gastrointestinal disorders were the most common (19% and 27%, respectively).509 patients had continuous treatment for at least 72 months. This cohort had a mean age of 42 years and a mean treatment duration of 84 months. The majority (51%) had switched from interferon or glatiramer acetate and 24% were treatment naïve.Significant improvements in mean values at 72 months of treatment compared to baseline were noted for MSSS, MSIS-29 Psychological, and EQ-5D (p<0.05). All other tests remained stable after 6 years of treatment. Number of relapses per 1000 patient years were improved from 199.6 before DMF treatment start to 23.0 during treatment with DMF.49 patients (10%) have discontinued DMF treatment in the 72 month cohort with a mean treatment duration of 84 months (range 70-97 months). The

Introduction: Epstein-Barr virus (EBV) infection may be a pre-condition for the development of multiple sclerosis (MS). EBV antibodies, predominantly anti-EBNA1, develop in the presymp-tomatic phase of virtually all MS patients. Using material from a serum repository, studies in advance of MS onset indicated that EBV seropositivity preceded the first expression of incipient axonal lesions, serum Neurofilament Light (sNFL) . Objectives: To determine the onset and individual order of appearance of EBV seroreactivity and the serum neuroaxonal injury marker neurofilament light (sNfL) in a wide age spectrum of presymptomatic MS patients. Aims: To characterize the presymptomatic appearance of anti-bodies against an intranuclear (EBNA1) and a surface EBV anti-gen (gp350) and sNfL.Methods: A nested case-control study in 669 pre-symptomati-cally acquired blood samples from persons who later received an MS diagnosis, and from 1:1 matched control persons. Serum lev-els of EBNA1, VCA and gp350 IgG antibodies and sNFL (n=519) were measured in individual presymptomatic samples and expressed as delta scores with matched controls in relation to time until MS onset. Results: Serum levels expressed as delta scores for anti EBV and NfL IgG showed an incipient increase for anti EBNA1 and gp350 from 15-20 years before MS debut. Significant (p=0.001 and p=0.002) from 10-15 years, with consistent delta-scores succes-sively closer to MS onset. These findings contrasted to the level of sNfL which increasingly diverged from matched controls from 5-10 years before the onset of MS. None of the individual sam-ples negative for both EBNA1 and VCA IgG antibodies in the pre-MS group (n = 36) showed any elevation of the sNfL level. Conclusions: In a pre-MS material, the seroreactivity against EBNA1 was followed by VCA and gp350, before increased sNFL appeared, indicating incipient axonal injury. Togeth

Introduction: Natalizumab (NTZ) is a highly effective disease modulatory treatment for relapsing-remitting multiple sclerosis (RRMS). Post-marketing surveillance is important for evaluation of long-term safety and effectiveness in a real-world setting. To this end the “Immunomodulation and Multiple Sclerosis Epidemiology Study” (IMSE 1) was initiated upon NTZ launch in Sweden (Aug 2006). Objectives/Aims: To follow-up the long-term effectiveness and safety of NTZ in a real-world setting. Methods: Adverse events (AEs), Serious AEs (SAEs), John Cunningham virus status (JCV) and clinical effectiveness measures; Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT) and Multiple Sclerosis Impact Scale (MSIS-29) data is collected from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using the Wilcoxon Signed Rank Test. Results: A total of 3622 NTZ patients were included in the IMSE 1 study from August 2006 until March 2022 (72% female; mean age 36 years; 80% RRMS; mean treatment duration 49 months) and 186 had been treated for at east 132 months. Of the 132-month cohort, 73% were female, the mean age was 36 years, 88% had RRMS, and the mean treatment duration was 155 months. The majority were treated with interferons and glatiramer acetate prior NTZ (64%). 25% (47/186) discontinued NTZ treatment of which 47% (n=22) discontinued due to JCV positive (JCV+). In total, 30% (55/186) of these patients were JCV+ with a mean JCV index of 1.2±1.0 (2% missing data). Relapses before treatment were reduced from 380/1000 patient years to 43/1000 during treatment, 71% were relapse-free and 18% had 1 relapse during the entire treatment period (15% missing data). Most clinical effectiveness measures, MSSS, MSIS-29 and SDMT showed statistically significant improvement between baseline and 132

Introduction: Cladribine is a deoxyadenosine analogue prodrug that selectively induces immune reconstitution by targeting B- and T-lymphocytes. Cladribine tablets (CladT) are administered in two courses, 12 months apart, for patients with relapsing multiple sclerosis (RMS). CladT are included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology”(IMSE). Objectives: To assess the safety and effectiveness of CladT with focus on patients treated at least 12 months. Methods: Data of Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - 5 Dimensions Test (EQ-5D), Visual Analog Scale (VAS), relapses and Adverse Events (AEs) is obtained from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using Wilcoxon Signed Rank Test and relapse rates were tested using paired samples T-test. Results: 208 patients were included in the IMSE 10 study since the Swedish market launch in April 2018 with an overall drug survival rate of 94.2%. 12 patients discontinued treatment, of which 1 later restarted. The most common reason for discontinuation was lack of effect (83%). 21 AEs were reported of which 7 were serious. The most common AE reported were infection and infestation (8 reports).139 patients were treated for at least 12 months. 29 % of the patients was treated with CladT as their first MS drug. 19 % were treated with natalizumab and 10 % with dimethyl fumarate prior to CladT. The number of relapses decreased significantly from 249 per 1,000 patient years before treatment start to 73 during treatment. 12 patients in this cohort have experienced a relapse during treatment. Significant improvements in mean values at 12 months of tre

Introduction: Baclofen is the first line drug choice for spasticity; a common MS feature influencing function and quality of life. Its prescription and discontinuation patterns among persons with MS (pwMS) are described incompletely. Objective & Aim: To characterize baclofen prescription patterns in a nationwide cohort study of people with prevalent (pMS) and incident (iMS) MS. Method: Data was linked from the Swedish MS register and national health registers for PwMS aged 18-65 years at diagnosis. Baclofen initiation was identified using the Prescription Drug Register excluding prescriptions from 1 July 2005—30 June 2006 (1st year of the register) and before MS diagnosis, to identify new prescriptions. Follow-up was from first dispensation until discontinuation, 31 Dec 2014 or death. Discontinuation was defined as no renewed prescription within gaps of 90, 150, or 180 days from last dispensation. Failure functions were plotted and Cox regression estimated hazard ratios. Results: A total of 188 (10%) of iMS (N=1826) and 628 (19%) of pMS (N=3519) received a new baclofen prescription. Discontinuation among iMS and pMS was similar using different time gaps: 49% (CI 0.42-0.57) iMS and 51% (CI 0.48-0.56) pMS discontinued within 150 days and approx. 90% discontinued overall. Approx. 65% of individuals discontinued within 1-year and 80% by 2-years. iMS with progressive course were treated for longer than relapsing course, and though similar among pMS differences between courses were less evident. Stratifying by EDSS (0-2.5, 3.0-5.5 and 6+) at baclofen initiation showed that PwMS with higher EDSS persisted longer than EDSS 0-2.5 but discontinuation was high among all groups. Cox regression showed EDSS associated with discontinuation, with iMS of EDSS 3-5.5 and 6+ 72% (CI 0.44-1.16) and 61% (CI 0.35-1.05); pMS 78% (CI 0.59-1.03) and 65% (CI 0.49-0.85) less likely to discontinue. No other MS characteristics (duration, age, course, sex, diagnosis/on

A natural hazard is a naturally occurring extreme event that has a negative effect on people and society or the environment. Natural hazards may have severe implications for human life and can potentially generate economic losses and damage ecosystems. A better understanding of their major causes, probability of occurrence, and consequences enables society to be better prepared to save human lives as well as to invest in adaptation options. Natural hazards related to climate change are identified as one of the Grand Challenges in the Baltic Sea region. Here, we summarize existing knowledge about extreme events in the Baltic Sea region with a focus on the past 200 years as well as on future climate scenarios. The events considered here are the major hydro-meteorological events in the region and include wind storms, extreme waves, high and low sea levels, ice ridging, heavy precipitation, sea-effect snowfall, river floods, heat waves, ice seasons, and drought. We also address some ecological extremes and the implications of extreme events for society (phytoplankton blooms, forest fires, coastal flooding, offshore infrastructure, and shipping). Significant knowledge gaps are identified, including the response of large-scale atmospheric circulation to climate change and also concerning specific events, for example, the occurrence of marine heat waves and small-scale variability in precipitation. Suggestions for future research include the further development of high-resolution Earth system models and the potential use of methodologies for data analysis (statistical methods and machine learning). With respect to the expected impacts of climate change, changes are expected for sea level, extreme precipitation, heat waves and phytoplankton blooms (increase), and cold spells and severe ice winters (decrease). For some extremes (drying, river flooding, and extreme waves), the change depends on the area and time period studied.

Background and purpose Infections with human herpesvirus 6A (HHV-6A) and Epstein-Barr virus (EBV) have been linked to multiple sclerosis (MS) development. For EBV, late infection has been proposed as a risk factor, but serological support is lacking. The objective of this study was to investigate how age affects the EBV and HHV-6A associated risks of developing MS. Methods In this nested case-control study, Swedish biobanks were accessed to find pre-symptomatically collected blood samples from 670 individuals who later developed relapsing MS and 670 matched controls. A bead-based multiplex assay was used to determine serological response against EBV and HHV-6A. Conditional logistic regression was used to calculate odds ratios and 95% confidence intervals. Results Seropositivity against EBV exhibited a pattern where associations switched from a decreased risk of developing MS in the group below 20 years of age to an increased risk amongst individuals aged 20-29 and 30-39 years (p for trend 0.020). The age of transition was estimated to be 18.8 years. In contrast, HHV-6A was associated with increased MS risk in all age groups (total cohort odds ratio 2.1, 95% confidence interval 1.6-2.7). Conclusions This study suggests EBV infection after adolescence and age independent HHV-6A infection as risk factors for MS., Funding Agencies|Swedish Research CouncilSwedish Research Council [2015-02419]; Swedish Brain Foundation; KAW Foundation; Margaretha af Ugglas Foundation; Horizon 2020 MultipleMS [733161]; Multiple Sclerosis Society of Canada [EGID 3045]

QC 20211206

Bipolar disorder is a heritable mental illness with complex etiology. We performed a genome-wide association study of 41,917 bipolar disorder cases and 371,549 controls of European ancestry, which identified 64 associated genomic loci. Bipolar disorder risk alleles were enriched in genes in synaptic signaling pathways and brain-expressed genes, particularly those with high specificity of expression in neurons of the prefrontal cortex and hippocampus. Significant signal enrichment was found in genes encoding targets of antipsychotics, calcium channel blockers, antiepileptics and anesthetics. Integrating expression quantitative trait locus data implicated 15 genes robustly linked to bipolar disorder via gene expression, encoding druggable targets such as HTR6, MCHR1, DCLK3 and FURIN. Analyses of bipolar disorder subtypes indicated high but imperfect genetic correlation between bipolar disorder type I and II and identified additional associated loci. Together, these results advance our understanding of the biological etiology of bipolar disorder, identify novel therapeutic leads and prioritize genes for functional follow-up studies.

QC 20211206

QC 20211206

Introduction: Data on how processing speed of relapsing-remitting multiple sclerosis patients (RRMS) evolve over time and its association with disability progression is scarce. We analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (CombatMS; NCT03193866), a nationwide observational drug trial in RRMS. Objectives: Identify trajectories of processing speed and disability and their connections after disease modulatory treatment (DMT) start within the RRMS population.Describe patient characteristics associated with trajectory groups. Aim: Model trajectories of processing speed and disability. Methods: We assessed trajectories of oral Symbol Digit Modalities Test (SDMT) and expanded disability status scale (EDSS) from first DMT start using a group-based modeling approach among 1,800 RRMS patients followed 2010-2021. We investigated predictors of trajectories using group membership assignments as a multinomial outcome and calculated conditional probabilities linking membership across the trajectories. Results: We identified four trajectories of processing speed: low SDMT score (mean starting values; MSV=36.7, standard deviation; SD=8.4)-stable (13%), medium score (MSV =50.8, SD=6.7)-minor decrease (52%), medium/high score (MSV=62.9, SD=8.6)-minor decrease (32%), and high score (MSV= 75.2, SD=9.7)-moderate decrease (3%), and four trajectories of disability: no disability-stable (23%), minimal signs-minor increase (45%), minimal disability-moderate increase (27%), and relatively severe disability-moderate increase (5%). Patients with natalizumab as first DMT were less likely to belong to the medium and high processing speed trajectories, relative to the low SDMT score-stable one. Sex, age at DMT start, and geographical region of treatment were associated with medium and high processing speed and with minimal signs and minimal dis-ability trajectories. There was 0% probability of belonging to the relatively severe disability-moderate increase EDSS tra

Background: Teriflunomide (TFM) is an oral therapy for relapsing-remitting multiple sclerosis (RRMS) included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE). Objectives: To assess the safety and effectiveness of TFM with focus on patients treated at least 48 months. Methods: Descriptive data of Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - 5 Dimensions Test (EQ-5D), Visual Analog Scale (VAS) and Adverse Events (AEs) is obtained from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using Wilcoxon Signed Rank Test and drug survival using Kaplan-Meier curve. Results: 645 patients were included in the IMSE 4 study from March 2014 to April 2021, 70% were female, mean age at treatment start was 46 years and mean treatment duration was 31 months. The most common prior treatment was interferon beta or glatiramer acetate (34%) and 17% were treatment naïve. One- two- and three- year drug survival rates were 74%, 59% and 49% respectively. 340 patients (53%) have discontinued treatment with main reasons for discontinuation being AEs (41%) and lack of effect (40%). Of 68 reported AEs, 20 were serious. For both serious and non-serious AEs, skin and subcutaneous tissue disorders were the most common (25% and 21%, respectively). At the cut-off date, 168 patients had been treated for at least 48 months. This cohort had a mean age of 48 years at treatment start and a mean treatment duration of 65 months. The majority (64%) had switched from interferon or glatiramer acetate and 12% were treatment naïve. Significant improvement in mean values at 48 months of treatment compared to baseline were noted for SDMT in the 48-month cohort (49.1 ± 8.2 to 50.5 ± 10.0, n=35, p=0.049) while a minor worsening were noted for EDSS (2.2 ± 1.7 to 2.6 ± 2.0, n=37

Background: Dimethyl fumarate (DMF) is an oral therapy for relapsing-remitting multiple sclerosis (RRMS). DMF is included in the Swedish post-market surveillance study “Immunomodulation and Multiple Sclerosis Epidemiology” (IMSE). Objectives: To assess the effectiveness and safety of DMF with focus on patients treated at least 60 months. Methods: Descriptive data of Extended Disability Status Scale (EDSS), Multiple Sclerosis Severity Scale (MSSS), Symbol Digit Modalities Test (SDMT), Multiple Sclerosis Impact Scale (MSIS-29), European Quality of Life - 5 Dimensions Test (EQ-5D), Visual Analog Scale (VAS) and Adverse Events (AEs) is obtained from the nationwide Swedish Neuro Registry (NeuroReg). Effectiveness measures were assessed using the Wilcoxon Signed Rank Test and drug survival using the Kaplan-Meier curve.Results: 2466 DMF-treated patients were included between March 2014 and April 2021 with an overall drug survival rate of 41.2% and a mean treatment duration of 34 months. The main reasons for discontinuation were AEs (49%) and lack of effect (30%). 198 AEs were reported of which 62 were serious. For both serious and non-serious AEs reported, gastrointestinal disorders were the most common (19% and 27%, respectively). 588 patients had continuous treatment for at least 60 months. This cohort had a mean age of 42.1 years and a mean treatment duration of 72.4 months. The majority (63%) had switched from interferon or glatiramer acetate and 22% were treatment naïve. Significant improvements in mean values at 60 months of treatment compared to baseline were noted for MSSS in the 60-month cohort (p<0.001). MSIS-29 Psychological showed a tendency for improvement while all other tests remained stable after 5 years of treatment. Number of relapses per 1000 patients years were improved from 198.9 before DMF treatment start to 27.9 during treatment with DMF. 69 patients (12%) have discontinued DMF treatment in the 60 month cohort with a mean treatment duration of 67