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Currently, there are limited therapeutic options for patients with non-active secondary progressive multiple sclerosis. Therefore, real-world studies have investigated differences between patients with relapsing-remitting multiple sclerosis, non-active secondary progressive multiple sclerosis and active secondary progressive multiple sclerosis. Here, we explore patterns and predictors of transitioning between these phenotypes. We performed a cohort study using data from The Danish Multiple Sclerosis Registry. We included patients with a relapsing-remitting phenotype, registered changes to secondary progressive multiple sclerosis and subsequent transitions between relapsing and non-relapsing secondary progressive multiple sclerosis, which was defined by the presence of relapses in the previous 2 years. We analysed predictors of transitioning from relapsing-remitting multiple sclerosis to relapsing and non-relapsing secondary progressive multiple sclerosis, as well as between the secondary progressive states using a multi-state Markov model. We included 4413 patients with relapsing-remitting multiple sclerosis. Within a median follow-up of 16.2 years, 962 were diagnosed with secondary progressive multiple sclerosis by their treating physician. Of these, we classified 729 as non-relapsing and 233 as relapsing secondary progressive multiple sclerosis. The risk of transitioning from relapsing-remitting to non-relapsing secondary progressive multiple sclerosis included older age (hazard ratio per increase of 1 year in age: 1.044, 95% confidence interval: 1.035-1.053), male sex (hazard ratio for female: 0.735, 95% confidence interval: 0.619-0.874), fewer relapses (hazard ratio per each additional relapse: 0.863, 95% confidence interval: 0.823-0.906), higher expanded disability status scale (hazard ratio per each additional point: 1.522, 95% confidence interval: 1.458-1.590) and longer time on disease-modifying therapies (hazard ratio per increase of 1 year in treatment, high-efficacy disease-modifying therapy: 1.095, 95% confidence interval: 1.051-1.141; hazard ratio, moderate-efficacy disease-modifying therapy: 1.073, 95% confidence interval: 1.051-1.095). We did not find significant predictors associated with the transition from relapsing secondary progressive multiple sclerosis to non-relapsing secondary progressive multiple sclerosis, whereas older age (hazard ratio per increase of 1 year in age: 0.956, 95% confidence interval: 0.942-0.971) prevented the transition from non-relapsing secondary progressive multiple sclerosis to relapsing secondary progressive multiple sclerosis. Our study suggests that transitioning from relapsing-remitting multiple sclerosis to non-relapsing secondary progressive multiple sclerosis depends on well-known factors affecting diagnosing secondary progressive multiple sclerosis. Further transitions between non-relapsing and relapsing secondary progressive multiple sclerosis are only affected by age. These findings add to the knowledge of non-active secondary progressive multiple sclerosis, a patient group with unmet needs in terms of therapies., Competing Interests: N.G. and S.S.G. are employees of Sanofi and may hold shares and/or stock options in the company. M.F.W.-H. has served on the scientific advisory board for Sanofi and has received honoraria for lecturing for Novartis and Sanofi. H.B.J. has served as advisory board member for Merck and Roche and has received speaker honoraria from Biogen and Novartis. Z.I. has received speakers’ honoraria and/or research grants from Biogen, Roche, Sanofi, Novartis, Merck, Alexion, Bristol Myers Squibb, Lundbeckfonden, Jascha Fonden and Scleroseforeningen, has been member of advisory boards at Alexion, Biogen, Sanofi, Merck, Roche and Novartis, has been member of adjudication relapse (clinical endpoint) committees in Phase 3 trials and has been principal investigator in studies sponsored by Biogen, Merck and Sanofi. R.M.J. has served on scientific advisory boards for Novartis and Merck and has received conference travel support from Biogen. T.S. has served in scientific advisory board for Biogen, Merck, Novartis, Roche and Sanofi and has received honoraria for lecturing from Biogen, Merck, Novartis, Roche and Sanofi. A.W. has served on scientific advisory boards for Merck, Roche and Sanofi, has received conference travel support from Biogen, Merck, Roche, Sanofi and Novartis and speaker honoraria from Roche, Merck and Sanofi. M.R.M. has received support for participation in scientific meetings from Merck and Novartis, as well as travel grants from The Danish Multiple Sclerosis Society. M.B.P. has served on scientific advisory boards for Merck and support for conference participation from Novartis and Merck. S.P. received honoraria for contributing to making a magazine and support for congress participation from Merck. M.S. has served on scientific advisory boards for, received support for congress participation or received speaker honoraria from Biogen, Merck, Novartis, Roche and Sanofi Genzyme. P.V.R. has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche and Sanofi Genzyme. K.B.S. has served as consultant for Takeda, has received travel grants from TEVA, Biogen Merck and Novartis and has been principal investigator in studies sponsored by Alexion, Roche and Sanofi. F.S. has served on scientific advisory boards for, served as consultant for, received support for congress participation or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Lundbeck, Merck, Novartis, Roche and Sanofi Genzyme. His laboratory has received research support from Biogen, Merck, Novartis, Roche and Sanofi Genzyme. M.M. has served on scientific advisory boards, served as a consultant, received support for congress participation or received speaker honoraria from Roche, Sanofi, Biogen, Merck, Novartis, Bristol Myers Squibb, Medscape, Alexion and Moderna. Her research group has contracts with Biogen, Merck, Novartis, Roche, Sanofi and Bristol Myers Squibb. All other authors report no competing interests., (© The Author(s) 2024. Published by Oxford University Press on behalf of the Guarantors of Brain.)

Background: Clinicians frequently rely on relapse counts, T2 MRI lesion load (T2L) and Expanded Disability Status Scale (EDSS) scores to guide treatment decisions for individuals diagnosed with multiple sclerosis (MS). This study evaluates how these factors, along with age and sex, influence prognosis during treatment with teriflunomide (TFL)., Methods: We conducted a nationwide cohort study using data from the Danish Multiple Sclerosis Registry.Eligible participants had relapsing-remitting MS or clinically isolated syndrome and initiated TFL as their first treatment between 2013 and 2019. The effect of age, pretreatment relapses, T2L and EDSS scores on the risk of disease activity on TFL were stratified by sex., Results: In total, 784 individuals were included (57.4% females). A high number of pretreatment relapses (≥2) was associated with an increased risk of disease activity in females only (OR and (95% CI): 1.76 (1.11 to 2.81)). Age group 50+ was associated with a lower risk of disease activity in both sexes (OR females=0.28 (0.14 to 0.56); OR males=0.22 (0.09 to 0.55)), while age 35-49 showed a different impact in males and females (OR females=0.79 (0.50 to 1.23); OR males=0.42 (0.24 to 0.72)). EDSS scores and T2L did not show any consistent associations., Conclusion: A high number of pretreatment relapses was only associated with an increased risk of disease activity in females, while age had a differential impact on the risk of disease activity according to sex. Clinicians may consider age, sex and relapses when deciding on TFL treatment., Competing Interests: Competing interests: MRM has received support from Merck for participation in a scientific meeting. MM has served on scientific advisory boards, served as a consultant, received support for congress participation, or received speaker honoraria from Roche, Sanofi, Biogen, Merck, Novartis, Bristol Myers Squibb, Medscape, Alexion, and Moderna. Her research group has contracts with Biogen, Merck, Novartis, Roche, Sanofi, and Bristol Myers Squibb. FE has received speaker honoraria from Roche and Sanofi. RPH has received speaker honoraria from Sanofi and Novartis, has served on an advisory board for Novartis, and has received a travel grant from The Danish Multiple Sclerosis Society. AW has served on advisory boards for Merck, Sanofi, Roche, and Biogen. He has also received honoraria for lecturing and manuscript writing from Sanofi, Merck, and Roche and has received financial support for congress participation from Biogen, Sanofi, Novartis, Merck and Roche. MBP reports support for congress participation from Novartis and Merck. ZI has received speaker honoraria, been a member of an advisory board, and received support for congress participation from Sanofi. TS has received travel grants from Sanofi and Merck, research grants from Biogen, Merck and Roche, served on advisory boards for Biogen, Merck, Novartis and Sanofi, and received honoraria for lecturing from Biogen, Merck, Novartis and Sanofi. MLS has received support for congress participation from Biogen, Merck, and Roche and has participated on advisory boards for Sanofi and Roche. PVR has served on scientific advisory boards, received support for congress participation or received speaker honoraria from Biogen, Merck, Novartis, Roche and Sanofi. FS has served on scientific advisory boards, served as a consultant, received support for congress participation or received speaker honoraria from Biogen, Bristol Myers Squibb, H. Lundbeck A/S, Merck, Novartis, Roche and Sanofi. His laboratory has received research support from Biogen, Merck, Novartis, Roche and Sanofi. In addition, FS is section editor of the journal Multiple Sclerosis and Related Disorders, chairman of the research board for the Danish Multiple Sclerosis Society, and member of the scientific steering committee for the International Progressive MS Alliance., (© Author(s) (or their employer(s)) 2024. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Targeted treatment is highly warranted for cerebral small vessel disease, a causal factor of one in four strokes and a major contributor to vascular dementia. Patients with cerebral small vessel disease have impaired cerebral blood flow and vessel reactivity. Tadalafil is a specific phosphodiesterase 5 inhibitor shown to improve vascular reactivity in the brain., Methods: The ETLAS-2 trial is a phase 2 double-blind, randomized placebo-controlled, parallel trial with the feasibility of tadalafil as the primary outcome. The trial aims to include 100 patients with small vessel occlusion stroke or transitory ischemic attacks and signs of cerebral small vessel disease more than 6 months before administration of study medication. Patients are treated for 3 months with tadalafil 20 mg or placebo daily and undergo magnetic resonance imaging (MRI) to evaluate changes in small vessel disease according to the STandards for ReportIng Vascular changes on nEuroimaging (STRIVE) criteria as well as cerebral blood flow, cerebrovascular reactivity, and neurovascular coupling in a functional MRI sub-study. The investigation includes comprehensive cognitive testing using paper-pencil tests and Cambridge Neuropsychological Test Automated Battery (CANTAB) tests in a cognitive sub-study., Discussion: The ETLAS-2 trial tests the feasibility of long-term treatment with tadalafil and explores vascular and cognitive effects in cerebral small vessel disease in trial sub-studies. The study aims to propose a new treatment target and improve the understanding of small vessel disease. Currently, 64 patients have been included and the trial is estimated to be completed in the year 2024., Trial Registration: Clinicaltrials.gov, NCT05173896. Registered on 30 December 2021., (© 2024. The Author(s).)

Background: Treatment switching is a common challenge and opportunity in real-world clinical practice. Increasing diversity in disease-modifying treatments (DMTs) has generated interest in the identification of reliable and robust predictors of treatment switching across different countries, DMTs, and time periods., Objective: The objective of this retrospective, observational study was to identify independent predictors of treatment switching in a population of relapsing-remitting MS (RRMS) patients in the Big Multiple Sclerosis Data Network of national clinical registries, including the Italian MS registry, the OFSEP of France, the Danish MS registry, the Swedish national MS registry, and the international MSBase Registry., Methods: In this cohort study, we merged information on 269,822 treatment episodes in 110,326 patients from 1997 to 2018 from five clinical registries. Patients were included in the final pooled analysis set if they had initiated at least one DMT during the relapsing-remitting MS (RRMS) stage. Patients not diagnosed with RRMS or RRMS patients not initiating DMT therapy during the RRMS phase were excluded from the analysis. The primary study outcome was treatment switching. A multilevel mixed-effects shared frailty time-to-event model was used to identify independent predictors of treatment switching. The contributing MS registry was included in the pooled analysis as a random effect., Results: Every one-point increase in the Expanded Disability Status Scale (EDSS) score at treatment start was associated with 1.08 times the rate of subsequent switching, adjusting for age, sex, and calendar year (adjusted hazard ratio [aHR] 1.08; 95% CI 1.07-1.08). Women were associated with 1.11 times the rate of switching relative to men (95% CI 1.08-1.14), whilst older age was also associated with an increased rate of treatment switching. DMTs started between 2007 and 2012 were associated with 2.48 times the rate of switching relative to DMTs that began between 1996 and 2006 (aHR 2.48; 95% CI 2.48-2.56). DMTs started from 2013 onwards were more likely to switch relative to the earlier treatment epoch (aHR 8.09; 95% CI 7.79-8.41; reference = 1996-2006)., Conclusion: Switching between DMTs is associated with female sex, age, and disability at baseline and has increased in frequency considerably in recent years as more treatment options have become available. Consideration of a patient's individual risk and tolerance profile needs to be taken into account when selecting the most appropriate switch therapy from an expanding array of treatment choices., Competing Interests: TSp received compensation for serving on scientific advisory boards, honoraria for consultancy and funding for travel from Biogen; and speaker honoraria from Novartis. MM has served on the scientific advisory board for Sanofi, Novartis, and Merck and has received honoraria for lecturing from Biogen, Merck, Novartis, Roche, Genzyme, and Bristol Myers Squibb. HB is an employee of Monash University and has accepted travel compensation from Merck; his institution receives honoraria for talks, steering committee activities, and research grants from Roche, Merck, Biogen, Novartis, UCB Pharma, Medical Research Future Fund Australia, NHMRC Australia, Trish MS Foundation, MS Australia, and the Pennycook Foundation. He receives personal compensation for steering group activities for the Brain Health Initiative from the Oxford Health Policy Forum and is funded by an NHMRC Australia Investigator Grant. SV received consulting and lecturing fees, travel grants, and research support from Biogen, Celgene, Genentech, Genzyme, Medday Pharmaceuticals, Merck Serono, Novartis, Roche, Sanofi Aventis, and Teva Pharma. MT has served on scientific advisory boards for Biogen, Novartis, Roche, and Genzyme; has received speaker honoraria and travel support from Biogen Idec, Sanofi Aventis, Merck Serono, Teva, Genzyme, and Novartis; and has received research grants for her institution from Biogen Idec, Merck Serono, and Novartis. PI has served on scientific advisory boards for Biogen Idec, Bayer, Teva, Roche, Merck Serono, Novartis, and Genzyme and has received funding for travel and/or speaker honoraria from Sanofi Aventis, Genzyme, Biogen Idec, Teva, Merck Serono, and Novartis. DH was supported by the Charles University Cooperation Program in Neuroscience, the project National Institute for Neurological Research (Programme EXCELES, ID Project No. LX22NPO5107) funded by the European Union (Next Generation EU), and by the General University Hospital in Prague project MH CZ-DRO-VFN64165. She also received compensation for travel, speaker honoraria, and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva, as well as support for research activities from Biogen Idec. FP is an employee of Biogen. RH is an employee of Biogen and holds stock. PD served on editorial boards and has been supported to attend meetings by EMD, Biogen, Novartis, Genzyme, and TEVA Neuroscience. He holds grants from the CIHR and the MS Society of Canada and has received funding for investigator-initiated trials from Biogen, Novartis, and Genzyme. JL-S received travel compensation from Novartis, Biogen, Roche, and Merck. Her institution receives honoraria for talks and advisory board commitments, as well as research grants from Biogen, Merck, Roche, TEVA, and Novartis. SS declared no competing interests. PL received honoraria for speaking and/or travel expenses from Biogen, Merck, Novartis, Roche; consulting fees from Biogen, GeNeuro, Merck, Novartis, Roche; and research support from Biogen, Merck, Novartis. None were related to this work. SE received speaker honoraria and consultant fees from Biogen Idec, Novartis, Merck, Bayer, Sanofi Genzyme, Roche, and Teva. RAI received honoraria as a speaker and for serving on scientific advisory boards from Bayer, Biogen, GSK, Merck, Novartis, Roche, and Sanofi-Genzyme. MT received travel grants from Novartis, Bayer-Schering, Merck, and Teva; and has participated in clinical trials by Sanofi Aventis, Roche, and Novartis. MG received consulting fees from Teva Canada Innovation, Biogen, Novartis, and Genzyme Sanofi; and lecture payments from Teva Canada Innovation, Novartis, and EMD. He has also received a research grant from the Canadian Institutes of Health Research. TK served on scientific advisory boards for MS International Federation and World Health Organization, BMS, Roche, Janssen, Sanofi Genzyme, Novartis, Merck, and Biogen; on the 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. FG received honoraria or research funding from Biogen, Genzyme, Novartis, Teva Neurosciences, and ATARA Pharmaceuticals. OS received honoraria and consulting fees from Bayer-Schering, Novartis, Merck, Biogen, and Genzyme. SK received compensation for scientific advisory board activity from Merck and Roche. BY received honoraria as a speaker and member of scientific advisory boards from Sanofi, Bayer, Biogen, Merck, Janssen, Novartis, Roche, and Aspen. MJ received consulting fees, speaker honoraria, and/or travel expenses for scientific meetings from Alexion, Bayer Healthcare, Biogen, Bristol Myers Squibb, Celgene, Janssen, Merck Serono, Novartis, Roche, Sanofi, and Teva. YB received speaker honoraria/consulting fees from Merck, Biogen, Roche, Bristol Myers Squibb, Novartis, Sanofi, and Sandoz. CO-G received honoraria as a consultant on scientific advisory boards from Biogen, Celgene, Merck, Novartis, Roche, Sanofi-Genzyme, and TEVA. AA received speaker honoraria from Novartis and Alexion. SH has received unrestricted educational grants or speaking honoraria from Biogen, Merck Serono, Novartis, Roche, and Sanofi Genzyme. PM received speaker fees and travel grants from Novartis, Biogen, T'évalua, and Sanofi. RAm received conference travel support from Novartis, Teva, Biogen, Bayer, and Merck and has participated in clinical trials by Biogen, Novartis, Teva, and Actelion. KdG served on scientific advisory boards for Roche, Janssen, Sanofi-Genzyme, Novartis, and Merck, received conference fees and travel support from Novartis, Biogen, Sanofi-Genzyme, Teva, AbbVie, and Merck, and received educational event support from Novartis. CM received honoraria as a consultant on scientific advisory boards for Genzyme, BMS, Janssen, Biogen, Merck, Roche, and Novartis; has received travel grants from Roche and Novartis. JP accepted travel compensation from Novartis, Biogen, Genzyme, Teva, and speaking honoraria from Biogen, Novartis, Genzyme, and Teva. NJ is a local principal investigator on commercial studies funded by Novartis, Biogen, Amicus, and Sanofi. JI declared no competing interests. FS has served on scientific advisory boards for, served as a consultant for, received support for congress participation, or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, and Sanofi Genzyme. His laboratory has received research support from Biogen, Merck, Novartis, Roche, and Sanofi Genzyme. HJ declared no competing interests. PR has served on scientific advisory boards for, served as consultant for, received support for congress participation, or received speaker honoraria from Alexion, Biogen, Bristol Myers Squibb, Merck, Novartis, Roche, and Sanofi Genzyme. TSe received and has served on scientific advisory boards for, served as a consultant for, received support for congress participation, or received speaker honoraria from Biogen, Merck, Novartis, Roche, and Sanofi. T. Sejbaeks received unrestricted research grants to his research institution from Biogen, Merck, and Roche and is currently engaged in sponsor-initiated research projects by Eisai, Lundbeck, Roche, and Sanofi. MP declared no competing interests. JC has received speaker honoraria from Biogen. MS has served on scientific advisory boards for, served as a consultant for, received support for congress participation, participated in industrial trials with, or received speaker honoraria from Bayer, Biogen, Merck, Novartis, Roche, and Sanofi Genzyme. JH has received honoraria for serving on advisory boards for Biogen, Sanofi-Genzyme, and Novartis and speaker's fees from Biogen, Novartis, Merck Serono, Bayer-Schering, Teva, and Sanofi-Genzyme. He has served as P.I. for projects or received unrestricted research support from BiogenIdec, Merck Serono, TEVA, Sanofi-Genzyme, and Bayer-Schering. His MS research is funded by the Swedish Research Council and the Swedish Brain Foundation. The authors declare that this study received funding from Biogen. The funder had the following involvement with the study: study design and manuscript review. The funder was not involved in the collection of data, analysis, writing of the article, or the decision to submit it for publication. The author(s) declared that they were an editorial board member of Frontiers, at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2023 Spelman, Magyari, Butzkueven, Van Der Walt, Vukusic, Trojano, Iaffaldano, Horáková, Drahota, Pellegrini, Hyde, Duquette, Lechner-Scott, Sajedi, Lalive, Shaygannejad, Ozakbas, Eichau, Alroughani, Terzi, Girard, Kalincik, Grand'Maison, Skibina, Khoury, Yamout, Sa, Gerlach, Blanco, Karabudak, Oreja-Guevara, Altintas, Hughes, McCombe, Ampapa, de Gans, McGuigan, Soysal, Prevost, John, Inshasi, Stawiarz, Manouchehrinia, Forsberg, Sellebjerg, Glaser, Pontieri, Joensen, Rasmussen, Sejbaek, Poulsen, Christensen, Kant, Stilund, Mathiesen, Hillert and the Big MS Data Network: a collaboration of the Czech MS Registry, the Danish MS Registry, Italian MS Registry, Swedish MS Registry, MSBase Study Group, and OFSEP.)

Objectives: In Denmark, 25% of hospital admissions with stroke are recurrent strokes. With thrombolytic treatment, more patients survive with only minor disability. This promising development should be followed up by intensive secondary prevention. Hypertension is the most important target. We aimed at testing the hypotheses that early follow-up in a preventive clinic would result in (a) a higher proportion of patients with blood pressure at target and (b) time to stroke recurrence, myocardial infarction, and death would be longer in the intervention group compared to controls., Materials and Methods: Eligible patients admitted to the stroke unit of Herlev Hospital were randomized shortly before discharge to intervention or control group. Of 78 included participants, data from 73 were available for follow-up 9 months after inclusion. Patients in the intervention group were seen in the clinic within 1 week. In case of hypertension, treatment was initiated or supplied with a new drug. We used individual targets for blood pressure according to diagnosis of stroke and patients' comorbidity. Patients in the intervention group had a median of five visits to the preventive clinic., Results: In the intervention group, blood pressure was treated to target in 25 patients (69%) versus 14 (38%) in the control group (p = .007). Median time to first event was 44 months (4-49) in the intervention group and 19 months (4-37) in controls (p = .316)., Conclusions: Treatment of hypertension to individual targets after stroke is feasible. It may postpone recurrent stroke and death in stroke survivors., (© 2020 The Authors. Brain and Behavior published by Wiley Periodicals LLC.)

Background: Fatigue is a common and often debilitating stroke sequela, and it is important to accurately define and detect post-stroke fatigue. Often questionnaires are used but a case definition has been developed and proposed as a better tool., Objectives: The aim of the study was to determine validity and inter-rater agreement of the case definition of post-stroke fatigue, and to determine optimal cutoff scores for marked fatigue on the Multidimensional Fatigue Inventory-20 and the Fatigue Severity Scale-7 questionnaires., Methods: Stroke patients were interviewed with the structured interview schedule for the case definition and asked to complete the two questionnaires. To examine the inter-rater agreement of the case definition a second interviewer did another interview blinded to the result of the first interview., Results: Seventy patients were enrolled, 44% women. The median age was 74 years (interquartile range: 67-80) and the median time from stroke to interview was 8 days. The median Fatigue Severity Scale-7 score and the median Multidimensional Fatigue Inventory-20 (General Fatigue subscale) score were higher in the case definition positive than in the negative group ( p < .001). The kappa value for the inter-rater agreement was 0.63. A cutoff score of 4.9 for the Fatigue Severity Scale-7 and a cutoff score of 12 on the Multidimensional Fatigue Inventory-20 were optimal to identify marked fatigue according to the case definition., Conclusions: The case definition was valid and had a substantial inter-rater agreement. A score ≥ 5 using the Fatigue Severity Scale-7 or a score ≥ 12 using the Multidimensional Fatigue Inventory-20 (General Fatigue subscale) may be used to detect potentially debilitating post-stroke fatigue in stroke survivors.

Aims Prolonged cardiac monitoring after stroke is recommended though there is no consensus on optimal methods. Short-term ECG recordings with a "thumb-ECG" device have shown promising preliminary results regarding effectiveness and cost benefit. We aimed to examine the performance of thumb-ECG and five days' Holter monitoring in a prospective trial. A secondary endpoint was the inter-observer agreement of the thumb-ECG. Methods Patients older than 65 years with no history of atrial fibrillation who suffered an acute stroke or transient ischemic attack of unknown origin were prospectively included. Patients were monitored for atrial fibrillation with five days' Holter and concurrent 30 s thumb-ECG twice daily, the latter continuing for 30 days. Inter-observer agreement for the thumb-ECG was determined. Results One hundred patients were included and 95 patients were analyzed. Paroxysmal atrial fibrillation was diagnosed in 20 patients with the thumb-ECG recordings and 17 patients on the Holter monitoring. Only 10 were diagnosed with both methods. The difference between the detection rates of the two devices was not significant ( p = 0.63). The inter-observer agreement of the thumb-ECG had a kappa value of 0.65. Conclusion Thirty days' thumb-ECG recordings twice daily for 30 s detect a high proportion of paroxysmal atrial fibrillation in a stroke or transient ischemic attack cohort. The proportion was comparable to five days' Holter monitoring but the agreement between the two methods was poor and the trial was not powered to detect a minor difference between the devices. The inter-observer agreement for the thumb-ECG was substantial. www.clinicalTrials.gov UI: NCT02261766.

Objective: To evaluate if home-based rehabilitation of inpatients improved outcome compared to standard care., Design: Interventional, randomised, safety/efficacy open-label trial., Setting: University hospital stroke unit in collaboration with three municipalities., Subjects: Seventy-one eligible stroke patients (41 women) with focal neurological deficits hospitalised in a stroke unit for more than three days and in need of rehabilitation., Interventions: Thirty-eight patients were randomised to home-based rehabilitation during hospitalization and for up to four weeks after discharge to replace part of usual treatment and rehabilitation services. Thirty-three control patients received treatment and rehabilitation following usual guidelines for the treatment of stroke patients., Main Measures: Ninety days post-stroke the modified Rankin Scale score was the primary endpoint. Other outcome measures were the modified Barthel-100 Index, Motor Assessment Scale, CT-50 Cognitive Test, EuroQol-5D, Body Mass Index and treatment-associated economy., Results: Thirty-one intervention and 30 control patients completed the study. Patients in the intervention group achieved better modified Rankin Scale score (Intervention median = 2, IQR = 2-3; Control median = 3, IQR = 2-4; P=0.04). EuroQol-5D quality of life median scores were improved in intervention patients (Intervention median = 0.77, IQR = 0.66-0.79; Control median = 0.66, IQR = 0.56 - 0.72; P=0.03). The total amount of home-based training in minutes highly correlated with mRS, Barthel, Motor Assessment Scale and EuroQol-5D™ scores (P-values ranging from P<0.00001 to P=0.01). Economical estimations of intervention costs were lower than total costs of standard treatment., Conclusion: Early home-based rehabilitation reduced disability and increased quality of life. Compared to standard care, home-based stroke rehabilitation was more cost-effective., (© The Author(s) 2015.)

Micronucleus (MN) frequency is a biomarker for early genetic effects which is often used in human biomonitoring studies. Increased frequency of micronuclei has been associated with high levels of traffic exposure. Further high MN frequency was found predictive for cancer development in several studies of adults. In the present study, the MN frequency in blood samples from the Danish participants of the European pilot project DEMOCOPHES was analysed and related to the area of residence, self-reported and calculated exposure to road traffic as well as to mercury in hair and blood concentrations of persistent organic pollutants and dioxin-like activity measured in the same participants. The MN frequency analysis was performed with the cytokinesis-block micronucleus (CBMN) assay and included 100 children and 119 mothers. We found a significant correlation between mothers and children in the levels of micronuclei in 1000 binucleated T lymphocytes (‰MNBN) and in the proliferation index. Further the levels of ‰MNBN were significantly higher in mothers compared with their children. No significant associations were found for ‰MNBN for traffic related exposure in neither children nor their mothers. In children, a 2.5 times higher micronuclei in mononuclear T lymphocytes were found in children living within 50 m of a busy road, however, this was not found in mothers or in MNBN and the effect of exposure to road traffic on MN frequency needs further investigation. No significant associations were found between MN frequencies and the other biomarkers measured in the same participants., (© The Author 2015. Published by Oxford University Press on behalf of the UK Environmental Mutagen Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Purpose: Poststroke fatigue is common and reduces quality of life. Current evidence for intervention is limited, and this is the first placebo-controlled trial to investigate treatment of poststroke fatigue with the wakefulness promoting drug modafinil., Methods: The trial was randomized, double-blinded, and placebo-controlled. Patients were treated with 400-mg modafinil or placebo for 90 days. Assessments were done at inclusion, 30, 90, and 180 days. The primary end point was fatigue at 90 days measured by the Multidimensional Fatigue Inventory-20 general fatigue domain. Secondary end points included the Fatigue Severity Scale, the Montreal Cognitive Assessment, the modified Rankin Scale and the Stroke-specific quality of Life questionnaire. Adult patients with a recent stroke achieving a score of ≥12 on the Multidimensional Fatigue Inventory-20 general fatigue domain were consecutively included. Exclusion criteria were severe cognitive disabilities and contraindications for modafinil treatment., Results: One thousand one hundred twenty-one patients with stroke were screened and 41 patients included, 21 received modafinil. The primary end point, the Multidimensional Fatigue Inventory-20 general fatigue score, did not differ between groups. Patients in the modafinil group obtained better scores on the Fatigue Severity Scale (P=0.02) and in some subscales of the stroke-specific quality of life questionnaire (0.001

Poly(A) (pA) tail binding proteins (PABPs) control mRNA polyadenylation, stability, and translation. In a purified system, S. cerevisiae PABPs, Pab1p and Nab2p, are individually sufficient to provide normal pA tail length. However, it is unknown how this occurs in more complex environments. Here we find that the nuclear exosome subunit Rrp6p counteracts the in vitro and in vivo extension of mature pA tails by the noncanonical pA polymerase Trf4p. Moreover, PABP loading onto nascent pA tails is controlled by Rrp6p; while Pab1p is the major PABP, Nab2p only associates in the absence of Rrp6p. This is because Rrp6p can interact with Nab2p and displace it from pA tails, potentially leading to RNA turnover, as evidenced for certain pre-mRNAs. We suggest that a nuclear mRNP surveillance step involves targeting of Rrp6p by Nab2p-bound pA-tailed RNPs and that pre-mRNA abundance is regulated at this level., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Yeast cleavage factor I (CF I) is an essential complex of five proteins that binds signal sequences at the 3' end of yeast mRNA. CF I is required for correct positioning of a larger protein complex, CPF, which contains the catalytic subunits executing mRNA cleavage and polyadenylation. CF I is composed of two parts, CF IA and Hrp1. The CF IA has only four subunits, Rna14, Rna15, Pcf11, and Clp1, but the structural organization has not been fully established. Using biochemical and biophysical methods, we demonstrate that CF IA can be reconstituted from bacterially expressed proteins and that it has 2:2:1:1 stoichiometry of its four proteins, respectively. We also describe mutations that disrupt the dimer interface of Rna14 while preserving the other subunit interactions. On the basis of our results and existing interaction data, we present a topological model for heterohexameric CF IA and its association with RNA and Hrp1.

The yeast THO complex and the associated RNA helicase Sub2p are important mRNP maturation factors. Transcripts produced in THO/sub2 mutants are subject to degradation by a surveillance mechanism that involves the nuclear RNA exosome. Here we show that inefficient polyadenylation forms the basis of this accelerated mRNA decay. A genetic screen reveals extensive interactions between deletions of THO subunits and mRNA 3' end processing mutants. Nuclear run-ons strengthen this link by showing premature transcription termination close to polyadenylation sites in THO/sub2 mutants in vivo. Moreover, in vitro, pre-mRNA substrates are poorly polyadenylated and consequently unstable in extracts from THO/sub2 mutant strains. Decreased polyadenylation correlates with a specific downregulation of the poly(A)-polymerase cofactor Fip1p by the ubiquitin/proteasome pathway. Both polyadenylation defects and Fip1p instability depend on the nuclear exosome component Rrp6p and its activator Trf4p. We suggest that removal of aberrant mRNA is facilitated by direct regulation of polyadenylation activity.

Chronic alcohol abuse has adverse effects on skeletal muscle, and reduced muscle strength is frequently seen in chronic alcoholics. In this study the acute effects of moderate alcohol intoxication on motor performance was evaluated in 19 non-alcoholic healthy subjects (10 women, 9 men). A randomised double-blinded placebo controlled design was applied to subjects receiving alcohol in juice and pure juice at two separate test periods. Isokinetic and isometric muscle strength and endurance were determined before, during, 24 and 48 h after the ingestion of alcohol in juice and juice (placebo). To detect a reduced activation of the central motor pathways superimposed external electrical stimulations during voluntary contractions were applied. Creatine kinase (CK) was measured to detect any alcohol-induced changes in sarcolemmal integrity. No change was seen in isokinetic as well as in isometric muscle performance during or following the alcohol intoxication as compared to the non-alcoholic condition. Also, no central activation failure was observed. No significant difference in CK increment was observed comparing the alcoholic- and non-alcoholic condition. In conclusion, a single episode of moderate alcohol intoxication (1,4 g/l) does not impair motor performance, and no accelerated exercise-induced muscle damage is seen.

Clinical usefulness and safety of percutaneous conchotome biopsy of the deltoid muscle and of the quadriceps muscle was compared in patients suspected to have a neuromuscular disorder. In 121 samples from the quadriceps muscle and in 39 samples from the deltoid muscle, the quantity of muscle fibers was equal and the fraction of biopsies resulting in a specific diagnosis was similar (50% and 56%, respectively). Also, biopsy from the 2 locations resulted in the same distribution of neurogenic, inflammatory, and myopathic disorders. After quadriceps muscle biopsy, 2 patients developed vasovagal syncopes and one patient a local hematoma, whereas no complications occurred in the patients subjected to deltoid muscle biopsy. We conclude that biopsy from the deltoid muscle is clinically as useful and safe as biopsy from the quadriceps muscle.

From 1.1.1982 to 31.12.1941 45 patients with 50 elbows were operated at Holstebro Central Hospital under the diagnosis epicondylitis lateralis humeri. The material consisted of 29 females and 16 males with an average at operation of 41.1 years (21-61 years). At that time the patients had had symptoms for approximately 2.8 years (0.5-25 years), and they had all received conservative treatment without effect. Forty-seven patients were operated with a tenotomy of caput commune extensorum, and three patients had a lengthening of the m. extensor carpi radialis performed. At follow-up at an average of 83.1 months postoperatively (16-127 months) 61% were working whereas none of them had been working preoperatively. Forty-six per cent were satisfied with the result. These results do not differ from what other authors have found, and today it seems that everybody agrees that only patients who have tried conservative treatment without improvement should be offered an operation. In a study recently published, histopathologic examination of the tissue of those patients who had no effect of conservative treatment showed degenerative changes rather than inflammatory changes, and this could be a reason why some patients have no effect of immobilisation and treatment with nonsteroidal antiinflammatory drugs.

The aim of the study was to investigate the changes in minor trauma treatment structure after a reduction in the number of general practitioners on call in a county, where minor trauma treatment is supposed to be carried out by general practitioners and only major trauma is supposed to be treated at the hospital Accident and Emergency Department. The design was a cross-sectional analysis of trauma treatment in Ringkøbing County before and after the reduction in the number of general practitioners on call. Over a four week period before and after the reduction in the number of general practitioners on call all trauma treatment at the Accident and Emergency Departments was registered together with trauma treatment by general practitioners. Furthermore a questionnaire was given before and after the reduction to a sample of the population regarding the population's behaviour and attitude towards minor trauma. Analysis showed that there was a minor reduction in the total number of trauma treatments after the reduction in the number of general practitioners on call was made. The percentage of patients that were treated at the Accident and Emergency Departments at hospital directly without being referred from general practitioners was reduced from 30% to 21%. The population's behaviour and attitude towards minor trauma was unchanged.

The aim of the study was to evaluate the results of treating subcapitular fractures of the fourth and fifth metacarpal bones with immediate mobilization and without splinting or reduction. Thirty-six such fractures were prospectively treated in this fashion and evaluated clinically. After four weeks only four patients (11.1%) had restricted movement of the metacarpal-phalangeal joint (less than 0-80 degrees of movement). The fracture was healed in 33 patients (91.7%) and 31 (86.1%) were fully satisfied. In order to investigate the types of treatment given in other accident and emergency departments in Denmark, a questionnaire was sent to all such departments. The results showed that most (90%) departments used plaster of Paris immobilization of the fracture. The average period of immobilization was 3.6 weeks (two to six). The indications given for reduction was an average volar angulation of 32 degrees (10-70). We conclude that treatment of subcapitular fractures of the fourth and fifth metacarpal bones without reduction and with a supporting bandage and mobilization to the pain-limit seems to secure a rapid restitution of function. These fractures are generally treated in Denmark with plaster immobilization and sometimes reduction, which appears to constitute overtreatment.

Until 1990, a total of 198 cases of renal haemangiomas have been reported; these patients often have to undergo partial or total nephrectomy. We report a case of a 37 year old female admitted with severe haematuria. Selective renal angiography revealed a haemangioma with arteriovenous shunting, situated centrally in her left kidney. Embolization of the artery supplying the shunt was performed with five coils, and four months later isotope renography showed that both kidneys were functioning equally well. The only observed side-effect was mild hypertension.

The closed casualty department function in the County of Ringkøbing was investigated during a period of four weeks. It was demonstrated that this functioned according to plan as the distribution general practice/casualty department was 3.4:1 and 70% of the patients in the casualty department were referred via general practice. The result of this was that the majority of minor injuries (removal of foreign bodies and treatment of wounds) were treated in general practice. In the casualty departments, there were fewer minor injuries and injuries which did not require specific treatment than are the case in open casualty departments. However, a definite diurnal variation was observed in the function of the closed casualty department as patients showed a greater tendency to seek treatment in the casualty department after working hours than during working hours and the general practitioners referred twice as many patients after working hours for continued treatment in the casualty departments. It is concluded that the closed casualty department system in the County of Ringkøbing functions well but that problems may be anticipated with the function if the duty-rosters for the general practitioners are altered so that the distances between general practitioners on duty increase and these have an increased work-load.

During a period of four weeks (17 September-14 October 1990) all treatments of injured persons in the five hospitals in the County of Ringkøbing were registered. In addition, the refund accounts for all additional services connected with injuries submitted by the 166 general practitioners to the Danish National Health Insurance were also registered. A total incidence rate (calculated on an annual basis) of injuries requiring treatment was found to be 229/1000 og the population per annum. As compared with a similar investigation carried out in 1969, increases in incidence rates of 2.1 for admissions, 3.8 for outpatient hospital treatments and 4.4 for treatment of injuries in general practice were found. An increase in the number of minor injuries is thus concerned, probably partly conditioned by an altered threshold for seeking treatment and partly a slighter increase in the number of more serious injuries. In addition, a significant difference in the frequency of injuries requiring treatment with more numerous treatments was found in the regions of Lemvig and Ringkøbing as compared with the remainder of the county. It is recommended that registration from casualty departments with collection of data for analysis of accidents be undertaken with the object of elucidating the background for the increase in the injuries and the differences between the individual regions in the county.

During the period 1.3.1976 to 31.5.1989, 158 patients were treated for in-growing toe-nail of the great toe by partial resection of the nail-forming matrix. The average age was 26 years and the period of observation was 83 months. A questionnaire was sent to all of the patients and 119 patients with 154 nails submitted to operation replied (75.3%). Ninety-five patients (79.8%) had no discomfort and seven (5.9%) stated that the condition had improved. Ten patients (8.4%) were submitted to reoperation. Seventy-six patients (63.9%) were completely satisfied with the cosmetic result of the treatment. Significantly better results as regards discomfort were obtained in patients who had been treated preoperatively by avulsion of the nail so that infection and inflammation had resolved (p less than 0.05). The authors conclude that partial resection of the nail-forming matrix is a certain and effective method of treating in-growing toe-nail of the great toe and they recommend that the nail is avulsed prior to operation.