Natalizumab treatment of multiple sclerosis — a Danish nationwide study with 13 years of follow-up

Background: Natalizumab is a widely used high-efficacy treatment in multiple sclerosis (MS). Real-world evidence regarding long-term effectiveness and safety is warranted. We performed a nationwide study evaluating prescription patterns, effectiveness, and adverse events. Methods: A nationwide cohort study using the Danish MS Registry. Patients initiating natalizumab between June 2006 and April 2020 were included. Patient characteristics, annualized relapse rates (ARRs), confirmed Expanded Disability Status Scale (EDSS) score worsening, MRI activity (new/enlarging T2- or gadolinium-enhancing lesions), and reported adverse events were evaluated. Further, prescription patterns and outcomes across different time periods (“epochs”) were analysed. Results: In total, 2424 patients were enrolled, with a median follow-up time of 2.7 years (interquartile range (IQR) 1.2–5.1). In recent epochs, patients were younger, had lower EDSS scores, had fewer pre-treatment relapses and were more often treatment naïve. At 13 years of follow-up, 36% had a confirmed EDSS worsening. On-treatment ARR was 0.30, corresponding to a 72% reduction from pre-initiation. MRI activity was rare, 6.8% had activity within 2–14 months from treatment start, 3.4% within 14–26 months, and 2.7% within 26–38 months. Approximately 14% of patients reported adverse events, with cephalalgia constituting the majority. During the study, 62.3% discontinued treatment. Of these, the main cause (41%) was due to JCV antibodies, while discontinuations due to disease activity (9%) or adverse events (9%) were less frequent. Conclusion: Natalizumab is increasingly used earlier in the disease course. Most patients treated with natalizumab are clinically stable with few adverse events. JCV antibodies constitute the main cause for discontinuation.</p

Real-world experience of cladribine treatment in relapsing-remitting multiple sclerosis:A Danish nationwide study

Background: Cladribine is a nucleoside analogue interfering with synthesis and repair of DNA. Treatment with cladribine leads to a preferential reduction in lymphocytes, resulting in profound depletion of B-cells with a rapid recovery of naïve B-cells, while T-cell show a lesser but long-lasting depletion It is approved for treatment of relapsing multiple sclerosis (MS). Cladribine tablets 3.5 mg/kg bodyweight are administered in two yearly treatment courses, each including two treatment series lasting 4 or 5 days, one at the start of the first month and the other at the start of the second month. Objective: To describe treatment patterns of cladribine in a real-world setting. Methods: Registry based observational cohort study with prospectively enrolled cases from December 2017 through June 2021. The data source is The Danish Multiple Sclerosis Registry, which is a near complete nationwide population-based registry. Outcomes were length of the treatment, preceding and following treatments, treatment response, and safety data. Results: In total 268 patients had started therapy with cladribine tablets, 89 men and 179 women, with a median age of 40 years (interquartile range (IQR) 32–48. The disease course was relapsing-remitting MS in 97.8% of the patients, and at treatment start the median time from disease onset was 8.1 years (IQR 4.2–14.5) and EDSS 2.5 (IQR 1.5–3.5). Thirty-four patients (12.7%) were treatment naïve while 56 (20.9%) had received one previous disease-modifying therapy (DMT), 67 (25.0%) two, and 111 (41.4%) three or more previous DMTs. In total, 214 (80.0%) patients had completed the full treatment of two courses of cladribine, while 54 (20.0%) had received only one course of cladribine tablets. The median follow-up time after cladribine initiation was 34.7 months (IQR 23.3–43.7). Compared with an annualized relapse rate (ARR) of 0.67 (95% CI [0.56, 0.79]) in the year prior to start of cladribine, ARR was reduced to 0.11 (95% CI [0.08, 0.15]) in year 0–2 after 3-month re-baseline with cladribine (84.8% reduction). Adverse events, reported in 44 (16.4%) of the patients, were mild or moderate, and herpes zoster was only reported in 2 patients. In total, 30 (11.2%) patients discontinued cladribine treatment, of whom 7 (2.6%) discontinued because of adverse effects and 12 (4.5%) discontinued because of disease activity. Conclusion: In this nationwide review of all Danish patients starting therapy with cladribine tablets in a real-world setting, cladribine treatment was safe, and the therapeutic response was as expected from previous clinical trials. A prolonged observation period is necessary to assess the long-term benefit and risk of cladribine.</p

Growth of Large-Area and Highly Crystalline MoS2 Thin Layers on Insulating Substrates

The two-dimensional layer of molybdenum disulfide (MoS2) has recently attracted much interest due to its direct-gap property and potential applications in optoelectronics and energy harvesting. However, the synthetic approach to obtain high quality and large-area MoS2 atomic thin layers is still rare. Here we report that the high temperature annealing of a thermally decomposed ammonium thiomolybdate layer in the presence of sulfur can produce large-area MoS2 thin layers with superior electrical performance on insulating substrates. Spectroscopic and microscopic results reveal that the synthesized MoS2 sheets are highly crystalline. The electron mobility of the bottom-gate transistor devices made of the synthesized MoS2 layer is comparable with those of the micromechanically exfoliated thin sheets from MoS2 crystals. This synthetic approach is simple, scalable and applicable to other transition metal dichalcogenides. Meanwhile, the obtained MoS2 films are transferable to arbitrary substrates, providing great opportunities to make layered composites by stacking various atomically thin layers.Comment: manuscript submitted on 11-Dec-2011, revision submitted on 16-Feb-201

Self-injury, suicidal ideation and -attempt and eating disorders in young people following the initial and second COVID-19 lockdown

Abstract Experts has raised concerns about young people’s mental health following the lockdowns implemented to mitigate the spread of COVID-19. An aggravation in mental health have been suggested in several studies, but the impact on self-injury, suicidality and eating disorders (EDs) are less elucidated. Using two different data setups i.e. longitudinal and repeated cross-sectional data, we compare self-reported self-injury, suicide ideation and -attempt and symptoms of EDs from before through different pandemic periods until spring 2021. The longitudinal data indicate a slight reduction in the proportion of self-injury and suicide ideation in both women and men, as well as symptoms of EDs in women. For suicide attempt no change was observed. In the repeated cross-sectional data, we observed no changes in self-injury, suicide ideation- and attempts or symptoms of EDs. Thus, our findings provide no support for increase in self-injury, suicidality, and symptoms of EDs following the lockdowns.</jats:p

Self-injury, suicidal ideation and -attempt and eating disorders in young people following the initial and second COVID-19 lockdown

SummaryBackgroundThe initial COVID-19 lockdowns have had negative effect on different mental health measures, especially in young women. However, the impact on self-injury, suicidality and eating disorder (ED) are less elucidated and remains inconsistent. We compare self-reported self-injury, suicide ideation and -attempt and symptoms of EDs from before through different pandemic periods until spring 2021.MethodsYoung participants in the Danish National Birth Cohort reported these measures in an 18-year follow-up in 2015-2021 and in a COVID-19 survey in spring 2021 when participants were aged 19-24 years. Changes in measures from pre to post lockdown were estimated with longitudinal data (N=7,597) and with repeated cross-sectional data (N=24,625) by linear regression.FindingsIn the longitudinal comparisons 14% of women and 7% of men reported self-injury pre lockdown, which decreased 6%-points (95% CI:-7%;-5%) for women and 3%-points (95% CI:-4%;-2%) for men during lockdown. For suicide ideation, the pre lockdown proportions were 25% and 18% for women and men respectively, and decreased 7%-points (95% CI:-8%;-6%) for women and 3%-points (95% CI:-5%;-1%) for men. For suicide attempt no change was observed. Pre lockdown 15% and 3% of women and men, respectively, had symptoms of EDs, which decreased 2%-points (95% CI:-3%;-1%) for women. We observed no changes in proportions of self-injury, suicide ideation or EDs in the repeated cross-sectional data.InterpretationOur findings provide no support for increase in self-injury, suicidality and EDs following the lockdowns, and if anything, indicate a reduction in self-injury and suicide ideation as well as EDs in women.</jats:sec

The impact of the initial and 2^ndnational COVID-19 lockdown on mental health in young people with and without pre-existing depressive symptoms

SummaryBackgroundThe evidence on mental well-being and loneliness among young people during the initial lockdown is mixed, and little is known about the long-lasting impact of the sequential lockdowns. We examine changes in young people’s mental health from before to during the initial and second more prolonged lockdown, and whether women and those with pre-existing depressive symptoms were disproportionally impacted.MethodsParticipants reported on mental health indicators in an ongoing 18-year data collection in the Danish National Birth Cohort and in a COVID-19 survey, including 8 data points: 7 in the initial lockdown, and 1 year post. Changes in quality of life (QoL), mental well-being, and loneliness were estimated with random effect linear regressions on longitudinal data (N=32,985), and linear regressions on repeated cross-sections (N=28,579).FindingsInterim deterioration in mental well-being and loneliness was observed during the initial lockdown, and only in those without pre-existing depressive symptoms. During the second lockdown, a modest deterioration was again observed for mental well-being and loneliness. QoL likewise only declined among those without pre-existing symptoms, where women showed a greater decline than men. QoL did not normalise during the initial lockdown and remained at lower levels during the second lockdown. These findings were not replicated in the repeated cross-sections.InterpretationExcept for an interim decrease in mental health during lockdown, and only in those without pre-existing depressive symptoms, this study’s findings do not suggest a substantial detrimental impact of the lockdowns. Potential methodological differences in-between studies are a possible explanation for the mixed evidence.FundingThe Velux FoundationResearch in contextEvidence before this studyWe searched PubMed, PsycINFO, MedrXiv, and PsyArXiv with the terms (“Mental*” OR “Psychological*” OR “Emotional*”) AND (“Youth” OR “Young Adult*”) AND (“COVID*” OR “Coronavirus” OR “Lockdown*”) for articles published in English between January 1st2020 and October 1st2021. Included studies varied in terms of quality of data used but overall studies reported a detrimental impact of the lockdowns on young people’s mental health. However, the evidence on mental well-being and loneliness has shown to be inconsistent and with signs of resilience. Young people, women, and those with a pre-existing mental disorder have been identified as vulnerable subgroups, but only a few studies investigating mental health in individuals with a pre-existing mental disorder included a pre-lockdown measurement. The included studies also demonstrated that there is a gap in the evidence in understanding how mental health changed week by week, as well as the long-term impact over the course of the lockdowns.Added value of this studyWith longitudinal data, this study shows an interim impact of the initial and second lockdown on mental health during the COVID-19 pandemic in young individuals without pre-existing symptoms in Denmark. Since commencement of the initial lockdown, the levels of mental health returned to before levels, but one year after the initial lockdown, the levels were still lower than before lockdown in young people without pre-existing depressive symptoms. Young individuals with pre-existing depressive symptoms did not experience more detrimental impact of the lockdown, but rather indication of resilience or even improvements in mental health were observed. A disproportional impact of the lockdown on women compared to men was only observed for QoL, as women without pre-exiting depressive symptoms experienced a greater decline in QoL than men without pre-existing depressive symptoms. However, findings based on the repeated cross-sectional data did not show similar interim impact – but instead no – or clinically irrelevant impact. Thus, taken together our findings do not suggest a substantial lasting impact of the lockdowns on mental health among young individuals.Implications of all available evidenceA great majority of earlier studies suggest that the lockdowns due to the COVID-19 pandemic have had substantial detrimental impact on mental health, and that women and those with a pre-existing mental disorder constitute vulnerable subgroups. However, these studies vary considerably in terms of method applied. Our findings emphasise the importance of the use of different data setups, as well as methodology applied for the investigation of mental health. More studies based on high-quality data used in different settings are needed to fully understand the impact of the lockdowns on young people’s mental health, including potential disproportional impact on vulnerable subgroups.</jats:sec