NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis (NORMIMS study): a randomised, placebo-controlled trial

Treatment of relapsing-remitting multiple sclerosis with interferon beta is only partly effective, and new more effective and safe strategies are needed. Our aim was to assess the efficacy of oral methylprednisolone as an add-on therapy to subcutaneous interferon beta-1a to reduce the yearly relapse rate in patients with relapsing-remitting multiple sclerosis. Methods: NORMIMS (NORdic trial of oral Methylprednisolone as add-on therapy to Interferon beta-1a for treatment of relapsing-remitting Multiple Sclerosis) was a randomised, placebo-controlled trial done in 29 neurology departments in Denmark, Norway, Sweden, and Finland. We enrolled outpatients with relapsing-remitting multiple sclerosis who had had at least one relapse within the previous 12 months despite subcutaneous interferon beta-1a treatment (44 microg three times per week). We randomly allocated patients by computer to add-on therapy of either 200 mg methylprednisolone or matching placebo, both given orally on 5 consecutive days every 4 weeks for at least 96 weeks. The primary outcome measure was mean yearly relapse rate. Primary analyses were by intention to treat. This trial is registered, number ISRCTN16202527. Findings: 66 patients were assigned to interferon beta and oral methylprednisolone and 64 were assigned to interferon beta and placebo. A high proportion of patients withdrew from the study before week 96 (26% [17 of 66] on methylprednisolone vs 17% [11 of 64] on placebo). The mean yearly relapse rate was 0.22 for methylprednisolone compared with 0.59 for placebo (62% reduction, 95% CI 39-77%; p<0.0001). Sleep disturbance and neurological and psychiatric symptoms were the most frequent adverse events recorded in the methylprednisolone group. Bone mineral density had not changed after 96 weeks. Interpretation: Oral methylprednisolone given in pulses every 4 weeks as an add-on therapy to subcutaneous interferon beta-1a in patients with relapsing-remitting multiple sclerosis leads to a significant reduction in relapse rate. However, because of the small number of patients and the high dropout rate, these findings need to be corroborated in larger cohorts

Respiratory dysfunction three months after severe COVID-19 is associated with gut microbiota alterations

Background: Although coronavirus disease 2019 (COVID-19) is primarily a respiratory infection, mounting evidence suggests that the gastrointestinal (GI) tract is involved in the disease, with gut barrier dysfunction and gut microbiota alterations being related to disease severity. Whether these alterations persist and are related to long-term respiratory dysfunction remains unknown. Methods: Plasma was collected during hospital admission and after three months from the NOR-Solidarity trial (n = 181) and analysed for markers of gut barrier dysfunction and inflammation. At the three-month follow-up, pulmonary function was assessed by measuring the diffusing capacity of the lungs for carbon monoxide (DLCO ). Rectal swabs for gut microbiota analyses were collected (n = 97) and analysed by sequencing the 16S rRNA gene. Results: Gut microbiota diversity was reduced in COVID-19 patients with respiratory dysfunction, defined as DLCO below the lower limit of normal three months after hospitalisation. These patients also had an altered global gut microbiota composition, with reduced relative abundance of 20 bacterial taxa and increased abundance of five taxa, including Veillonella, potentially linked to fibrosis. During hospitalisation, increased plasma levels of lipopolysaccharide-binding protein (LBP) were strongly associated with respiratory failure, defined as pO2 /fiO2 -(P/F ratio)Respiratory dysfunction three months after severe COVID-19 is associated with gut microbiota alterationsacceptedVersio

Efficacy and safety of baricitinib in hospitalized adults with severe or critical COVID‑19 (Bari‑SolidAct): a randomised, double‑blind, placebo‑controlled phase 3 trial

Background Baricitinib has shown efcacy in hospitalized patients with COVID-19, but no placebo-controlled trials have focused specifcally on severe/critical COVID, including vaccinated participants. Methods Bari-SolidAct is a phase-3, multicentre, randomised, double-blind, placebo-controlled trial, enrolling participants from June 3, 2021 to March 7, 2022, stopped prematurely for external evidence. Patients with severe/ critical COVID-19 were randomised to Baricitinib 4 mg once daily or placebo, added to standard of care. The primary endpoint was all-cause mortality within 60 days. Participants were remotely followed to day 90 for safety and patient related outcome measures. Results Two hundred ninety-nine patients were screened, 284 randomised, and 275 received study drug or placebo and were included in the modifed intent-to-treat analyses (139 receiving baricitinib and 136 placebo). Median age was 60 (IQR 49–69) years, 77% were male and 35% had received at least one dose of SARS-CoV2 vaccine. There were 21 deaths at day 60 in each group, 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute diference and 95% CI −0.1% [−8·3 to 8·0]). In sensitivity analysis censoring observations after drug discontinuation or rescue therapy (tocilizumab/increased steroid dose), proportions of death were 5.8% versus 8.8% (−3.2% [−9.0 to 2.7]), respectively. There were 148 serious adverse events in 46 participants (33.1%) receiving baricitinib and 155 in 51 participants (37.5%) receiving placebo. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. In a subsequent post hoc analysis there was a signifcant interac‑ tion between vaccination status and treatment allocation on the occurrence of serious adverse events, with more respiratory complications and severe infections in vaccinated participants treated with baricitinib. Vaccinated partici‑ pants were on average 11 years older, with more comorbidities. Conclusion This clinical trial was prematurely stopped for external evidence and therefore underpowered to con‑ clude on a potential survival beneft of baricitinib in severe/critical COVID-19. We observed a possible safety signal in vaccinated participants, who were older with more comorbidities. Although based on a post-hoc analysis, these fnd‑ ings warrant further investigation in other trials and real-world studies

The Analysis of Continuous Mark-Recapture Data

The purpose of this thesis is to develop a general methodology for the analysis of continuously sampled data from open populations. The thesis consists of four parts and one appendix. The four parts may be read independently of each other. The appendix consists of a submitted article based on the developments in Part III. The aim of Part I is to present the major contributions to the mark-recapture methodology over the last century. It is not a complete reference to the subject, but gives the reader an introduction to mark-recapture models. In addition to the classic models, some recent development of interest is included. The introduction of Bayesian statistics to mark-recapture models is covered, in addition to the analysis of continuously sampled data from closed populations. With the ever increasing amount of models available, the need for model selection tools is grave. We look at some of the most used methods such as the Likelihood Ratio Test (LRT) and the Akaike Information Criterion in connection with mark-recapture models. For the Bayesian models, we review some of the latest developments in model selection such as the Deviance Information Criterion. Part II addresses the challenge of analysing a set of continuously sampled markrecapture data from a Norwegian coastal cod population (the Risør data set). These data are already analysed with discrete models by Julliard et al. (2001), but it is suggested that this approach may lead to biased estimates of the survival. The approach taken in Part II is to renounce the discrete models for mark-recapture data, and to develop an new, continuous model. The analysis of this model is preformed by a Monte Carlo EM algorithm. The survival and capture estimates are presented and compared with the estimates of Julliard et al. (2001). The Risør data set contains much auxilliary information such as size at release and capture, release location and capture gear. A semi-parametric multiplicative hazard model is implemented to include some of this information. The EM algorithm from Part II is developed further in Part III. Instead of a Monte Carlo simulation in the E step of the algorithm, an analytic solution is presented. The algorithm is developed for the discrete Cormack-Jolly-Seber(CJS) model, and shows nice convergence and stability properties for this model. An argument is then given for applying the CJS model directly to continuous data. The stability of the EM algorithm makes it suitable for such analysis. When covariate information is to be included into the analysis of continuous data, the CJS model is no longer appropriate. A semi-parametric multiplicative model for the survial and capture processes is presented as an answer to this challenge. The EM algorithm is still used for analysis. The methodology is applied to a set of continuously sampled data on the Eurpean Dipper, gathered by G. Marzolin (Marzolin (2002)). These data have been analysed discretely by Lebreton et al. (1992) (frequentistic) and by Brooks et al. (2000) (Bayesian). One of the assumptions of the CJS model is that the sampling is done instantaneously. The aim of Part IV is to assess the consequences of violating this assumption. A simulation analysis showes that there is potential for substantial bias of the survival estimates when the sampling periods are long

Involvement of the multidisciplinary team and outcomes in inpatient rehabilitation among patients with inflammatory rheumatic disease

Background: The last decades have for patients with inflammatory rheumatic diseases seen a shift towards more physically active rehabilitation programs, often provided as out-patients with less use of inpatient facilities. There is little research on which effect the multidisciplinary team has on health outcomes for patients with rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, and connective tissue disease. This study examined patient reported outcomes for patients with inflammatory rheumatic diseases receiving rehabilitation care as inpatients in departments of rheumatology, and studied how number of consultations with the multidisciplinary team affected these clinical outcomes. Methods: Patients with inflammatory rheumatic diseases were included in a multi-center prospective observational study if rehabilitation was considered a focus during an inpatient stay at four departments of rheumatology. At admission, discharge, and after 3 and 6 months, 317 patients were assessed with patients reported outcomes (PRO) including health assessment questionnaire (HAQ), short-form 36 (SF-36), pain, fatigue, patient global assessment of disease activity, self-efficacy scales, rheumatoid arthritis disease activity index (RADAI), and SF-6D utility. Patients stated consultations with the multidisciplinary team. Results: Improvements were short-lived, and at 6 months follow-up period only mental health, pain and utility remained improved with small effect sizes. Extensive involvement of health professionals was not associated with improved outcomes. Conclusions: Patients with inflammatory rheumatic disease receiving inpatient multidisciplinary rehabilitation had small and mainly short-term improvements in most PROs. High use of the multidisciplinary team did not enhance or preserve rehabilitation outcomes in inflammatory rheumatic conditions when admitted as inpatients

Performance development from age 11 to 18 in running and jumping disciplines.

<p>Data are mean ± SD for 60 m (panel A), 800 m (panel B) long jump (panel C) and high jump (panel D) for top 100 Norwegian male and female performers in each discipline.</p

Sex difference (%) for performance in running and jumping disciplines from age 11 to 18.

<p>Data are mean and 95% CIs for 60 m (panel A), 800 m (panel B), long jump (panel C) and high jump (panel D) for top 100 Norwegian male and female performers in each discipline.</p

Sex ratio in running and jumping performance for 11–18 yr old males and females.

<p>Data are calculated from mean results of top 100 Norwegian male and female performers in each discipline.</p><p>Sex ratio in running and jumping performance for 11–18 yr old males and females.</p

Opportunistic treatment of hepatitis C virus infection (OPPORTUNI-C): study protocol for a pragmatic stepped wedge cluster randomized trial of immediate versus outpatient treatment initiation among hospitalized people who inject drugs

Background: Scaled-up direct-acting antiviral (DAA) treatment of hepatitis C virus (HCV) infection among people who inject drugs (PWID) is crucial to reach the World Health Organization HCV elimination targets within 2030. One of the critical obstacles to HCV care in this population is the lack of treatment models within specialist healthcare adapted to marginalized individuals. Methods: OPPORTUNI-C is a pragmatic stepped wedge cluster randomized trial comparing the efficacy of immediate initiation of HCV treatment with the current standard of care among PWID admitted for inpatient care. Screening for HCV RNA will be performed as soon as possible after admission. The intervention includes immediate non-invasive liver disease assessment, counseling, and initiation of pan-genotypic DAA treatment with individualized follow-up. Standard of care is a referral to outpatient care at discharge. To mimic usual clinical practice as closely as possible, we will use a pragmatic clinical trial approach utilizing clinical infrastructure, broad eligibility criteria, flexible intervention delivery, clinically relevant outcomes, and collection of data readily available from the electronic patient files. The stepped wedge design involves a sequential rollout of the intervention over 16 months, in which seven participating clusters will be randomized from standard of care to intervention in a stepwise manner. Randomization will be stratified according to cluster size to keep high prevalence clusters separated. The trial will include approximately 220 HCV RNA positive individuals recruited from departments of internal medicine, addiction medicine, and psychiatry at Akershus University Hospital, Oslo University Hospital, and Lovisenberg Diaconal Hospital, Oslo, Norway. Individuals not able or willing to give informed consent and those with ongoing HCV assessment or treatment will be excluded. The primary outcome is treatment completion, defined as dispensing of the final prescribed DAA package from the pharmacy within 6 months after inclusion. Secondary outcomes include treatment uptake, virologic response, reinfection incidence, and resistance-associated substitutions. Discussion: Representing a novel model of care suited to reach and engage marginalized PWID in HCV care, this study will inform HCV elimination efforts locally and internationally. If the model proves efficacious and feasible, it should be considered for broader implementation, replacing the current standard of care