Influence of perioperative SARS-CoV-2 infection on mortality in orthopaedic inpatients with surgically treated traumatic fractures.

BACKGROUND: SARS-CoV-2 has had an extensive influence on orthopaedic surgery practice and has been associated with an increased risk of mortality. There is limited evidence of how this pertains to acute orthopaedic surgery with inpatient care. METHODS: A retrospective cohort study on traumatic fracture patients requiring inpatient care between February 25, 2020 and March 25, 2021 was conducted. Patients were grouped by perioperative SARS-CoV-2 infection, defined as a positive SARS-CoV-2 test from 7 days before to 7 days after orthopaedic surgery, and compared using linear regression and Cox proportional hazards model for primary outcome 30-day mortality and secondary outcome hospital length of stay. RESULTS: In total, 5174 adults with a length of stay ≥ 48 h and an orthopaedic procedure due to a registered traumatic fracture were admitted from February 25, 2020 and discharged before March 26, 2021. Among the 5174 patients, 65% (3340/5174) were female, 22% (1146/5174) were 60-74 years and 56% (2897/5174) were 75 years or older. In total, 144 (3%) had a perioperative SARS-CoV-2 infection. Perioperative SARS-CoV-2 infection was associated with an increased 30-day mortality (aOR 4.19 [95% CI 2.67-6.43], p < 0.001). The median (IQR) length of stay after surgery was 13 days (IQR 6-21) for patients with, and 7 days (IQR 2-13) for patients without, perioperative SARS-CoV-2 infection. CONCLUSIONS: Perioperative SARS-CoV-2 infection increased 30-day mortality risk and hospital length of stay for traumatic fracture patients requiring inpatient surgical care. Pre- and postoperative infection were both associated with similar increases in mortality risk.

Differential effects on blood and cerebrospinal fluid immune protein markers and kynurenine pathway metabolites from aerobic physical exercise in healthy subjects.

Mounting evidence shows that physical exercise modulates systemic inflammation. However, its effect on cerebrospinal fluid (CSF) immune-marker profiles in man are largely unknown. We here report a study on healthy subjects (n = 27, males = 12, mean age 28.7, range 22-52) allocated to either an acute exercise setting over four consecutive days, or a training intervention over 4 weeks. Paired plasma and CSF samples collected at baseline, after 7 days of exercise abstention, and the day after completion of the exercise interventions, were analyzed for protein inflammation markers using a multiplex proximity extension assay and neurotransmitters and kynurenine pathway (KP) metabolites using liquid chromatography, respectively. Routine cell counts, and albumin, immunoglobulin G and neurofilament light chain concentrations in CSF remained unchanged in both paradigms, while several inflammatory proteins became upregulated after acute exercise. However, only changes in three CSF (vascular endothelial growth factor-A, interleukin-7 and matrix metalloproteinase-10) and 12 plasma proteins reached significance levels after adjustment for multiple comparisons and exclusion of less stable proteins. Similarly, KP metabolites only changed among participants after acute exercise, while neurotransmitter levels, except for increased CSF serine, remained stable. Both in plasma and CSF changes in KP metabolites and inflammatory proteins correlated, suggesting that these processes are functionally linked. These findings suggest that acute aerobic physical exercise affects immune markers and KP metabolites systemically and in the CSF.

A novel, robust method for quantification of multiple kynurenine pathway metabolites in the cerebrospinal fluid.

Aim: Kynurenine metabolites are potential modulators of psychiatric disease. We aimed to develop a highly sensitive biochemical analysis of cerebrospinal fluid (CSF) tryptophan (TRP) metabolites, to investigate the stability of metabolites and to confirm our previous findings of aberrant CSF quinolinic acid (QUIN) and picolinic acid (PIC) in suicide attempters using this method. Methodology & results: Ten CSF TRP metabolites were analyzed with ultraperformance LC-MS/MS. The method showed small intra- and interassay variation. Metabolites were stable following freeze-thaw cycles. A decreased CSF PIC/QUIN ratio was found in suicide attempters. Conclusion: The feasibility of reliably determining CSF TRP metabolites were demonstrated, including separation of the two isomers PIC and nicotinic acid (NA) and the finding of a reduced PIC/QUIN ratio replicated in suicide attempters.

Comparative effectiveness of dimethyl fumarate as the initial and secondary treatment for MS.

BACKGROUND: Population-based real-world evidence studies of the effectiveness and tolerability of dimethyl fumarate in relation to common treatment alternatives are still limited. OBJECTIVE: To evaluate the clinical effectiveness and tolerability of dimethyl fumarate (DMF) as the initial and secondary treatment for relapsing-remitting multiple sclerosis (RRMS) patients compared with common treatment alternatives in Sweden. METHODS: We conducted a nationwide retrospective observational cohort study of all RRMS patients identified through the Swedish MS registry initiating DMF (n = 641) or interferons/glatiramer acetate (IFN/GA; n = 555) as the initial therapy, or DMF (n = 703) or fingolimod (FGL; n = 194) after switch from IFN/GA between 1 January 2014 and 31 December 2016. RESULTS: The discontinuation rate was lower with DMF as the initial treatment than IFN/GA (adjusted hazard rate (HR): 0.46, 95% confidence interval (CI): 0.37-0.58, p < 0.001), but higher than FGL as the secondary treatment (HR: 1.51, CI: 1.08-2.09, p < 0.05). Annualized relapse rate (ARR) was lower with DMF compared to IFN/GA (0.04, CI: 0.03-0.06 vs 0.10, CI: 0.07-0.13; p < 0.05), but not FGL (0.03, CI: 0.02-0.05 vs 0.02, CI: 0.01-0.04; p = 0.41). Finally, time to first relapse (TTFR) was longer with DMF as the initial, but not secondary, therapy (p < 0.05 and p = 0.20, respectively). CONCLUSION: Our findings indicate that DMF performs better than IFN/GA as the initial treatment for RRMS. Compared to FGL, DMF displayed a lower tolerability, but largely similar effectiveness outcomes.

Therapeutic efficacy of dimethyl fumarate in relapsing-remitting multiple sclerosis associates with ROS pathway in monocytes.

Dimethyl fumarate (DMF) is a first-line-treatment for relapsing-remitting multiple sclerosis (RRMS). The redox master regulator Nrf2, essential for redox balance, is a target of DMF, but its precise therapeutic mechanisms of action remain elusive. Here we show impact of DMF on circulating monocytes and T cells in a prospective longitudinal RRMS patient cohort. DMF increases the level of oxidized isoprostanes in peripheral blood. Other observed changes, including methylome and transcriptome profiles, occur in monocytes prior to T cells. Importantly, monocyte counts and monocytic ROS increase following DMF and distinguish patients with beneficial treatment-response from non-responders. A single nucleotide polymorphism in the ROS-generating NOX3 gene is associated with beneficial DMF treatment-response. Our data implicate monocyte-derived oxidative processes in autoimmune diseases and their treatment, and identify NOX3 genetic variant, monocyte counts and redox state as parameters potentially useful to inform clinical decisions on DMF therapy of RRMS.

Comparative Effectiveness of Rituximab and Other Initial Treatment Choices for Multiple Sclerosis.

Importance: Comparative real-world effectiveness studies of initial disease-modifying treatment (DMT) choices for relapsing-remitting multiple sclerosis (RRMS) that include rituximab are lacking. Objective: To assess the effectiveness and drug discontinuation rates of rituximab among patients with newly diagnosed RRMS compared with injectable DMTs, dimethyl fumarate, fingolimod, or natalizumab. Design, Setting, and Patients: This retrospective cohort study used prospectively collected data to examine specialized care of 2 Swedish county-based community samples of patients with RRMS. Patients with RRMS who received diagnoses from January 1, 2012, to October 31, 2015, who resided in Stockholm or Västerbotten Counties were identified from a Swedish multiple sclerosis registry. Main Outcomes and Measures: All reasons for drug discontinuation of initial treatment choice (main outcome) and specific reasons for switching (secondary outcomes) were analyzed with multivariable Cox regression, including propensity scores. Results: Among 494 patients (median [interquartile range] age, 34.4 [27.4-43.4] years; 158 men [32.0%]), 215 received an injectable DMT (43.5%); 86 (17.4%), dimethyl fumarate; 17 (3.4%), fingolimod; 50 (10.1%), natalizumab; 120 (24.3%), rituximab; and 6 (1.2%), other DMT. Regional preferences were pronounced, with 42 of 52 (81%) and 78 of 442 (18%) receiving rituximab in Västerbotten and Stockholm, respectively. The annual discontinuation rate for rituximab, injectable DMTs, dimethyl fumarate, fingolimod, and natalizumab were 0.03, 0.53, 0.32, 0.38, and 0.29, respectively. Continued disease activity was the main reason for discontinuation of injectable DMTs, dimethyl fumarate, and fingolimod; positive John Cunningham virus serology results were the main reason for discontinuation of natalizumab. Rate of clinical relapses and/or neuroradiologic disease activity were significantly lower for rituximab compared with injectable DMTs and dimethyl fumarate, with a tendency for lower relapse rates also compared with natalizumab and fingolimod. The annual discontinuation rate of initial treatment choice was significantly lower in Västerbotten compared with Stockholm (0.09 and 0.37, respectively). Conclusions and Relevance: Rituximab was superior to all other DMT in terms of drug discontinuation and displayed better clinical efficacy compared with injectable DMTs and dimethyl fumarate with borderline significance compared with natalizumab and fingolimod. The county where rituximab constituted the main initial treatment choice displayed better outcomes in most measured variables. Collectively, our findings suggest that rituximab performs better than other commonly used DMTs in patients with newly diagnosed RRMS.

Depression and fatigue in multiple sclerosis: Relation to exposure to violence and cerebrospinal fluid immunomarkers.

Multiple sclerosis (MS) is a neuroinflammatory condition characterized by chronic dysregulation of immune responses leading to repeated episodes of inflammation in the central nervous system. Depression and fatigue are common among MS patients, even in early disease phases, and the disease course can be negatively affected by stressful events. IL-6 and IL-8 have been associated with depression and stressful life events in non-MS patients. The aim of this study was to examine the relationships between depression, fatigue, and exposure to violence, with IL-6 and IL-8 levels in the cerebrospinal fluid (CSF) of MS patients. Levels of IL-6 and -8 were analyzed in the CSF of 47 patients with relapsing-remitting MS. Correlations between IL-6 and IL-8 levels and self-rated depression and fatigue symptoms, as well as clinician-rated history of being exposed to interpersonal violence, were analyzed with correction for age, sex and MS disability status. IL-6 correlated significantly (p < 0.05) with depressive symptoms (adjusted Spearman's ρ = 0.39), fatigue (ρ = 0.39), and exposure to violence in adult life (ρ = 0.35). Depression correlated with both fatigue and being exposed to violence. Associations were not present among patients exposed to disease modifying drugs. In exploratory analyses, the relationship between exposure to violence and IL-6 was non-significant when controlled for depression. Further research should focus on replication of these results, as well as exploring the impact of stressful life events on immune regulation and the clinical characteristics and prognosis of MS patients.

Successful combined targeting of B- and plasma cells in treatment refractory anti-NMDAR encephalitis.

We describe an extremely severe case of therapy refractory NMDA receptor encephalitis (NMDAe) in a 26-year-old woman. After rituximab, bilateral oophorectomy, repeated cycles of high dose methylprednisolone and plasma exchange, she received repeated cyclophosphamide, tocilizumab (interleukin-6 inhibitor) and finally bortezomib (plasma cell depleting drug) leading to remission after 204days in intensive care. Two years after disease onset her cognitive functions are still affected, but slowly improving and the cerebral atrophy has been partly reversed. The cerebrospinal fluid biomarker profile suggests an early synaptic/dendritic process, with subsequent neuroaxonal degeneration motivating aggressive treatment early on.

Memory-reliant Post-error Slowing Is Associated with Successful Learning and Fronto-occipital Activity.

Negative feedback after an action in a cognitive task can lead to devaluing that action on future trials as well as to more cautious responding when encountering that same choice again. These phenomena have been explored in the past by reinforcement learning theories and cognitive control accounts, respectively. Yet, how cognitive control interacts with value updating to give rise to adequate adaptations under uncertainty is less clear. In this fMRI study, we investigated cognitive control-based behavioral adjustments during a probabilistic reinforcement learning task and studied their influence on performance in a later test phase in which the learned value of items is tested. We provide support for the idea that functionally relevant and memory-reliant behavioral adjustments in the form of post-error slowing during reinforcement learning are associated with test performance. Adjusting response speed after negative feedback was correlated with BOLD activity in right inferior frontal gyrus and bilateral middle occipital cortex during the event of receiving the feedback. Bilateral middle occipital cortex activity overlapped partly with activity reflecting feedback deviance from expectations as measured by unsigned prediction error. These results suggest that cognitive control and feature processing cortical regions interact to implement feedback-congruent adaptations beneficial to learning.