Search

Henning Søndergaard Danish Kidney Association, Taastrup, DenmarkCorrespondence: Henning Søndergaard, Danish Kidney Association, Blekinge Blvd. 2, 2630 Taastrup, Denmark, Tel +45 61654865, Email hs@nyre.dkAbstract: The inclusion of patient representatives as study consultants brings diverse perspectives, insights, and experiences to clinical trial design and execution, and their role in the clinical trial development process is being increasingly recognized and valued. The APPETIZE study evaluated the palatability of, and preference for, three potassium binders for treating hyperkalemia in patients with chronic kidney disease. A core aspect of the development of this study was the inclusion of a patient representative during the design stage. Here, I describe the process of patient involvement in the APPETIZE study design (ClinicalTrials.gov Identifier: NCT04566653), the resultant positive impacts, and key learnings. A patient with chronic kidney disease was invited to be a member of the APPETIZE trial design team. This patient representative attended study team meetings and provided invaluable input into protocol development, questionnaire selection, design of patient information sheets and consent forms, and primary manuscript structure. These critical insights resulted in an enhanced trial design and generation of high-quality, patient-relevant data. APPETIZE provides an excellent example of a patient preference study that relied on input from multiple stakeholder groups, including, most notably, the patients themselves. This approach may serve as a model for early and deep patient engagement in the design and interpretation of clinical trials.Keywords: clinical trials, patient representation, chronic kidney disease, hyperkalemia

Objectives: Sensitivity to sex‐steroid hormone fluctuations may increase risk for perinatal depression. We aimed to identify genome‐wide biological profiles in women demonstrating sensitivity to pharmacological sex‐hormone manipulation with gonadotrophin‐releasing hormone agonist (GnRHa). Methods: Longitudinal gene expression (Illumina Human HT12.v4) and DNA methylation data (Infinium HumanMethylation450K BeadChip) from 60 women (30 GnRHa, 30 placebo) were generated (Trial ID: NCT02661789). Differences between baseline and two follow‐up points (initial stimulation‐ and subsequent early suppression phase) in the biphasic ovarian hormone response to GnRHa were assessed using linear mixed effects models. Results: Genome‐wide analysis revealed 588 probes differentially expressed from GnRHa intervention to first stimulatory phase follow‐up (intervention group × time) after 10% fdr multiple testing correction. Of these, 54% genes were also significantly associated with estradiol changes over time (proxy for GnRHa response magnitude), 9.5% were associated with changes in depressive symptoms, and 38% were associated with changes in neocortical serotonin transporter binding. The genes were implicated in TGF beta signaling, adipogenesis, regulation of actin cytoskeleton, and focal adhesion pathways and enriched for DNA methylation changes (P = 0.006). Conclusions: These findings point toward an altered peripheral blood transcriptomic landscape in a pharmacological model of sex‐hormone‐induced depressive symptoms. [ABSTRACT FROM AUTHOR]

Background: Subtypes of white blood cell counts are known biomarkers of systemic inflammation and a high neutrophil-to-lymphocyte ratio (NLR) has been associated with several autoimmune diseases. Few studies have investigated the NLR in multiple sclerosis (MS). Objective: To examine the association between NLR, MS and disability measured by the MS severity score (MSSS). Methods: Patients were included from the Danish Multiple Sclerosis Biobank. Information on patient NLR was obtained just before their first treatment and clinical information was provided by the Danish Multiple Sclerosis Treatment Register. Information on NLR from controls was collected from the Danish Blood Donor Study. Patients and controls were 1:2 propensity score matched by baseline confounders. Results: Propensity score matching left 740 of 743 MS patients and 1420 of 4691 controls for further analyses. Odds-ratio (OR) was 3.64 (95% confidence interval 2.87-4.60, p<0.001) for MS disease per unit increase of logarithmically transformed NLR (ln-NLR), corresponding to an OR of 2.68 for each doubling of NLR. Mean NLR was 2.12 for patients and 1.72 for controls (p<0.001). Ln-NLR correlated weakly with patient MSSS (R²=0.019, p = 0.008). Conclusion: Patients with early MS had increased levels of NLR compared to healthy controls and NLR was weakly correlated with MSSS. [ABSTRACT FROM AUTHOR]

Using the nonaccelerated murine nephrotoxic nephritis (NTN) as a model of chronic kidney disease (CKD) could provide an easily inducible model that enables a rapid test of treatments. Originally, the NTN model was developed as an acute model of glomerulonephritis, but in this study we evaluate the model as a CKD model and compare CD1 and C57BL/6 female and male mice. CD1 mice have previously showed an increased susceptibility to CKD in other CKD models. NTN was induced by injecting nephrotoxic serum (NTS) and evaluated by CKD parameters including albuminuria, glomerular filtration rate (GFR), mesangial expansion, and renal fibrosis. Both strains showed significant albuminuria on days 2-3 which remained significant until the last time point on days 36-37 supporting dysfunctional filtration also observed by a significantly declined GFR on days 5-6, 15–17, and 34–37. Both strains showed early progressive mesangial expansion and significant renal fibrosis within three weeks suggesting CKD development. CD1 and C57BL/6 females showed a similar disease progression, but female mice seemed more susceptible to NTS compared to male mice. The presence of albuminuria, GFR decline, mesangial expansion, and fibrosis showed that the NTN model is a relevant CKD model both in C57BL/6 and in CD1 mice. [ABSTRACT FROM AUTHOR]

Introduction The most serious complication in haemophilia A ( HA) replacement therapy with coagulation factor VIII ( FVIII) is neutralizing antibodies, i.e. inhibitors. It has been hypothesized that danger signals generated during a bleed might have an adjuvant effect on the immune response to FVIII in on-demand treatment, increasing the inhibitor risk. Aim To compare the antibody response to treatment with recombinant human FVIII (rh FVIII) in relation to induced knee joint bleeds and treatment without concurrent bleeds in a HA rat model. Method HA rats were divided into two groups: one group ( n = 10) receiving three needle induced knee joint bleeds 14 days apart and a control group ( n = 9) receiving three sham procedures. Three hours after each injury/sham 50 IU kg−1 rh FVIII was administrated intravenously. Subsequently, both groups continued rh FVIII treatment for another 9 weeks. Binding antibodies were analysed using an enzyme-linked immunosorbent assay and neutralizing antibodies using a Bethesda-like assay. Results Rats in the knee-bleed group developed a significantly faster inhibitor response and reached significantly higher inhibitor levels. In the knee-bleed group, 80% developed inhibitors vs. 33% in the control group, demonstrating a 2.4 times higher inhibitor risk when treating concurrent with bleeds. Conclusion FVIII treatment in relation to a bleed potentiates inhibitor development compared to FVIII treatment alone in this HA rat, indicating that bleeding is a potential danger signal. Our results support the theory that FVIII replacement therapy concurrent with a bleeding episode increases the inhibitor risk, which to the best of our knowledge, has not been confirmed in an animal model before. [ABSTRACT FROM AUTHOR]

In haemophilia A ( HA) management, antidrug antibodies, or inhibitors, are a serious complication that renders factor VIII ( FVIII) replacement therapy ineffective, increases morbidity and reduces quality of life for affected patients. Inhibitor development aetiology is multifactorial and covers both genetic and therapy related risk factors. Many therapy-related risk factors have proven difficult to confirm due to several confounding factors and the small study populations available. However, clinical studies indicate that e.g. on-demand treatment and surgery affect inhibitor development, and explanations for this association are being investigated. A potential explanation is the danger signal effect, where the immune response is activated by endogenous or exogenous danger or damage signals present at the time and site of FVIII administration. The danger theory explains how alarm signals from stressed, injured or dying cells can activate an immune reaction, without the involvement of foreign antigens. Bleeds, trauma, surgery or concomitant infection could be events initiating danger signalling in HA patients, resulting in an immune reaction towards administered FVIII that otherwise would pass unnoticed. This role of danger in HA inhibitor formation has previously been suggested, but a thorough discussion of this subject is lacking. The present review will discuss the potential role of danger signals in haemophilia and inhibitor development, with focus on treatment related risk factors with a suspected danger signal aetiology; on-demand treatment, treatment during major bleeds or surgery, and treatment during infection or vaccination. Clinical studies as well as animal experiments addressing these factors will be reviewed. [ABSTRACT FROM AUTHOR]

Quantitative real-time PCR (q PCR) involves the need of a proper standard for normalizing the gene expression data. Different studies have shown the validity of reference genes to vary greatly depending on tissue, cell subsets and experimental context. This study aimed at the identification of suitable reference genes for q PCR studies using different peripheral blood cell subsets (whole blood ( WB) cells, peripheral blood mononuclear cells ( PBMCs) and PBMC subsets ( CD4+ T cells, CD8+ T cells, NK cells, monocytes, B cells and dendritic cells) from healthy controls ( HC), patients with relapsing-remitting multiple sclerosis ( RRMS) and interferon- β-treated patients with RRMS ( RRMS- IFN- β). Eight candidate reference genes ( CASC3 , EEF1A1, GAPDH, HPRT1, RPLP0, UBC, UBE2D2 and YWHAZ) were analysed using normfinder and genorm algorithms to identify the most stably expressed genes. We found reference gene expression varied most across cell subsets, and less variation between the donor groups. UBE2D2 was the most stably expressed gene across both HC and RRMS patients and across cell subsets, while UBC was the most stably expressed gene between HC, RRMS and RRMS- IFN- β patients. UBE2D2 and HPRT1 was the most stable combination for analyses of cell subsets between HC and RRMS patients, while the combination of UBC and YWHAZ was superior for analysis of cell subsets between HC, RRMS and RRMS- IFN- β groups. GAPDH was generally unsuitable for blood cell subset studies in multiple sclerosis. In conclusion, we found that blood cell subsets result in marked variation in reference gene expression, and we identified suitable reference genes for studies involving PBMC subsets, RRMS patients and interferon- β treatment. [ABSTRACT FROM AUTHOR]

We recently reported the circulatory and muscle oxidative capacities of the arm after prolonged low-intensity skiing in the arctic ( Boushel et al., 2014). In the present study, leg VO2 was measured by the Fick method during leg cycling while muscle mitochondrial capacity was examined on a biopsy of the vastus lateralis in healthy volunteers (7 male, 2 female) before and after 42 days of skiing at 60% HR max. Peak pulmonary VO2 (3.52 ± 0.18 L.min−1 pre vs 3.52 ± 0.19 post) and VO2 across the leg (2.8 ± 0.4L.min−1 pre vs 3.0 ± 0.2 post) were unchanged after the ski journey. Peak leg O2 delivery (3.6 ± 0.2 L.min−1 pre vs 3.8 ± 0.4 post), O2 extraction (82 ± 1% pre vs 83 ± 1 post), and muscle capillaries per mm2 (576 ± 17 pre vs 612 ± 28 post) were also unchanged; however, leg muscle mitochondrial OXPHOS capacity was reduced (90 ± 3 pmol.sec−1.mg−1 pre vs 70 ± 2 post, P < 0.05) as was citrate synthase activity (40 ± 3 μmol.min−1.g−1 pre vs 34 ± 3 vs P < 0.05). These findings indicate that peak muscle VO2 can be sustained with a substantial reduction in mitochondrial OXPHOS capacity. This is achieved at a similar O2 delivery and a higher relative ADP-stimulated mitochondrial respiration at a higher mitochondrial p50. These findings support the concept that muscle mitochondrial respiration is submaximal at VO2max, and that mitochondrial volume can be downregulated by chronic energy demand. [ABSTRACT FROM AUTHOR]

Background: An observational study has suggested that relapsing–remitting multiple sclerosis patients with helminth infections have lower disease activity and progression than uninfected multiple sclerosis patients. Objective: To evaluate the safety and efficacy on MRI activity of treatment with TSO in relapsing MS. Methods: The study was an open-label, magnetic resonance imaging assessor-blinded, baseline-to-treatment study including ten patients with relapsing forms of multiple sclerosis. Median (range) age was 41 (24–55) years, disease duration 9 (4–34) years, Expanded Disability Status Scale score 2.5 (1–5.0), and number of relapses within the last two years 3 (2–5). Four patients received no disease modifying therapy, while six patients received IFN-β. After an observational period of 8 weeks, patients received 2500 ova from the helminth Trichuris suis orally every second week for 12 weeks. Patients were followed with serial magnetic resonance imaging, neurological examinations, laboratory safety tests and expression of immunological biomarker genes. Results: Treatment with Trichuris suis orally was well-tolerated apart from some gastrointestinal symptoms. Magnetic resonance imaging revealed 6 new or enlarged T2 lesions in the run-in period, 7 lesions in the early period and 21 lesions in the late treatment period. Two patients suffered a relapse before treatment and two during treatment. Eight patients developed eosinophilia. The expression of cytokines and transcription factors did not change. Conclusions: In a small group of relapsing multiple sclerosis patients, Trichuris suis oral therapy was well tolerated but without beneficial effect. [ABSTRACT FROM AUTHOR]

Objective Single nucleotide polymorphisms ( SNPs) in the genes encoding interferon response factor ( IRF)-5, IRF-8 and glypican-5 ( GPC5) have been associated with disease activity in multiple sclerosis ( MS) patients treated with interferon ( IFN)- β. We analysed whether SNPs in the IRF5, IRF8 and GPC5 genes are associated with clinical disease activity in MS patients beginning de novo treatment with IFN- β. Methods The SNPs rs2004640, rs3807306 and rs4728142 in IRF5, rs13333054 and rs17445836 in IRF8 and rs10492503 in GPC5 were genotyped in 575 patients with relapsing-remitting MS followed prospectively after the initiation of their first treatment with IFN- β. Results 62% of patients experienced relapses during the first 2 years of treatment, and 32% had disability progression during the first 5 years of treatment. Patients with a pretreatment annualized relapse rate >1 had an increased risk of relapse (hazard ratio 1.53, 95% confidence interval 1.24-1.90) and progression (hazard ratio 1.48, 95% confidence interval 1.10-1.99) on treatment and patients with breakthrough relapses in the form of relapses during the first 2 years of treatment had an increased risk of progression during the first 5 years of treatment (hazard ratio 2.04, 95% confidence interval 1.47-2.85).The gene variants in IRF5, IRF8 and GPC5 were not associated with risk of relapse or disease progression. Conclusions Pretreatment relapse rate and clinical disease activity during the first 2 years of treatment may be associated with disease progression in MS patients treated with IFN- β. Genetic analysis of the studied gene variants do not provide additional information. [ABSTRACT FROM AUTHOR]

Objective The chemokine receptor CCR5 may be important for the recruitment of pathogenic T cells to the CNS in multiple sclerosis ( MS). We hypothesized that this chemokine receptor might still be important for T-cell migration during treatment with anti-very late antigen ( VLA)-4 antibody. We therefore analysed whether natalizumab-treated MS patients carrying the CCR5 Δ32 deletion allele, which results in reduced expression of CCR5 on the cell surface, had lower disease activity. Methods CCR5 Δ32 was analysed in 212 natalizumab-treated MS patients. Results CCR5 Δ32 status had no significant impact on the frequency of relapses 1 year prior to natalizumab treatment or during the first 48 weeks of treatment. The multiple sclerosis severity score ( MSSS) was significantly lower at baseline in patients carrying CCR5 Δ32 ( P = 0.031). Conclusions CCR5 Δ32 is not associated with lower disease activity in MS patients treated with natalizumab. We found lower MSSS scores in patients carrying CCR5 Δ32 compared with the remaining patients, which is consistent with previous studies reporting an association with a more favourable disease course. Further studies are, however, needed before the relationship between CCR5 Δ32 and disease activity in MS can be definitely established. [ABSTRACT FROM AUTHOR]

Dysregulated T cells are a hallmark of several autoimmune and inflammatory diseases; thus, models to study human T cells in vivo are advantageous, but limited by lacking insight into human T cell functionality in mice. Using non-obese diabetic ( NOD), severe combined immunodeficient ( SCID) or recombination activating gene-1 ( RAG1)−/− and interleukin-2 receptor gamma-chain ( IL-2Rγ)−/− mice reconstituted with human peripheral blood mononuclear cells ( PBMCs), we have studied the mechanisms of human T cell expansion and activation in mice. Injection of human PBMCs into mice caused consistent xeno-engraftment with polyclonal expansion and activation of functional human T cells and production of human cytokines. Human T cell expansion coincided with development of a graft- versus-host disease ( GVHD)-like condition observed as weight loss, multi-organ immune infiltration and liver damage. CD8+ T cells alone were sufficient for expansion and required for disease development; in contrast, CD4+ T cells alone expanded but did not induce acute disease and, rather, exerted regulatory capacity through CD25+ CD4+ T cells. Using various anti-inflammatory compounds, we demonstrated that several T cell-activation pathways controlled T cell expansion and disease development, including calcineurin-, tumour necrosis factor-α and co-stimulatory signalling via the CD80/ CD86 pathway, indicating the diverse modes of action used by human T cells during expansion and activation in mice as well as the pharmacological relevance of this model. Overall, these data provide insight into the mechanisms used by human T cells during expansion and activation in mice, and we speculate that PBMC-injected mice may be useful to study intrinsic human T cell functions in vivo and to test T cell-targeting compounds. [ABSTRACT FROM AUTHOR]

Emergency stroke care has become a natural part of the emerging discipline of neurocritical care and demands close cooperation between the neurologist and neurointerventionists, neurosurgeons, and anesthesiologists. Endovascular treatment ( EVT), including intra-arterial thrombolysis, mechanical thrombectomy and angioplasty/stenting, is under rapid development. Although EVT has yet to be shown in randomized controlled trials to improve clinical outcome compared to intravenous thrombolysis, it is far better in achieving recanalization of occluded large cerebral vessels, which is crucial for rescuing the penumbra. Moreover, decompressive craniectomy is now a well-established treatment option for malignant middle cerebral artery infarction and cerebellar stroke. Using a case-based approach, this article reviews recent achievements in advanced treatment options for patients with acute ischemic stroke. [ABSTRACT FROM AUTHOR]

Background and purpose Measurements of binding antibodies ( BAbs), neutralizing antibodies ( NAbs) and MX1 mRNA expression are used to analyse the immunological reactions in patients with MS treated with IFN-β. The correlations between these are yet not fully understood. Methods We measured BAbs and NAbs to IFN-β in 110 serum samples from 83 patients with MS treated with IFN-β, and in a subgroup, antibody titre was compared with corresponding expressions of MX1 mRNA. The methods used were capture ELISA assay, luciferase reporter gene assay and mRNA RT- PCR for MX1 gene expression. Results There were significant correlations between binding, neutralizing and MX1 results. Cut-off values are suggested for the definition of samples of BAbs and NAbs as negative, positive and grey zones. Naturally occurring groups of low and high antibody titres were identified by the correlation between BAbs and NAbs, probably as a result of an immunological maturation process of antibodies. The low-titre group had lower correlations between BAbs and NAbs than the high-titre group. Conclusions High correlation is demonstrated between the results obtained by the three methods, and we suggest the possibility of using ELISA measurements of BAbs to identify patients with high titres of anti- IFN-β antibodies that block the biological response to IFN-β. Ιn patients with low titres, we suggest to supplement ELISA with measurement of MX1 mRNA to establish whether the bioavailability of IFN-β is preserved. [ABSTRACT FROM AUTHOR]

An immune activation response resembling virus or type I interferon responses has been observed in untreated multiple sclerosis (MS), but its pathogenic significance is uncertain. We studied the relationship between a type I interferon-like response in untreated patients with MS and disease activity. Gene expression was analyzed by real-time reverse transcriptase polymerase chain reaction (PCR) in whole blood samples and by microarray analysis of mononuclear cells from untreated patients with MS, patients with MS treated with IFN-β, and patients with MS with anti-IFN-β neutralizing antibodies (NAb). Disease activity was assessed by gadolinium-enhanced magnetic resonance imaging. Eight of 36 untreated patients with MS had spontaneously increased expression of the type I IFN-induced gene MX1. Microarray gene expression analysis demonstrated that patients with increased spontaneous MX1 expression also had increased expression of other genes induced by regular IFN-β treatment of MS. MX1 expression correlated with FOXP3 and IL10 expression, and IL10 expression correlated negatively with disease activity on magnetic resonance imaging. Further, in vivo IL10 expression was lower in NAb-positive patients than in untreated patients with MS and healthy controls. Finally, ex vivo treatment of mononuclear blood cells with IFN-β induced the expression of IL10, and this was blocked by the addition of serum from NAb-positive patients with MS. Our findings suggest that endogenous IFN-β may induce the expression of immunoregulatory IL10 in MS and that this might be associated with dampening of inflammatory disease activity. [ABSTRACT FROM AUTHOR]

The aim of this study was to characterize untrained Nandi boys (mean age 16.6 years) from a town ( n = 11) and from a rural area ( n = 19) in western Kenya (altitude 2000 m.a.s.l.) in regard to their body dimensions, oxygen uptake and physical activity level. The town boys had a mean maximal oxygen uptake (VO 2max ) of 50 (range: 45-60) mL kg -1 min -1 , whereas the village boys reached a value of 55 (37-63) mL kg -1 min -1 ( p <0.01) in VO 2max . The running economy, determined as the oxygen cost at a given running speed, was 221 mL kg -1 km -1 (597 mL kg -0.75 km -1 ) for town as well as for village boys. The body mass index (BMI) was very low for town as well as for village boys (18.6 vs 18.4 kg m -2 ). The daily mean time spent working in the field during secondary school and doing sports were significantly higher in village boys compared to town boys (working in the field: 44.2 (0-128) vs 1.3 (0-11) min, p <0.01; sports: 32.0 (11-72) vs 12.8 (0-35) min, p <0.01, respectively). A positive correlation between the daily time spent doing sports and VO 2max was found when pooling the data from the town and the village boys ( R = 0.55, p <0.01). It is concluded that the body dimensions of adolescent Nandi town and village boys corresponds well with findings in Kenyan elite runners. They are very slender with relatively long legs. In addition, the VO 2max of the village boys was higher than that of the town boys, which is probably due to a higher physical activity level of the village boys during secondary school. [ABSTRACT FROM AUTHOR]

To unravel the mechanisms by which maximal oxygen uptake (VO[sub 2 max]) is reduced with severe acute hypoxia in humans, nine Danish lowlanders performed incremental cycle ergometer exercise to exhaustion, while breathing room air (normoxia) or 10.5% O[sub 2] in N[sub 2] (hypoxia, ∼5,300 m above sea level). With hypoxia, exercise Pa[sub O[sub 2]] dropped to 31-34 mmHg and arterial O[sub 2] content (Ca[sub O[sub 2]]) was reduced by 35% (P < 0.001). Forty-one percent of the reduction in Ca[sub O[sub 2]] was explained by the lower inspired O[sub 2] pressure (PI[sub O[sub 2]]) in hypoxia, whereas the rest was due to the impairment of the pulmonary gas exchange, as reflected by the higher alveolar-arterial O[sub 2] difference in hypoxia (P < 0.05). Hypoxia caused a 47% decrease in VO[sub 2 max] (a greater fall than accountable by reduced Ca[sub O[sub 2]]). Peak cardiac output decreased by 17% (P < 0.01), due to equal reductions in both peak heart rate and stroke volume (P < 0.05). Peak leg blood flow was also lower (by 22%, P < 0.01). Consequently, systemic and leg O[sub 2] delivery were reduced by 43 and 47%, respectively, with hypoxia (P < 0.001) correlating closely with VO[sub 2 max] (r = 0.98, P < 0.001). Therefore, three main mechanisms account for the reduction of Vo[sub 2 max] in severe acute hypoxia: 1) reduction of PI[sub O[sub 2]], 2) impairment of pulmonary gas exchange, and 3) reduction of maximal cardiac output and peak leg blood flow, each explaining about one-third of the loss in Vo[sub 2 max]. [ABSTRACT FROM AUTHOR]

Acute hypoxia (AH) reduces maximal O[sub 2] consumption (Vo[sub 2 max]), but after acclimatization, and despite increases in both hemoglobin concentration and arterial O[sub 2] saturation that can normalize arterial O[sub 2] concentration ([O[sub 2]]), VO[sub 2 max] remains low. To determine why, seven lowlanders were studied at VO[sub 2 max] (cycle ergometry) at sea level (SL), after 9-10 wk at 5,260 m [chronic hypoxia (CH)], and 6 mo later at SL in AH (FI[sub O[sub 2]] = 0.105) equivalent to 5,260 m. Pulmonary and leg indexes of O[sub 2] transport were measured in each condition. Both cardiac output and leg blood flow were reduced by ∼15% in both AH and CH (P < 0.05). At maximal exercise, arterial [O[sub 2]] in AH was 31% lower than at SL (P < 0.05), whereas in CH it was the same as at SL due to both polycythemia and hyperventilation. O[sub 2] extraction by the legs, however, remained at SL values in both AH and CH. Although at both SL and in AH, 76% of the cardiac output per. fused the legs, in CH the legs received only 67%. Pulmonary VO[sub 2 max] (4.1 ± 0.3 1/min at SL) fell to 2.2 ± 0.1 l/min in AH (P < 0.05) and was only 2.4 ± 0.2 l/min in CH (P < 0.05). These data suggest that the failure to recover VO[sub 2 max] after acclimatization despite normalization of arterial [O[sub 2]] is explained by two circulatory effects of altitude: 1) failure of cardiac output to normalize and 2) preferential redistribution of cardiac output to nonexercising tissues. Oxygen transport from blood to muscle mitochondria, on the other hand, appears unaffected by CH. [ABSTRACT FROM AUTHOR]

We hypothesized that reliance on lactate as a means of energy distribution is higher after a prolonged period of acclimatization (9 wk) than it is at sea level due to a higher lactate R[sub a] and disposal from active skeletal muscle. To evaluate this hypothesis, six Danish lowlanders (25 ± 2 yr) were studied at rest and during 20 min of bicycle exercise at 146 W at sea level (SL) and after 9 wk of acclimatization to 5,260 m (Alt). Whole body glucose R[sub a] was similar at SL and Alt at rest and during exercise. Lactate R[sub a] was also similar for the two conditions at rest; however, during exercise, lactate R[sub a] was substantially lower at SL (65 µmol·min[sup -1]·kg body wt[sup -1]) than it was at Alt (150 µmol·min[sup -1]·kg body wt[sup -1]) at the same exercise intensity. During exercise, net lactate release was ∼6-fold at Alt compared with SL, and related to this, tracer-calculated leg lactate uptake and release were both 3- or 4-fold higher at Alt compared with SL. The contribution of the two legs to glucose disposal was similar at SL and Alt; however, the contribution of the two legs to lactate R[sub a] was significantly lower at rest and during exercise at SL (27 and 81%) than it was at Alt (45 and 123%). In conclusion, at rest and during exercise at the same absolute workload, CHO and blood glucose utilization were similar at SL and at Alt. Leg net lactate release was severalfold higher, and the contribution of leg lactate release to whole body lactate R[sub a] was higher at Alt compared with SL. During exercise, the relative contribution of lactate oxidation to whole body CHO oxidation was substantially higher at Alt compared with SL as a result of increased uptake and subsequent oxidation of lactate by the active skeletal muscles. [ABSTRACT FROM AUTHOR]

• Tight junction proteins contribute to maintenance of epithelial and endothelial barriers. • Circulating occludin levels are higher in newly diagnosed, untreated RRMS patients compared with HC. • Reduced occludin after 12 months of DMT may reflect a repair of the BBB and/or the intestinal barrier. • Occludin and ZO-1 did not predict disease activity at baseline or after 12 months. Tight junction proteins contribute to maintenance of epithelial and endothelial barriers such as the intestinal barrier and the blood brain barrier (BBB). Increased permeability of these barriers has been linked to disease activity in MS and there is currently a lack of easily accessible biomarkers predicting disease activity in MS. To investigate whether levels of circulating tight junction proteins occludin and zonula occludens-1 (ZO-1) are associated with biomarkers of inflammation and disease activity; and to determine whether they could serve as clinical biomarkers. We prospectively included 72 newly diagnosed patients with relapsing remitting MS or clinically isolated syndrome with no prior disease modifying therapy (DMT) use and 50 healthy controls (HCs). Patients were followed with blood samples, 3 tesla MRI, and clinical evaluation for 12 months. Occludin, ZO-1, calprotectin and soluble urokinase-type plasminogen activator receptor (suPAR) were measured by ELISA; serum neurofilament light (NfL) and IL-6 by single-molecule array (SIMOA). The mRNA expression of IFNG, IL1R1, IL10, IL1B, ARG1 and TNF was measured by quantitative real time polymerase chain reaction (qPCR) in whole blood. Plasma occludin levels were higher in MS patients compared with HCs. After 12 months on DMT, occludin levels were reduced by approximately 25% irrespective of 1st or 2nd line DMT (p <0.001). Furthermore, NfL and calprotectin levels were significantly reduced by 31% and 29%, respectively. Occludin and ZO-1 did not correlate with biomarkers of inflammation and did not predict disease activity at baseline or after 12 months. Higher levels of occludin suggest an increased permeability of the BBB and/or the intestinal barrier in MS patients. The reduction of occludin after 12 months on DMTs might reflect repair of these barriers upon treatment. However, plasma levels of ZO-1 and occludin could not predict clinical or MRI disease activity as determined by regression and ROC-curve analysis. Our results do not indicate a clear clinically relevant role for circulating tight junction proteins as biomarkers of disease activity in MS and further investigations in larger cohorts are needed to clarify this issue. [ABSTRACT FROM AUTHOR]

• Serum calprotectin and NfL levels are higher in MS patients compared with healthy controls • Serum calprotectin levels are associated with disease activity in MS • Serum calprotectin could represent a biomarker of innate immune activation in MS • Biomarkers of epithelial barrier function were not altered in newly diagnosed MS There is a lack of reliable biomarkers predicting disability and disease activity in multiple sclerosis (MS). Recent evidence suggests an involvement of intestinal and pulmonary epithelial barrier function related to immune activation and the pathophysiology of MS. Blood biomarkers of epithelial barrier function have, however, not been widely studied in MS. To examine biomarkers of inflammation and epithelial barrier function in relapsing remitting MS (RRMS) patients compared with healthy controls (HCs), and to assess associations between biomarkers and disease activity. A panel of 30 biomarkers were measured in serum or plasma from 49 newly diagnosed, untreated RRMS patients and 58 HCs with electrochemiluminescence or ELISA. Neurofilament light chain (NfL) was measured with single-molecule array. Validation was performed in a second independent cohort of 68 newly diagnosed, treatment naive RRMS patients and 50 HCs. Patients were divided into groups of active and inactive disease based on NfL levels and the presence of gadolinium enhancing magnetic resonance imaging lesions. Patients with active MS showed significantly higher serum levels of calprotectin and soluble urokinase plasminogen activator receptor compared with inactive MS in the exploratory cohort. Validation confirmed higher levels of calprotectin in active compared with inactive MS, and HCs. Biomarkers of intestinal and pulmonary epithelial barrier function did not differ significantly between groups. The measured biomarkers of epithelial barrier function do not seem to play a major role in the pathophysiology of MS, but serum calprotectin could represent a clinically useful biomarker of innate immune activation and disease activity. [ABSTRACT FROM AUTHOR]

Aim: We examined the Fick components together with mitochondrial O2 affinity (p50mito) in defining O2 extraction and O2 uptake during exercise with large and small muscle mass during normoxia (NORM) and hyperoxia (HYPER). Methods: Seven individuals performed 2 incremental exercise tests to exhaustion on a bicycle ergometer (BIKE) and 2 on a 1‐legged knee extension ergometer (KE) in NORM or HYPER. Leg blood flow and VO2 were determined by thermodilution and the Fick method. Maximal ADP‐stimulated mitochondrial respiration (OXPHOS) and p50mito were measured ex vivo in isolated mitochondria. Mitochondrial excess capacity in the leg was determined from OXPHOS in permeabilized fibres and muscle mass measured with magnetic resonance imaging in relation to peak leg O2 delivery. Results: The ex vivo p50mito increased from 0.06 ± 0.02 to 0.17 ± 0.04 kPa with varying substrate supply and O2 flux rates from 9.84 ± 2.91 to 16.34 ± 4.07 pmol O2·s−1·μg−1 respectively. O2 extraction decreased from 83% in BIKE to 67% in KE as a function of a higher O2 delivery and lower mitochondrial excess capacity. There was a significant relationship between O2 extraction and mitochondrial excess capacity and p50mito that was unrelated to blood flow and mean transit time. Conclusion: O2 extraction varies with mitochondrial respiration rate, p50mito and O2 delivery. Mitochondrial excess capacity maintains a low p50mito which enhances O2 diffusion from microvessels to mitochondria during exercise. [ABSTRACT FROM AUTHOR]

Background: Dialysis modalities and their various treatment schedules result from complex compromises ('trade-offs') between medical, financial, technological, ergonomic, and ecological factors. This study targets summarizing the mutual influence of these trade-offs on (trans)portable, wearable, or even (partially) implantable haemodialysis (HD) systems, identify what systems are in development, and how they might improve quality of life (QoL) for patients with kidney failure., Methods: HD as defined by international standard IEC 60601-2-16 was applied on a PUBMED database query regarding (trans)portable, wearable, and (partly) implantable HD systems. Out of 159 search results, 24 were included and scanned for specific HD devices and/or HD systems in development. Additional information about weight, size, and development status was collected by the internet and/or contacting manufacturers. International airplane hand baggage criteria formed the boundary between transportable and portable. Technology readiness levels (TRLs) were assigned by combining TRL scales from the European Union and NATO medical staff., Results: The query revealed 13 devices/projects: seven transportable (six TRL9, one TRL5); two portable (one TRL6-7, one TRL4); two wearable (one TRL6, one frozen); and two partly implantable (one TRL4-5, one TRL2-3)., Discussion: Three main categories of technical approaches were distinguished: single-pass, dialysate regenerating, and implantable HD filter with extracorporeal dialysate regeneration (in climbing order of mobility)., Conclusions: Kidneys facilitate mobility by excreting strongly concentrated waste solutes with minimal water loss. Mimicking this kidney function can increase HD system mobility. Dialysate-regenerating HD systems are enablers for portability/wearability and, combined with durable implantable HD filters (once available), they may enable HD without needles or intravascular catheters. However, lack of funding severely hampers progress., Competing Interests: None declared., (© The Author(s) 2024. Published by Oxford University Press on behalf of the ERA.)

Background: Kidney failure is associated with a high disease burden and high mortality rates. National and international guidelines recommend health professionals involve patients with kidney failure in making decisions about end-of-life care, but implementation of these conversations within kidney services varies. We developed the DESIRE (ShareD dEciSIon-making for patients with kidney failuRE to improve end-of-life care) intervention from our studies investigating multiple decision maker needs and experiences of end-of-life care in kidney services. The DESIRE intervention's three components are a training programme for health professionals, a patient decision aid, and a kidney service consultation held to facilitate shared decision-making conversations about planning end-of-life care., Objectives: To assess the feasibility and acceptability of integrating the DESIRE intervention within kidney services., Design: A pilot study using a multicentre randomised controlled design., Setting: Four Danish nephrology departments., Participants: Patients with kidney failure who were 75 years of age or above, their relatives, and health professionals., Methods: Patients were randomised to either the intervention or usual care. Feasibility data regarding delivering the intervention, the trial design, and outcome measures were collected through questionnaires and audio recordings at four points in time: before, during, post, and 3 months after the intervention. Acceptability data were collected through semi-structured interviews with patients and relatives, as well as a focus group with health professionals post the intervention., Results: Twenty-seven patients out of the 32 planned were randomised either to the intervention ( n = 14) or usual care ( n = 13). In addition, four relatives and 12 health professionals participated. Follow-up was completed by 81 % ( n = 22) of patient participants. We found that both feasibility and acceptability data suggested health professionals improved their decision support and shared decision-making skills via the training. Patient and relative participants experienced the intervention as supporting a shared decision-making process; from audio recordings, we showed health professionals were able to support proactively decision-making about end-of-life care within these consultations. All stakeholders perceived the intervention to be effective in promoting shared decision-making and relevant for supporting end-of-life care planning., Conclusions: Participant feedback indicated that the DESIRE intervention can be integrated into practice to support patients, relatives, and health professionals in planning end-of-life care alongside the management of worsening kidney failure. Minimising exhaustion and enhancing engagement with the intervention should be a focus for subsequent refinement of the intervention., Registration: The study has been registered at ClinicalTrials.gov with the identifier: NCT05842772. Date of first recruitment: March 20, 2023 ., Competing Interests: None., (© 2024 The Authors. Published by Elsevier Ltd.)

Aim: To investigate the decisional needs in Denmark of people with kidney failure, relatives, and health professionals when planning end-of-life care., Design: A qualitative interview study., Methods: Individual semi-structured interviews were carried out with people with kidney failure, relatives and health professionals from November 2021 to June 2022. Malterud's systematic text condensation was used to analyse transcripts., Results: A total of 13 patients, 10 relatives, and 12 health professionals were interviewed. Overall, four concepts were agreed on: (1) Talking about end of life is difficult, (2) Patients and relatives need more knowledge and information, (3) Health professionals need more tools and training, and (4) Experiencing busyness as a barrier to conversations about end of life., Conclusion: People with kidney failure, relatives, and health professionals shared certain decisional needs while also having some different decisional needs about end-of-life care. To meet these various needs, end-of-life conversations should be systematic and organized according to the patients' needs and wishes., Impact: Non-systematic end-of-life care decision-making processes limit patients' involvement. Patients and relatives need more knowledge about end-of-life care, and health professionals need more competences and time to discuss decisional needs. A shared decision-making intervention for people with kidney failure when making end-of-life care decisions will be developed., Reporting Method: This empirical qualitative research is reported according to the Consolidated Criteria for Reporting Qualitative Research (COREQ) checklist., Patient or Public Contribution: Patients, relatives, and health professionals have been involved throughout the research process as part of the research team and advisory board. The patients are people with kidney failure and the relatives are relatives of a person with kidney failure. For this study, the advisory board has particularly contributed to the validation of the invitation letter for participation, the interview guides and the preparation of the manuscript., (© 2024 John Wiley & Sons Ltd.)

Aim: To describe the development of a shared decision making intervention for planning end-of-life care for patients with kidney failure, their relatives and health professionals in kidney services., Background: End-of-life care conversations within standard disease management consultations are challenging for patients with kidney failure, their relatives and health professionals. End-of-life care planning is about making difficult decisions in advance, which is why health professionals need shared decision making skills to be able to initiate end-of-life conversations. Health professionals report needing more skills to raise the issue of end-of-life care options within consultations and patients want to be able to discuss issues important to them about future care plans., Methods: The development design was guided by the UK Medical Research Council's framework and a user-centred approach was applied. Four workshops were conducted with end users. The Template for Intervention Description and Replication for Population Health and Policy interventions was used to shape which questions needed to be answered through the workshops and to present the intervention. The International Patient Decision Aid Standards (IPDAS) criteria set the standards to be achieved., Results: Areas considered significant to a shared decision making intervention were training of health professionals, conversations about end-of-life care, planning and evaluation of the decisions, reporting decisions in health records and repetition of consultation. The development process went through 14 iterations., Conclusion: An intervention named DESIRE was developed that comprises: (1) a training programme for health professionals; (2) shared decision making conversations; and (3) a patient decision aid. The intervention met 30 out of 33 IPDAS criteria., Implications for Practice: DESIRE is intended to support shared decision making about planning end-of-life care among patients with kidney failure, their relatives and health professionals. The study provides important tools for the stakeholders engaged that can be used within different models of care., Impact: What problem did the study address? International guidelines recommend health professionals involve patients with kidney failure in making decisions about end-of-life care, but there is variation in how this is implemented within and across kidney services. Furthermore, patients, relatives and health professionals find it challenging to initiate conversations about end-of-life care. What were the main findings? The study resulted in the development of a complex intervention, called DESIRE, about shared decision making and planning end-of-life care for patients with kidney failure, their relatives and health professionals in kidney services, including a training programme for health professionals, shared decision making conversations and a patient decision aid. Where and on whom will the research have an impact? The research contributes a shared decision making intervention to patients in the later stage of kidney failure, their relatives and health professionals. We believe that the DESIRE intervention could be introduced during consultations with health professionals at an earlier stage of the patient's illness trajectory, as well as being applied to other chronic diseases., Reporting Method: This intervention development research is reported according to the GUIDance for the rEporting of intervention Development (GUIDED) checklist and the DEVELOPTOOLS Reporting Checklist., Patient or Public Contribution: Patients, relatives and health professionals have been involved throughout the research process as part of the research team and advisory board. For this study, the advisory board has particularly contributed to the development process of the DESIRE intervention by actively participating in the four workshops, in the iterations between the workshops and in the preparation of the manuscript., (© 2024 The Authors. Journal of Clinical Nursing published by John Wiley & Sons Ltd.)

Background: Neurofilament light chain (NFL) is a biomarker for monitoring disease activity and treatment response in multiple sclerosis (MS). However, while most agree that NFL levels predict disease activity and worsening, the predictive value of NFL on future relapse risk remains uncertain., Objective: The primary aim was to evaluate the predictive value of age-corrected serum NFL (sNFL) ratio on relapse risk in highly active relapsing-remitting MS patients (RRMS) treated with natalizumab. A secondary aim was to investigate the predictive value of sNFL ratios for MRI activity., Methods: From January 1, 2006, to December 31, 2010, 355 patients initiated natalizumab treatment at the Danish Multiple Sclerosis Center. 305 patients were anti-natalizumab antibodies negative and had at least one blood sample available for sNFL analysis using single molecule array analysis at baseline, three, six, or 12 months. The patients were either treatment-naïve (n = 8), switching from interferon-β or glatiramer acetate (n = 253), or switching from mitoxantrone (n = 44). An age-corrected ratio was calculated for sNFL. Time to first relapse was calculated from baseline and after re-baseline at 90 days. Data were collected from baseline until the two-year follow-up or end of treatment and included disease duration, expanded disability status scale, previous treatments, relapses 12 months prior to natalizumab initiation, smoking intensity, body mass index, and body weight. In addition, the patients underwent annual MRI of the brain., Results: The sNFL ratio was increased in 173 of 287 samples (60.3 %) at baseline, in 119 of 246 samples (48.8 %) at month three, in 109 of 287 samples (38.0 %) at month six, and in 82 of 270 samples (30.4 %) at month 12. The sNFL ratio continuously declined over 12 months with significant decreases for every measuring timepoint: baseline vs. three months p = 3.0 × 10 -6 ; three months vs. six months p = 3.2 × 10 -5 ; six months vs. 12 months p = 0.002. Univariate Cox regression analysis showed that time to first relapse from 1) natalizumab initiation and from 2) re-baseline was associated with the number of relapses in the previous 12 months (hazard ratio 1.31 per relapse, 95 % CI = 1.2-1.5, p = 2.0 × 10 -6 ; and 1.21 per relapse, 95 % CI = 1.1-1.4, p = 0.002, respectively). sNFL ratio at re-baseline was negatively associated with relapse risk (hazard ratio 0.82 per unit; 95 % CI = 0.7-1.0; p = 0.049). A multivariable Cox regression analysis of relapse risk from re-baseline showed that the number of relapses in the 12 months prior to natalizumab treatment (hazard ratio 1.29; 95 % CI = 1.1-1.5; p = 6.0 × 10 -4 ) and smoking (hazard ratio 1.51 per 20 cigarettes per day; 95 % CI = 1.0-2.2; p = 0.030) were associated with increased risk of relapse; sNFL ratio was associated with a lower risk of relapse (hazard ratio = 0.736 per unit; 95 % CI = 0.6-0.9 p = 0.007). In univariate logistic regression analyses, the sNFL ratio at 12 months and values above the 75th and the 90th percentile predicted MRI activity in the following year (odds ratio [OR] = 2.0, 95 % CI = 1.2-3.6, p = 0.012; OR = 2.2, 95 % CI = 1.2-4.1, p = 0.014; and OR = 2.8, 95 % CI = 1.1-6.7, p = 0.026)., Conclusion: In this highly active RRMS cohort, high sNFL ratios reflected previous relapse activity and decreased after initiation of treatment but were not associated with increased relapse risk in the following two years. Pre-treatment relapses and smoking on treatment were predictors of relapse risk after re-baselining at 90 days. MRI activity in year two was predicted by sNFL ratios at month 12., Competing Interests: Declaration of competing interest H. Højsgaard Chow reports non-financial support from Merck, non-financial support from Teva, non-financial support from Biogen, non-financial support from Roche, outside the submitted work and personal support from the Warwara Larsen Foundation. E. Rosa Petersen has nothing to declare. A. Olsson has nothing to declare. J. Hejgaard Laursen has nothing to declare. M. Bredahl Hansen has nothing to declare. A. Bang Oturai has nothing to declare. P. Soelberg Sørensen has received personal compensation for consultations, serving on scientific advisory boards, steering committees, independent data monitoring committees or have received honoraria as speaker from Biogen, Merck, Novartis, TEVA, and BMS/Celgene. H. Bach Søndergaard has nothing to declare. F. Sellebjerg reports grants from Biogen, grants from Danish Multiple Sclerosis Society, during the conduct of the study; grants and personal fees from Biogen, personal fees from Lundbeck, grants and personal fees from Merck, grants and personal fees from Novartis, grants and personal fees from Roche, grants and personal fees from Sanofi Genzyme, outside the submitted work; and Professor F. Sellebjerg is section editor on Multiple Sclerosis and Related Disorders., (Copyright © 2024. Published by Elsevier B.V.)

Objectives: Traditional potassium (K + ) binders for treating hyperkalaemia are unpalatable and poorly tolerated. Newer K + binders are reportedly better tolerated; however, no published data describe their palatability, a determinant of long-term adherence. This study evaluated the palatability of and preference for three K + binders: sodium and calcium polystyrene sulfonate (S/CPS), sodium zirconium cyclosilicate (SZC) and calcium patiromer sorbitex (patiromer)., Design: Phase 4, randomised, participant-blinded, cross-over study. Participants were randomised to one of six taste sequences and, using a 'sip and spit' approach, tasted each K + binder before completing a survey., Setting: 17 centres across the USA, Canada and European Union., Participants: 144 participants with chronic kidney disease, hyperkalaemia and no recent use of K + binders., Main Outcome Measures: For the primary (USA) and key secondary (Canada and European Union) endpoints, participants rated palatability attributes (taste, texture, smell and mouthfeel) and willingness to take each K + binder on a scale of 0-10 (rational evaluation). Feelings about each attribute, and the idea of taking the product once daily, were evaluated using a non-verbal, visual measure of emotional response. Finally, participants ranked the K + binders according to palatability., Results: In each region, SZC and patiromer outperformed S/CPS on overall palatability (a composite of taste, texture, smell and mouthfeel), based on rational evaluation and emotional response. Taking the product once daily was more appealing for SZC and patiromer, creating greater receptivity than the idea of taking S/CPS. The emotional response to mouthfeel had the strongest influence on feelings about taking each product. In each region, a numerically greater proportion of participants ranked SZC as the most preferred K + binder versus patiromer or S/CPS., Conclusions: Preference for more palatable K + binders such as SZC and patiromer may provide an opportunity to improve adherence to long-term treatment of hyperkalaemia., Trial Registration Number: NCT04566653., Competing Interests: Competing interests: DCW reports an ongoing consultancy contract with AstraZeneca and honoraria/speaker fees from Astellas, Bayer, Boehringer Ingelheim, George Clinical, GSK, Gilead, Janssen, Merck Sharp and Dohme, ProKidney, Tricida, Vifor and Zydus. HS has nothing to disclose. KH, JH, AA, H-LC, MN, GS, EW and JK are employees of and may hold stock in AstraZeneca. JM and CG are employees of AdSAM., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Patient and public involvement in health-related research is a new discipline in Denmark. In 2021, a national conference titled 'Patient and Public Involvement in Complex Intervention Research' provided a forum for discussion between patient partners, researchers and clinicians on involving patients as partners in complex intervention research., Methods: We aimed to describe specific challenges to and initiatives for patient partner involvement in order to develop recommendations for creating successful partnerships in complex intervention research. Through a collaborative learning process, 140 researchers identified the most important challenges for them in patient partner involvement and potential initiatives to improve such involvement. At a subsequent workshop, four patient partners identified the challenges and initiatives from their perspective as patient partners. They also gave feedback on the challenges and initiatives suggested by the researchers and helped shape three recommendations for practice. Three of the patient partners were involved in writing this paper., Results: The five most important challenges identified by researchers were time, recruitment, ethics, power and inequality. Between four and seven initiatives to overcome these challenges were suggested. The three most important challenges identified by patient partners were communication, when you get information that is hard to handle and recruitment. They suggested three to four initiatives for improvement. Patient partners confirmed the importance of all the researcher identified challenges when presented with them, they also provided additional comments on the researchers' initiatives. This led to the formation of recommendations for involving patient partners., Conclusions: A collaborative learning process was shown to be a suitable method for patient partner involvement. Consistency was seen between the challenges and initiatives identified by researchers and patient partners. Based on these observations, three recommendations were developed: (1) create specific programmes that aim to involve all kind of patients (including but limited to vulnerable patients) as patient partners, (2) produce ethical guidelines for the involvement of patient partners, and (3) develop a national strategy for patient partner involvement. To build on these recommendations, a joint workshop with both researchers and patient partners is needed., (© 2024. The Author(s).)

Objective: The objective of this review was to investigate and map empirical evidence of patient involvement interventions to support patients with kidney failure making end-of-life care decisions in kidney services., Introduction: Clinical guidance integrating end-of-life care within kidney failure management pathways varies. Advance care planning interventions aimed at involving patients with kidney failure in their end-of-life care planning are established in some countries. However, there is limited evidence of the other types of patient involvement interventions integrated within services to support patients with kidney failure in making decisions about their end-of-life care., Inclusion Criteria: This scoping review included studies exploring patient involvement interventions evaluated for patients with kidney failure considering end-of-life care, their relatives, and/or health professionals in kidney services. Studies of children under the age of 18 years were excluded., Methods: The review was informed by JBI methodology and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses extension for Scoping Review guidelines. MEDLINE, Scopus, Embase, and CINAHL were searched for full-text studies in English, Danish, German, Norwegian, or Swedish. Two independent reviewers assessed the literature against the inclusion criteria. A relational analysis framework was used to synthesize the data extracted from the included studies, and to investigate and map different patient involvement interventions., Results: The search identified 1628 articles, of which 33 articles met the inclusion criteria. A total of 23 interventions were described. Interventions targeted patients (n=3); health professionals (n=8); patients and health professionals (n=5); and patients, relatives, and health professionals (n=7). Intervention components included patient resources (eg, information, patient decision aids), consultation resources (eg, advance care planning, shared decision-making), and practitioner resources (eg, communication training). Patient involvement interventions were delivered within hospital-based kidney services., Conclusions: The review identified several ways to support patients with kidney failure to be involved in end-of-life care decisions. Future interventions may benefit from adopting a complex intervention framework to engage multiple stakeholders in the research and design of an intervention for shared decision-making between patients with kidney failure, their relatives, and health professionals about integrating end-of-life care options into their kidney disease management pathway., Competing Interests: The authors declare no conflict of interest., (Copyright © 2023 JBI.)

Introduction: Dimethyl fumarate treatment is approved in Europe for patients with relapsing-remitting multiple sclerosis (MS) and in the US for relapsing forms of MS. We recently published the results of the first randomized placebo-controlled trial of 48 weeks of treatment with dimethyl fumarate or placebo in primary progressive MS (PPMS) (clinicaltrial.gov NCT02959658). The placebo-controlled phase of the trial did not meet its primary endpoint (reduction in cerebrospinal fluid concentrations of neurofilament light chain [NFL])., Aim: To investigate the effects of dimethyl fumarate treatment in the open-label extension phase of the trial (week 48-96), where all patients were treated with DMF., Methods: Reported data are from screening, week 48, and week 96 visits. Patients were clinically evaluated with Expanded Disability Status Scale (EDSS), 9-Hole Peg Test (9HPT), Timed 25-Foot Walk (T25FW) test, Symbol Digit Modalities Test (SDMT), California Verbal Learning Test, and Brief Visuospatial Memory-Revised. Serum NFL concentrations were measured by single-molecule array analysis. MRI was performed on a 3 tesla MRI scanner and included: new/enlarging lesions, volume of lesions, cortical grey matter, putamen, thalamus, and normal-appearing white matter, and additional diffusion tensor imaging and magnetization transfer ratio measures., Results: Forty-two patients entered the open-label treatment phase, and 33 patients (61%) had complete data sets at week 96. The remaining 39% did not complete the trial and were not evaluated at week 96. We found no evidence of differences in clinical and MRI measures between patients initially treated with dimethyl fumarate and patients initially treated with placebo from baseline to week 48 and from week 48-96, where all patients were treated with dimethyl fumarate. Serum NFL concentrations remained stable in both groups over 96 weeks. Assessed with either EDSS, T25FW, or 9HPT at week 96, progression was observed for 14 patients (45%). Interestingly, another 15 patients (46%) had improvement in one or more of these domains. Applying a cut-off of 8 points, 2 (6%) patients worsened on SDMT, 25 (78%) did not change, and 5 (16%) improved., Conclusions: Dimethyl fumarate treatment showed no effects on neither clinical nor MRI outcomes or changes in serum concentrations of NFL. An expected number of patients showed evidence of progression on standard clinical scales; however, this was matched by an equal number of patients improving. The reasons for the physical improvement in an unexpectedly high proportion of patients must be addressed in future studies., (Copyright © 2022. Published by Elsevier B.V.)