1. |
- Jons, D., et al.
(författare)
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Increase in Epstein Barr virus serologies precedes neuroaxonal damage in pre-symptomatic multiple sclerosis
- 2022
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Ingår i: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 28:Suppl. 3, s. 86-87
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Epstein-Barr virus (EBV) infection may be a pre-condition for the development of multiple sclerosis (MS). EBV antibodies, predominantly anti-EBNA1, develop in the presymp-tomatic phase of virtually all MS patients. Using material from a serum repository, studies in advance of MS onset indicated that EBV seropositivity preceded the first expression of incipient axonal lesions, serum Neurofilament Light (sNFL) .Objectives: To determine the onset and individual order of appearance of EBV seroreactivity and the serum neuroaxonal injury marker neurofilament light (sNfL) in a wide age spectrum of presymptomatic MS patients.Aims: To characterize the presymptomatic appearance of anti-bodies against an intranuclear (EBNA1) and a surface EBV anti-gen (gp350) and sNfL.Methods: A nested case-control study in 669 pre-symptomati-cally acquired blood samples from persons who later received an MS diagnosis, and from 1:1 matched control persons. Serum lev-els of EBNA1, VCA and gp350 IgG antibodies and sNFL (n=519) were measured in individual presymptomatic samples and expressed as delta scores with matched controls in relation to time until MS onset.Results: Serum levels expressed as delta scores for anti EBV and NfL IgG showed an incipient increase for anti EBNA1 and gp350 from 15-20 years before MS debut. Significant (p=0.001 and p=0.002) from 10-15 years, with consistent delta-scores succes-sively closer to MS onset. These findings contrasted to the level of sNfL which increasingly diverged from matched controls from 5-10 years before the onset of MS. None of the individual sam-ples negative for both EBNA1 and VCA IgG antibodies in the pre-MS group (n = 36) showed any elevation of the sNfL level.Conclusions: In a pre-MS material, the seroreactivity against EBNA1 was followed by VCA and gp350, before increased sNFL appeared, indicating incipient axonal injury. Together with its biological characteristics this temporal order confirms the role of EBV as a trigger of MS.
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2. |
- Alping, P., et al.
(författare)
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Effectiveness of initial MS treatments in the COMBAT-MS trial : injectables, dimethyl fumarate, natalizumab and rituximab
- 2021
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Ingår i: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 27:Suppl. 2, s. 21-22
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Direct comparisons across multiple disease-modifying therapies (DMTs) for relapsing-remitting multiple sclerosis (RRMS) are valuable in clinical decision making. COMBAT-MS (NCT03193866) is an observational drug trial capturing data on clinical relapses, lesions on magnetic resonance imaging (MRI), Expanded Disability Status Scale (EDSS), and drug survival, at all Swedish university clinics.Objective: Compare the effectiveness of the most common initial MS therapies in Sweden.Methods: All first-ever MS treatments with injectables (INJ, interferon-β/glatiramer acetate), dimethyl fumarate (DMF), natalizumab (NTZ), and rituximab (RTX), started 2011-01-01 to 2020-12-14, were identified with prospectively recorded outcome data in the Swedish MS Register. Follow-up continued even if the therapy ended. Missing data were imputed using multiple imputation and potential confounding was adjusted for using stabilized inverse probability of treatment weighting with baseline variables: age, sex, MS duration, geographical region, EDSS, and relapses. All comparisons are made against RTX.Results: We included 1936 first-ever therapy episodes: 856 INJ, 341 DMF, 270 NTZ, and 469 RTX. Baseline characteristics differed by DMT, with natalizumab having the youngest patients, shortest MS duration, and the most previous relapses.After adjustment, the hazard ratio (HR) for first relapse vs RTX was for INJ 5.9 (95% confidence interval 3.7; 9.5), DMF 2.8 (1.7; 4.8), and NTZ 1.8 (1.0; 3.3). Similarly, the relative three-year lesion rate was for INJ 6.06 (3.75; 9.80), DMF 3.52 (2.01; 6.17), and NTZ 2.03 (1.14; 3.64). EDSS differences at three years were only marginally different: INJ 0.25 (0.06; 0.44), DMF 0.05 (-0.16; 0.26), and NTZ 0.00 (-0.23; 0.24). In contrast, HR for treatment discontinuation was marked: INJ 32.5 (19.0; 55.7), DMF 20.2 (11.5; 35.4), and NTZ 16.2 (8.9; 29.5).Conclusions: In treatment-naïve patients, RTX was associated with the lowest risk of relapses and MRI lesions, and by far the lowest probability of switching to a second therapy. In contrast, EDSS at 3 years was similar for RTX, DMF, and NTZ, and only slightly higher for INJ. The apparent difference in effectiveness between NTZ and RTX could possibly be explained by the vulnerable period after switching from NTZ, mainly due to JC virus positivity. These findings underscore the importance of tracking long-term outcomes from first DMT start, while considering subsequent therapy switches.
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3. |
- Bridel, Claire, et al.
(författare)
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Diagnostic Value of Cerebrospinal Fluid Neurofilament Light Protein in Neurology : A Systematic Review and Meta-analysis
- 2019
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Ingår i: JAMA Neurology. - : American Medical Association (AMA). - 2168-6149 .- 2168-6157. ; 76:9, s. 1035-1048
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Forskningsöversikt (refereegranskat)abstract
- Importance Neurofilament light protein (NfL) is elevated in cerebrospinal fluid (CSF) of a number of neurological conditions compared with healthy controls (HC) and is a candidate biomarker for neuroaxonal damage. The influence of age and sex is largely unknown, and levels across neurological disorders have not been compared systematically to date.Objectives To assess the associations of age, sex, and diagnosis with NfL in CSF (cNfL) and to evaluate its potential in discriminating clinically similar conditions.Data Sources PubMed was searched for studies published between January 1, 2006, and January 1, 2016, reporting cNfL levels (using the search terms neurofilament light and cerebrospinal fluid) in neurological or psychiatric conditions and/or in HC.Study Selection Studies reporting NfL levels measured in lumbar CSF using a commercially available immunoassay, as well as age and sex.Data Extraction and Synthesis Individual-level data were requested from study authors. Generalized linear mixed-effects models were used to estimate the fixed effects of age, sex, and diagnosis on log-transformed NfL levels, with cohort of origin modeled as a random intercept.Main Outcome and Measure The cNfL levels adjusted for age and sex across diagnoses.Results Data were collected for 10 059 individuals (mean [SD] age, 59.7 [18.8] years; 54.1% female). Thirty-five diagnoses were identified, including inflammatory diseases of the central nervous system (n = 2795), dementias and predementia stages (n = 4284), parkinsonian disorders (n = 984), and HC (n = 1332). The cNfL was elevated compared with HC in a majority of neurological conditions studied. Highest levels were observed in cognitively impaired HIV-positive individuals (iHIV), amyotrophic lateral sclerosis, frontotemporal dementia (FTD), and Huntington disease. In 33.3% of diagnoses, including HC, multiple sclerosis, Alzheimer disease (AD), and Parkinson disease (PD), cNfL was higher in men than women. The cNfL increased with age in HC and a majority of neurological conditions, although the association was strongest in HC. The cNfL overlapped in most clinically similar diagnoses except for FTD and iHIV, which segregated from other dementias, and PD, which segregated from atypical parkinsonian syndromes.Conclusions and Relevance These data support the use of cNfL as a biomarker of neuroaxonal damage and indicate that age-specific and sex-specific (and in some cases disease-specific) reference values may be needed. The cNfL has potential to assist the differentiation of FTD from AD and PD from atypical parkinsonian syndromes.
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4. |
- Christiansen, Evald H, et al.
(författare)
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Instantaneous Wave-free Ratio versus Fractional Flow Reserve to Guide PCI.
- 2017
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Ingår i: The New England journal of medicine. - : Massachussetts Medical Society. - 1533-4406 .- 0028-4793. ; 376:19, s. 1813-1823
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Tidskriftsartikel (refereegranskat)abstract
- The instantaneous wave-free ratio (iFR) is an index used to assess the severity of coronary-artery stenosis. The index has been tested against fractional flow reserve (FFR) in small trials, and the two measures have been found to have similar diagnostic accuracy. However, studies of clinical outcomes associated with the use of iFR are lacking. We aimed to evaluate whether iFR is noninferior to FFR with respect to the rate of subsequent major adverse cardiac events.We conducted a multicenter, randomized, controlled, open-label clinical trial using the Swedish Coronary Angiography and Angioplasty Registry for enrollment. A total of 2037 participants with stable angina or an acute coronary syndrome who had an indication for physiologically guided assessment of coronary-artery stenosis were randomly assigned to undergo revascularization guided by either iFR or FFR. The primary end point was the rate of a composite of death from any cause, nonfatal myocardial infarction, or unplanned revascularization within 12 months after the procedure.A primary end-point event occurred in 68 of 1012 patients (6.7%) in the iFR group and in 61 of 1007 (6.1%) in the FFR group (difference in event rates, 0.7 percentage points; 95% confidence interval [CI], -1.5 to 2.8; P=0.007 for noninferiority; hazard ratio, 1.12; 95% CI, 0.79 to 1.58; P=0.53); the upper limit of the 95% confidence interval for the difference in event rates fell within the prespecified noninferiority margin of 3.2 percentage points. The results were similar among major subgroups. The rates of myocardial infarction, target-lesion revascularization, restenosis, and stent thrombosis did not differ significantly between the two groups. A significantly higher proportion of patients in the FFR group than in the iFR group reported chest discomfort during the procedure.Among patients with stable angina or an acute coronary syndrome, an iFR-guided revascularization strategy was noninferior to an FFR-guided revascularization strategy with respect to the rate of major adverse cardiac events at 12 months. (Funded by Philips Volcano; iFR SWEDEHEART ClinicalTrials.gov number, NCT02166736 .).
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5. |
- Escaned, Javier, et al.
(författare)
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Safety of the Deferral of Coronary Revascularization on the Basis of Instantaneous Wave-Free Ratio and Fractional Flow Reserve Measurements in Stable Coronary Artery Disease and Acute Coronary Syndromes
- 2018
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Ingår i: JACC. - : Elsevier. - 1936-8798 .- 1876-7605. ; 11:15, s. 1437-1449
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES The aim of this study was to investigate the clinical outcomes of patients deferred from coronary revascularization on the basis of instantaneous wave-free ratio (iFR) or fractional flow reserve (FFR) measurements in stable angina pectoris (SAP) and acute coronary syndromes (ACS). BACKGROUND Assessment of coronary stenosis severity with pressure guidewires is recommended to determine the need for myocardial revascularization. METHODS The safety of deferral of coronary revascularization in the pooled per-protocol population (n = 4,486) of the DEFINE-FLAIR (Functional Lesion Assessment of Intermediate Stenosis to Guide Revascularisation) and iFR-SWEDEHEART (Instantaneous Wave-Free Ratio Versus Fractional Flow Reserve in Patients With Stable Angina Pectoris or Acute Coronary Syndrome) randomized clinical trials was investigated. Patients were stratified according to revascularization decision making on the basis of iFR or FFR and to clinical presentation (SAP or ACS). The primary endpoint was major adverse cardiac events (MACE), defined as the composite of all-cause death, nonfatal myocardial infarction, or unplanned revascularization at 1 year. RESULTS Coronary revascularization was deferred in 2,130 patients. Deferral was performed in 1,117 patients (50%) in the iFR group and 1,013 patients (45%) in the FFR group (p < 0.01). At 1 year, the MACE rate in the deferred population was similar between the iFR and FFR groups (4.12% vs. 4.05%; fully adjusted hazard ratio: 1.13; 95% confidence interval: 0.72 to 1.79; p = 0.60). A clinical presentation with ACS was associated with a higher MACE rate compared with SAP in deferred patients (5.91% vs. 3.64% in ACS and SAP, respectively; fully adjusted hazard ratio: 0.61 in favor of SAP; 95% confidence interval: 0.38 to 0.99; p = 0.04). CONCLUSIONS Overall, deferral of revascularization is equally safe with both iFR and FFR, with a low MACE rate of about 4%. Lesions were more frequently deferred when iFR was used to assess physiological significance. In deferred patients presenting with ACS, the event rate was significantly increased compared with SAP at 1 year. (C) 2018 The Authors. Published by Elsevier on behalf of the American College of Cardiology Foundation.
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6. |
- Longinetti, E., et al.
(författare)
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COVID-19 clinical outcomes and DMT of MS patients and population-based controls
- 2022
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Ingår i: Annals of Clinical and Translational Neurology. - : Wiley. - 2328-9503. ; 9:9, s. 1449-1458
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To estimate risks for all-cause mortality and for severe COVID-19 in multiple sclerosis patients and across relapsing-remitting multiple sclerosis patients exposed to disease-modifying therapies. Methods: We conducted a Swedish nationwide population-based multi-register linkage cohort study and followed all multiple sclerosis patients (n = 17,692 in March 2020), individually age-, sex-, and region-matched to five population-based controls (n = 86,176 in March 2020) during March 2020-June 2021. We compared annual all-cause mortality within and across cohorts, and assessed incidence rates and relative risks for hospitalization, intensive care admission, and death due to COVID-19 in relation to disease-modifying therapy use, using Cox regression. Results: Absolute all-cause mortality among multiple sclerosis patients was higher from March to December 2020 than in previous years, but relative risks versus the population-based controls were similar to preceding years. Incidence rates of hospitalization, intensive care admission, and death due to COVID-19 remained in line with those for all-cause hospitalization, intensive care admission, and mortality. Among relapsing-remitting patients on rituximab, trends for differences in risk of hospitalization due to COVID-19 remained in the demographics-, socioeconomic status-, comorbidity-, and multiple sclerosis severity-adjusted model. Interpretation: Risks of severe COVID-19-related outcomes were increased among multiple sclerosis patients as a whole compared to population controls, but risk increases were also seen for non-COVID-19 hospitalization, intensive care admission, and mortality, and did not significantly differ during the pandemic compared to pre-pandemic years. The risk conveyed by disease-modifying therapies was smaller than previously assumed, likely as a consequence of the possibility to better control for confounders.
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7. |
- Longinetti, E., et al.
(författare)
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SARS-COV2 exposure rates and serological response of people living with MS
- 2022
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Ingår i: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 28:Suppl. 3, s. 515-516
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Some multiple sclerosis (MS) disease-modifying therapies (DMTs) are associated with blunted humoral vaccination responses, but relevance for SARS-CoV-2 infection is unclear.Objectives: To determine SARS-CoV-2 exposure rates and formation of antibody memory among participants of the COMparison Between All immunoTherapies for MS (COMBAT-MS; NCT03193866) and the Immunomodulation and MS Epidemiology (IMSE) studies.Aim: To determine SARS-CoV2 serological response of people living with MS (pwMS).Methods: Using a multiplex bead-based assay we determined SARS-CoV-2 spike and nucleocapsid antibody levels in 3,723 pwMS in paired serum samples (n=7,157) donated prior (Results: Specificity and sensitivity of the assay for SARS-CoV-2 was 100% and 99.7%, respectively. The proportion of positive samples for SARS-CoV-2 differed moderately across DMTs with the highest values among cladribine-treated (7.4%) and the lowest number among rituximab-treated pwMS (3.9%). Similarly, the proportion of positive cases not reported in the Swedish MS registry varied from 100% for cladribine to 33.3% among untreated pwMS. Comparing levels of antibodies titers showed that levels were lower among those treated with rituximab or fingolimod vs interferon treated pwMS. Point estimates indicated a similar trend comparing rituximab or fingolimod vs untreated pwMS.Conclusions: Overall rates of SARS-CoV-2 antibody positivity after the first COVID-19 wave differed only moderately across DMTs, while antibody levels were lower with rituximab or fingolimod compared to interferon-treated pwMS. This indicates quantitative rather than qualitative differences in the humoral response to infection.
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8. |
- Longinetti, E., et al.
(författare)
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Trajectories of processing speed, disability, and their connections, over the years following disease modulatory treatment initiation among relapsing-remitting multiple sclerosis patients
- 2021
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Ingår i: Multiple Sclerosis Journal. - : Sage Publications. - 1352-4585 .- 1477-0970. ; 27:Suppl. 2, s. 677-678
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Tidskriftsartikel (övrigt vetenskapligt/konstnärligt)abstract
- Introduction: Data on how processing speed of relapsing-remitting multiple sclerosis patients (RRMS) evolve over time and its association with disability progression is scarce. We analysed the COMparison Between All immunoTherapies for Multiple Sclerosis (CombatMS; NCT03193866), a nationwide observational drug trial in RRMS.Objectives: Identify trajectories of processing speed and disability and their connections after disease modulatory treatment (DMT) start within the RRMS population.Describe patient characteristics associated with trajectory groups.Aim: Model trajectories of processing speed and disability.Methods: We assessed trajectories of oral Symbol Digit Modalities Test (SDMT) and expanded disability status scale (EDSS) from first DMT start using a group-based modeling approach among 1,800 RRMS patients followed 2010-2021. We investigated predictors of trajectories using group membership assignments as a multinomial outcome and calculated conditional probabilities linking membership across the trajectories.Results: We identified four trajectories of processing speed: low SDMT score (mean starting values; MSV=36.7, standard deviation; SD=8.4)-stable (13%), medium score (MSV =50.8, SD=6.7)-minor decrease (52%), medium/high score (MSV=62.9, SD=8.6)-minor decrease (32%), and high score (MSV= 75.2, SD=9.7)-moderate decrease (3%), and four trajectories of disability: no disability-stable (23%), minimal signs-minor increase (45%), minimal disability-moderate increase (27%), and relatively severe disability-moderate increase (5%). Patients with natalizumab as first DMT were less likely to belong to the medium and high processing speed trajectories, relative to the low SDMT score-stable one. Sex, age at DMT start, and geographical region of treatment were associated with medium and high processing speed and with minimal signs and minimal dis-ability trajectories.There was 0% probability of belonging to the relatively severe disability-moderate increase EDSS trajectory if belonging to the high score-moderate decrease SDMT trajectory, and 8% probability of belonging to the no disability-stable EDSS trajectory if belonging to the low score-stable SDMT trajectory.Conclusions: Patients with lower SDMT scores at DMT start did not decline over the years, whereas those with minimal or relatively severe disability moderately lost function. Our results also suggest an inverse link between processing speed and disability trajectories after DMT start.
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9. |
- Olsson, J., et al.
(författare)
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Detection and quantification of ochratoxin A and deoxynivalenol in barley grains by GC-MS and electronic nose
- 2002
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Ingår i: International Journal of Food Microbiology. - : Elsevier. - 0168-1605 .- 1879-3460. ; 72:3, s. 203-214
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Tidskriftsartikel (refereegranskat)abstract
- Mycotoxin contamination of cereal grains can be detected and quantified using complex extraction procedures and analytical techniques. Normally, the grain odour, i.e. the presence of non-grain volatile metabolites, is used for quality classification of grain. We have investigated the possibility of using fungal volatile metabolites as indicators of mycotoxins in grain. Ten barley samples with normal odour, and 30 with some kind of off-odour were selected from Swedish granaries. The samples were evaluated with regard to moisture content, fungal contamination, ergosterol content, and levels of ochratoxin A (OA) and deoxynivalenol (DON). Volatile compounds were also analysed using both an electronic nose and gas chromatography combined with mass spectrometry (GC-MS). Samples with normal odour had no detectable ochratoxin A and average DON contents of 16 mug kg(-1) (range 0-80), while samples with off-odour had average OA contents of 76 mug kg(-1) (range 0-934) and DON contents of 69 mug kg(-1) (range 0-857). Data were evaluated by multivariate data analysis using projection methods such as principal component analysis (PCA) and partial least squares (PLS). The results show that it was possible to classify the OA level as below or above the maximum limit of 5 mug kg(-1) cereal grain established by the Swedish National Food Administration, and that the DON level could be estimated using PLS. Samples with OA levels below 5 mug kg(-1) had higher concentration of aldehydes (nonanal, 2-hexenal) and alcohols (1-penten-3-ol, 1-octanol). Samples with OA levels above 5 mug kg(-1) had higher concentrations of ketones (2-hexanone, 3-octanone). The GC-MS system predicted OA concentrations with a higher accuracy than the electronic nose, since the GC-MS misclassified only 3 of 37 samples and the electronic nose 7 of 37 samples. No correlation was found between odour and OA level, as samples with pronounced or strong off-odours had OA levels both below and above 5 mug kg(-1). We were able to predict DON levels in the naturally contaminated barley samples using the volatile compounds detected and quantified by either GC-MS or the electronic nose. Pentane, methylpyrazine, 3-pentanone, 3-octene-2-ol and isooctylacetate showed a positive correlation with DON, while ethylhexanol, pentadecane, toluene, 1-octanol, 1-nonanol, and 1-heptanol showed a negative correlation with DON. The root mean square error of estimation values for prediction of DON based on GC-MS and electronic nose data were 16 and 25 mug kg(-1) respectively.
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10. |
- Olsson, J., et al.
(författare)
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Volatiles for mycological quality grading of barley grains : determinations using gas chromatography-mass spectrometry and electronic nose
- 2000
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Ingår i: International Journal of Food Microbiology. - : Elsevier. - 0168-1605 .- 1879-3460. ; 59:3, s. 167-178
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Tidskriftsartikel (refereegranskat)abstract
- The possibility of using an electronic nose or gas chromatography combined with mass spectrometry (GC-MS) to quantify ergosterol and colony forming units (CFU) of naturally contaminated barley samples was investigated. Each sample was split into three parts for (i) ergosterol and CFU analysis, (ii) measurements with the electronic nose and (iii) identification of volatiles collected on an adsorbent with a GC-MS system. Forty samples were selected after sensory analysis to obtain 10 samples with normal odour and 30 with some degree of off-odour. The data set of volatile compounds and the data collected from the electronic nose were evaluated by multivariate analyse techniques. SIMCA classification (soft independent modelling of class analogy) was used for objective evaluation of the usefulness of the data from the GC-MS or electronic nose measurements for classification of grain samples as normal or with off-odour. The main volatile compounds of grain with normal odour were 2-hexenal, benzaldehyde and nonanal, while 3-octanone, methylheptanone and trimethylbenzene were the main volatile compounds of grain with off-odours. Using data from the electronic nose three samples of 40 were misclassified, while data analysis of the volatile compounds detected with the GC-MS, led to six misclassified samples. Regression models (partial least-squares, PLS) were built to predict ergosterol- and CFU-levels with data from the GC-MS or electronic nose measurements. PLS models based on both GC-MS and electronic nose data could be used to predict the ergosterol levels with high accuracy and with low root mean square error of prediction (RMSEP). CFU values from naturally infected grain could not be predicted with the same degree of confidence.
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