| 1. |
- Aartsen, M. G., et al.
(författare)
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Neutrino interferometry for high-precision tests of Lorentz symmetry with IceCube
- 2018
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Ingår i: Nature Physics. - : NATURE PUBLISHING GROUP. - 1745-2473 .- 1745-2481. ; 14:9, s. 961-966
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Tidskriftsartikel (refereegranskat)abstract
- Lorentz symmetry is a fundamental spacetime symmetry underlying both the standard model of particle physics and general relativity. This symmetry guarantees that physical phenomena are observed to be the same by all inertial observers. However, unified theories, such as string theory, allow for violation of this symmetry by inducing new spacetime structure at the quantum gravity scale. Thus, the discovery of Lorentz symmetry violation could be the first hint of these theories in nature. Here we report the results of the most precise test of spacetime symmetry in the neutrino sector to date. We use high-energy atmospheric neutrinos observed at the IceCube Neutrino Observatory to search for anomalous neutrino oscillations as signals of Lorentz violation. We find no evidence for such phenomena. This allows us to constrain the size of the dimension-four operator in the standard-model extension for Lorentz violation to the 10(-28) level and to set limits on higher-dimensional operators in this framework. These are among the most stringent limits on Lorentz violation set by any physical experiment.
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| 2. |
- Aartsen, M. G., et al.
(författare)
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Neutrino emission from the direction of the blazar TXS 0506+056 prior to the IceCube-170922A alert
- 2018
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Ingår i: Science. - : American Association for the Advancement of Science (AAAS). - 0036-8075 .- 1095-9203. ; 361:6398, s. 147-151
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Tidskriftsartikel (refereegranskat)abstract
- A high-energy neutrino event detected by IceCube on 22 September 2017 was coincident in direction and time with a gamma-ray flare from the blazar TXS 0506+056. Prompted by this association, we investigated 9.5 years of IceCube neutrino observations to search for excess emission at the position of the blazar. We found an excess of high-energy neutrino events, with respect to atmospheric backgrounds, at that position between September 2014 and March 2015. Allowing for time-variable flux, this constitutes 3.5 sigma evidence for neutrino emission from the direction of TXS 0506+056, independent of and prior to the 2017 flaring episode. This suggests that blazars are identifiable sources of the high-energy astrophysical neutrino flux.
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| 3. |
- Aartsen, M. G., et al.
(författare)
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Constraints on Galactic Neutrino Emission with Seven Years of IceCube Data
- 2017
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 849:1
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Tidskriftsartikel (refereegranskat)abstract
- The origins of high-energy astrophysical neutrinos remain a mystery despite extensive searches for their sources. We present constraints from seven years of IceCube Neutrino Observatory muon data on the neutrino flux coming from the Galactic plane. This flux is expected from cosmic-ray interactions with the interstellar medium or near localized sources. Two methods were developed to test for a spatially extended flux from the entire plane, both of which are maximum likelihood fits but with different signal and background modeling techniques. We consider three templates for Galactic neutrino emission based primarily on gamma-ray observations and models that cover a wide range of possibilities. Based on these templates and in the benchmark case of an unbroken E-2.5 power-law energy spectrum, we set 90% confidence level upper limits, constraining the possible Galactic contribution to the diffuse neutrino flux to be relatively small, less than 14% of the flux reported in Aartsen et al. above 1 TeV. A stacking method is also used to test catalogs of known high-energy Galactic gamma-ray sources.
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| 4. |
- Aartsen, M. G., et al.
(författare)
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Search for Astrophysical Sources of Neutrinos Using Cascade Events in IceCube
- 2017
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Ingår i: Astrophysical Journal. - : American Astronomical Society. - 0004-637X .- 1538-4357. ; 846:2
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Tidskriftsartikel (refereegranskat)abstract
- The IceCube neutrino observatory has established the existence of a flux of high-energy astrophysical neutrinos, which is inconsistent with the expectation from atmospheric backgrounds at a significance greater than 5 sigma. This flux has been observed in analyses of both track events from muon neutrino interactions and cascade events from interactions of all neutrino flavors. Searches for astrophysical neutrino sources have focused on track events due to the significantly better angular resolution of track reconstructions. To date, no such sources have been confirmed. Here we present the first search for astrophysical neutrino sources using cascades interacting in IceCube with deposited energies as small as 1 TeV. No significant clustering was observed in a selection of 263 cascades collected from 2010 May to 2012 May. We show that compared to the classic approach using tracks, this statistically independent search offers improved sensitivity to sources in the southern sky, especially if the emission is spatially extended or follows a soft energy spectrum. This enhancement is due to the low background from atmospheric neutrinos forming cascade events and the additional veto of atmospheric neutrinos at declinations less than or similar to-30 degrees.
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| 5. |
- Aartsen, M. G., et al.
(författare)
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Search for neutrinos from dark matter self-annihilations in the center of the Milky Way with 3 years of IceCube/DeepCore
- 2017
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Ingår i: European Physical Journal C. - : SPRINGER. - 1434-6044 .- 1434-6052. ; 77:9
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Tidskriftsartikel (refereegranskat)abstract
- We present a search for a neutrino signal from dark matter self-annihilations in the Milky Way using the Ice-Cube Neutrino Observatory (IceCube). In 1005 days of data we found no significant excess of neutrinos over the background of neutrinos produced in atmospheric air showers from cosmic ray interactions. We derive upper limits on the velocity averaged product of the darkmatter self-annihilation cross section and the relative velocity of the dark matter particles . Upper limits are set for darkmatter particle candidate masses ranging from 10GeV up to 1TeV while considering annihilation through multiple channels. This work sets the most stringent limit on a neutrino signal from dark matter with mass between 10 and 100GeV, with a limit of 1.18 . 10-23 cm(3)s(-1) for 100GeV dark matter particles self-annihilating via iota(+)iota(-) t-to neutrinos (assuming the Navarro-Frenk-White dark matter halo profile).
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| 6. |
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| 7. |
- 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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| 8. |
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| 9. |
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| 10. |
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| 11. |
- Heyckendorf, J, et al.
(författare)
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Prediction of anti-tuberculosis treatment duration based on a 22-gene transcriptomic model
- 2021
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Ingår i: The European respiratory journal. - : European Respiratory Society (ERS). - 1399-3003 .- 0903-1936. ; 58:3
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Tidskriftsartikel (refereegranskat)abstract
- The World Health Organization recommends standardised treatment durations for patients with tuberculosis (TB). We identified and validated a host-RNA signature as a biomarker for individualised therapy durations for patients with drug-susceptible (DS)- and multidrug-resistant (MDR)-TB.MethodsAdult patients with pulmonary TB were prospectively enrolled into five independent cohorts in Germany and Romania. Clinical and microbiological data and whole blood for RNA transcriptomic analysis were collected at pre-defined time points throughout therapy. Treatment outcomes were ascertained by TBnet criteria (6-month culture status/1-year follow-up). A whole-blood RNA therapy-end model was developed in a multistep process involving a machine-learning algorithm to identify hypothetical individual end-of-treatment time points.Results50 patients with DS-TB and 30 patients with MDR-TB were recruited in the German identification cohorts (DS-GIC and MDR-GIC, respectively); 28 patients with DS-TB and 32 patients with MDR-TB in the German validation cohorts (DS-GVC and MDR-GVC, respectively); and 52 patients with MDR-TB in the Romanian validation cohort (MDR-RVC). A 22-gene RNA model (TB22) that defined cure-associated end-of-therapy time points was derived from the DS- and MDR-GIC data. The TB22 model was superior to other published signatures to accurately predict clinical outcomes for patients in the DS-GVC (area under the curve 0.94, 95% CI 0.9–0.98) and suggests that cure may be achieved with shorter treatment durations for TB patients in the MDR-GIC (mean reduction 218.0 days, 34.2%; p<0.001), the MDR-GVC (mean reduction 211.0 days, 32.9%; p<0.001) and the MDR-RVC (mean reduction of 161.0 days, 23.4%; p=0.001).ConclusionBiomarker-guided management may substantially shorten the duration of therapy for many patients with MDR-TB.
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| 12. |
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| 13. |
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| 14. |
- 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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| 15. |
- 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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| 16. |
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| 17. |
- 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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| 18. |
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| 19. |
- Miyake, F., et al.
(författare)
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A Single-Year Cosmic Ray Event at 5410 BCE Registered in 14C of Tree Rings
- 2021
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Ingår i: Geophysical Research Letters. - 0094-8276. ; 48:11
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Tidskriftsartikel (refereegranskat)abstract
- The annual 14C data in tree rings is an outstanding proxy for uncovering extreme solar energetic particle (SEP) events in the past. Signatures of extreme SEP events have been reported in 774/775 CE, 992/993 CE, and ∼660 BCE. Here, we report another rapid increase of 14C concentration in tree rings from California, Switzerland, and Finland around 5410 BCE. These 14C data series show a significant increase of ∼6‰ in 5411–5410 BCE. The signature of 14C variation is very similar to the confirmed three SEP events and points to an extreme short-term flux of cosmic ray radiation into the atmosphere. The rapid 14C increase in 5411/5410 BCE rings occurred during a period of high solar activity and 60 years after a grand 14C excursion during 5481–5471 BCE. The similarity of our 14C data to previous events suggests that the origin of the 5410 BCE event is an extreme SEP event.
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| 20. |
- Salzer, HJF, et al.
(författare)
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Diagnosis and Management of Systemic Endemic Mycoses Causing Pulmonary Disease
- 2018
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Ingår i: Respiration. - : S. Karger AG. - 1423-0356 .- 0025-7931. ; 96:3, s. 283-301
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Tidskriftsartikel (refereegranskat)abstract
- Systemic endemic mycoses cause high rates of morbidity and mortality in certain regions of the world and the real impact on global health is not well understood. Diagnosis and management remain challenging, especially in low-prevalence settings, where disease awareness is lacking. The main challenges include the variability of clinical presentation, the fastidious and slow-growing nature of the fungal pathogens, the paucity of diagnostic tests, and the lack of options and toxicity of antifungal drugs. Coccidioidomycosis and paracoccidioidomycosis are restricted to the Americas only, and while histoplasmosis and blastomycosis also occur predominantly in the Americas, these mycoses have also been reported on other continents, especially in sub-Saharan Africa. Talaromycosis is endemic in tropical and subtropical regions in South-East Asia and southern China. Systemic endemic mycoses causing pulmonary disease are usually acquired via the airborne route by inhalation of fungal spores. Infections can range from asymptomatic or mild with flu-like illnesses to severe pulmonary or disseminated diseases. Skin involvement is frequent in patients with paracoccidioidomycosis, blastomycosis, sporotrichosis, and talaromycosis and manifests as localized lesions or diffuse nodules in disseminated disease, but can also occur with other endemic mycoses. Culture and/or characteristic histopathology from clinical samples is the diagnostic standard for endemic mycoses. Immunological assays are often not available for the diagnosis of most endemic mycoses and molecular amplification methods for the detection of fungal nucleic acids are not standardized at present. The first-line treatment for mild to moderate histoplasmosis, paracoccidioidomycosis, blastomycosis, sporotrichosis, and talaromycosis is itraconazole. Severe illness is treated with amphotericin B. Patients with severe coccidioidomycosis should receive fluconazole. Treatment duration depends on the specific endemic mycosis, the severity of disease, and the immune status of the patient, ranging between 6 weeks and lifelong treatment.
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| 21. |
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| 22. |
- Alping, P., et al.
(författare)
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Rituximab versus Fingolimod after Natalizumab in Multiple Sclerosis Patients
- 2016
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Ingår i: Annals of Neurology. - : Wiley. - 0364-5134 .- 1531-8249. ; 79:6, s. 950-958
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Tidskriftsartikel (refereegranskat)abstract
- Objective: Many JC virus antibody-positive relapsing-remitting multiple sclerosis (RRMS) patients who are stable on natalizumab switch to other therapies to avoid progressive multifocal leukoencephalopathy. Methods: We compared outcomes for all RRMS patients switching from natalizumab due to JC virus antibody positivity at 3 Swedish multiple sclerosis centers with different preferential use of rituximab and fingolimod (Stockholm, n = 156, fingolimod 51%; Gothenburg, n = 64, fingolimod 88%; Umea, n = 36, fingolimod 19%), yielding a total cohort of N = 256 (fingolimod 55%). Results: Within 1.5 years of cessation of natalizumab, 1.8% (rituximab) and 17.6% (fingolimod) of patients experienced a clinical relapse (hazard ratio for rituximab = 0.10, 95% confidence interval [CI] = 0.02-0.43). The hazard ratio (favoring rituximab) for adverse events (5.3% vs 21.1%) and treatment discontinuation (1.8% vs 28.2%) were 0.25 (95% CI = 0.10-0.59) and 0.07 (95% CI = 0.02-0.30), respectively. Furthermore, contrast-enhancing lesions were found in 1.4% (rituximab) versus 24.2% (fingolimod) of magnetic resonance imaging examinations (odds ratio = 0.05, 95% CI = 0.00-0.22). Differences remained when adjusting for possible confounders (age, sex, disability status, time on natalizumab, washout time, follow-up time, and study center). Interpretation: Our findings suggest an improved effectiveness and tolerability of rituximab compared with fingolimod in stable RRMS patients who switch from natalizumab due to JC virus antibody positivity. Although residual confounding factors cannot be ruled out, the shared reason for switching from natalizumab and the preferential use of either rituximab or fingolimod in 2 of the centers mitigates these concerns.
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| 23. |
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| 24. |
- Boremalm, Malin, et al.
(författare)
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Natalizumab, rituximab and fingolimod as escalation therapy in multiple sclerosis
- 2019
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Ingår i: European Journal of Neurology. - : Wiley. - 1351-5101 .- 1468-1331. ; 26:8, s. 1060-1067
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Tidskriftsartikel (refereegranskat)abstract
- Background and purpose Breakthrough disease on first-line injectables in relapsing-remitting multiple sclerosis (RRMS) is a common clinical situation where comparative studies between different escalation therapies are lacking. The aim of this study was to compare the efficacy, safety and medication persistence of natalizumab (NTZ), rituximab (RTX) and fingolimod (FGL) as escalation therapy in RRMS. Methods Patients switching from interferon or glatiramer acetate to NTZ, RTX or FGL due to breakthrough disease were identified through the Swedish multiple sclerosis (MS) registry at four large MS centers in this retrospective observational study. Data were collected from the MS registry and medical charts. Hazard ratios (HRs) for relapses, adverse events and drug discontinuation with 95% confidence interval (CI) were calculated using multivariable confounder-adjusted Cox proportional hazard models. Results A total of 241 patients were included. The annualized relapse rates were 0.02 for NTZ, 0.03 for RTX and 0.07 for FGL. Compared with NTZ, the adjusted HR for relapse was 1.0 (95% CI, 0.2-5.6) for RTX and 3.4 (95% CI, 1.3-9.2) for FGL. The annualized drug discontinuation rates were 0.15, 0.01 and 0.15 for NTZ, RTX and FGL, respectively. The adjusted HR for drug discontinuation was 0.05 (95% CI, 0.01-0.38) for RTX and 1.0 (95% CI, 0.6-1.7) for FGL vs. NTZ. Conclusions In patients with RRMS on interferon/glatiramer acetate with breakthrough disease, switching to NTZ or RTX was associated with less disease activity compared with FGL. RTX displayed superior medication persistence compared with both NTZ and FGL.
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| 25. |
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