| 1. |
- Paluch, Amanda E., et al.
(författare)
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Daily steps and all-cause mortality : a meta-analysis of 15 international cohorts
- 2022
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Ingår i: The Lancet Public Health. - : Elsevier. - 2468-2667. ; 7:3, s. e219-e228
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Although 10 000 steps per day is widely promoted to have health benefits, there is little evidence to support this recommendation. We aimed to determine the association between number of steps per day and stepping rate with all-cause mortality.METHODS: In this meta-analysis, we identified studies investigating the effect of daily step count on all-cause mortality in adults (aged ≥18 years), via a previously published systematic review and expert knowledge of the field. We asked participating study investigators to process their participant-level data following a standardised protocol. The primary outcome was all-cause mortality collected from death certificates and country registries. We analysed the dose-response association of steps per day and stepping rate with all-cause mortality. We did Cox proportional hazards regression analyses using study-specific quartiles of steps per day and calculated hazard ratios (HRs) with inverse-variance weighted random effects models.FINDINGS: We identified 15 studies, of which seven were published and eight were unpublished, with study start dates between 1999 and 2018. The total sample included 47 471 adults, among whom there were 3013 deaths (10·1 per 1000 participant-years) over a median follow-up of 7·1 years ([IQR 4·3-9·9]; total sum of follow-up across studies was 297 837 person-years). Quartile median steps per day were 3553 for quartile 1, 5801 for quartile 2, 7842 for quartile 3, and 10 901 for quartile 4. Compared with the lowest quartile, the adjusted HR for all-cause mortality was 0·60 (95% CI 0·51-0·71) for quartile 2, 0·55 (0·49-0·62) for quartile 3, and 0·47 (0·39-0·57) for quartile 4. Restricted cubic splines showed progressively decreasing risk of mortality among adults aged 60 years and older with increasing number of steps per day until 6000-8000 steps per day and among adults younger than 60 years until 8000-10 000 steps per day. Adjusting for number of steps per day, comparing quartile 1 with quartile 4, the association between higher stepping rates and mortality was attenuated but remained significant for a peak of 30 min (HR 0·67 [95% CI 0·56-0·83]) and a peak of 60 min (0·67 [0·50-0·90]), but not significant for time (min per day) spent walking at 40 steps per min or faster (1·12 [0·96-1·32]) and 100 steps per min or faster (0·86 [0·58-1·28]).INTERPRETATION: Taking more steps per day was associated with a progressively lower risk of all-cause mortality, up to a level that varied by age. The findings from this meta-analysis can be used to inform step guidelines for public health promotion of physical activity.FUNDING: US Centers for Disease Control and Prevention.
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| 2. |
- Fanaroff, Alexander C., et al.
(författare)
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Frequency, Regional Variation, and Predictors of Undetermined Cause of Death in Cardiometabolic Clinical Trials : A Pooled Analysis of 9259 Deaths in 9 Trials
- 2019
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Ingår i: Circulation. - 0009-7322 .- 1524-4539. ; 139:7, s. 863-873
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Modern cardiometabolic clinical trials often include cardiovascular death as a component of a composite primary outcome, requiring central adjudication by a clinical events committee to classify cause of death. However, sometimes the cause of death cannot be determined from available data. The US Food and Drug Administration has indicated that this circumstance should occur only rarely, but its prevalence has not been formally assessed. METHODS: Data from 9 global clinical trials (2009-2017) with long-term follow-up and blinded, centrally adjudicated cause of death were used to calculate the proportion of deaths attributed to cardiovascular, noncardiovascular, or undetermined causes by therapeutic area (diabetes mellitus/pre-diabetes mellitus, stable atherosclerosis, atrial fibrillation, and acute coronary syndrome), region of patient enrollment, and year of trial manuscript publication. Patient-and trial-level variables associated with undetermined cause of death were identified using a logistic model. RESULTS: Across 127 049 enrolled participants from 9 trials, there were 9259 centrally adjudicated deaths: 5012 (54.1%) attributable to cardiovascular causes, 2800 (30.2%) attributable to noncardiovascular causes, and 1447 (15.6%) attributable to undetermined causes. There was variability in the proportion of deaths ascribed to undetermined causes by trial therapeutic area, region of enrollment, and year of trial manuscript publication. On multivariable analysis, acute coronary syndrome or atrial fibrillation trial (versus atherosclerotic vascular disease or diabetes mellitus/pre-diabetes mellitus), longer time from enrollment to death, more recent trial manuscript publication year, enrollment in North America (versus Western Europe), female sex, and older age were associated with greater likelihood of death of undetermined cause. CONCLUSIONS: In 9 cardiometabolic clinical trials with long-term followup, approximately 16% of deaths had undetermined causes. This provides a baseline for quality assessment of clinical trials and informs operational efforts to potentially reduce the frequency of undetermined deaths in future clinical research.
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| 3. |
- Gerstner, Christina, et al.
(författare)
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Functional and Structural Characterization of a Novel HLA-DRB1*04:01-Restricted alpha-Enolase T Cell Epitope in Rheumatoid Arthritis
- 2016
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Ingår i: Frontiers in Immunology. - : Frontiers Media SA. - 1664-3224. ; 7
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Tidskriftsartikel (refereegranskat)abstract
- Antibodies to citrullinated proteins, common in rheumatoid arthritis (RA) patients, are strongly associated to a specific set of HLA-DR alleles including HLA-DRB1*04:01, *04:04, and *01:01. Here, we first demonstrate that autoantibody levels toward the dominant citrullinated B cell epitope from alpha-enolase are significantly elevated in HLA-DRB1*04:01-positive RA patients. Furthermore, we identified alpha-enolase-derived T cell epitopes and demonstrated that native and citrullinated versions of several peptides bind with different affinities to HLA-DRB1*04:01, *04:04, and *01:01. The citrulline residues in the eight identified peptides are distributed throughout the entire length of the presented epitopes and more specifically, localized at peptide positions p-2, p2, p4, p6, p7, p10, and p11. Importantly, in contrast to its native version peptide 26 (TSKGLFRAAVPSGAS), the HLA-DRB1*04:01-restricted citrullinated peptide Cit26 (TSKGLFCitAAVPSGAS) elicited significant functional T cell responses in primary cells from RA patients. Comparative analysis of the crystal structures of HLA-DRB1*04:01 in complex with peptide 26 or Cit26 demonstrated that the posttranslational modification did not alter the conformation of the peptide. And since citrullination is the only structural difference between the two complexes, this indicates that the neo-antigen Cit26 is recognized by T cells with high specificity to the citrulline residue.
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| 4. |
- Pieper, Jennifer, et al.
(författare)
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Memory T cells specific to citrullinated alpha-enolase are enriched in the rheumatic joint
- 2018
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Ingår i: Journal of Autoimmunity. - : ACADEMIC PRESS LTD- ELSEVIER SCIENCE LTD. - 0896-8411 .- 1095-9157. ; 92, s. 47-56
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Tidskriftsartikel (refereegranskat)abstract
- ACPA-positive rheumatoid arthritis (RA) is associated with distinct HLA-DR alleles and immune responses to many citrullinated self-antigens. Herein we investigated the T cell epitope confined within alpha-enolase(326-340) in the context of HLA-DRB1*04:01 and assessed the corresponding CD4(+) T cells in both the circulation and in the rheumatic joint. Comparative crystallographic analyses were performed for the native and citrullinated alpha-enolase(326-340) peptides in complex with HLA-DRB1*04:01. HLA-tetramers assembled with either the native or citrullinated peptide were used for ex vivo and in vitro assessment of a enolase-specific T cells in peripheral blood, synovial fluid and synovial tissue by flow cytometry. The native and modified peptides take a completely conserved structural conformation within the peptide binding cleft of HLA-DRB1*04:01. The citrulline residue-327 was located N-terminally, protruding towards TCRs. The frequencies of T cells recognizing native eno(326-340) were similar in synovial fluid and peripheral blood, while in contrast, the frequency of T cells recognizing cit-eno(326-340) was significantly elevated in synovial fluid compared to peripheral blood (3.6-fold, p = 0.0150). Additionally, citrulline-specific T cells with a memory phenotype were also significantly increased (1.6-fold, p = 0.0052) in synovial fluid compared to peripheral blood. The native T cell epitope confined within alpha-enolase(326-340) does not appear to lead to complete negative selection of cognate CD4(+) T cells. In RA patient samples, only T cells recognizing the citrullinated version of alpha-enolase(326-340) were found at elevated frequencies implicating that neo-antigen formation is critical for breach of tolerance. (C) 2018 Elsevier Ltd. All rights reserved.
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| 5. |
- Pieper, Jennifer
(författare)
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Proinflammatory and antigen-specific CD4+ T cells in rheumatoid arthritis
- 2014
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease primarily affecting peripheral joints. In this thesis work we aimed to increase the knowledge about proinflammatory and antigen-specific CD4+ T cell subsets involved in RA pathogenesis and I also investigated the effect of T cell directed therapy (abatacept) on CD4+ T cell subsets. Abatacept (CTLA4-Ig) is a biologic therapy that blocks T cell co-stimulation by interfering with the binding of CD28 to CD80/86. Treatment of abatacept leads to reduced TH1 and TH17 cytokine production in ACPA-positive RA patients and diminished frequencies of several Treg subsets. This was also confirmed by in vitro studies where abatacept was added in vitro to cell cultures. Approximately 60% of RA patients have antibodies against citrullinated proteins (ACPA) and their presence is associated to HLA-DRB1*04, one of the strongest genetic risk factors associated with RA. It is believed that T cells recognizing citrullinated epitopes presented by HLA-DRB1*04 alleles may drive the development of ACPA and disease. We have used MHC class II tetramer technology in order to identify and enumerate autoantigen-specific T cells in blood and synovial fluid of RA patients. Several citrullinated epitopes of CILP, a-enolase, fibrinogen and vimentin were identified. The frequency of citrulline-specific T cells was higher in the blood of RA patients compared to HLA-matched healthy controls and the citrulline-specific T cells in RA patients were of a memory TH1 phenotype. Furthermore, we enumerated and characterized a-enolase native and citrulline-specific T cells in blood and synovial fluid of HLA-DRB1*04:01 RA patients. Higher frequencies of citrullinated a-enolase specific T cells were present in synovial fluid compared to blood and T cells recognizing the citrullinated variant of a-enolase were also more often of a memory phenotype (i.e. had encountered their cognate antigen in vivo) than those recognizing the native a-enolase epitope. Some T cells showed cross-reactivity between the two investigated epitopes. HLA-DRB1*04:01-IE transgenic mice were used to substantiate our findings. Another potentially contributing T cell subset to RA pathology is an expanded T cell subset that lacks the co-stimulatory molecule CD28, often referred to as CD4+CD28null T cells, which are present in approximately 1/3 of RA patients. These are proinflammatory cells and their frequency in blood can be up to 50 % of all CD4+ T cells, but they are infrequent in synovial fluid. CD28null T cells are different than conventional CD4+ T cells in several aspects, but we demonstrate that even within the CD28null subset there are differences due to their localization. We compared cells from blood and synovial fluid. CD28null cells from synovial fluid expressed more CXCR3 and CCR6 than those form the circulation and CD28null cells from synovial fluid were able to produce IL-17 even though they displayed a hypomethylated IFNG promoter. During my thesis studies, several novel HLA-DRB1*04:01 restricted citrullinated T cell epitopes have been identified. The auto-reactive T cells did not overlap with the CD28null phenotype. We have demonstrated the proof of principle that auto-reactive T cells can be identified by MHC class II tetramer technology in an assay not dependent on in vitro stimulation.
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