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- Ahlqvist, Viktor H., et al.
(author)
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Birth weight and grip strength in young Swedish males : a longitudinal matched sibling analysis and across all body mass index ranges
- 2019
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In: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 9
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Journal article (peer-reviewed)abstract
- Low birth weight is associated with a lower grip strength later in life. However, associations between birth weight among infants born at-term and factors driving associations between birth weight and grip strength are largely unknown. A cohort of 144,369 young men born at-term, including 10,791 individuals who had at least one male sibling/s, were followed until conscription where they performed a grip strength test. We used linear and non-linear regression analyses in the full cohort, and fixed-effects regression analyses in the sibling cohort, to address confounding by factors that are shared between siblings. After adjustment, each unit increase in birth weight z-score was associated with increases of 17.7 (95% CI, 17.2-18.2) and 13.4 (10.1-16.6) newton grip strength, which converts to approximately 1.8 and 1.4 kilogram-force in the full and within-families cohorts, respectively. The associations did not vary with young adulthood BMI. Birth weight, within the at-term range, is robustly positively associated with grip strength in young adulthood among men across all BMI categories and associations appears to be mainly driven by factors that are not shared between siblings. These findings underline the importance of recognizing the influence of low birth weight, also within the at-termrange, on young adulthood muscle strength.
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- Ahlqvist, Viktor H., et al.
(author)
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Elective and nonelective cesarean section and obesity among young adult male offspring : A Swedish population-based cohort study
- 2019
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In: PLoS Medicine. - : PUBLIC LIBRARY SCIENCE. - 1549-1277 .- 1549-1676. ; 16:12
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Journal article (peer-reviewed)abstract
- Background: Previous studies have suggested that cesarean section (CS) is associated with offspring overweight and obesity. However, few studies have been able to differentiate between elective and nonelective CS, which may differ in their maternal risk profile and biological pathway. Therefore, we aimed to examine the association between differentiated forms of delivery with CS and risk of obesity in young adulthood.Methods and findings: Using Swedish population registers, a cohort of 97,291 males born between 1982 and 1987 were followed from birth until conscription (median 18 years of age) if they conscripted before 2006. At conscription, weight and height were measured and transformed to World Health Organization categories of body mass index (BMI). Maternal and infant data were obtained from the Medical Birth Register. Associations were evaluated using multinomial and linear regressions. Furthermore, a series of sensitivity analyses were conducted, including fixed-effects regressions to account for confounders shared between full brothers. The mothers of the conscripts were on average 28.5 (standard deviation 4.9) years old at delivery and had a prepregnancy BMI of 21.9 (standard deviation 3.0), and 41.5% of the conscripts had at least one parent with university-level education.Out of the 97,291 conscripts we observed, 4.9% were obese (BMI ≥ 30) at conscription. The prevalence of obesity varied slightly between vaginal delivery, elective CS, and nonelective CS (4.9%, 5.5%, and 5.6%, respectively), whereas BMI seemed to be consistent across modes of delivery. We found no evidence of an association between nonelective or elective CS and young adulthood obesity (relative risk ratio 0.96, confidence interval 95% 0.83–1.10, p = 0.532 and relative risk ratio 1.02, confidence interval 95% 0.88–1.18, p = 0.826, respectively) as compared with vaginal delivery after accounting for prepregnancy maternal BMI, maternal diabetes at delivery, maternal hypertension at delivery, maternal smoking, parity, parental education, maternal age at delivery, gestational age, birth weight standardized according to gestational age, and preeclampsia. We found no evidence of an association between any form of CS and overweight (BMI ≥ 25) as compared with vaginal delivery. Sibling analysis and several sensitivity analyses did not alter our findings. The main limitations of our study were that not all conscripts had available measures of anthropometry and/or important confounders (42% retained) and that our cohort only included a male population.Conclusions: We found no evidence of an association between elective or nonelective CS and young adulthood obesity in young male conscripts when accounting for maternal and prenatal factors. This suggests that there is no clinically relevant association between CS and the development of obesity. Further large-scale studies are warranted to examine the association between differentiated forms of CS and obesity in young adult offspring.Trial registration: Registered as observational study at ClinicalTrials.gov Identifier: NCT03918044.
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- Askling, J., et al.
(author)
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How comparable are rates of malignancies in patients with rheumatoid arthritis across the world? A comparison of cancer rates, and means to optimise their comparability, in five RA registries
- 2016
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In: Annals of the Rheumatic Diseases. - : BMJ. - 0003-4967 .- 1468-2060. ; 75:10, s. 1789-1796
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Journal article (peer-reviewed)abstract
- Background The overall incidence of cancer in patients with rheumatoid arthritis (RA) is modestly elevated. The extent to which cancer rates in RA vary across clinical cohorts and patient subsets, as defined by disease activity or treatment is less known but critical for understanding the safety of existing and new antirheumatic therapies. We investigated comparability of, and means to harmonise, malignancy rates in five RA registries from four continents. Methods Participating RA registries were Consortium of Rheumatology Researchers of North America (CORRONA) (USA), Swedish Rheumatology Quality of Care Register (SRR) (Sweden), Norfolk Arthritis Register (NOAR) (UK), CORRONA International (several countries) and Institute of Rheumatology, Rheumatoid Arthritis (IORRA) (Japan). Within each registry, we analysed a main cohort of all patients with RA from January 2000 to last available data, and sensitivity analyses of sub-cohorts defined by disease activity, treatment change, prior comorbidities and restricted by calendar time or follow-up, respectively. Malignancy rates with 95% CIs were estimated, and standardised for age and sex, based on the distributions from a typical RA clinical trial programme population (fostamatinib). Results There was a high consistency in rates for overall malignancy excluding non-melanoma skin cancer (NMSC), for malignant lymphomas, but not for all skin cancers, across registries, in particular following age/sex standardisation. Standardised rates of overall malignancy excluding NMSC varied from 0.56 to 0.87 per 100 person-years. Within each registry, rates were generally consistent across sensitivity analyses, which differed little from the main analysis. Conclusion In real-world RA populations, rates of both overall malignancy and of lymphomas are consistent.
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- Berglind, D, et al.
(author)
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Cross-sectional and prospective associations of meeting 24-h movement guidelines with overweight and obesity in preschool children.
- 2018
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In: Pediatric Obesity. - : Wiley. - 2047-6302 .- 2047-6310. ; 13:7, s. 442-449
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Journal article (peer-reviewed)abstract
- BACKGROUND: Cross-sectional studies report that meeting the newly developed 24-h movement guidelines (≥60 min moderate to vigorous physical activity (MVPA), ≤120 min screen time and 9-11 h sleep duration) are associated with lower adiposity indicators in children. However, prospective data are absent.METHODS: The study sample consisted of 830 children from the PRIMROSE study with GT3X+ accelerometer measured physical activity and parent reported screen time and sleep duration at age 4 years and objectively measured anthropometrics at age 4 and 5 years. The main outcome variables were weight status, body mass index (BMI) and BMI z-score at ages 4 and 5 years. Exposure variables were defined as meeting vs. not meeting the 24-h movement guidelines and combinations of these recommendations.RESULTS: On average, 18.4% of the total study sample met the combination of MVPA, sleep duration and screen time recommendations. In isolation, the MVPA, screen time and sleep guidelines were met by 31%, 63% and 98% of the total study sample, respectively. Adherence to any single recommendation, or any combination of recommendations at age 4 years, was not associated with being overweight or obese nor with BMI and BMI z-score at age 4 or 5 years.CONCLUSIONS: In contrast to previous cross-sectional studies, neither individual movement behaviours nor combinations of behaviours at age 4 years was associated with overweight or obesity, BMI or BMI z-score at age 4 or 5 years. More prospective data are needed before effects on weight status from meeting the 24-h movement guidelines are elucidated.
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- Berglund, U. W., et al.
(author)
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Validation and development of MTH1 inhibitors for treatment of cancer
- 2016
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In: Annals of Oncology. - : Elsevier BV. - 0923-7534 .- 1569-8041. ; 27:12, s. 2275-2283
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Journal article (peer-reviewed)abstract
- Background: Previously, we showed cancer cells rely on the MTH1 protein to prevent incorporation of otherwise deadly oxidised nucleotides into DNA and we developed MTH1 inhibitors which selectively kill cancer cells. Recently, several new and potent inhibitors of MTH1 were demonstrated to be non-toxic to cancer cells, challenging the utility of MTH1 inhibition as a target for cancer treatment. Material and methods: Human cancer cell lines were exposed in vitro to MTH1 inhibitors or depleted of MTH1 by siRNA or shRNA. 8-oxodG was measured by immunostaining and modified comet assay. Thermal Proteome profiling, proteomics, cellular thermal shift assays, kinase and CEREP panel were used for target engagement, mode of action and selectivity investigations of MTH1 inhibitors. Effect of MTH1 inhibition on tumour growth was explored in BRAF V600E-mutated malignant melanoma patient derived xenograft and human colon cancer SW480 and HCT116 xenograft models. Results: Here, we demonstrate that recently described MTH1 inhibitors, which fail to kill cancer cells, also fail to introduce the toxic oxidized nucleotides into DNA. We also describe a new MTH1 inhibitor TH1579, (Karonudib), an analogue of TH588, which is a potent, selective MTH1 inhibitor with good oral availability and demonstrates excellent pharmacokinetic and anti-cancer properties in vivo. Conclusion: We demonstrate that in order to kill cancer cells MTH1 inhibitors must also introduce oxidized nucleotides into DNA. Furthermore, we describe TH1579 as a best-in-class MTH1 inhibitor, which we expect to be useful in order to further validate the MTH1 inhibitor concept.
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| 10. |
- Bergmann, Berglind, et al.
(author)
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Antibiotics with Interleukin-15 inhibition reduces joint inflammation and bone erosions but not cartilage destruction in Staphylococcus aureus-induced arthritis.
- 2018
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In: Infection and immunity. - 1098-5522. ; 86:5
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Journal article (peer-reviewed)abstract
- Background:Staphylococcus aureus-induced arthritis causes rapid joint destruction, often leading to disabling joint damage despite antibiotics. We have previously shown that IL-15 inhibition without antibiotics is beneficial in S. aureus-induced arthritis. We therefore hypothesized that inhibition of IL-15, in combination with antibiotics, might represent a useful therapy that would both reduce inflammation and joint destruction, but preserve the host's ability to clear the infection.Methods: Female wildtype C57BL/6 mice were intravenously inoculated with the TSST-1-producing LS-1 strain of S. aureus with 0.8x108S. aureus LS-1/mouse. Three days later the treatment was started consisting of cloxacillin followed by flucloxacillin, together with either anti-IL-15 antibodies (aIL-15ab) or control antibodies. Outcomes included survival, weight change, bacterial clearance, and joint damage.Results: The addition of aIL-15ab to antibiotics in S. aureus-induced arthritis reduced synovitis and bone erosions compared to controls. The number of bone-resorbing osteoclasts in the joints was reduced, whereas cartilage destruction was not significantly altered. Importantly, the combination therapy did not adversely affect the clinical outcome of S. aureus-induced arthritis, such as survival, weight change or compromise the host's ability to clear the infection.Conclusions: As the clinical outcome of S. aureus-induced arthritis was not affected, the addition of aIL-15ab to antibiotics ought to be safe. Taken together, the combination of aIL-15ab and antibiotics is a beneficial, but not optimal, treatment of S. aureus-induced arthritis as it reduces synovitis and bone erosions but has a limited effect on cartilage destruction.
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