Published in 2020

OBJECTIVES: Glucocorticoid treatment is fundamental in polymyalgia rheumatica (PMR) and giant cell arteritis (GCA), but carries a risk of glucocorticoid-induced adrenal insufficiency. Adrenal insufficiency can cause reluctance to stop glucocorticoid treatment after disease remission as symptoms can resemble PMR/GCA flare. We aimed to determine the prevalence of adrenal insufficiency in prednisolone-treated patients with PMR/GCA.

METHODS: We included 47 patients with PMR (n = 37), GCA (n = 1) or both (n = 9), treated with prednisolone for ≥5.4 months, current dose 2.5-10 mg/day. Adrenal function was evaluated using a corticotropin (Synacthen®) stimulation test following 48 h prednisolone pause. Two years' clinical follow-up data are provided.

RESULTS: Seven patients (15%) had adrenal insufficiency, 4 (11%) of the 37 patients with PMR alone, and 3 (30%) of the 10 patients with GCA. Corticotropin-stimulated P-cortisol was significantly associated with current prednisolone dose, mean daily dose the last 3 and 6 months before testing, and basal P-cortisol, but not with total dose or treatment duration. Adrenal insufficiency occurred with all current prednisolone doses (2.5-10 mg/day). Five (71%) of the glucocorticoid-insufficient patients could discontinue prednisolone treatment; two of them recovered glucocorticoid function, whereas three still needed hydrocortisone replacement 2 years later. Two patients experienced in total four acute hospital admissions with symptoms of adrenal crises.

CONCLUSION: Glucocorticoid-induced adrenal insufficiency occurred in 15% of patients with PMR/GCA. Mean prednisolone dose the last 3 months and basal P-cortisol were the best and simplest predictors of adrenal function. Most of the glucocorticoid-insufficient patients could discontinue prednisolone with appropriate treatment for adrenal insufficiency.

Originalsprog Engelsk
Tidsskrift Rheumatology (Oxford, England)
ISSN 1462-0332
DOI
Status Udgivet - 7 feb. 2020

Bibliografisk note

© The Author(s) 2020. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

Chances of live birth after exposure to vitamin D-fortified margarine in women with fertility problems: results from a Danish population-based cohort study

Jensen, A., Nielsen, M. L., Guleria, S., Kjaer, S. K., Heitmann, B. L. & Kesmodel, U. S., 2020, I : Fertility and Sterility. 113, 2, s. 383-391 9 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

OBJECTIVE: To study the association between extra vitamin D from a mandatory margarine fortification program and chance of live birth among infertile women.

DESIGN: Nationwide cohort study.

SETTING: Not applicable.

PATIENT(S): The study population consisted of 16,212 women diagnosed with infertility from June 1, 1980, to August 31, 1991.

INTERVENTIONS(S): We took advantage of the mandatory vitamin D fortification program of margarine in Denmark that was abruptly stopped on May 31, 1985. The termination of the vitamin D fortification served as a cutoff point to separate the study population into various exposure groups.

MAIN OUTCOME MEASURE(S): Odds ratios and 95% confidence intervals for the association between vitamin D exposure status and chance of a live birth within 12, 15, and 18 months after first infertility diagnosis.

RESULT(S): Women who were diagnosed with infertility during the vitamin D-exposed period had an increased chance of a live birth compared with women diagnosed with infertility during the nonexposed period. For women diagnosed with infertility during the wash-out period, the chance of a live birth was also increased, but somewhat lower. Similar estimates were obtained with longer follow-up, in women with anovulatory infertility, and little seasonal variation was observed when calendar period of conception was applied.

CONCLUSION(S): Our findings suggest that infertile women exposed to extra vitamin D from a margarine fortification program had an increased chance of live birth compared with women not exposed to extra vitamin D from fortification.

Originalsprog Engelsk
Tidsskrift Fertility and Sterility
Vol/bind 113
Udgave nummer 2
Sider (fra-til) 383-391
Antal sider 9
ISSN 0015-0282
DOI
Status Udgivet - 2020

Bibliografisk note

Copyright © 2019 American Society for Reproductive Medicine. Published by Elsevier Inc. All rights reserved.

Objective: To investigate whether a dose-response relationship exists between volume of exercise and discontinuation of glucose-lowering medication treatment in patients with type 2 diabetes. Patients and Methods: Secondary analyses of a randomized controlled exercise-based lifestyle intervention trial (April 29, 2015 to August 17, 2016). Patients with non–insulin-dependent type 2 diabetes were randomly assigned to an intensive lifestyle intervention (U-TURN) or standard-care group. Both groups received lifestyle advice and objective target-driven medical regulation. Additionally, the U-TURN group received supervised exercise and individualized dietary counseling. Of the 98 randomly assigned participants, 92 were included in the analysis (U-TURN, n=61, standard care, n=31). Participants in the U-TURN group were stratified into tertiles based on accumulated volumes of exercise completed during the 1-year intervention. Results: Median exercise levels of 178 (interquartile range [IQR], 121-213; lower tertile), 296 (IQR, 261-310; intermediate tertile), and 380 minutes per week (IQR, 355-446; upper tertile) were associated with higher odds of discontinuing treatment with glucose-lowering medication, with corresponding odds ratios of 12.1 (95% CI, 1.2-119; number needed to treat: 4), 30.2 (95% CI, 2.9-318.5; 3), and 34.4 (95% CI, 4.1-290.1; 2), respectively, when comparing with standard care. Cardiovascular risk factors such as glycated hemoglobin A1c levels, fitness, 2-hour glucose levels, and triglyceride levels were improved significantly in the intermediate and upper tertiles, but not the lower tertile, compared with the standard-care group. Conclusion: Exercise volume is associated with discontinuation of glucose-lowering medication treatment in a dose-dependent manner, as are important cardiovascular risk factors in well-treated participants with type 2 diabetes and disease duration less than 10 years. Further studies are needed to support these findings. Study Registration: ClinicalTrials.gov registration (NCT02417012).

Originalsprog Engelsk
Tidsskrift Mayo Clinic Proceedings
ISSN 0025-6196
DOI
Status Udgivet - 1 jan. 2020

Early development of tendinopathy in humans: Sequence of pathological changes in structure and tissue turnover signaling

Tran, P. H. T., Malmgaard-Clausen, N. M., Puggaard, R. S., Svensson, R. B., Nybing, J. D., Hansen, P., Schjerling, P., Zinglersen, A. H., Couppé, C., Boesen, M., Magnusson, S. P. & Kjaer, M., jan. 2020, I : FASEB Journal. 34, 1, s. 776-788 13 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Overloading of tendon tissue with resulting chronic pain (tendinopathy) is a common disorder in occupational-, leisure- and sports-activity, but its pathogenesis remains poorly understood. To investigate the very early phase of tendinopathy, Achilles and patellar tendons were investigated in 200 physically active patients and 50 healthy control persons. Patients were divided into three groups: symptoms for 0-1 months (T1), 1-2 months (T2) or 2-3 months (T3). Tendinopathic Achilles tendon cross-sectional area determined by ultrasonography (US) was ~25% larger than in healthy control persons. Both Achilles and patellar anterior-posterior diameter were elevated in tendinopathy, and only later in Achilles was the width increased. Increased tendon size was accompanied by an increase in hypervascularization (US Doppler flow) without any change in mRNA for angiogenic factors. From patellar biopsies taken bilaterally, mRNA for most growth factors and tendon components remained unchanged (except for TGF-beta1 and substance-P) in early tendinopathy. Tendon stiffness remained unaltered over the first three months of tendinopathy and was similar to the asymptomatic contra-lateral tendon. In conclusion, this suggests that tendinopathy pathogenesis represents a disturbed tissue homeostasis with fluid accumulation. The disturbance is likely induced by repeated mechanical overloading rather than a partial rupture of the tendon.

Originalsprog Engelsk
Tidsskrift FASEB Journal
Vol/bind 34
Udgave nummer 1
Sider (fra-til) 776-788
Antal sider 13
ISSN 0892-6638
DOI
Status Udgivet - jan. 2020

Bibliografisk note

© 2019 Federation of American Societies for Experimental Biology.

BACKGROUND: Myocardial injury after non-cardiac surgery occurs in a high number of patients, resulting in increased mortality in the post-operative period. The use of high inspiratory oxygen concentrations may cause hyperoxia, which is associated with impairment of coronary blood flow. Furthermore, the surgical stress response increases reactive oxygen species, which is involved in several perioperative complications including myocardial injury and death. Avoidance of hyperoxia and substitution of reactive oxygen species scavengers may be beneficial. Our primary objective is to examine the effect of oxygen and added antioxidants for prevention of myocardial injury assessed by area under the curve for troponin measurements during the first three post-operative days.

METHODS: The VIXIE trial (VitamIn and oXygen Interventions and cardiovascular Events) is an investigator-initiated, blinded, 2 × 2 factorial multicentre clinical trial. We include 600 patients with cardiovascular risk factors undergoing major non-cardiac surgery. Participants are randomised to an inspiratory oxygen fraction of 0.80 or 0.30 during and for 2 hours after surgery and either an intravenous bolus of vitamin C and an infusion of N-acetylcysteine or matching placebo of both. The primary outcome is the area under the curve for high-sensitive cardiac troponin release during the first three post-operative days as a marker of the extent of myocardial injury. Secondary outcomes are mortality, non-fatal myocardial infarction and non-fatal serious adverse events within 30 days.

PERSPECTIVE: The current trial will provide further evidence for clinicians on optimal administration of perioperative oxygen in surgical patients with cardiovascular risks and the clinical effects of two common antioxidants.

Originalsprog Engelsk
Tidsskrift Acta Anaesthesiologica Scandinavica
Vol/bind 64
Udgave nummer 3
Sider (fra-til) 400-409
Antal sider 10
ISSN 0001-5172
DOI
Status Udgivet - mar. 2020

Bibliografisk note

© 2019 The Acta Anaesthesiologica Scandinavica Foundation. Published by John Wiley & Sons Ltd.

Novel insights into cerebral palsy

Bartels, E. M., Korbo, L. & Harrison, A. P., 17 feb. 2020, I : Journal of muscle research and cell motility.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Cerebral palsy (CP) is a neurodevelopmental disorder characterized by abnormalities of muscle tone, movement and motor skills, and is attributed to injury to the developing brain. CP affects about 1 in 500 neonates. CP shows clinical features which evolve with age, and these may over time lead to deterioration of motor function although the lesion to the developing brain is non-progressive. The underlying causes for CP remain unclear. Based on recent research we are able to give a physiological explanation on the appearance and development of the condition. The damage to the central nervous system causes a change in collagen structure, with a higher level of deposition of collagen around the muscles, increasing throughout life. Assuming this premise is correct, the question is, will it by any treatment be possible to delay or prevent this collagen accumulation in the CP muscles, thereby giving CP patients a better prognosis in the future.

Originalsprog Engelsk
Tidsskrift Journal of muscle research and cell motility
ISSN 0142-4319
DOI
Status Udgivet - 17 feb. 2020

OBJECTIVE: To investigate the association between pain and perfusion in bone marrow lesions with and without cysts assessed dynamic contrast-enhanced (DCE)-MRI in patients with knee osteoarthritis.

SUBJECTS AND METHODS: In a cross-sectional setting, perfusion in bone marrow lesions was assessed using 3 Tesla MRI and correlated (Spearman's rank correlation) to pain using the knee injury and osteoarthritis outcome score (KOOS). Bone marrow lesions were assessed across the whole knee with DCE-MRI using heuristic variable and non-contrast-enhanced-MRI using MRI osteoarthritis knee score.

RESULTS: Data were available from 107 participants. The participants had a mean age of 60.8 years, mean BMI of 34.5 kg/m2, mean KOOS-pain of 63.7 (0-100 scale), and mean bone marrow lesion sum score of 6.5 (0-45 scale). The bivariate association between KOOS-pain and the heuristic perfusion variable time to peak in bone marrow lesions containing subchondral cysts showed a statistically significant correlation (r = 0.40; p = 0.002). The perfusion variables were not correlated with KOOS-pain in bone marrow lesions without cysts.

CONCLUSION: In this cross-sectional study, the rate of perfusion (TTP) in bone marrow lesions containing subchondral cysts was associated with pain in patients with knee OA. DCE-MRI has a potential to be used for separating subtypes of OA.

Originalsprog Engelsk
Tidsskrift Skeletal Radiology
Vol/bind 49
Udgave nummer 5
Sider (fra-til) 757-764
Antal sider 8
ISSN 0364-2348
DOI
Status Udgivet - maj 2020

Prenatal exposure to perfluorodecanoic acid is associated with lower circulating concentration of adrenal steroid metabolites during mini puberty in human female infants. The Odense Child Cohort

Jensen, R. C., Glintborg, D., Gade Timmermann, C. A., Nielsen, F., Kyhl, H. B., Frederiksen, H., Andersson, A-M., Juul, A., Sidelmann, J. J., Andersen, H. R., Grandjean, P., Andersen, M. S. & Jensen, T. K., mar. 2020, I : Environmental Research. 182, s. 109101

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

BACKGROUND: Fetal programming of the endocrine system may be affected by exposure to perfluoroalkyl substances (PFAAs), as they easily cross the placental barrier. In vitro studies suggest that PFAAs may disrupt steroidogenesis. "Mini puberty" refers to a transient surge in circulating androgens, androgen precursors, and gonadotropins in infant girls and boys within the first postnatal months. We hypothesize that prenatal PFAA exposure may decrease the concentrations of androgens in mini puberty.

OBJECTIVES: To investigate associations between maternal serum PFAA concentrations in early pregnancy and serum concentrations of androgens, their precursors, and gonadotropins during mini puberty in infancy.

METHODS: In the prospective Odense Child Cohort, maternal pregnancy serum concentrations of five PFAAs: Perfluorohexane sulfonic acid (PFHxS), perfluorooctane sulfonic acid (PFOS), perfluorooctanoic acid (PFOA), perfluorononanoic acid (PFNA), and perfluorodecanoic acid (PFDA) were measured at median gestational week 12 (IQR: 10, 15) in 1628 women. Among these, offspring serum concentrations of dehydroepiandrosterone (DHEA), dehydroepiandrosterone-sulfate (DHEAS), androstenedione, 17-hydroxyprogesterone (17-OHP), testosterone, luteinizing (LH) and follicle stimulating hormones (FSH) were measured in 373 children (44% girls; 56% boys) at a mean age of 3.9 (±0.9 SD) months. Multivariate linear regression models were performed to estimate associations.

RESULTS: A two-fold increase in maternal PFDA concentration was associated with a reduction in DHEA concentration by -19.6% (95% CI: -32.9%, -3.8%) in girls. In girls, also, the androstenedione and DHEAS concentrations were decreased, albeit non-significantly (p < 0.11), with a two-fold increase in maternal PFDA concentration. In boys, no significant association was found between PFAAs and concentrations of androgens, their precursors, and gonadotropins during mini puberty.

CONCLUSION: Prenatal PFDA exposure was associated with significantly lower serum DHEA concentrations and possibly also with lower androstenedione and DHEAS concentrations in female infants at mini puberty. The clinical significance of these findings remains to be elucidated.

Originalsprog Engelsk
Tidsskrift Environmental Research
Vol/bind 182
Sider (fra-til) 109101
ISSN 0013-9351
DOI
Status Udgivet - mar. 2020

Bibliografisk note

Copyright © 2020 Elsevier Inc. All rights reserved.

PURPOSE: The primary objective was to examine the reliability of the Copenhagen Achilles length measure (CALM) in patients with an Achilles tendon rupture and secondary to examine the reliability of Achilles tendon resting angle (ATRA) and Achilles tendon length measure (ATLM).

METHOD: The study was executed as a cross-sectional study on two different groups: one focused on CALM and the other on ATRA/ATLM. CALM was performed on 56 patients at four timepoints during the first year after injury, whereas ATRA/ATLM were carried out on 28 patients. Intra- and inter-rater reliabilities were determined using the intra-class correlation coefficient (ICC), the standard error of the measurement (SEM), and the minimal detectable change (MDC).

RESULTS: For CALM, all measurements, both for injured and non-injured sides as well as for elongation, indicated excellent relative reliability (ICC ≥ 0.75). During the four timepoints, the inter-rater absolute reliability had an SEM that ranged between 0.3 and 0.8 cm (1-4 SEM%) for injured and non-injured sides and 0.3-0.6 cm (18-29 SEM%) for elongation. On an individual level, the inter-rater absolute reliability had an MDC ranging between 0.8 and 2.2 cm (4-11 MDC%) for injured and non-injured sides and 0.8-1.7 cm (47-81 MDC%) for elongation. In the case of ATRA, relative reliability was excellent (ICC ≥ 0.75), and for ATLM, it was fair to excellent (ICC 0.58-0.79). ATRA presented a lower measurement error than ATLM.

CONCLUSION: Copenhagen Achilles length measure showed excellent relative reliability, but had a significant measurement error at four timepoints the first year following an Achilles tendon rupture.

LEVEL OF EVIDENCE: II.

Originalsprog Engelsk
Tidsskrift Knee surgery, sports traumatology, arthroscopy : official journal of the ESSKA
Vol/bind 28
Udgave nummer 1
Sider (fra-til) 281-290
Antal sider 10
ISSN 0942-2056
DOI
Status Udgivet - jan. 2020

OBJECTIVE: To evaluate the structural effects of weight loss on hip or knee osteoarthritis (OA) and to summarize which structural joint pathologies have been examined and the evidence for the outcome measurement instruments applied.

DESIGN: Based on a pre-specified protocol (available: PROSPERO CRD42017065263), we conducted a systematic search of the bibliographic databases, Medline, Embase and Web of Science identifying longitudinal articles reporting the effects of weight loss on structural imaging outcomes in OA of the hip or knee in people who are overweight or obese.

RESULTS: From 1625 potentially eligible records, 14 articles (from 6 cohorts) were included. 2 cohorts were derived from RCTs. Evaluated pathologies were: articular cartilage (n = 7), joint space width (n = 3), bone marrow lesions (n = 5), synovitis (n = 2), effusion (n = 1), meniscus (n = 3), bone marrow density (n = 1) and infrapatellar fat pad (IPFP; n = 2). Cartilage showed conflicting results when evaluating cartilage thickness by direct thickness measurements. Compositional dGEMRIC and T2 mapping measures in early knee OA showed trends towards reduced cartilage degeneration. Joint space width on conventional radiographs showed no change. Weight loss reduced the size of the IPFP. Synovitis and effusion were not affected. Following weight loss DXA showed bone loss at the hip.

CONCLUSION: We did not find consistent evidence of the effects of weight loss on OA structural pathology in people who are overweight or obese. There is a need to achieve consensus on which structural pathologies and measurements to apply in weight loss and OA research.

Originalsprog Engelsk
Tidsskrift Osteoarthritis and Cartilage
Vol/bind 28
Udgave nummer 1
Sider (fra-til) 10-21
Antal sider 12
ISSN 1063-4584
DOI
Status Udgivet - jan. 2020

Bibliografisk note

Copyright © 2019 Osteoarthritis Research Society International. Published by Elsevier Ltd. All rights reserved.

Published in 2019

A Phase II Trial of Lutikizumab, an Anti-Interleukin-1α/β Dual Variable Domain Immunoglobulin, in Knee Osteoarthritis Patients With Synovitis

Fleischmann, R. M., Bliddal, H., Blanco, F. J., Schnitzer, T. J., Peterfy, C., Chen, S., Wang, L., Feng, S., Conaghan, P. G., Berenbaum, F., Pelletier, J-P., Martel-Pelletier, J., Vaeterlein, O., Kaeley, G. S., Liu, W., Kosloski, M. P., Levy, G., Zhang, L., Medema, J. K. & Levesque, M. C., jul. 2019, I : Arthritis & rheumatology (Hoboken, N.J.). 71, 7, s. 1056-1069 14 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

OBJECTIVE: To assess the efficacy and safety of the anti-interleukin-1α/β (anti-IL-1α/β) dual variable domain immunoglobulin lutikizumab (ABT-981) in patients with knee osteoarthritis (OA) and evidence of synovitis.

METHODS: Patients (n = 350; 347 analyzed) with Kellgren/Lawrence grade 2-3 knee OA and synovitis (determined by magnetic resonance imaging [MRI] or ultrasound) were randomized to receive placebo or lutikizumab 25, 100, or 200 mg subcutaneously every 2 weeks for 50 weeks. The coprimary end points were change from baseline in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) pain score at week 16 and change from baseline in MRI-assessed synovitis at week 26.

RESULTS: The WOMAC pain score at week 16 had improved significantly versus placebo with lutikizumab 100 mg (P = 0.050) but not with the 25 mg or 200 mg doses. Beyond week 16, the WOMAC pain score was reduced in all groups but was not significantly different between lutikizumab-treated and placebo-treated patients. Changes from baseline in MRI-assessed synovitis at week 26 and other key symptom- and most structure-related end points at weeks 26 and 52 were not significantly different between the lutikizumab and placebo groups. Injection site reactions, neutropenia, and discontinuations due to neutropenia were more frequent with lutikizumab versus placebo. Reductions in neutrophil and high-sensitivity C-reactive protein levels plateaued with lutikizumab 100 mg, with further reductions not observed with the 200 mg dose. Immunogenic response to lutikizumab did not meaningfully affect systemic lutikizumab concentrations.

CONCLUSION: The limited improvement in the WOMAC pain score and the lack of synovitis improvement with lutikizumab, together with published results from trials of other IL-1 inhibitors, suggest that IL-1 inhibition is not an effective analgesic/antiinflammatory therapy in most patients with knee OA and associated synovitis.

Originalsprog Engelsk
Tidsskrift Arthritis & rheumatology (Hoboken, N.J.)
Vol/bind 71
Udgave nummer 7
Sider (fra-til) 1056-1069
Antal sider 14
ISSN 2326-5191
DOI
Status Udgivet - jul. 2019

Bibliografisk note

© 2019, American College of Rheumatology.

A portfolio of biologic self-injection devices in rheumatology: how patient involvement in device design can improve treatment experience

van den Bemt, B. J. F., Gettings, L., Domańska, B., Bruggraber, R., Mountian, I. & Kristensen, L. E., dec. 2019, I : Drug Delivery . 26, 1, s. 384-392 9 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Biologic drugs (e.g. anti-tumor necrosis factors) are effective treatments for multiple chronic inflammatory diseases including rheumatoid arthritis, axial spondyloarthritis, and psoriatic arthritis. Administration of biologic drugs is usually via subcutaneous self-injection, which provides many patient benefits compared to infusions including increased flexibility, reduced costs, and reduced caregiver burden. However, it is also associated with challenges such as needle phobia, patient treatment misconceptions and incorrect drug administration, and can be impacted by dexterity problems. Evidence suggests these problems, along with other drug administration challenges (e.g. patient forgetfulness, busy lifestyles, and polypharmacy), can reduce patient adherence to treatment. To combat these challenges, patient feedback has been used to develop a range of self-injection devices, including pre-filled syringes, pre-filled pens, and electronic injection devices. Providing different devices for drug administration gives patients the opportunity to choose a device that addresses the challenges they face as an individual. Research suggests involving patients in medical device development, providing patients with a choice of devices and enrolling individuals in patient support programs can empower patients to take control of their treatment journey. By providing a portfolio of self-injection devices, designed based on patient needs, patient experience will improve, potentially improving adherence and hence, long-term treatment outcomes.

Originalsprog Engelsk
Tidsskrift Drug Delivery
Vol/bind 26
Udgave nummer 1
Sider (fra-til) 384-392
Antal sider 9
ISSN 1071-7544
DOI
Status Udgivet - dec. 2019

A systematic literature review of the relation between iron status/anemia in pregnancy and offspring neurodevelopment

Janbek, J., Sarki, M., Specht, I. O. & Heitmann, B. L., dec. 2019, I : European Journal of Clinical Nutrition. 73, 12, s. 1561-1578 18 s.

Publikation: Bidrag til tidsskriftReviewForskningpeer review

BACKGROUND: The fetal brain starts developing early and animal studies have suggested that iron plays several roles for the development, but results from epidemiological studies investigating associations between gestational iron and offspring neurodevelopment are inconsistent.

OBJECTIVE: To systematically examine results from observational studies and RCTs on gestational iron and offspring neurodevelopment, with focus on the importance of four domains: iron status indicators, exposure timing, neurodevelopmental outcomes, and offspring age.

METHODS: PRISMA guidelines were followed. Embase, PsychInfo, Scopus, and The Cochrane library were searched in September 2017 and February 2018. Overall, 3307 articles were identified and 108 retrieved for full-text assessment. Pre-specified eligibility criteria were used to select studies and 27 articles were included;19 observational and 8 RCTs.

RESULTS: Iron status in pregnancy was associated with offspring behavior, cognition, and academic achievement. The direction of associations with behavioral outcomes were unclear and the conclusions related to cognition and academic achievement were based on few studies, only. Little evidence was found for associations with motor development. Observed associations were shown to persist beyond infancy into adolescence, and results depended on iron status indicator type but not on the timing of exposure.

CONCLUSION: We conclude that there is some evidence that low pregnancy iron, possibly particularly in the 3rd trimester, may be associated with adverse offspring neurodevelopment. As most previous research used Hemoglobin, inferring results to iron deficiency should be done with caution. No conclusions could be reached regarding associations beyond early childhood, and supplementation with iron during pregnancy did not seem to influence offspring neurodevelopment.

Originalsprog Engelsk
Tidsskrift European Journal of Clinical Nutrition
Vol/bind 73
Udgave nummer 12
Sider (fra-til) 1561-1578
Antal sider 18
ISSN 0954-3007
DOI
Status Udgivet - dec. 2019

Adaptive Trial Designs in Rheumatology: Report from the OMERACT Special Interest Group

Pickles, T., Alten, R., Boers, M., Bykerk, V., Christensen, J., Christensen, R., van Hoogstraten, H., Simon, L. S., Tam, L-S. & Choy, E. H., okt. 2019, I : Journal of Rheumatology. 46, 10, s. 1406-1408 3 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

OBJECTIVE: Adaptive trial design was developed initially for oncology to improve trial efficiency. If optimized for rheumatology, it may improve trial efficiency by reducing sample size and time.

METHODS: A systematic review assessed design of phase II clinical trials in rheumatoid arthritis.

RESULTS: Fifty-six trials were reviewed. Most trials had 4 groups (1 control and 3 intervention), with an average group size of 34 patients. American College of Rheumatology 20 measured at 16 weeks was the most commonly used primary endpoint.

CONCLUSION: The next step is to undertake a systematic review of adaptive designs used in early-phase trials in nonrheumatic conditions.

Originalsprog Engelsk
Tidsskrift Journal of Rheumatology
Vol/bind 46
Udgave nummer 10
Sider (fra-til) 1406-1408
Antal sider 3
ISSN 0315-162X
DOI
Status Udgivet - okt. 2019

Added value of combining methotrexate with a biological agent compared to biological monotherapy in rheumatoid arthritis patients: A systematic review and meta-analysis of randomised trials

Tarp, S., Jørgensen, T. S., Furst, D. E., Dossing, A., Taylor, P. C., Choy, E. H., Suarez-Almazor, M. E., Lyddiatt, A., Kristensen, L. E., Bliddal, H. & Christensen, R., jun. 2019, I : Seminars in Arthritis and Rheumatism. 48, 6, s. 958-966 9 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

OBJECTIVES: To assess the efficacy and safety of methotrexate (MTX) in combination with an approved biological agent compared to biological monotherapy, in the management of patients with rheumatoid arthritis (RA).

METHODS: MEDLINE, EMBASE, CENTRAL and other sources were searched for randomised trials evaluating a biological agent plus MTX versus the same biological agent in monotherapy. Co-primary outcomes were ACR50 and the number of patients who discontinued due to adverse events (AEs). Random-effects models were applied for meta-analyses with risk ratio and 95% confidence intervals and the GRADE approach was used to assess confidence in the estimates.

RESULTS: The analysis comprised 16 trials (4965 patients), including all biological agents approved for RA except anakinra and certolizumab. The overall likelihood of responding to therapy (i.e. ACR50) after 6 months was 32% better when MTX was given concomitantly with biological agents (1.32 [1.20-1.45]; P < 0.001) corresponding to 11 more out of 100 patients (7-16 more); Moderate Quality Evidence. Discontinuing due to AEs from concomitant use of MTX was potentially 20% increased (1.21 [0.97-1.50]; P = 0.09) compared to biological monotherapy corresponding to 1 more out of 100 patients (0-3 more); Moderate Quality Evidence.

CONCLUSIONS: Randomised trials provide Moderate Quality Evidence for a favourable benefit-harm balance supporting concomitant use of MTX rather than monotherapy when prescribing a biological agent in patients with RA although in absolute terms only 7-16 more out of 100 patients will achieve an ACR50 response after 6 months of this combination therapy.

Originalsprog Engelsk
Tidsskrift Seminars in Arthritis and Rheumatism
Vol/bind 48
Udgave nummer 6
Sider (fra-til) 958-966
Antal sider 9
ISSN 0049-0172
DOI
Status Udgivet - jun. 2019

Bibliografisk note

Copyright © 2018 Elsevier Inc. All rights reserved.

Adolescent wine consumption is inversely associated with long-term weight gain: results from follow-up of 20 or 22 years

Poudel, P., Ismailova, K., Andersen, L. B., Larsen, S. C. & Heitmann, B. L., 10 sep. 2019, I : Nutrition Journal. 18, 1, s. 56

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

BACKGROUND: Several studies have suggested a link between the type of alcoholic beverage consumption and body weight. However, results from longitudinal studies have been inconsistent, and the association between adolescent alcohol consumption long-term weight gain has generally not been examined.

METHODS: The study was based on data from 720 Danish adolescents aged between 15 to 19 years at baseline from the Danish Youth and Sports Study (YSS). Self-reported alcohol use, height, weight, smoking, social economic status (SES) and physical activity levels were assessed in baseline surveys conducted in 1983 and 1985, and in the follow up survey which was conducted in 2005. Multiple linear regression analyses were used to examine the association between alcohol consumption in adolescence and subsequent weight gain later in midlife.

RESULTS: There was no significant association between total alcohol consumption during adolescence and change in BMI into midlife (P = 0.079) (β - 0.14; 95% CI -0.28, 0.005). Wine consumption was found to be inversely associated to subsequent BMI gain (P = 0.001) (β - 0.46; 95% CI -0.82, - 0.09) while the results were not significant for beer and spirit. The relationship did not differ by gender, but smoking status was found to modify the relationship, and the inverse association between alcohol and BMI gain was seen only among non-smokers (P = 0.01) (β - 0.24; 95% CI -0.41, - 0.06) while no association was found among smokers. Neither adolescent nor attained socioeconomic status in adulthood modified the relationship between alcohol intake and subsequent BMI gain.

CONCLUSION: Among non-smoking adolescents, consumption of alcohol, and in particular wine, seems to be associated with less weight gain until midlife.

TRIAL REGISTRATION: The YSS cohort was retrospectively registered on August 2017. (Study ID number: NCT03244150 ).

Originalsprog Engelsk
Tidsskrift Nutrition Journal
Vol/bind 18
Udgave nummer 1
Sider (fra-til) 56
ISSN 1475-2891
DOI
Status Udgivet - 10 sep. 2019
Originalsprog Engelsk
Artikelnummer P19
Tidsskrift Endocrine Abstracts
Vol/bind 58
Antal sider 1
ISSN 0804-4643
Status Udgivet - 2019

Age at natural menopause and risk of incident cardiovascular disease: a pooled analysis of individual patient data

Zhu, D., Chung, H-F., Dobson, A. J., Pandeya, N., Giles, G. G., Bruinsma, F., Brunner, E. J., Kuh, D., Hardy, R., Avis, N. E., Gold, E. B., Derby, C. A., Matthews, K. A., Cade, J. E., Greenwood, D. C., Demakakos, P., Brown, D. E., Sievert, L. L., Anderson, D., Hayashi, K., Lee, J. S., Mizunuma, H., Tillin, T., Simonsen, M. K., Adami, H-O., Weiderpass, E. & Mishra, G. D., nov. 2019, I : The Lancet Public Health. 4, 11, s. e553-e564

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

BACKGROUND: Early menopause is linked to an increased risk of cardiovascular disease mortality; however, the association between early menopause and incidence and timing of cardiovascular disease is unclear. We aimed to assess the associations between age at natural menopause and incidence and timing of cardiovascular disease.

METHODS: We harmonised and pooled individual-level data from 15 observational studies done across five countries and regions (Australia, Scandinavia, the USA, Japan, and the UK) between 1946 and 2013. Women who had reported their menopause status, age at natural menopause (if postmenopausal), and cardiovascular disease status (including coronary heart disease and stroke) were included. We excluded women who had hysterectomy or oophorectomy and women who did not report their age at menopause. The primary endpoint of this study was the occurrence of first non-fatal cardiovascular disease, defined as a composite outcome of incident coronary heart disease (including heart attack and angina) or stroke (including ischaemic stroke or haemorrhagic stroke). We used Cox proportional hazards models to estimate multivariate hazard ratios (HRs) and 95% CIs for the associations between age at menopause and incident cardiovascular disease event. We also adjusted the model to account for smoking status, menopausal hormone therapy status, body-mass index, and education levels. Age at natural menopause was categorised as premenopausal or perimenopausal, younger than 40 years (premature menopause), 40-44 years (early menopause), 45-49 years (relatively early), 50-51 years (reference category), 52-54 years (relatively late), and 55 years or older (late menopause).

FINDINGS: Overall, 301 438 women were included in our analysis. Of these 301 438 women, 12 962 (4·3%) had a first non-fatal cardiovascular disease event after menopause, of whom 9369 (3·1%) had coronary heart disease and 4338 (1·4%) had strokes. Compared with women who had menopause at age 50-51 years, the risk of cardiovascular disease was higher in women who had premature menopause (age <40 years; HR 1·55, 95% CI 1·38-1·73; p<0·0001), early menopause (age 40-44 years; 1·30, 1·22-1·39; p<0·0001), and relatively early menopause (age 45-49 years; 1·12, 1·07-1·18; p<0·0001), with a significantly reduced risk of cardiovascular disease following menopause after age 51 years (p<0·0001 for trend). The associations persisted in never smokers, and were strongest before age 60 years for women with premature menopause (HR 1·88, 1·62-2·20; p<0·0001) and early menopause (1·40, 1·27-1·54; p<0·0001), but were attenuated at age 60-69 years, with no significant association observed at age 70 years and older.

INTERPRETATION: Compared with women who had menopause at age 50-51 years, women with premature and early menopause had a substantially increased risk of a non-fatal cardiovascular disease event before the age of 60 years, but not after age 70 years. Women with earlier menopause need close monitoring in clinical practice, and age at menopause might also be considered as an important factor in risk stratification of cardiovascular disease for women.

FUNDING: Australian National Health and Medical Research Council.

Originalsprog Engelsk
Tidsskrift The Lancet Public Health
Vol/bind 4
Udgave nummer 11
Sider (fra-til) e553-e564
ISSN 2468-2667
DOI
Status Udgivet - nov. 2019

Bibliografisk note

© 2019 World Health Organization; licensee Elsevier. This is an Open Access article published under the CC BY NC ND 3.0 IGO license which permits users to download and share the article for non-commercial purposes, so long as the article is reproduced in the whole without changes, and provided the original source is properly cited. This article shall not be used or reproduced in association with the promotion of commercial products, services or any entity. There should be no suggestion that WHO endorses any specific organisation, products or services. The use of the WHO logo is not permitted. This notice should be preserved along with the article's original URL.

An acoustic myography functional assessment of cerebral palsy subjects compared to healthy controls during physical exercise

Pingel, J., Andersen, I. T., Broholm, R., Harder, A., Bartels, E. M., Bülow, J. & Harrison, A., mar. 2019, I : Journal of muscle research and cell motility. 40, 1, s. 53-58 6 s.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Individuals with cerebral palsy (CP) participate in reduced levels of physical activity and spend an increased amount of time in a sedentary state compared with healthy control subjects. Whether this in part can be explained by impaired muscle function is still unclear. The aim of the present study was to elucidate differences in muscle fibre recruitment during treadmill exercise between CP subjects and healthy age-, sex- and BMI-matched controls. This is a case-control study. Acoustic myography (AMG), a method recording fibre use and efficiency from contracting muscles, was applied during a period of treadmill exercise. The recorded AMG parameters revealed that the CP subjects had a significantly lower initial S-score (spatial summation) than the controls (P < 0.01). However, the T-score (temporal summation) and the E-score (efficiency) showed no significant differences between individuals with CP and the healthy control subjects. The present findings indicate that CP subjects use a higher degree of spatial summation (more fibres recruited) to keep up the same speed during treadmill exercise when compared to healthy matched control subjects. Our results suggest that individuals with CP have a tendency to recruit far more muscle fibres during bouts of exercise than healthy individuals. This may partly explain why CP subjects experience premature fatigue.

Originalsprog Engelsk
Tidsskrift Journal of muscle research and cell motility
Vol/bind 40
Udgave nummer 1
Sider (fra-til) 53-58
Antal sider 6
ISSN 0142-4319
DOI
Status Udgivet - mar. 2019

Analgesics use and withdrawal in people with dementia - a register-based Danish study and a systematic review

Sørensen, A. M. S., Tarp, S., Johannsen, P., Lolk, A., Bandak, E., Pedersen, H., Saxtrup, N., Kallehauge, H., Solem, E. J. & Christensen, M. B., dec. 2019, I : Danish Medical Journal. 66, 12, s. A5578

Publikation: Bidrag til tidsskriftReviewForskningpeer review

INTRODUCTION: Pain assessment in people with dementia is difficult, and withdrawal of analgesics may allow for assessment of treatment efficacy whilst decreasing pill burden, adverse events and interactions. We aimed to describe the use of analgesics among elderly in Denmark and to compile the evidence for withdrawal of analgesics among people with dementia.

METHODS: With respect to analgesics use, we employed data from national registries on the analgesic prescription use (opioids, nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen) in 2017 among elderly people with and without dementia. Trial evidence was produced by performing a systematic search in MEDLINE, Embase and Cinahl for trials evaluating withdrawal of analgesics in people with dementia.

RESULTS: Opioids were prescribed more frequently (p = 0.026) and NSAIDs less frequently (p = 0.026) to people with dementia. With respect to trial evidence, we identified two studies: An observational cross-over study (n = 3) reporting acetaminophen withdrawal leading to increases in pain frequency and duration, and a cluster-randomised clinical trial (n = 352) reporting changes in mobilization-observation-behaviour-intensity-dementia-2 (MOBID-2) pain score during a four-week withdrawal period (acetaminophen, opioids and/or pregabaline) from a mean ± standard deviation of 2.3 ± 2.1 to 2.9 ± 2.6 compared with 3.5 ± 2.6 to 3.5 ± 2.5 in the control group.

CONCLUSIONS: In Denmark, use of opioids is higher in elderly with dementia compared to elderly without dementia. The evidence suggests that withdrawal of analgesics may aggravate pain but increases in pain scores may be of little clinical relevance in most people. Clinical trials investigating analgesics withdrawal are warranted.

Originalsprog Engelsk
Tidsskrift Danish Medical Journal
Vol/bind 66
Udgave nummer 12
Sider (fra-til) A5578
ISSN 1603-9629
Status Udgivet - dec. 2019

Bibliografisk note

Articles published in the DMJ are “open access”. This means that the articles are distributed under the terms of the Creative Commons Attribution Non-commercial License, which permits any non-commercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.

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