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Objective: The effects of levothyroxine (LT4)/liothyronine (LT3) combination therapy on quality of life (QoL) in hypothyroid patients former on LT4 monotherapy have been disappointing. We therefore wanted to test the effects of LT3 monotherapy on QoL in hypothyroid patients with residual symptoms despite thyroid stimulating hormone (TSH) values within the reference range., Design: Female hypothyroid patients with residual symptoms on LT4 monotherapy or combination LT4/LT3 therapy received LT3 and LT4 monotherapy, respectively for 12 weeks in a non-blinded randomized crossover study., Methods: Fifty-nine patients aged 18-65 years were included. QoL was assessed using one disease-specific questionnaire (ThyPRO) and two generic questionnaires (Fatigue Questionnaire and SF-36) at baseline and at the end of the two treatment periods. Clinical indices of cardiovascular health (resting heart rate and blood pressure), as well as thyroid tests, were assessed at baseline and at the end of the two treatment periods., Results: After 12 weeks of LT3 treatment, 12 of the 13 domains of the ThyPRO questionnaire (physical, mental and social domains) showed significant improvements. The most pronounced improvements were less tiredness (mean -21 ± 26; P <0.0001) and cognitive complaints (mean -20 ± 20; P <0.0001). LT4 monotherapy exerted minor effects on two domains only (cognitive complaints and impaired daily life). All three dimensions' scores in the Fatigue Questionnaire (physical, mental and total fatigue) improved after LT3 treatment compared to baseline ( P <0.001), and in the SF-36 questionnaire 7 of 8 scales showed significantly better scores after LT3 treatment compared to baseline. There were no differences in blood pressure or resting heart rate between the two treatment groups. TSH in patients on LT3 was slightly higher (median 1.33 mU/L (interquartile range (IQR) 0.47-2.26)) than in patients on LT4 (median 0.61 mU/L (IQR 0.25-1.20; P <0.018). Five patients on LT3 dropped out of the study due to subjectively reported side effects, compared to only one on LT4., Conclusions: LT3 treatment improved QoL in women with residual hypothyroid symptoms on LT4 monotherapy or LT4/LT3 combination therapy. Short-term LT3 treatment did not induce biochemical or clinical hyperthyroidism, and no cardiovascular adverse effects were recorded. Further studies are needed to assess the long-term safety and efficacy of LT3 monotherapy., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03627611., Competing Interests: Authors SSH and EFE were employed by Pilestredet Park Specialist Center and LJO was employed by Balderklinikken. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be constructed as a potential conflict of interest., (Copyright © 2022 Bjerkreim, Hammerstad, Gulseth, Berg, Omdal, Lee-Ødegård and Eriksen.)

Background: Randomized controlled trials (RCT) are regarded as the gold standard for effect evaluation in clinical interventions. However, RCTs may not produce relevant results to all patient groups. We aimed to assess the external validity of a multicenter RCT (DelPhi trial)., Methods: The DelPhi RCT investigated whether elderly patients with displaced proximal humeral fractures (PHFs) receiving reversed total shoulder prosthetic replacement (RTSA) gained better functional outcomes compared to open reduction and internal fixation (ORIF) using an proximal humerus locking plate (PHILOS). Eligible patients were between 65 and 85 years old with severely displaced 11-B2 or 11-C2 fractures (AO/OTA-classification, 2007). We compared baseline and follow-up data of patients for two of the seven hospitals that were included in the DelPhi trial (n = 54) with non-included patients (n = 69). Comparisons were made based on reviewing medical records regarding demographic, health and fracture parameters., Results: Forty-four percent of the eligible patients were included in the DelPhi trial. Comparing included and non-included patients indicated higher incidences of serious heart disease (P = 0.044) and a tendency toward higher tobacco intake (P = 0.067) in non-included patients. Furthermore, non-included patients were older (P = 0.040) and had higher ASA classification (P < 0.001) and were in more need for resident aid (in-home assistance) (P = 0.022) than included patients. The cause of PHF was more frequently related to fall indoors in non-included vs. included patients (P = 0.018) and non-included patients were more prone to other concomitant fractures (P = 0.004). Having concomitant fractures was associated with osteoporosis (P = 0.014). We observed no significant differences in rates of complications or deaths between included and non-included patients within 3 months after treatment. In descending order, non-included patients were treated conservatively, with PHILOS, RTSA, anatomic hemi-prothesis or an alternative type of ORIF. RTSA was the preferred treatment choice for C2-type fractures (P < 0.001)., Conclusions: Results from the DelPhi RCT may not directly apply to older PHFs patients with lower health status or concomitant fractures., Level of Evidence: Level 4., (© 2021. The Author(s).)

Background: Thyroid hormones are essential for the full thermogenic response of brown adipose tissue (BAT) and have been implicated in dermal temperature regulation. Nevertheless, persistent cold-intolerance exists among a substantial proportion of hypothyroid patients on adequate levothyroxine (LT4) substitution., Materials and Methods: To assess if skin temperature and activation of BAT during treatment with liothyronine (LT3) differs from that of LT4 treatment, fifty-nine female hypothyroid patients with residual symptoms on LT4 or LT4/LT3 combination therapy were randomly assigned in a non-blinded crossover study to receive monotherapy with LT4 or LT3 for 12 weeks each. Change in supraclavicular (SCV) skin temperature overlying BAT, and sternal skin temperature not overlying BAT, during rest and cold stimulation were assessed by infrared thermography (IRT). In addition, abundance of exosomal miR-92a, a biomarker of BAT activation, was estimated as a secondary outcome., Results: Cold stimulated skin temperatures decreased less with LT3 vs . LT4 in both SCV (mean 0.009°C/min [95% CI: 0.004, 0.014]; P <0.001) and sternal areas (mean 0.014°C/min [95% CI: 0.008, 0.020]; P <0.001). No difference in serum exosomal miR-92a abundance was observed between the two treatment groups., Conclusion: LT3 may reduce dermal heat loss. Thermography data suggested increased BAT activation in hypothyroid patients with cold-intolerance. However, this finding was not corroborated by assessment of the microRNA biomarker of BAT activation., Clinical Trial Registration: ClinicalTrials.gov, identifier NCT03627611., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Bjerkreim, Hammerstad, Gulseth, Berg, Lee-Ødegård, Rangberg, Jonassen, Budge, Morris, Law, Symonds and Eriksen.)

Pregnancy is a valuable model to study the association between DNA methylation and several cardiometabolic traits, due to its direct potential to influence mother's and child's health. Epigenetics in Pregnancy (EPIPREG) is a population-based sample with the aim to study associations between DNA-methylation in pregnancy and cardiometabolic traits in South Asian and European pregnant women and their offspring. This cohort profile paper aims to present our sample with genetic and epigenetic data and invite researchers with similar cohorts to collaborative projects, such as replication of ours or their results and meta-analysis. In EPIPREG we have quantified epigenome-wide DNA methylation in maternal peripheral blood leukocytes in gestational week 28±1 in Europeans (n = 312) and South Asians (n = 168) that participated in the population-based cohort STORK Groruddalen, in Norway. DNA methylation was measured with Infinium MethylationEPIC BeadChip (850k sites), with technical validation of four CpG sites using bisulphite pyrosequencing in a subset (n = 30). The sample is well characterized with few missing data on e.g. genotype, universal screening for gestational diabetes, objectively measured physical activity, bioelectrical impedance, anthropometrics, biochemical measurements, and a biobank with maternal serum and plasma, urine, placenta tissue. In the offspring, we have repeated ultrasounds during pregnancy, cord blood, and anthropometrics up to 4 years of age. We have quantified DNA methylation in peripheral blood leukocytes in nearly all eligible women from the STORK Groruddalen study, to minimize the risk of selection bias. Genetic principal components distinctly separated Europeans and South Asian women, which fully corresponded with the self-reported ethnicity. Technical validation of 4 CpG sites from the methylation bead chip showed good agreement with bisulfite pyrosequencing. We plan to study associations between DNA methylation and cardiometabolic traits and outcomes., Competing Interests: The authors have declared that no competing interests exist.

Background: Epigenetic clocks have been recognized for their precise prediction of chronological age, age-related diseases, and all-cause mortality. Existing epigenetic clocks are based on CpGs from the Illumina HumanMethylation450 BeadChip (450 K) which has now been replaced by the latest platform, Illumina MethylationEPIC BeadChip (EPIC). Thus, it remains unclear to what extent EPIC contributes to increased precision and accuracy in the prediction of chronological age., Results: We developed three blood-based epigenetic clocks for human adults using EPIC-based DNA methylation (DNAm) data from the Norwegian Mother, Father and Child Cohort Study (MoBa) and the Gene Expression Omnibus (GEO) public repository: 1) an Adult Blood-based EPIC Clock (ABEC) trained on DNAm data from MoBa (n = 1592, age-span: 19 to 59 years), 2) an extended ABEC (eABEC) trained on DNAm data from MoBa and GEO (n = 2227, age-span: 18 to 88 years), and 3) a common ABEC (cABEC) trained on the same training set as eABEC but restricted to CpGs common to 450 K and EPIC. Our clocks showed high precision (Pearson correlation between chronological and epigenetic age (r) > 0.94) in independent cohorts, including GSE111165 (n = 15), GSE115278 (n = 108), GSE132203 (n = 795), and the Epigenetics in Pregnancy (EPIPREG) study of the STORK Groruddalen Cohort (n = 470). This high precision is unlikely due to the use of EPIC, but rather due to the large sample size of the training set., Conclusions: Our ABECs predicted adults' chronological age precisely in independent cohorts. As EPIC is now the dominant platform for measuring DNAm, these clocks will be useful in further predictions of chronological age, age-related diseases, and mortality.

Objective: The aim of this study was to assess if any of the different types of radiographic damage [true joint space narrowing (JSN), (sub)luxation and erosions] are preferentially related to disability in patients with RA., Methods: Longitudinal data from 167 RA patients from the European Research on Incapacitating Diseases and Social Support study over 10 years were analysed to investigate the relationship between the three types of radiographic damage and disability [grip strength, HAQ and the dexterity scale in the Arthritis Impact Measurement Scales (AIMS)]. A longitudinal analysis including separate models per type of damage and joint group and combined models including all information was conducted., Results: All types of damage were inversely related to grip strength in the analysis of separate models, but only true JSN independently remained statistically significant in the combined analysis [β = -0.087 (95% CI -0.151, -0.022)]. Neither JSN, (sub)luxation nor erosions were associated with HAQ score, while erosions were associated with AIMS dexterity only in the analysis of separate models. After stratifying for hand joint group, erosions at MCP joints [β = -0.288 (95% CI -0.556, -0.019)] and true JSN at the wrist [β = -0.132 (95% CI -0.234, -0.030)] were significantly related to grip strength. Erosions at the PIP [β = 0.017 (95% CI 0.005, 0.028)] and MCP joints [β = 0.114 (95% CI 0.010, 0.217)] was the only type of damage associated with HAQ and AIMS dexterity, respectively., Conclusion: All types of radiographically visible joint damage interfere with important aspects of physical functions. True JSN is most closely related to hand function., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Background: Several epidemiological studies on the association between primary headaches and insomnia have been published in recent years. Both disorders are frequent, and our purpose was to review results from population-based studies exploring this association., Methods: We performed a literature search in PubMed for "insomnia" (or sleep disturbance) and "headache" (or migraine) linked with "epidemiology." Two hundred and eight records were identified. Three longitudinal and 10 cross-sectional studies met our inclusion criteria: population-based design with at least 200 participants including a numerical estimate of the association between headache and insomnia., Results and Conclusions: In nearly all studies, primary headaches, including migraine and tension-type headache, were significantly related to insomnia symptoms with OR estimates ranging from 1.4 to 1.7. The odds were even greater, from 2.0 to 2.6, for frequent, comorbid or severe headache. Recent large longitudinal studies from Norway found a bidirectional, possibly causal, association between headache and insomnia. However, not all studies used standardized diagnostic criteria for either headache or insomnia. Further research should use well defined and validated diagnostic criteria both for insomnia and headache types in order to improve the comparability between studies, investigate causality and clarify the relevance of the findings for clinical practice., (© International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav.)

Background: Rheumatoid arthritis (RA) is a chronic, inflammatory and systemic disease which affects the musculoskeletal system. Exercise programmes are reported to improve physical functioning in patients with RA. Tai Chi is a traditional Chinese martial art which combines slow and gentle movements with mental focus. The purpose of this study was to study in which way Tai Chi group exercise impacted on disease activity, physical function, health status and experience in RA patients, applying quantitative and qualitative methods., Methods: Fifteen patients with RA (13 females, age 33-70 years) were recruited from a rheumatology department into a single group study. The patients were instructed in Tai Chi exercise twice weekly for 12 weeks. Assessments at baseline, 12 weeks, and 12 weeks follow-up were performed with a wide range of measures, including disease activity, self-reported health status, physical performance tests (Walking in Figure of Eight, Timed-Stands Test, and Shoulder Movement Impairment Scale). Qualitative data were obtained from a focus group interview conducted after completed intervention with taping and verbatim transcription. Review of the transcripts identified themes important to patients practicing Tai Chi., Results: Within the group, Tai Chi practice lead to improved lower-limb muscle function at the end of intervention and at 12 weeks follow-up. Qualitative analyses showed that patients experienced improved physical condition, confidence in moving, balance and less pain during exercise and in daily life. Other experience included stress reduction, increased body awareness, confidence in moving and indicated that Tai Chi was a feasible exercise modality in RA., Conclusions: Improved muscle function in lower limbs was also reflected when patient experiences with Tai Chi were studied in depth in this explorative study. The combination of qualitative and quantitative research methods shows that Tai Chi has beneficial effects on health not related to disease activity and standardised health status assessment, and may contribute to an understanding of how Tai Chi exerts its effects., Trial Registration: NCT00522054.

Many rheumatic diseases, including rheumatoid arthritis (RA) are more frequent in females than males. The objective of this article was to examine the female versus male perspective regarding prevalence/incidence, etiological factors, disease severity/outcomes, access to therapy and therapeutic responses. We also present results from some new analyses from the patient registers in Oslo to supplement existing literature in this area. We found that the prevalence of RA is higher in females than males, the incidence is 4-5 times higher below the age of 50, but above 60-70 years the female/male ratio is only about 2. Smoking is a consistent predictor of RA in males, but findings have been more inconsistent in females. We could not confirm that health status is worse in females than males when corrections were made for different disease duration and for the underlying tendency of healthy females to report worse subjective health status than males. Some studies and data presented here indicate that females have less access to health services. We also found that female sex reduces the likelihood of achieving treatment response with methotrexate and anti-tumor necrosis factor (anti-TNF) drugs by 30-50%. More research is needed to fully describe the differences between males and females regarding epidemiological data.

Objective: The purpose of this study is to examine positive affect (PA) as a factor of resilience in the relationships between pain and negative affect (NA) in a sample of patients with rheumatoid arthritis., Methods: Forty-three patients (30 women; mean age, 57 years) were interviewed weekly by telephone for 8 weeks. Multilevel modeling was applied to study the within-week relationships among the variables., Results: There was a Pain x PA interaction effect on NA (beta=-0.05, P<.01) indicating a weaker relationship between pain and NA in weeks with more PA. Pain (beta=0.37, P<.002), interpersonal stress (beta=2.42, P<.001), depression (beta=0.26, P<.01), average perceived stress (beta=10.80, P<.001), and also weekly PA (beta=-0.1, P<.01) had a main effect upon NA., Conclusion: Positive affect is most influential in reducing NA during weeks of higher pain and may be a factor of resilience, helping patients experiencing pain fluctuations as less distressful than at lower levels of PA.