Epigenome-wide association study of DNA methylation in maternal blood leukocytes with BMI in pregnancy and gestational weight gain.

OBJECTIVES: We aimed to discover CpG sites with differential DNA methylation in peripheral blood leukocytes associated with body mass index (BMI) in pregnancy and gestational weight gain (GWG) in women of European and South Asian ancestry. Furthermore, we aimed to investigate how the identified sites were associated with methylation quantitative trait loci, gene ontology, and cardiometabolic parameters. METHODS: In the Epigenetics in pregnancy (EPIPREG) sample we quantified maternal DNA methylation in peripheral blood leukocytes in gestational week 28 with Illumina's MethylationEPIC BeadChip. In women with European (n = 303) and South Asian (n = 164) ancestry, we performed an epigenome-wide association study of BMI in gestational week 28 and GWG between gestational weeks 15 and 28 using a meta-analysis approach. Replication was performed in the Norwegian Mother, Father, and Child Cohort Study, the Study of Assisted Reproductive Technologies (MoBa-START) (n = 877, mainly European/Norwegian). RESULTS: We identified one CpG site significantly associated with GWG (p 5.8 × 10-8) and five CpG sites associated with BMI at gestational week 28 (p from 4.0 × 10-8 to 2.1 × 10-10). Of these, we were able to replicate three in MoBa-START; cg02786370, cg19758958 and cg10472537. Two sites are located in genes previously associated with blood pressure and BMI. DNA methylation at the three replicated CpG sites were associated with levels of blood pressure, lipids and glucose in EPIPREG (p from 1.2 × 10-8 to 0.04). CONCLUSIONS: We identified five CpG sites associated with BMI at gestational week 28, and one with GWG. Three of the sites were replicated in an independent cohort. Several genetic variants were associated with DNA methylation at cg02786379 and cg16733643 suggesting a genetic component influencing differential methylation. The identified CpG sites were associated with cardiometabolic traits. GOV REGISTRATION NO: Not applicable.

Headache and insomnia in population-based epidemiological studies.

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.

Prediction of radiographic progression in rheumatoid arthritis and the role of antibodies against mutated citrullinated vimentin: results from a 10-year prospective study.

OBJECTIVES: Anti-citrullinated peptide antibodies (ACPAs) are established as useful predictors of radiographic progression in rheumatoid arthritis (RA). The main objective of this study was to test the prognostic capacity of the recently developed test for anti-mutated citrullinated vimentin (anti-MCV). METHODS: A cohort of 238 patients with RA was followed longitudinally for 10 years; 125 patients with complete x ray sets were included in the main analyses. Radiographs were scored according to the van der Heijde modified Sharp score (SHS). Patients were analysed for anti-MCV and anti-cyclic citrullinated peptide (CCP), and were genotyped for human leukocyte antigen (HLA)-DRB1 "shared epitope" (SE) and protein tyrosine phosphatase, non-receptor type 22 (PTPN22) 1858T. RESULTS: Anti-MCV and anti-CCP were strongly associated with regard to status and level. Both antibodies were associated with SE, but only anti-MCV was significantly associated with PTPN22 1858T. A positive anti-MCV test increased the odds of radiographic progression by 7.3 (95% confidence interval (CI) 3.2 to 16.5) compared to 5.7 (95% CI 2.6 to 12.5) for a positive anti-CCP. Presence of MCV antibodies gave an average increase in the total SHS of 30 U compared to an average increase of 25 U for the presence of CCP antibodies. Anti-MCVs were more strongly associated to progression in erosions than joint space narrowing. Associations remained after adjustment for other predictors of radiographic progression. The odds of progression increased with increasing anti-MCV level. CONCLUSIONS: Presence of anti-MCV predicted joint damage, and the strength of this prediction was at least as strong as for anti-CCP. Antibody status showed a stronger association to bone than to cartilage destruction. This study also indicates that higher anti-MCV levels add prognostic information compared to their mere presence or absence.

Calprotectin (a major S100 leucocyte protein) predicts 10-year radiographic progression in patients with rheumatoid arthritis.

BACKGROUND: Plasma levels of calprotectin, a major S100 leucocyte protein, are cross-sectionally associated with clinical and laboratory markers of inflammation and with radiographic damage in rheumatoid arthritis (RA). High amounts of calprotectin are found in synovial fluid from patients with RA. OBJECTIVE: To examine whether calprotectin might be an independent predictor of joint destruction over time. METHODS: 124 patients with RA were assessed at baseline and after 10 years with inflammatory markers (calprotectin, C-reactive protein (CRP), erythrocyte sedimentation rate (ESR)), serological variables (antibodies to cyclic citrullinated peptide (anti-CCP), IgA rheumatoid factor (RF) and IgM RF) and radiographic and clinical assessments of joint damage (hand radiographs and Rheumatoid Arthritis Articular Damage (RAAD) score). Progression of radiographic damage was assessed according to the van der Heijde modified Sharp score. RESULTS: At both examinations the highest calprotectin levels were found in patients positive for anti-CCP, IgA and IgM RF. Calprotectin had moderate to good correlations with inflammatory and serological markers (r = 0.41-0.67). Patients with normal baseline calprotectin levels had a lower degree of joint damage. High univariate associations were found between baseline calprotectin levels and progression in the Sharp score as well as the RAAD score. Baseline calprotectin was independently associated with progression in the Sharp score and with the RAAD score in multiple linear regression analyses, including baseline levels of CRP, ESR, anti-CCP in addition to demographic variables. CONCLUSION: Calprotectin was an independent predictor of clinical and radiographic joint damage after 10 years. These findings support the proposal that calprotectin may be a prognostic biomarker for erosive disease in patients with RA.

Improving quality by introducing enhanced recovery after surgery in a gynaecological department: consequences for ward nursing practice.

INTRODUCTION: Enhanced Recovery After Surgery (ERAS) is a perioperative treatment protocol that can improve individual recovery. This allows patients to leave hospital earlier, implying a cost reduction. The programme seems to spread slowly. ERAS was introduced at the Department of Obstetrics and Gynaecology at Akershus University Hospital in 2005. The objective of this study was to monitor changes in the workload and work environment of the ward nursing staff when ERAS was introduced at the department. METHODS: A pre-postintervention prospective design was used. Triangulated data were collected immediately before introduction (Phase 1), soon after (Phase 2), and 1 year after introduction (Phase 3). Data sources in all phases were registrations of time spent caring for individual patients during their stay, personnel survey responses and verbal interviews with informants from different staff groups. Patients were included consecutively, the aim being to include a minimum of 40 per phase. RESULTS: Time registration showed that during the observation period, there was a 28% reduction in mean length of stay (-1.3 days, 95% CI -1.63 to -0.97, p<0.001) and 39% reduction in total time used in nursing activities per stay (-162 min, 95% CI -239.3 to -84.4, p<0.001). The personnel survey had a 100% response rate and presented few changes other than decreasing workload. The interview data from four informants described a successful change. CONCLUSION: The findings confirmed the successful introduction of ERAS in the gynaecological department of a large university hospital. The experiences we made indicate that the expected gains of implementing ERAS are achieved without compromising the workload or work environment of ward nursing staff.

Cortical hand bone loss after 1 year in early rheumatoid arthritis predicts radiographic hand joint damage at 5-year and 10-year follow-up.

OBJECTIVE: To examine 1-year hand bone loss in early rheumatoid arthritis (RA) as a predictor of radiographic damage at 5-year and 10-year follow-up METHODS: A total of 136 patients with RA (disease duration 0-4 years) were followed for 10 years with clinical data and hand radiographs. Joint damage was scored according to the van der Heijde modification of the Sharp method (vdH Sharp score) and hand bone mineral density (BMD) was measured by digital x ray radiogrammetry (DXR). Group comparisons, correlation analyses and multivariate analyses were performed to evaluate the relationship between hand bone loss and radiographic joint damage. RESULTS: Patients with hand BMD loss at 1 year had a higher median increase in vdH Sharp score compared to patients without loss at 5 years (12 vs 2, p = 0.001) and 10 years (22 vs 4, p = 0.002). In a linear regression model adjusting for age, gender, baseline C-reactive protein (CRP), anti-cyclic citrullinated peptide (CCP), IgM rheumatoid factor (RF) and radiographic damage, absolute hand DXR-BMD loss at 1 year was an independent predictor of radiographic outcome at 5 years (p<0.01) and 10 years (p = 0.02). In a logistic regression model the odds ratio (95% CI) for radiographic progression among patients with hand BMD loss was 3.5 (1.4 to 8.8) and 3.5 (1.4 to 8.4) at 5 and 10 years, respectively. CONCLUSION: Early hand bone loss measured by DXR-BMD is an independent predictor of subsequent radiographic damage. Our findings support that quantitative hand bone loss in RA precedes radiographic joint damage and may be used as a tool for assessment of bone involvement in RA.

Serum IgG antibodies to peptidylarginine deiminase 4 in rheumatoid arthritis and associations with disease severity.

BACKGROUND: Antibodies targeting citrullinated antigens are specific for rheumatoid arthritis (RA). Citrullination is catalysed by the peptidylarginine deiminase (PAD) enzyme family. Critical enzymes are often targeted by disease-specific antibodies in complex immune-mediated diseases. Here, we have tested for autoantibodies against human recombinant PAD4 (hPAD4) in Caucasian RA patients. METHODS: A time-resolved fluorometric immunoassay based on hPAD4 was developed to analyse sera from two RA cohorts (n = 237 and n = 177), one systemic lupus erythaematosus (SLE) cohort (n = 84) and 148 healthy controls. Simple and multiple analyses were performed to examine possible associations between anti-hPAD4 and disease variables. RESULTS: Raised levels of anti-hPAD4 IgG were found in both RA cohorts compared to the controls, and 23% of the RA patients were anti-hPAD4 IgG positive. Anti-hPAD4 was associated with anti-cyclic citrullinated peptide (CCP) and rheumatoid factor (RF), as well as increased physical disability. Anti-hPAD4 was also associated with higher longitudinal radiographic damage scores and increased clinical joint pathology, but weaker than anti-CCP. No associations were found between anti-hPAD4 and selected Human leukocyte antigen (HLA)-DRB1 variants. CONCLUSIONS: Approximately 23% of Caucasian RA patients have serum IgG antibodies against hPAD4. The presence of serum anti-hPAD4 IgG was in simple analyses associated with a more severe disease phenotype, and the association with physical disability was maintained in multiple analyses.

High anti-cyclic citrullinated peptide levels and an algorithm of four variables predict radiographic progression in patients with rheumatoid arthritis: results from a 10-year longitudinal study.

OBJECTIVES: New effective therapies with particularly good effect on joint destruction have highlighted the need for reliable predictors of radiographic progression in rheumatoid arthritis (RA). Our objective was to assess the combined predictive role of a set of laboratory markers with regard to 10-year radiographic progression, and to examine the effect of anti-cyclic citrullinated peptide (anti-CCP) level. METHODS: A cohort of 238 patients with RA was followed longitudinally for 10 years with the collection of clinical data and serum samples. 125 patients with radiographs of the hands available at both baseline and after 10 years were included in this study. Radiographs were scored according to the van der Heijde modified Sharp score. Baseline sera were analysed for C-reactive protein, erythrocyte sedimentation rate (ESR), anti-CCP, IgA rheumatoid factor (RF) and IgM RF. Logistic regression analyses were used to identify predictors of radiographic progression and to examine the effect of anti-CCP level. RESULTS: Anti-CCP (OR 4.0; 95% CI 1.6 to 10.0) was the strongest independent predictor of radiographic progression. Female gender (OR 3.3; 95% CI 1.3 to 7.6), high ESR (OR 3.2; 95% CI 1.2 to 7.6) and a positive IgM RF (OR 3.1; 95% CI 1.2 to 7.9) were also independent predictors. Compared with the anti-CCP-negative patients, patients with low to moderate levels of anti-CCP (OR 2.6; 95% CI 0.9 to 7.2) and patients with high levels of anti-CCP (OR 9.9; 95% CI 2.7 to 36.7) were more likely to develop radiographic progression. CONCLUSIONS: Anti-CCP, IgM RF, ESR and female gender were independent predictors of radiographic progression and could be combined into an algorithm for better prediction. Patients with high levels of anti-CCP were especially prone to radiographic progression, indicating that the anti-CCP level may add prognostic information.

Work disability in rheumatoid arthritis is predicted by physical and psychological health status: a 7-year study from the Oslo RA register.

OBJECTIVE: To explore the prevalence of work disability (WD) and to identify bio-psychological factors that predicts future WD in rheumatoid arthritis (RA) over a 7-year period. METHODS: Patients were selected from the Oslo RA register. The prevalence of WD was studied cross-sectionally among respondents <67 years (n = 526) in a postal survey. Mean age (SD) was 51.1 (11.9) years, mean disease duration 11.3 (9.4) years, and 49% of patients were RF-positive. The patients studied for predictive factors for WD were respondents in postal surveys both at baseline and at the 7-year follow-up, in work at baseline and still in working age (<67 years) at follow-up (n = 159). Mean age at baseline (SD) was 44.5 (9.7) years, mean disease duration 8.4 (6.6) years, mean years of formal education 12.7 (3.1) years, 48% were RF-positive. Assessments included socio-demographic variables and health status measures (MHAQ, AIMS2, SF-36, fatigue and pain on VAS 0-100 mm, self efficacy, and RAI as a measure for helplessness). RESULTS: Among the 526 respondents at baseline <67 years, the prevalence of WD was 40%. A high level of education was a predictor of reduced risk of work disability [odds ratio (OR) = 0.4, 95% confidence interval (CI) 0.1; 0.9], while female gender (OR 3.0, 95% CI 1.1; 8.0), physical disability (MHAQ-score) (OR = 3.9, 95% CI 1.2; 12.5) and helplessness over median RAI-score (OR = 3.0, 95% CI 1.4; 6.7) were independent predictors of increased risk for new work disability over 7 years. CONCLUSION: Physical disability, increased helplessness, low formal education, and female gender were found to be independent risk factors for new work disability over the 7-year study period.

Conversion electron cascades in 254(102)No.

The spectrum of prompt conversion electrons emitted by excited 254No nuclei has been measured, revealing discrete lines arising from transitions within the ground state band. A striking feature is a broad distribution that peaks near 100 keV and comprises high multiplicity electron cascades, probably originating from M1 transitions within rotational bands built on high K states.

Evidence for second-phonon nuclear wobbling.

The nucleus 163Lu has been populated through the reaction 139La(29Si,5n) with a beam energy of 157 MeV. Three triaxial, strongly deformed (TSD) bands have been observed with very similar rotational properties. The first excited TSD band has earlier been assigned as a one-phonon wobbling excitation built on the lowest-lying (yrast) TSD band. The large B(E2)(out)/B(E2)(in) value obtainable for one of four observed transitions between the second and first excited TSD bands is in good agreement with particle-rotor calculations for a two-phonon wobbling excitation.

Evidence for the wobbling mode in nuclei.

The nucleus (163)Lu has been populated through the fusion-evaporation reaction (139)La((29)Si,5n)(163)Lu with a beam energy of 152 MeV. The electromagnetic properties of several connecting transitions between two presumably triaxial, strongly deformed (TSD) bands have been studied. Evidence is presented for the assignment of the excited TSD band as a wobbling mode built on the yrast TSD band, based on comparisons to new calculations in which an aligned particle is coupled to a strongly deformed triaxial rotor. The wobbling mode is uniquely related to triaxiality in nuclei.

Knowledge of diabetes among personnel in home-based care: how does it relate to medical mishaps?

OBJECTIVE: To assess the influence of knowledge about diabetes on the performance of diabetes care for the elderly involving insulin treatment, with special attention to aspects of patient safety in home care. DESIGN: A questionnaire was administered to nurse's aides and assistant nurses (n = 3144). Answers to questions about knowledge of diabetes were related to "relevant" or "risky measures" as judged from a hypothetical diabetes case. A 94% response rate was obtained. The study took place in January 1997 in 15 of Sweden's 289 municipalities. RESULTS: Insufficient theoretical knowledge about how the blood sugar is related to an insulin reaction led to an almost threefold increased risk of taking a "risky measure". Insufficient knowledge about reasons for an insulin reaction also resulted in a higher risk, as was the case for personnel working in home based care in contrast to those working solely in Institutional care. In addition, the risk that a nurse's aide would take a "risky measure" was higher than that for an assistant nurse. This may indicate that the basic theoretical knowledge of nurse's aides is inadequate. CONCLUSION: Deficiencies in basic knowledge of diabetes among nurse's aides and assistant nurses constitute a major cause of potentially serious mishaps in home care of elderly diabetic patients treated with insulin.

[Health care safety should be focused on prevention. Lessons to be learned from aviation, nuclear power plants and offshore industries]. / Säkerheten i vården bör fokusera på prevention. Lär av flyget, kärnkraftsverken och offshore-industrin!

In many respects the approach to questions of safety adopted in the aviation, nuclear energy and offshore oil industries is highly relevant to safety in the health care sector, even where legislation is concerned. Characteristic features are the emphasis on risk-factor identification, and such demands as risk analysis, knowledge checks, and the limitation of working hours. In addition, there is a need of disaster inquiries in cases of serious incidents, and of an organisation specifically responsible for safety issues. Regarding the development of an incident report system for use in health care, the importance of which increases with the risks involved, a commendable model is the risk report system adopted by civil aviation authorities in the USA, where those submitting reports are guaranteed immunity.

[[The Swedish lex Maria--then and now. Injuries in health care in a historic perspective]. / Den svenska lex Maria--då och nu. Skador i vården i ett historiskt perspektiv.

The Swedish system concerning injuries in the health care sector has its origin in an incident 1936 at the Maria hospital in Stockholm. Four patients died following injection of mercury oxycyanide instead of a local anaesthetic. The first law in 1937 focused on disciplinary actions with prescribed duties to report patient injuries both to the National Board of Health and Welfare and the local police. The regulations, often called lex Maria, have changed during the past 60 years. It is now stressed, beside the punitive aspects, that also incidents not causing injuries should be reported, that organisational factors should be considered in the evaluations of incidents and that a main aspect of the system is prevention.