Early-life stress and amyloidosis in mice share pathogenic pathways involving synaptic mitochondria and lipid metabolism

Introduction: Early-life stress (ES) increases the risk for Alzheimer's disease (AD). We and others have shown that ES aggravates amyloid-beta (Aβ) pathology and promotes cognitive dysfunction in APP/PS1 mice, but underlying mechanisms remain unclear.Methods: We studied how ES affects the hippocampal synaptic proteome in wild-type (WT) and APP/PS1 mice at early and late pathological stages, and validated hits using electron microscopy and immunofluorescence.Results: The hippocampal synaptosomes of both ES-exposed WT and early-stage APP/PS1 mice showed a relative decrease in actin dynamics-related proteins and a relative increase in mitochondrial proteins. ES had minimal effects on older WT mice, while strongly affecting the synaptic proteome of advanced stage APP/PS1 mice, particularly the expression of astrocytic and mitochondrial proteins.Discussion: Our data show that ES and amyloidosis share pathogenic pathways involving synaptic mitochondrial dysfunction and lipid metabolism, which may underlie the observed impact of ES on the trajectory of AD

Quality of care in rheumatology. Translating evidence into practice

Contains fulltext : 160313.pdf (publisher's version ) (Open Access)3 oktober 2016Promotores : Hulscher, M.E.J.L., Vollenhoven, R.F. van Co-promotor : Broeder, A.A. de

Practice what you preach? An exploratory multilevel study on rheumatoid arthritis guideline adherence by rheumatologists

Contains fulltext : 171223.pdf (publisher's version ) (Open Access)OBJECTIVES: To assess variation in and determinants of rheumatologist guideline adherence in patients with rheumatoid arthritis (RA), in daily practice. METHODS: In this retrospective observational study, guideline adherence in the first year of treatment was assessed for 7 predefined parameters on diagnostics, treatment and follow-up in all adult patients with RA with a first outpatient clinic visit at the study centre, from September 2009 to March 2011. Variation in guideline adherence was assessed on parameter and rheumatologist level. Determinants for guideline adherence were assessed in patients (demographic characteristics, rheumatoid factor (RF) and/or anti-cyclic citrullinated peptide antibody (aCCP) positivity, erythrocyte sedimentation rate, erosive disease, comorbidity and the number of available disease modifying anti-rheumatic drug (DMARD) treatment options) and rheumatologists (demographic and practice characteristics, guideline knowledge and agreement, outcome expectancy, cognitive bias, thinking style, numeracy and personality). RESULTS: A total of 994 visits in 137 patients with RA were reviewed. Variation in guideline adherence among parameters was present (adherence between 21% and 72%), with referral to the physician assistant as lowest scoring and referral to a specialised nurse as highest scoring parameter. Variation in guideline adherence among rheumatologists was also present (adherence between 22% and 100%). Patient sex, the number of DMARD options, presence of erosions, comorbidity, RF/aCCP positivity, type of patient and the rheumatologists' scientific education status were associated with adherence to 1 or more guideline parameters. CONCLUSIONS: Guideline adherence varied considerably among the guideline parameters and rheumatologists, showing that there is room for improvement. Guideline adherence in our sample was related to several patient and rheumatologist determinants

Choosing wisely in daily practice: a mixed methods study on determinants of antinuclear antibody testing by rheumatologists

Item does not contain fulltextOBJECTIVES: To explore the relationship between antinuclear antibody (ANA) overuse and rheumatologist-related factors before and after an intervention aimed at reducing ANA overuse. METHOD: In this mixed methods study we performed surveys among rheumatologists (n = 20) before and after the ANA intervention (education and feedback). We identified clinician-related determinants of ANA overuse (demographic characteristics, cognitive bias, numeracy, personality, thinking styles, and knowledge) by multivariate analysis. Two focus group meetings with rheumatologists were held 6 months after the intervention to explore self-reported determinants. RESULTS: Questionnaires were completed by all rheumatologists and eight participated in the focus groups. Rheumatologists with more work experience and a less extravert personality ordered more ANA tests before the intervention [beta = 0.01, 95% confidence interval (CI) 0.003 to 0.02, p = 0.01 and beta = -0.11, 95% CI -0.21 to -0.01, p = 0.04, respectively; R2 = 47%]. After the intervention, female rheumatologists changed less than their male colleagues with regard to the number of ANA tests ordered (beta = 0.15, 95% CI 0.03-0.26, p = 0.02; R2 = 25%). During the focus groups, seven themes were identified that influenced improvement in ANA overuse: determinants related to the intervention and the study, individual health professionals, patients, professional interactions, incentives and resources, capacity for organizational change, and social, political, and legal factors. CONCLUSIONS: We identified several determinants that together explained a sizable part of the variance observed in the ANA outcomes at baseline and in the change in ANA outcomes afterwards. Furthermore, the focus groups yielded additional factors suggesting a complex interplay of determinants influencing rheumatologists' ANA ordering behaviour

The effects of an educational meeting and subsequent computer reminders on the ordering of laboratory tests by rheumatologists: an interrupted time series analysis

Item does not contain fulltextOBJECTIVES: To examine the effects of an educational meeting and subsequent computer reminders on the number of ordered laboratory tests. METHODS: Using interrupted time series analysis we assessed whether trends in the number of laboratory tests ordered by rheumatologists between September 2012 and September 2015 at the Sint Maartenskliniek (the Netherlands) changed following an educational meeting (September 2013) and the introduction of computer reminders into the Computerised Physician Order Entry System (July 2014). The analyses were done for the set of tests on which both interventions had focussed (intervention tests; complement, cryoglobulins, immunoglobins, myeloma protein) and a set of control tests unrelated to the interventions (alanine transferase, anti-cyclic citrullinated peptide, C-reactive protein, creatine, haemoglobin, leukocytes, mean corpuscular volume, rheumatoid factor and thrombocytes). RESULTS: At the start of the study, 101 intervention tests and 7660 control tests were ordered per month by the rheumatologists. After the educational meeting, both the level and trend of ordered intervention and control tests did not change significantly. After implementation of the reminders, the level of ordered intervention tests decreased by 85.0 tests (95%-CI -133.3 to -36.8, p<0.01), the level of control tests did not change following the introduction of reminders. CONCLUSIONS: In summary, an educational meeting alone was not effective in decreasing the number of ordered intervention tests, but the combination with computer reminders did result in a large decrease of those tests. Therefore, we recommend using computer reminders in addition to education if reduction of inappropriate test use is aimed for

Rheumatologists' guideline adherence in rheumatoid arthritis: a randomised controlled study on electronic decision support, education and feedback

Item does not contain fulltextOBJECTIVES: To assess the effects of education, feedback and a computerised decision support system (CDSS) versus education and feedback alone on rheumatologists' rheumatoid arthritis (RA) guideline adherence. METHODS: A single-centre, randomised controlled pilot study was performed among clinicians (rheumatologists, residents and physician assistants; n=20) working at the study centre, with a 1:1 randomisation of included clinicians. A standardized sum score (SSS) on guideline adherence was used as the primary outcome (patient level). The SSS was calculated from 13 dichotomous indicators on quality of RA monitoring, treatment and follow-up. The randomised controlled design was combined with a before-after design in the control group to assess the effect education and feedback alone. RESULTS: Twenty clinicians (mean age 44.3+/-10.9 years; 55% female) and 990 patients (mean age 62 +/- 13 years; 69% female; 72% rheumatoid factor and/or anti-CCP positive) were included. Addition of CDSS to education and feedback did not result in significant better quality of RA care than education and feedback alone (SSS difference 0.02; 95%-CI -0.04 to 0.08; p=0.60). However, before/after comparison showed that education and feedback alone resulted in a significant increase in the SSS from 0.58 to 0.64 (difference 0.06; 95%-CI 0.02 to 0.11; p<0.01). CONCLUSIONS: Our results suggest that CDSS did not have added value with regard to guideline adherence, whereas education and feedback can lead to a small but significant improvement of guideline adherence

The value of routine creatine kinase and thyroid stimulating hormone testing in patients with suspected fibromyalgia: a cross-sectional study

OBJECTIVE: The aim was to examine the prevalence of abnormal creatine kinase (CK) and thyroid stimulating hormone (TSH) values and previously unknown myopathy or thyroid disease in patients with suspected FM syndrome (FMS). METHODS: All adult patients with suspected FMS referred to the study hospital between November 2011 and April 2014 could participate. Patients with a history of myopathy or a previous diagnosis of thyroid disorder were excluded. Outcome measures were the percentages of abnormal CK and TSH values and the final diagnosis in those patients. RESULTS: Three hundred and seventy-three patients were included in this study (94% female, mean age 42 years). Of these patients, 7.5% (95% CI: 5.2, 10.6%) had an abnormal CK according to the local reference values. Applying the European Federation of the Neurological Societies guideline, this changed to 0.5% (95% CI: 0.2, 1.9%). In none of these patients was hyperCKaemia-related myopathy diagnosed, and the final diagnosis was FMS in 89% of the patients. Of the total number of patients, 3.5% (95% CI: 2.1, 5.9%) had an elevated TSH and 1.4% (95 CI: 0.6, 3.1%) a lowered TSH, with one patient having a somewhat lowered free thyroid hormone level. The final diagnosis was FMS in all these patients. CONCLUSION: Abnormal CK and TSH values are rare in patients with suspected FMS and do not result in an alternative diagnosis. Therefore, it seems that routine testing of CK and TSH levels in patients with suspected FMS referred to secondary care does not contribute to the diagnostic process

Choosing Wisely in Daily Practice: An Intervention Study on Antinuclear Antibody Testing by Rheumatologists

OBJECTIVE: To assess the effect of a simple intervention on antinuclear antibody (ANA) test overuse by rheumatologists. METHODS: This was an explorative, pragmatic, before-and-after, controlled implementation study among rheumatologists working at 3 rheumatology departments in secondary and tertiary care centers in The Netherlands. The intervention was given in all study centers separately and combined education with feedback. Six outcome measures describe the intervention effects: the ANA/new patient ratio (APR), difference with the target APR, percentage of positive ANA tests, percentage of repeated ANA testing, percentage of ANA-associated diseases, and APR variation between rheumatologists. Outcomes were compared between the pre- and postintervention period (both 12 months) using (multilevel) logistic regression or F testing. Results are reported together for centers 1 and 2, and separately for center 3, because ANA tests could not be linked to an individual rheumatologist in center 3. RESULTS: The APR decreased from 0.37 to 0.11 after the intervention in centers 1 and 2 (odds ratio [OR] 0.19, 95% confidence interval [95% CI] 0.17-0.22, P < 0.001) and from 0.45 to 0.30 in center 3 (OR 0.53, 95% CI 0.45-0.62, P < 0.001). The percentage of repeated ANA requests in all centers and the APR variation for centers 1 and 2 decreased significantly. Only in center 3 did the percentage of ANA-associated diseases increase significantly. CONCLUSION: A simple intervention resulted in a relevant and significant decrease in the numbers of ANA tests requested by rheumatologists, together with an improvement on 3 other outcome measures