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ObjectivesGiant cell arteritis (GCA) and polymyalgia rheumatica (PMR) are age-associated inflammatory diseases that frequently overlap. Both diseases require long-term treatment with glucocorticoids (GCs), often associated with comorbidities. Previous population-based cohort studies reported that an unhealthier metabolic profile might prevent the development of GCA. Here, we report metabolic features before start of treatment and during treatment in patients with GCA and PMR.MethodsIn the Dutch GCA/PMR/SENEX (GPS) cohort, we analysed metabolic features and prevalence of comorbidities (type 2 diabetes, hypercholesterolaemia, hypertension, obesity and cataract) in treatment-naïve patients with GCA (n=50) and PMR (n=42), and compared those with the population-based Lifelines cohort (n=91). To compare our findings in the GPS cohort, we included data from patients with GCA (n=52) and PMR (n=25) from the Aarhus cohort. Laboratory measurements, comorbidities and GC use were recorded for up to 5 years in the GPS cohort.ResultsGlycated haemoglobin levels tended to be higher in treatment-naïve patients with GCA, whereas high-density lipoprotein, low-density lipoprotein and cholesterol levels were lower compared with the Lifelines population. Data from the Aarhus cohort were aligned with the findings obtained in the GPS cohort. Presence of comorbidities at baseline did not predict long-term GC requirement. The incidence of diabetes, obesity and cataract among patients with GCA increased upon initiation of GC treatment.ConclusionData from the GCA and PMR cohorts imply a metabolic dysregulation in treatment-naïve patients with GCA, but not in patients with PMR. Treatment with GCs led to the rise of comorbidities and an unhealthier metabolic profile, stressing the need for prednisone-sparing targeted treatment in these vulnerable patients.

ObjectivesThe aim of this study, was to introduce stereology as a versatile and robust tool for quantitative image analysis of volume and attenuation characteristics (Hounsfield Units (HU's)), in a blinded control case study investigating lungs of drowning victims compared to a control group on post mortem computed tomography (PMCT) data.Materials and MethodsPMCT scans of the lungs from 14 drowned cases and 14 matched opioid-overdose-controls was included. Quantitative CT-analysis was performed using a stereological approach adapted to PMCT data that allowed for precise extraction of volume and HU-values using stereological point-probes assigned manually to individual lung-structures. Qualitative radiological image interpretation performed by a trained radiologist was compared to the quantitative analyses.ResultsNo significant difference was found for total lung volume, volumes of consolidations, ground glass opacities, bronchi, and air-filled lung tissue. When comparing drowning cases with opioid overdose cases as controls, the extracted HU-values did not show statistically significant changes in mean attenuation characteristics. No major discrepancies were found between the quantitative analysis and qualitative analysis.ConclusionConventional radiological evaluation of PMCT images rely on the radiologists’ ability to distinguish normal from pathological. Quantitative image analysis offers, to name a few, precise estimations of structure volume and HU-statistics. Although the used 14 matched cases data failed to significantly aid the diagnosis of drowning statistically, we envisage that quantitative PMCT analysis using stereology could become a valuable tool to improve objective forensic radiological interpretation.

OBJECTIVES: Measurement of serum biomarkers at disease onset may improve prediction of disease course in patients with early rheumatoid arthritis (RA). We evaluated the multi-biomarker disease activity (MBDA) score and early changes in MBDA score for prediction of 28-joint Disease Activity Score based on C-reactive protein (DAS28-CRP) remission and radiographic progression in the double-blinded OPERA trial.METHOD: Treatment-naïve RA patients (N = 180) with moderate or high DAS28 were randomized to methotrexate (MTX) + adalimumab (n = 89) or MTX + placebo (n = 91) in combination with glucocorticoid injection into swollen joints. X-rays of hands and feet were evaluated at months 0 and 12 (n = 164) by the total Sharp van der Heijde score (TSS). The smallest detectable change (1.8 TSS units) defined radiographic progression (∆TSS ≥ 2). Clinical remission (DAS28-CRP < 2.6) was assessed at baseline and 6 months. MBDA score was determined at 0 and 3 months and tested in a multivariable logistic regression model for predicting DAS28 remission at 6 months and radiographic progression at 1 year.RESULTS: Baseline MBDA score was independently associated with radiographic progression at 1 year [odds ratio (OR) = 1.03/unit, 95% confidence interval (CI) = 1.01-1.06], and changes in MBDA score from baseline to 3 months with clinical remission at 6 months [OR = 0.98/unit, 95% CI 0.96-1.00). In anti-cyclic citrullinated peptide antibody (anti-CCP)-positive patients, 35 of 89 with high MBDA score (> 44) showed radiographic progression (PPV = 39%), compared with 0 of 15 patients (NPV = 100%) with low/moderate MBDA score (≤ 44) (p = 0.003).CONCLUSION: Early changes in MBDA score were associated with clinical remission based on DAS28-CRP at 6 months. In anti-CCP-positive patients, a non-high baseline MBDA score (≤ 44) had a clinical value by predicting very low risk of radiographic progression at 12 months.

OBJECTIVE: To investigate serum interleukin-6 (IL-6), serum chitinase-3-like protein-1 (YKL-40), and plasma vascular endothelial growth factor (VEGF) as measures of disease activity and predictors of clinical remission and radiographic progression in two early rheumatoid arthritis (RA) randomized controlled trials (RCTs).METHOD: Treatment-naïve patients with early RA (< 6 months' duration) and active disease, participating in two investigator-initiated RCTs, were treated according to a predefined treat-to-target algorithm aiming at inflammatory control, using methotrexate (MTX) + cyclosporine versus MTX + placebo (CIMESTRA study, n = 150, 5 year follow-up) or MTX + adalimumab versus MTX + placebo (OPERA study, n = 180, 2 year follow-up). The 28-joint Disease Activity Score (DAS28) and conventional radiography [bilateral hands and feet at baseline, 2 years and 5 years (only CIMESTRA)] were obtained at baseline and during follow-up. Serum IL-6, serum YKL-40, and plasma VEGF were measured in baseline blood samples and during follow-up. Hypotheses regarding the biomarkers' relation with DAS28 and ability to predict clinical remission (DAS28 < 2.6) and radiographic progression (change in total Sharp van der Heijde score ≥ 2) were generated in CIMESTRA and validated in OPERA, by Spearman's correlation and logistic regression analyses.RESULTS: Baseline IL-6, YKL-40, and VEGF correlated significantly with DAS28 in CIMESTRA (r = 0.50, r = 0.36, r = 0.36, respectively, all p < 0.01) and these results were confirmed in OPERA patients (r = 0.52, p < 0.01; r = 0.18, p = 0.01; r = 0.23, p = 0.002, respectively). None of the biomarkers (absolute values or change) was predictive of clinical remission or radiographic progression at 2 or 5 years in either study.CONCLUSION: Serum IL-6, serum YKL-40, and plasma VEGF were significantly correlated with DAS28 at baseline, but did not have consistent predictive value for clinical remission or radiographic progression in two early RA RCTs.

OBJECTIVE: Intestinal inflammation is frequent in patients with spondyloarthritis (SpA). Here, we test the validity of faecal calprotectin as a marker of intestinal inflammation in SpA patients and evaluate the response of adalimumab in patients with and without intestinal lesions.METHOD: Patients were included on the basis of active SpA with a Bath Ankylosing Spondylitis Disease Activity Index ≥ 4. After a 4 week non-steroidal anti-inflammatory drug washout period, patients were divided into two groups based on faecal calprotectin level (> 100 mg/kg, n = 15, and < 50 mg/kg, n = 15). Adalimumab 40 mg every other week was initiated. Patients with calprotectin >100 mg/kg received an additional 40 mg of adalimumab at baseline. Patients were followed with clinical examination at weeks 12, 20, and 52; magnetic resonance imaging (MRI) at weeks 0, 20, and 52; and endoscopy at weeks 0 and 20.RESULTS: The groups were similar with regard to clinical disease activity measures at baseline. Faecal calprotectin above 100 mg/kg accurately identified patients with intestinal inflammation. Twelve of the 15 patients with elevated calprotectin had bowel lesions, compared to only one patient in the control group. On MRI, the group with elevated calprotectin had more inflammation in the sacroiliac joints. Finally, the group with intestinal inflammation had a better clinical response to adalimumab, as evaluated by the Ankylosing Spondylitis Disease Activity Score.CONCLUSION: Elevated faecal calprotectin accurately identified SpA patients with bowel inflammation and more inflammation on MRI. Elevated faecal calprotectin at baseline may predict a better treatment response.

Background Studies in established rheumatoid arthritis (RA) have shown that radiographic progression is associated with increasing health assessment questionnaire (HAQ) score. However, most studies have failed to demonstrate this association at the early stage of the disease. In addition, little is known about how specific pathologies, e.g. joint inflammation, tenosynovitis and joint damage, contribute to different patient-reported outcomes (PROs). Objectives To examine the association between MRI wrist inflammation and damage with PROs in patients with early RA. Methods MRIs of the wrist and hand were obtained from 210 early RA patients participating in two investigator-initiated, randomized, controlled studies (CIMESTRA/OPERA), which aimed at achieving inflammatory control by use of conventional and/or biologic drugs combined with intra-articular injection of glucocorticoids. The image-sets were assessed according to the RA MRI scoring system (RAMRIS) for inflammation (synovitis, tenosynovitis, osteitis) and damage (bone erosions, joint space narrowing) at baseline (n=210), 1 (n=206) and 5 (n=113) years follow-up. Data from the two studies were pooled and assessed for associations between MRI features and HAQ, patient global visual analogue scales (VAS-PtGlobal) and VAS pain using Spearman correlation for status and change scores, univariate and multivariable linear regression analyses for change scores and generalized estimating equations for status and change scores. MRI features were further tested for trends against specific hand-related HAQ questions using the Jonckheere trend test. Results MRI inflammation, but not damage, showed statistically significant associations with HAQ, VAS-PtGlobal and VAS pain for status and change scores, independently of swollen joint count and level of C-reactive protein. Synovitis and tenosynovitis were the MRI features most consistently associated with PROs, particularly VAS-PtGlobal and VAS pain (Table 1). MRI synovitis and tenosynovitis mean scores increased with the level of difficulty to cut meat and open a milk carton (p Conclusions MRI-assessed inflammation, but not damage, in the early RA wrist is associated with patient-reported physical impairment, global disease activity and pain, and the amount of wrist inflammation influences physical hand function. Disclosure of Interest D. Glinatsi: None declared, J. Baker: None declared, M. Hetland Grant/research support from: BMS, AbbVie, Pfizer, UCB-Nordic, MSD, K. Horslev-Petersen Consultant for: AbbVie and UCB, B. Ejbjerg: None declared, K. Stengaard-Pedersen: None declared, P. Junker: None declared, T. Ellingsen: None declared, H. Lindegaard: None declared, I. Hansen: None declared, T. Lottenburger: None declared, J. Moller: None declared, L. Ornbjerg: None declared, A. Vestergaard: None declared, A. G. Jurik: None declared, H. Thomsen: None declared, T. Torfing: None declared, S. Bisgaard: None declared, M. Axelsen Grant/research support from: Abbvie, M. Ostergaard Grant/research support from: Abbvie, BMS, Janssen and Merck, Consultant for: Abbvie, BMS, Boehringer-Ingelheim, Celgene, Eli-Lilly, Centocor, GSK, Hospira, Janssen, Merck, Mundipharma, Novartis, Novo, Orion, Pfizer, Regeneron, Schering-Plough, Roche, Takeda, UCB, and Wyeth

Capturing financial network linkages and contagion in stress test models are important goals for banking supervisors and central banks responsible for micro- and macroprudential policy. However, granular data on financial networks is often lacking, and instead the networks must be reconstructed from partial data. In this paper, we conduct a horse race of network reconstruction methods using network data obtained from 25 different markets spanning 13 jurisdictions. Our contribution is two-fold: first, we collate and analyze data on a wide range of financial networks. And second, we rank the methods in terms of their ability to reconstruct the structures of links and exposures in networks.

OBJECTIVES: To investigate whether a treat-to-target strategy based on methotrexate (MTX) and intra-articular (IA) betamethasone suppresses magnetic resonance imaging (MRI)-determined measures of disease activity and reduces joint destruction in early rheumatoid arthritis (eRA) patients, and to investigate whether concomitant cyclosporin A (CyA) provides an additional effect.METHOD: In the 2-year randomized, double-blind, treat-to-target trial CIMESTRA, 160 patients with eRA (< 6 months) were randomized to MTX, intra-articular betamethasone and CyA, or placebo CyA. A total of 129 patients participated in the MRI substudy, and had contrast-enhanced MR images of the non-dominant hand at months 0, 6, 12, and 24. MR images were evaluated for osteitis, synovitis, tenosynovitis, bone erosion, and joint space narrowing (JSN), using validated scoring methods.RESULTS: Significant reductions were seen at 6 months in all inflammatory parameters [synovitis, mean change -1.6 (p < 0.001, Wilcoxon), tenosynovitis, -3.5 (p < 0.001), and osteitis, -1.3 (p < 0.05)] and at 12/24 months in synovitis and tenosynovitis [-1.6/-2.2 and -3.6/-3.8, respectively; all p < 0.001]. MRI signs of inflammation were not fully eliminated, and increases in erosion and JSN scores were observed at 6 months [0.4 (p < 0.01)/0.1 (p < 0.05)], 12 months [0.8 (p < 0.001)/0.3 (p < 0.01)], and 24 months [1.0 (p < 0.001)/0.4 (p < 0.001)]. Clinical measures decreased significantly (p < 0.001) at all time points. There were no consistent statistically significant differences between treatment groups.CONCLUSIONS: In this eRA treat-to-target trial, MTX and intra-articular glucocorticoids markedly reduced, but did not eliminate, MRI osteitis, synovitis, and tenosynovitis. Accordingly, minimal but statistically significant increases in bone erosion and JSN were observed. No additional effect of CyA was demonstrated.

Following oral administration of trimethoprim (TMP) in doses varying from 4.0 to 11.2 mg TMP per kg body weight per 24 hours over a period of 1-5 days, the concentration was determined in lung tissue (obtained by open biopsy), bronchial secretion or saliva, in a total of 51 cases. A microbiological method was used to determine the concentration, using B. pumilus as test organism. The concentrations of TMP found in the lung tissue, bronchial secretion and saliva (6-13 hours after the last administration of TMP) were at a therapeutically active level (≥ MIC × 5) with regard to the majority of those bacteria usually occurring in respiratory tract infections. In 14 out of 17 patients, TMP was found in the lung tissue in concentrations which were 1 1/2 to 3 1/2 times higher than the corresponding serum concentration. In the other 3 patients, the concentrations found were 4 1/2 times, 7 times and 14 times higher in the lung tissue than in the serum. In the case of bronchial secretion, 6 patients showed a TMP concentration which was 1/2 to 4 times the corresponding serum concentration, while in 14 patients, an examination of the saliva showed a TMP concentration which was 1-8 1/2 times that of the corresponding serum concentration.

A new method for the homogenization of bone tissue is introduced. The method includes a reproducible size of particles (median 0.89 μ) and allows investigation of tissue samples down to 100 mg. Using this method of bone homogenization, the penetration of trimethoprim (TMP) into normal human bone was examined in 10 patients with fracture of the femoral neck. A microbiological method was used to determine the concentration, using Bacillus pumilus as test organism. Separate determinations were made of the TMP concentration in bone marrow, spongy bone and compact bone. Evaluated on the basis of the sensitivity of Staphylococcus aureus to TMP, a therapeutic level of TMP seems to be obtained in bone marrow and spongy bone, but not in compact bone.

Objective To investigate the short-term and long-term efficacy of intra-articular betamethasone injections, and the impact of joint area, repeated injections, MRI pathology, anticyclic citrullinated peptide (CCP) and immunoglobulin M rheumatoid factor (IgM-RF) status in patients with early rheumatoid arthritis (RA). Methods During 2 years of follow-up in the CIMESTRA trial, 160 patients received intra-articular betamethasone in up to four swollen joints/visit in combination with disease-modifying antirheumatic drugs. Short-term efficacy was assessed by EULAR good response. Long-term efficacy by Kaplan–Meier plots of the joint injection survival (ie, the time between injection and renewed flare). Potential predictors of joint injection survival were tested. Results 1373 Unique joints (ankles, elbows, knees, metacarpophalangeal (MCP), metatarsophalangeal, proximal interphalangeal (PIP), shoulders, wrists) were injected during 2 years. 531 Joints received a second injection, and 262 a third. At baseline, the median numbers of injections (dose of betamethasone) was 4 (28 mg), declining to 0 (0 mg) at subsequent visits. At weeks 2, 4 and 6, 50.0%, 58.1% and 61.7% had achieved a EULAR good response. After 1 and 2 years, respectively, 62.3% (95% CI 58.1% to 66.9%) and 55.5% (51.1% to 60.3%) of the joints injected at baseline had not relapsed. All joint areas had good 2-year joint injection survival, longest for the PIP joints: 73.7% (79.4% to 95.3%). 2-Year joint injection survival was higher for first injections: 56.6% (53.7% to 59.8%) than for the second: 43.4% (38.4% to 49.0%) and the third: 31.3% (25.0% to 39.3%). Adverse events were mild and transient. A high MRI synovitis score of MCP joints and anti-CCP-negativity were associated with poorer joint injection survival, whereas IgM-RF and C-reactive protein were not. Conclusion In early RA, intra-articular injections of betamethasone in small and large peripheral joints resulted in rapid, effective and longlasting inflammatory control. The cumulative dose of betamethasone was low, and the injections were well tolerated.

Objective To investigate the possibility that inhalation of raspberry powder at work can cause occupational asthma. Methods We report the case of a 35-year-old, nonsmoking woman who complained of hay fever symptoms, wheezing, and shortness of breath two or three times a month exclusively in association with coating chewing gum with raspberry powder. Prick test extracts with the five types of fruit powder were produced. Peak expiratory flow rate monitoring five times daily was performed for an 8-week period while the patient was at work. Specific IgE and histamine release tests for raspberry powder were performed. Breathing zone dust measurements were taken. Results Baseline lung function and histamine provocation test results were normal. During the 8-week monitoring period, 5 episodes of reduced peak expiratory flow rate were demonstrated. Each period was directly related to working with raspberry powder. A 9-mm prick test result positive for raspberry powder was seen (histamine control, 9 mm). In addition, the result of a radioallergosorbent test for raspberry was positive (0.84 kUA/L). The result of a histamine release test with raspberry powder from work was negative. Breathing zone total dust measurement was 5.9 mg/m 3 . Conclusions To our knowledge, this is the first description of occupational asthma due to the inhalation of raspberry powder. The symptoms of the patient described herein disappeared after she was moved to another part of the factory. Hygienic improvements were performed at the workplace to reduce the sensitization risk of other workers.

In a pharmacolinetic study on a new semisynthetic penicillin, alpha-sulfobenzylpenicillin, sulbenicillin, serum level, serum half-life, apparent distribution volume, renal clearance, urinary excretion, and metabolism were determined after a 4-gm intravenous dose and compared to that of carbenicillin in 5 patients with normal renal function. In the case of sulbenicillin, the mean serum concentration at 1 hr was 157 plus or minus 25 mug/ml, the mean serum half-life was 70 plus or minus 10 min, the renal clearance was 95 plus or minus 25 ml/min, and the total urinary recovery after 24 hr was about 80% of the dose. The only metabolite detected in the urine was the penicilloic acid derivative, in an amount usually less than 5% of the dose. Serum values, serum half-live, renal clearances, and excretion pattern did not differ significantly from that of carbenicillin. In 8 patients with decreased renal function (creatinine clearance less than 50 ml/min) there was an inverse correlation between creatinine clearance and serum half-life.

Following oral administration of trimethoprim (TMP) in doses varying from 5.7 to 9.8 mg TMP per kg body weight per 24 h over a period of 1–22 days, the concentration was determined in normal and patho

10 of 20 workers in an envelope-making factory developed contact dermatitis. The cause was dibutyl maleinate, which was added to a polyvinylacetate glue. Dibutyl maleinate is a strong sensitizer and should be withdrawn from industrial use.

The penetration of lincomycin into normal bone was studied in 10 patients with fracture of the neck of the femur, a separate determination being made of the lincomycin concentration in serum, bone marrow, spongy bone and compact bone. The concentration of lincomycin in bone marrow was found to be at the same level as that in the serum. The concentration in spongy bone amounted in most cases to 50 to 75 percent of the concentration in the serum, whereas the concentration in compact bone varied from 0 to 15 percent of that in the serum.

Following the administration of trimethoprim (TMP) by mouth in doses varying from 5.0 to 8.1 mg TMP per kg body weight per 24 hours over a period of 24–48 hours, the concentration was examined in either the prostatic tissue or the prostatic secretion, in a total of 13 patients. A microbiological method was employed to determine the concentration, using B. ptrmilis as test organism. A method of collecting the prostatic secretion was used which excluded the admixture of urine with higher antibiotic content than that of the secretion. Tissue was examined which was obtained both by open and closed (transperineal) biopsy. The concentrations of TMP found in both the secretion and the tissue (9–12 hours after the last administration of TMP) were at a thera-peutically active level (≥MIC × 5) with respect to the majority of those bacteria usually occurring in urinary tract infection.

(1) Background: VALUEWASTE, a European Commission Horizon 2020 project, is attempting to find new and sustainable sources of protein and fertiliser products using biowaste as a resource. Introducing these products to the market is essential to understand the social acceptance, behavioural changes and socioeconomic impacts related to products and value chains. (2) Methods: The applied framework provides insights from market, socioeconomic, and community acceptance points of view. Initially, we designed the context and targets of the study. The acceptance levels were tested in two study regions: the cities of Murcia (Spain) and Kalundborg (Denmark). Secondly, we established a survey questionnaire (N = 523) combining social acceptance and life-cycle assessment methodology questions. Lastly, we performed a scenario-based workshop discussing behavioural changes related to the introduction of new bio-products to customers. (3) Results: Our study of developing new bio-products (food, feed, fertiliser) from biowaste produced forceful comparative results from the two regions regarding three aspects of social acceptance: market, socioeconomic, and community. (4) Conclusions: The present study, engaging citizens, consumers, producers, and policy makers, provides insights into what is important for the social acceptance of new protein sources for food, feed, and recycled fertilisers from bio-waste in the Murcia and Kalundborg city regions. Our observations, based on analyses applying three dimensions of social acceptance, can be directly applied elsewhere, guiding decision makers on how to fortify social acceptance regarding new circular economy business models and the bioeconomy in Europe.