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Background: Comprehensive measures to evaluate the effectiveness of medical interventions in extremely preterm infants are lacking. Although length of stay is used as an indicator of overall health among preterm infants in clinical studies, it is confounded by nonmedical factors (e.g. parental readiness and availability of home nursing support)., Objectives: To develop the PREMature Infant Index (PREMII ™ ), an electronic content-valid clinician-reported outcome measure for assessing functional status of extremely preterm infants (<28 weeks gestational age) serially over time in the neonatal intensive care unit. We report the development stages of the PREMII, including suggestions for scoring., Methods: We developed the PREMII according to US Food and Drug Administration regulatory standards. Development included five stages: (1) literature review, (2) clinical expert interviews, (3) Delphi panel survey, (4) development of items/levels, and (5) cognitive interviews/usability testing. Scoring approaches were explored via an online clinician survey., Results: Key factors reflective of functional status were identified by physicians and nurses during development of the PREMII, as were levels within each factor to assess functional status. The resulting PREMII evaluates eight infant health factors: respiratory support, oxygen administration, apnea, bradycardia, desaturation, thermoregulation, feeding, and weight gain, each scored with three to six gradations. Factor levels are standardized on a 0-100 scale; resultant scores are 0-100. No usability issues were identified. The online clinician survey identified optimal scoring methods to capture functional status at a given time point., Conclusions: Our findings support the content validity and usability of the PREMII as a multifunction outcome measure to assess functional status over time in extremely preterm infants. Psychometric validation is ongoing.

Objective : Few studies have investigated the efficacy of subcutaneous tocilizumab (TCZ-SC) on ultrasound-detected inflammation. This study aimed to explore the clinical efficacy of TCZ-SC treatment in rheumatoid arthritis (RA) patients and to evaluate the response by ultrasound compared to Composite Disease Activity Scores (CDAS). Method : This open-label, single-arm study enrolled RA patients with inadequate response to conventional synthetic disease-modifying anti-rheumatic drugs initiating TCZ-SC 162 mg once weekly for 24 weeks, with clinical assessments at baseline, 2, 4, 8, 12, 16, 20, and 24 weeks. Ultrasound examinations [semi-quantitative score (0-3) of 36 joints and four tendons] were performed at baseline, 4, 12, and 24 weeks. CDAS and American College of Rheumatology/European League Against Rheumatism (ACR/EULAR) response, and sum scores of ultrasound grey scale/Doppler were calculated. Changes during follow-up were explored by the Mann-Whitney test and correlations by Spearman's rho. Results : In total, 133 patients (mean ± sd age 55.9 ± 12.0 years) were assessed clinically and 110 patients were also examined with ultrasound. All clinical and ultrasound scores decreased significantly after 4 weeks (p < 0.001). At 24 weeks there was EULAR good response in 87.7% and ACR 70% response in 47.4%. Ultrasound scores had no or low correlations with patient-reported outcomes. At 24 weeks, CDAS remission was achieved in 27.4-83.5% and a sum score Doppler of 0 was found in 53.3%. Conclusions : Clinical and ultrasound scores decreased rapidly. Ultrasound scores were not associated with patient-reported variables. Half of the patients reached ultrasound remission, while there were large discrepancies in the percentage of patients reaching remission based on different CDAS.Trial registration: Study ML28691, registered 28 January 2014, ClinicalTrials.gov identifier: NCT02046616.

Objective : The aim of this study was to evaluate the risk of septic arthritis (SA) in patients who received an intra-articular (IA) glucocorticoid (GC) injection and to describe the characteristics of these patients. Methods : All patients undergoing IA procedures at the orthopaedic and rheumatological departments on the Danish island of Funen from January 2006 to December 2013 were identified in the central database and included by register extraction. Patients who developed a clinically inflamed joint and positive synovial fluid culture within 14 days after IA GC injection were considered as having SA. Retrospectively, data on age, gender, affected joint location, bacterial agent, pre-existing inflammatory disorder, and death within 30 days were extracted from the patient files. According to local recommendations, a non-touch sterile technique was used for IA procedures. Patients were informed about the risk of SA and advised to seek medical attention on suspicion of infection or lack of improvement. Results : In total, 22 370 IA procedures were performed. Among these, 14 118 GC injections and 8252 arthrocenteses were undertaken. Only 11 patients were diagnosed with SA (0.08%, 95% confidence interval 0.03-0.12). Risk factors for SA were male gender, age, and pre-existing joint disease. Conclusion : We found a low frequency of SA subsequent to IA GC injections. Older patients with pre-existing joint disease are at higher risk of developing SA.

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.

Objectives: To evaluate the 30-day mortality rate of septic arthritis (SA) in adults in Funen, central Denmark, and to explore whether, at the time of SA presentation, risk factors for the 30-day mortality rate could be revealed. Our secondary objective was to describe the microbiological aetiologies, systemic signs of inflammation, and co-morbidity., Method: A descriptive study identifying patients with SA from central Denmark, during the period 2006-2013, by the use of joint fluid culture data retrieved from the electronic database at the Department of Clinical Microbiology, Odense University Hospital. Patients with a positive joint fluid culture were considered eligible and their medical records were examined., Results: We identified 215 patients with SA, mean age 64.8 years. At presentation, mean C-reactive protein (CRP) was 204 mg/L, mean white blood cell count (WBC) 11.9 × 10 9 /L, and mean body temperature 37.6°C. A total of 101 patients (47%) had a prosthetic joint, 46 (21%) had an inflammatory joint disease, and 24 (11%) had diabetes mellitus (DM). Staphylococcus aureus was the most common pathogen (104 patients, 48.4%). The 30-day mortality rate was 9.3% and the significant risk factor for death was liver disease at time of presentation [odds ratio (OR) 40.40, 95% confidence interval (CI) 5.38-303]. The other factors tested such as age > 65 years, elevated temperature, rheumatoid arthritis (RA), prostheses, and diabetes mellitus (DM) did not reach statistical significance., Conclusions: In our sample of patients with SA, we found a 30-day mortality rate in almost one in 10 adults. Among possible explanations, our study indicates that liver disease is a clinically relevant risk factor.

Objectives: To investigate the impact of enhanced infusion rate of tocilizumab on the occurrence of infusion reactions, overall safety, and efficacy in rheumatoid arthritis (RA)., Method: We conducted a 24-week multicentre, open-label, randomized parallel group study comparing adverse event (AE) and effect profiles following tocilizumab IV 8 mg/kg every 4 weeks over 31 min vs. standard 60-min infusions in patients with RA and an inadequate clinical response to disease-modifying anti-rheumatic drugs (DMARDs) and/or tumour necrosis factor (TNF)-α inhibitors., Results: A total of 47 patients were enrolled in the study and randomized to fast infusions (n = 25) and controls (n = 22). Incidences of infusion reactions were similar between the two groups, neither of them leading to withdrawal. Likewise, the incidence of additional AEs did not differ between the treatment arms. Two serious adverse events (SAEs) were reported, in the control group. Four patients withdrew due to AEs, two from each arm. Efficacy at week 24 was comparable between groups., Conclusions: In RA, monthly tocilizumab infusions of 8 mg/kg provided over 31 or 60 min during 24 weeks did not differ concerning safety or efficacy.

Objectives: To determine to what extent shared epitopes, smoking, and anti-cyclic citrullinated peptide (anti-CCP) antibodies are associated with disease activity and erosive disease in patients with rheumatoid arthritis (RA) at disease onset., Method: RA patients not previously treated with disease-modifying anti-rheumatic drugs (DMARDs) and with a disease duration of < 6 months (CIMESTRA study) were examined for shared epitopes, anti-CCP antibodies, immunoglobulin M rheumatoid factor (IgM-RF) and IgA-RF, radiographic erosive changes in hands and feet, and clinical disease activity., Results: The study comprised 153 patients, of whom 104 (68%) were ever-smokers. The prevalence of patients with 0, 1, or 2 shared epitopes was 40 (48%), 71 (49%), and 33 (23%), respectively. Anti-CCP antibodies, IgM-RF, and IgA-RF were present in 89 (58%), 99 (65%), and 82 (54%) patients, respectively. Among smokers, erosive disease was associated with anti-CCP antibodies [odds ratio (OR) 3.9, 95% confidence interval (CI) 1.6-9.3], IgM-RF (OR 4.9, 95% CI 1.9-12), and IgA-RF (OR 2.8, 95% CI 1.2-6.4) but absent with regard to shared epitopes. Among never-smokers, erosive disease was not associated with either shared epitopes or antibodies. All antibody levels measured were associated with smoking and shared epitopes., Conclusions: Shared epitopes and smoking were associated with the production of anti-CCP antibodies and rheumatoid factors of IgM and IgA isotypes, which again were associated with erosive disease at presentation only in smokers. As shared epitopes and smoking were not directly associated with erosive disease, smoking may enhance the development of erosive disease in RA at different levels or through separate pathways.

Objectives: The aim of this study was to measure, in early rheumatoid arthritis (RA) patients, the concentration of CC-chemokine ligand 19 (CCL19) in plasma and the cell-surface expression of CC-chemokine receptor 7 (CCR7) on circulating monocytes and CD4+ T lymphocytes and to analyse correlations with disease activity and 5-year radiographic progression., Method: In disease-modifying anti-rheumatic drug (DMARD)-naïve RA patients (disease duration < 6 months), we measured plasma CCL19 by enzyme-linked immunosorbent assay (ELISA) (n = 160) and CCR7 cell-surface expression on monocytes and CD4+ T lymphocytes by flow cytometry (n = 40) at baseline and after 1 year of treatment with methotrexate (MTX) or methotrexate+cyclosporin A (MTX/CyA). Radiographic progression was scored by the van der Heijde-modified Total Sharp Score (TSS) from 0 to 5 years., Results: Increased baseline CCL19 (median 85 pg/mL, range 31-1008 pg/mL, p = 0.01) decreased after 1 year (median 31 pg/mL, range 31-1030 pg/mL, p < 0.001) and 5 years (median 31 pg/mL, range 31-247 pg/mL, p < 0.001) to a level below the controls (n = 45) (median 60 pg/mL, range 31-152 pg/mL). Baseline plasma CCL19 levels [p = 0.011, 95% confidence interval (CI) 0.0030-0.0176], anti-cyclic citrullinated peptide (anti-CCP) antibody status (p = 0.002, 95% CI 0.61-2.38), and TSS > 0 at baseline (p < 0.001, 95% CI 1.21-3.16) were independent predictors of 5-year radiographic progression evaluated by multiple logistic regression in contrast to never smoked, C-reactive protein (CRP), gender, age, number of tender (NTJ) and swollen joints (NSJ), and 28-joint Disease Activity Score (DAS28). Increased CCR7 expression on monocytes (p = 0.008) correlated to CRP (p = 0.006, r = 0.52) and normalized (n = 15) after 1 year (p = 0.02)., Conclusions: In DMARD-naïve RA patients, CCL19 plasma level and CCR7 surface expression on monocytes were upregulated and normalized after 1 year of treatment. Increased baseline plasma CCL19 level, anti-CCP antibody status, and TSS > 0 at baseline correlated independently with 5-year radiographic progression.

Recent studies on blood vessels, the heart, trachea and esophagus have shown that these organs in the zero-stress state are not closed circular cross-sections of rings, but open sectors. Any analysis of stress and strain must begin with organs in the zero-stress state. This report presents data on morphometry of the zero-stress and no-load states of the porcine ureter, and on residual strains and opening angles. The zero-stress state of the ureter is demonstrated by cutting the ureter into rings and cutting the rings into sectors; each sector is characterized by an opening angle. The outer and inner circumferences, the cross-sectional area of the ureteral wall and the number of buckles showed axial variation, with the highest values proximally in the ureter. Residual strain in the circumferential direction was significant, but showed no axial variation. The opening angles were approximately 30 degrees at the most distal and proximal sites and approximately 90 degrees in mid-ureter. The opening angle showed positive correlation to the wall thickness in the zero-stress state, residual strain at the outer circumference and negative correlation to the length of the outer circumference in the zero-stress state. Residual strains must be taken into account when studying physiological problems in which the stresses and strains are important, e.g. the urine transport function of the ureter.

The main objective of this study was to investigate the effects of pasteurisation, UHT processing and fermentation on the concentration of folate-binding proteins (FBP) and their folate binding capacity in comparison with the retention of the most predominant folate from, 5-CH3THF. The amount of folate-binding protein (FBP) was analysed using enzyme-linked immunosorbent assay (ELISA). Unprocessed milk and pasteurised milk were found to contain similar amounts, 211 and 168 nmol/l, of FBP, respectively. UHT-processed milk and Yoghurt naturelle, both processed at temperatures above 90 degrees C, contained only 5.2 and 0.2 nmol/l FBP, respectively. As an indication of the protein-binding capacity free and protein-bound folates were analysed after charcoal treatment using the radio-protein binding assay method (RPBA). These results indicated that all folates in unprocessed milk and pasteurised milk were protein-bound, while folates in UHT-processed milk and Yoghurt naturelle occurred freely which is supported by our findings on FBP. High-performance liquid chromatography analysis indicated that unprocessed milk, pasteurised milk, UHT-processed milk and Yoghurt naturelle contained 44.8 +/- 2.1 (n = 10), 41.1 +/- 0.9 (n = 10), 36.1 +/- 1.8 (n = 10) and 35.6 +/- 9.1 micrograms/l (n = 10) 5-methyltetrahydrofolates (5-CH3THF), respectively, after deconjugation. Corresponding values for total milk folates analysed using radio-protein binding assay were 80.4 +/- 0.9 (n = 10), 64.2 +/- 2.7 (n = 10), 48.2 +/- 1.8 (n = 10) and 54.0 +/- 8.2 micrograms/l (n = 10), respectively. Hence, both methods indicated significant (P < 0.05) losses of 5-CH3THF as a result of pasteurisation, UHT processing and fermentation, compared with unprocessed milk. In spite of apparent discrepancies in folate concentrations obtained using the two different methods, these results support the equimolar ratio of FBP and folates in unprocessed and pasteurised milk when data on 5-CH3THF, obtained using HPLC were corrected for differences in recovery. Thus, heat processing of milk not only reduced the amount of 5-CH3 THF significantly, but also changed the concentration of FBP and the folate-binding capacity of FBP, which may have implications on the bioavailability of milk folates.