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BackgroundGLORIA is an ongoing large pragmatic trial that examines harm, benefit and costs of low-dose glucocorticoids added to the standard treatment of RA patients of 65 years or older. The eligibility criteria are non-restrictive: RA, age ≥65 years, disease activity score (DAS28) of ≥2.6, and no current glucocorticoid treatment. Patients with comorbidity are expressly included, and the impact of trial procedures on normal care is minimal. Nevertheless, inclusion proves to be challenging. We have prospectively sampled all the reasons for ineligibility across a number of centres in different countries participating in the GLORIA trial.MethodsRheumatologists from 8 centres in Germany, Hungary, The Netherlands, Portugal and Romania screened the patient list of at least two full clinic days. For each patient, the eligibility and all possible reasons of exclusion were recorded.Abstract AB0364 – Table 1Percentage of patients ineligible for the GLORIA trial, per reason (patients can have more than one reason)ResultsIn total, 385 patients were screened. Of these patients, 15 (4%) were eligible to participate in the GLORIA trial. In Germany, Romania and Portugal (Lisbon) none of the screened patients proved eligible.The most common reasons for ineligibility were inactive disease and age (both 58%) (table 1). Current glucocorticoid use was reported in 28%, 5% had a temporary reason (i.e. recent switch of therapy or glucocorticoid use), and 51% had more than one reason for ineligibility. We found remarkable differences between the sites in the distribution of the main reasons for ineligibility (table 1).Of the eligible patients, 1 was already participating, 3 were included after this screening, and 2 were currently considering participation; 9 declined participation (most common reasons: fear of glucocorticoids, not interested to participate, preference for GC injections or declining additional therapy).ConclusionsIn this prospective study, we found remarkable differences between countries in reasons for non-participation in our ongoing GLORIA trial. The willingness of eligible patients to participate was low in this elderly population, despite the pragmatic design. Earlier studies also showed that it is challenging to include elderly patients in a clinical trial.1 2 Pre-screening of patients in potential sites can provide important information on the potential to recruit patients in a trial, but the actual willingness of patients to participate remains hard to predict.References[1] Calamia M, et al. I’d Do Anything for Research, But I Won’t Do That: Interest in Pharmacological Interventions in Older Adults Enrolled in a Longitudinal Aging Study. PLoS One2016;11:e0159664.[2] Denson AC, et al. Participation of the elderly population in clinical trials: barriers and solutions. Cancer Control2014;21:209–14.AcknowledgementsThis project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 6 34 886.Disclosure of InterestNone declared

BackgroundTreatment of Paget's Disease of Bone (PDB) has been revolutionized by the use of zolendronic acid (ZA). Patients usually have a dramatic response to treatment with normalization serum alkaline phosphataise (ALP) levels and a longer period of clinical remission, compared with other class agents. Data from long-term use are scarse.ObjectivesEvaluate the effectiveness and safety of ZA in PDB patients, as well as remission, re-treatment rates and side effects in our outpatient population since 2005.MethodsA retrospective study of PDB patients treated with 5 mg ZA intravenous infusion at our day-care center. Follow up time, demographic and clinical characteristics, previous therapeutic agents, rate of response, number and reasons of re-treatment(s) and rates of adverse events were collected. A descriptive statistic analysis was made.Results48 patients, 60% female, mean age of 75 years, with a median time since the diagnosis of 12.3 years. The disease was poliostotic in 73% of the patients and pelvis (65%), skull (29%) and spine (27%) were the most common pagetic localizations. Deafness was present in 12.5% and 65% had hip involvement. 44% patients had been treated with another biphosphonate agent previously. Response rates were 97.9% at 1 year, 87.2% after 2 years and 95.1% after 3 years. The mean ALP levels before ZA infusion was 290 UI/L and after 112 UI/L. Sixteen patients needed a re-treatment in the period of follow up, minimum of 1 year after the ZA infusion and maximum of 8 years after. 56.3% due to raised of ALP levels and 43.8% due pain/ hip involvement. Four patients needed a third infusion due to hip involvement, and 2 of them a forth infusion due to the same reason. All of the patients re-treated due to hip involvement had severe hip involvement at time of diagnosis. In our population, 2 patients achieved 10 years remission, 5 patients 9 years remission and 10 patients 8 years remission with a single ZA infusion. Recording adverse effects were: 14.6% Flu like symptoms (7 patients), 2% assintomatic hypocalcemia (1 patient) and no reports of osteonecrosis or fractures. All of these effects were reported after the first ZA infusion.ConclusionsIn our population, we find high long-term sustained remission rate. Only sixteen patients needed re-treatment. Patients maintained sustained remission up to 10 years of a single ZA infusion. Incidence of adverse events was similar to the reported in the literature.ReferencesReid IR, Miller P, Lyles K et al. Comparison of a Single Infusion of Zolendronic Acid with Risendronate for Paget's Disease. N Eng J Med. 2005 Set:353(9):898–908Reid IR, Brown JP, Levitt N et al. Re-treatment of relapse Paget's disease of bone with zolendronic acid: results from an open-label study. Natur BoneKEy Report 2. 2013 Nov: 442: 1–3Reid IR, Lyles K, Brown JP et al. A Single Infusion of Zolendronic Acid Produces Sustained Remissions in Paget Disease: Data from 6.5 years, JBMR. 2011 Sep 26 (9):2261–70Devogelaer JP, Geusen P, Daci E et al. Remission over 3 years in patients with Paget disease of bone treated with a single intravenous infusion of 5 mg zolendronic acid. Calcif Tissue Int. 2014 Mar:94(3):311–8Disclosure of InterestNone declared

Actinobaculum schaalii is an emerging pathogen particularly involved in urinary tract infection of elderly people and/or patient with urological risk factors of urinary tract infection. This microorganism is a difficult-to-diagnose pathogen and is rarely involved in systemic or deep infections. Here, we report the first case of prosthetic joint infection due to A. schaalii in an 84-year-old man with a benign prostatic hyperplasia associated with chronic retention of urine. This case underlines the importance to optimize the diagnosis of emerging uropathogens as A. schaalii , to prevent systemic infections, particularly in patients with orthopaedic implants.

BackgroundLow-dose glucocorticoid (GC) therapy is widely used in rheumatoid arthritis (RA) but the balance of benefit and harm is still unclear.MethodsThe GLORIA (Glucocorticoid LOw-dose in RheumatoId Arthritis) pragmatic double-blind randomised trial compared 2 years of prednisolone, 5 mg/day, to placebo in patients aged 65+ with active RA. We allowed all cotreatments except long-term open label GC and minimised exclusion criteria, tailored to seniors. Benefit outcomes included disease activity (disease activity score; DAS28, coprimary) and joint damage (Sharp/van der Heijde, secondary). The other coprimary outcome was harm, expressed as the proportion of patients with ≥1 adverse event (AE) of special interest. Such events comprised serious events, GC-specific events and those causing study discontinuation. Longitudinal models analysed the data, with one-sided testing and 95% confidence limits (95% CL).ResultsWe randomised 451 patients with established RA and mean 2.1 comorbidities, age 72, disease duration 11 years and DAS28 4.5. 79% were on disease-modifying treatment, including 14% on biologics. 63% prednisolone versus 61% placebo patients completed the trial. Discontinuations were for AE (both, 14%), active disease (3 vs 4%) and for other (including covid pandemic-related disease) reasons (19 vs 21%); mean time in study was 19 months. Disease activity was 0.37 points lower on prednisolone (95% CL 0.23, p<0.0001); joint damage progression was 1.7 points lower (95% CL 0.7, p=0.003). 60% versus 49% of patients experienced the harm outcome, adjusted relative risk 1.24 (95% CL 1.04, p=0.02), with the largest contrast in (mostly non-severe) infections. Other GC-specific events were rare.ConclusionAdd-on low-dose prednisolone has beneficial long-term effects in senior patients with established RA, with a trade-off of 24% increase in patients with mostly non-severe AE; this suggests a favourable balance of benefit and harm.Trial registration number NCT02585258.

Here, a hemoglobin gene from the nitrogen-fixing actinorhizal plant Myrica gale was isolated, cloned and sequenced. The gene (MgHb) was a class I hemoglobin with strong sequence homology to non-symbiotic hemoglobin genes. MgHb is highly expressed in symbiotic root nodules, but transcripts and protein were also detected in leaves of M. gale. In Arabidopsis thaliana the MgHb promoter, linked to a β-glucuronidase coding region, directed expression in the vascular tissue, in shoot meristem and at root branch point - a pattern very similar to the combined expression pattern of the two non-symbiotic A. thaliana hemoglobin promoters AHb1 and AHb2. The results points to a symbiotic as well as a non-symbiotic specificity of MgHb similar to a hemoglobin gene identified in Parasponia andersonii, but different from the situation in Casuarina glauca - a close actinorhizal relative of M. gale.

Background Denosumab (DMAb) reduces the risk of new vertebral, nonvertebral and hip fractures (Cummings NEJM 2009). It is associated with greater gains in bone mineral density (BMD) and decreases in bone turnover markers than alendronate, in both treatment-naïve subjects and those previously treated with alendronate (Brown JBMR 2009; Kendler JBMR 2010). Objectives To compare the efficacy and safety of DMAb and risedronate (RIS) over 12 months in postmenopausal women considered suboptimally adherent to prior daily or weekly alendronate therapy. Methods This study randomised postmenopausal women aged ≥55 years to open-label DMAb 60 mg SC Q6M or open-label RIS 150 mg PO QM for 12 months. Primary endpoint: % change from baseline in total hip (TH) BMD at month 12. Other endpoints: % change from baseline in femoral neck (FN) and lumbar spine (LS) BMD at month 12; % change from baseline in serum CTX at months 1 and 6; and safety. Results In 870 subjects (435 DMAb, 435 RIS), mean (SD) age was 68 (7) years, mean (SD) BMD T-scores at TH, FN and LS were –1.6 (0.9), –1.9 (0.7) and –2.2 (1.2), respectively, and median CTX was 0.3 ng/mL. DMAb significantly increased mean (95% confidence interval) BMD from baseline to month 12 compared with RIS at TH [2.0% (1.8%, 2.3%) vs 0.5% (0.2%, 0.7%), respectively], FN [1.4% (1.0%, 1.7%) vs 0% (-0.4%, 0.3%)] and LS [3.4% (3.1%, 3.8%) vs 1.1% (0.7%, 1.5%); all p<0.0001]. DMAb significantly decreased CTX compared with RIS at month 1 (median change from baseline: –78% vs –17%) and month 6 (–61% vs –23%; both p<0.0001). Overall adverse events (AEs) and serious AEs were similar between groups. Conclusions In postmenopausal women suboptimally adherent to alendronate treatment, switching to DMAb was more effective than to RIS, based on significantly greater increases in BMD at all measured sites and greater reductions in CTX with DMAb. Acknowledgements This study and abstract were sponsored by Amgen and GSK. Disclosure of Interest C. Roux Grant/research support from: Amgen, Bongrain, MSD, Consultant for: Amgen, Lilly, MSD, Novartis, Roche, A. Fahrleitner-Pammer: None Declared, P. Ho Shareholder of: Amgen, Employee of: Amgen, F. Hawkins: None Declared, L. Hofbauer: None Declared, M. Micaelo: None Declared, S. Minisola Consultant for: Amgen, Bruno Farmaceutici, Eli Lilly, Merck Sharp & Dohme, Pfizer, Sigma Tau, Stroder, Speakers bureau: Abiogen, Amgen., Bruno Farmaceutici, Merck Sharp & Dohme, Nycomed, Novartis, Pfizer, Sigma Tau, N. Papaioannou Grant/research support from: Eli Lilly, Amgen, Consultant for: Amgen, Speakers bureau: Eli Lilly, Amgen, Servier, M. Stone: None Declared, J. Wark: None Declared, M. Zillikens: None Declared, I. Ferreira Shareholder of: Bristol Myers-Squibb, Novartis and Amgen, Employee of: Amgen, S. Siddhanti: None Declared, R. Wagman Shareholder of: Amgen, Employee of: Amgen, J. Brown Grant/research support from: Amgen, Eli Lilly, Merck, Novartis, Pfizer, Servier, Roche, Takeda, Warner Chilcott, Consultant for: Amgen, Eli Lilly, Merck, Speakers bureau: Amgen, Eli Lilly, Merck

The catalytic properties of enzymes in nonaqueous solvents are known to be dependent on the nature of the solvent. Here we present a molecular modeling study of the enantioselective properties of the enzyme cutinase in hexane under varying hydration conditions. Previous simulation studies have shown that for this model enzyme in hexane, the structural and dynamical properties are affected by the amount of water associated with the protein, being more similar to the aqueous simulation at 5–10% of water content. The implications of the hydration levels on the enzyme resolution of (R,S)-1-phenylethanol and (R,S)-2-phenyl-1-propanol are investigated using free energy calculations of the tetrahedral intermediate (TI) model. With this model system we show that the enzyme enantioselective properties are under the control of the amount of water present in the organic media. Maximum enantioselectivity is achieved at 10% water content. The stabilizing effects of the catalytic histidine on the TI are evaluated at different water contents and shown to be correlated. The correlation between the amount of water present in the media and the structural, dynamical, and thermodynamic properties of the enzyme are examined as well as the active site discriminative power.

Antiamoebin I (AAM-I) and zervamicin II (Zrv-IIB) are peptaibols that exert antibiotic activity through the insertion/disruption of cell membranes. In this study, we investigated how the folding of these peptaibols are affected when some of their native residues are replaced with proline analogues and asymmetrical D -α,α-dialkyl glycines (two classes of noncanonical amino acids). Systematic substitutions of native Aib, Pro, Hyp, and Iva residues were performed to elucidate the folding properties of the modified peptaibols incorporating noncanonical residues. The secondary structure of a peptaibol influences its ability to incorporate into membranes and therefore its function. Our findings reveal that native Zrv-IIB unfolds considerably in water. The presence of Iva and the noncanonical proline analogue cis -3-amino- L -proline (ALP) in both peptaibols induces helical structures. Inserting asymmetric glycines such as α-methyl- D -leucine (MDL) and α-methyl- D -phenylalanine (MDP) into the peptaibols induces folding. This preorganization in water may help to overcome the energy barrier required for peptaibol insertion into the membrane, as well as to facilitate the formation of transmembrane channels. Graphical abstract AAM-I and Zrv-IIB peptidomimetics carrying MDL and ALP noncanonical amino acids, exhibiting improved helical secondary structure in water

The availability of population-specific normative data regarding disease severity measures is essential for patient assessment. The goals of the current study were to characterize the pattern of ankylosing spondylitis (AS) in Portuguese patients and to develop reference centile charts for BASDAI, BASFI, BASMI and mSASSS, the most widely used assessment tools in AS. AS cases were recruited from hospital outpatient clinics, with AS defined according to the modified New York criteria. Demographic and clinical data were recorded. All radiographs were evaluated by two independent experienced readers. Centile charts for BASDAI, BASFI, BASMI and mSASSS were constructed for both genders, using generalized linear models and regression models with duration of disease as independent variable. A total of 369 patients (62.3% male, mean ± (SD) age 45.4 ± 13.2 years, mean ± (SD) disease duration 11.4 ± 10.5 years, 70.7% B27-positive) were included. Family history of AS in a first-degree relative was reported in 17.6% of the cases. Regarding clinical disease pattern, at the time of assessment 42.3% had axial disease, 2.4% peripheral disease, 40.9% mixed disease and 7.1% isolated enthesopatic disease. Anterior uveitis (33.6%) was the most common extra-articular manifestation. The centile charts suggest that females reported greater disease activity and more functional impairment than males but had lower BASMI and mSASSS scores. Data collected through this study provided a demographic and clinical profile of patients with AS in Portugal. The development of centile charts constitutes a useful tool to assess the change of disease pattern over time and in response to therapeutic interventions.

Background We aimed to determine the circulating miRNA expression profile associated with BAV and aortic dilation to provide diagnostic and prognostic biomarkers for BAV and/or aortic dilation. Methods and results We applied a miRNome-wide microarray approach using plasma samples (n = 24) from healthy tricuspid aortic valve individuals, BAV patients and BAV patients with aortic dilation to compare and identify the specific miRNAs associated with BAV and aortic dilation. In a second stage, the expression patterns of the miRNA candidates were validated by RT-qPCR in an independent cohort (n = 43). The miRNA microarray data and RT-qPCR analyses revealed that the expression levels of circulating miR-122, miR-130a and miR-486 are significantly influenced by the morphology of the aortic valve (bicuspid/tricuspid) and could be functionally involved in the regulation of TGF-β 1 signalling. Furthermore, the expression pattern of miR-718 in the plasma was strongly influenced by dilation of the ascending aorta. miR-718 expression was inversely correlated with the aortic diameter (R = −0.63, p = 3.1 × 10 −5 ) and was an independent predictor of aortic dilation (β = −0.41, p = 0.022). The genes targeted by miR-718 are involved in the regulation of vascular remodelling. Conclusions We propose that miR-122, miR-130a, miR-486 and miR-718 are new molecular features associated with BAV and aortic dilation principally by the activation of TGF-β 1 pathway and vascular remodelling mediated by VEGF signalling pathways.