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The rs6265 single nucleotide polymorphism (SNP) in the gene for brain-derived neurotrophic factor is a common variant that alters therapeutic outcomes for individuals with Parkinson’s disease (PD). We previously investigated the effects of this SNP on the experimental therapeutic approach of neural grafting, demonstrating that young adult parkinsonian rats carrying the variant Met allele exhibited enhanced graft function compared to wild-type rats and also exclusively developed aberrant graft-induced dyskinesias (GID). Aging is the primary risk factor for PD and reduces graft efficacy. Here we investigated whether aging interacts with this SNP to further alter cell transplantation outcomes. We hypothesized that aging would reduce enhancement of graft function associated with this genetic variant and exacerbate GID in all grafted subjects. Unexpectedly, beneficial graft function was maintained in aged rs6265 subjects. However, aging was permissive to GID induction, regardless of genotype, with the greatest incidence and severity found in rs6265-expressing animals.

Background Chronic kidney disease (CKD) limits the treatment options in acute gouty arthritis (GA) patients due to intolerance and contraindications to available therapies. Efficacy and safety of canakinumab (CAN), a selective, fully human, anti-IL-1β monoclonal antibody, formulated as a lyophilized (CAN-LYO) powder requiring reconstitution with water vs triamcinolone acetonide (TA) in patients with acute GA was demonstrated in previous phase III trials. Objectives To evaluate efficacy and safety of CAN liquid formulation (CAN-PFS) vs TA in a subgroup of patients with CKD stage ≥3. Methods This was a 12-week, multicenter, double-blind, active controlled study. The design and methodology of the study have been reported earlier1. Here, we report results from a post-hoc analysis of the 12-week data for GA patients with CKD stage ≥3 (estimated Glomerular Filtration Rate (eGFR) <60ml/min). The primary endpoint was pain intensity in the target joint, measured on 0-100 mm VAS scale at 72 h post-dose. Secondary endpoints included time to first new attack, and safety over 12 weeks. Results Of 388 patients, 76 had CKD stage ≥3 at baseline (CAN-PFS, n=24; CAN-LYO, n=28; TA, n=24). CAN-PFS provided a statistically significant reduction in pain intensity in the target joint vs TA from 72 h post-dose (estimated difference, -14.6mm; 95% CI:-29.0, -0.1, p≤0.05) until 7 days post-dose (-16.1mm; 95% CI: -28.4, -3.7, p=0.0115). The two CAN treatment arms were comparable. Over 12 weeks, a single dose of CAN-PFS showed a significant relative risk reduction of 90% for time to first new gout attack vs TA [HR 0.10, 95% CI (0.01, 0.78); p≤0.05]. Adverse events (AEs) were reported in 12 (50%), 11 (39.3%) and 10 (41.7%) patients in CAN-PFS, CAN-LYO and TA groups, respectively. The most frequent AEs were infections (CAN-PFS, n=3 (12.5%); CAN-LYO, n=6 (21.4%); TA, n=2 (8.3%). Serious AEs were reported in a total of 7 patients (CAN-PFS, n=2 (8.3%); CAN-LYO, n=4 (14.3%); TA, n=1 (4.2%), with infections (CAN-PFS, n=1 (4.2%); CAN-LYO, n=2 (7.1%); TA, n=0), being the most common SAEs. No deaths were reported during the study. Conclusions This post-hoc analysis provides evidence for the efficacy of CAN-PFS compared with a potent long-acting corticosteroid in providing significant pain relief and reducing incidence of new attacks in GA patients with CKD stage ≥3 with limited treatment options. The safety profile in this sub population was consistent with that of the overall study population and with that known from previous studies. References Sunkureddi et al. Arthirits & Rheum 2013; 65. Disclosure of Interest P. Sunkureddi Consultant for: Novartis, Bristol Myers Squibb, Speakers bureau: Pfizer, Takeda, Bristol Myers Squibb, UCB, Amgen, Abbott, Shinogi, Savient, E. Toth: None declared, J. Brown Grant/research support: Amgen, Bristol Myers Squibb, Eli Lilly, Novartis, Merck, Pfizer, Roche, Servier, Sanofi-Aventis, Takeda, Warner Chilcott, Consultant for: Amgen, Eli Lilly, Merck, Warner Chilcott, Sanofi–Aventis, Speakers bureau: Amgen, Eli Lilly, Novartis, Merck, A. Kivitz Grant/research support: Novartis, A. Stancati Shareholder of: Novartis, Employee of: Novartis, D. Richard Shareholder of: Novartis, Employee of: Novartis, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, R. Möricke: None declared DOI 10.1136/annrheumdis-2014-eular.1850

Background Canakinumab (CAN), a selective, fully human anti-IL-1β monoclonal antibody, is the only approved biologic in the European Union for the symptomatic treatment of adult patients (pts) with difficult-to-treat gouty arthritis (GA). A liquid formulation, presented as pre-filled syringe (CAN-PFS) has been developed to improve upon the lyophilized form (CAN-LYO) that requires reconstitution. Here, we report results from a post-hoc analysis of the 12-week data of a Phase III trial. Objectives To evaluate the efficacy and safety of CAN-PFS vs triamcinolone acetonide (TA) in a subset of difficult-to-treat GA pts defined as a) unable to use NSAIDs and colchicine due to contraindication, intolerance or lack of efficacy, and b) currently on urate-lowering therapy (ULT), or previously failed ULT or in whom ULT is otherwise contraindicated. Methods This was a 12-week, multicenter, double-blind, active controlled study. The design and methodology of the study have been reported earlier1. The primary efficacy measure was overall pain intensity in the most affected joint measured on VAS scale (0-100 mm) at 72 h post-dose. Secondary endpoints included time to first new attack and safety over 12 weeks. Results Of the 397 GA pts randomized, 106 (CAN-PFS, n=34; CAN-LYO, n=43; TA, n=29) met the subgroup definition. CAN-PFS provided a statistically significant reduction in pain intensity at 72 h post dose vs TA (estimated difference, -30.7mm; 95%CI: -42.1, -19.3, p≤0.05). The least square mean pain scores at 72 h post-dose for CAN -PFS and LYO, were14.7mm and 19.3mm, respectively; both lower than that for TA (45.4mm). CAN-PFS treatment significantly delayed time to first new attack vs TA with a relative risk reduction of 92% (HR, 0.08; 95%CI: 0.01, 0.63, p≤0.05) over 12 weeks. Adverse events (AEs) were reported in 12 (35.3%), 16 (37.2%) and 14 (48.3%) pts in CAN-PFS, CAN-LYO and TA groups, respectively. Serious AEs were reported in 7 pts [CAN-PFS, n=1 (2.9%); CAN-LYO, n=5 (11.6%); TA, n=1 (3.4%)], with infections [CAN-PFS, n=1 (2.9%); CAN-LYO, n=2 (4.7%); TA, n=0)] being the most common SAEs. One patient in the CAN-LYO group had serious aortitis, which was coded under vascular disorders system organ class, but adjudicated as an opportunistic infection by the independent adjudication committee. No deaths were reported during the study. Conclusions This analysis provides evidence for the efficacy of CAN in difficult-to-treat GA pts either in pre-filled syringe or lyophilized formulation compared to a potent long acting systemic corticosteroid. CAN-PFS provided better pain relief and reduced the risk of new attacks compared to TA. The safety profile in this population was consistent with that of the overall study population and with that known from previous studies. References Sunkureddi et al. Arthirits & Rheum 2013; 65. Disclosure of Interest P. Sunkureddi Consultant for: Novartis, Bristol Myers Squibb, Speakers bureau: Pfizer, Takeda, Bristol Myers Squibb, UCB, Amgen, Abbott, Shinogi, Savient, E. Toth: None declared, J. Brown Grant/research support: Amgen, Bristol Myers Squibb, Eli Lilly, Novartis, Merck, Pfizer, Roche, Servier, Sanofi-aventis, Takeda, Warner Chilcott, Consultant for: Amgen, Eli Lilly, Merck, Warner Chilcott, Sanofi-aventis, Speakers bureau: Amgen, Eli Lilly, Novartis, Merck, A. Kivitz Grant/research support: Novartis, A. Stancati Shareholder of: novartis, Employee of: novartis, D. Richard Shareholder of: Novartis, Employee of: Novartis, K. Lheritier Shareholder of: Novartis, Employee of: Novartis, R. Möricke: None declared DOI 10.1136/annrheumdis-2014-eular.1846

Functional disability and quality of life in rheumatoid arthritis (RA) are key outcomes that determine patient’s demand for care, and influence their compliance and satisfaction with treatment. In the recent years the demand to collect outcome data is ever increasing as a means for the validation of quality care, and the development of effective outcome measures has become a major thrust of health research and has contributed to better understanding the relationship between outcomes and specific elements of health care. There are several disease-generic and specific instruments available that have proven valuable in outcome testing in RA. The first instruments provide a broad picture of health status across a range of conditions, whereas the latter are more sensitive to the disorder under consideration and are therefore more likely to reflect clinically important changes. When necessary, this kind of scales can be supplemented with specialised domain-specific scales (for the assessment of psychological well-being, social role functioning, or other). As in other fields, these measurement instruments mainly focus on: a) clinical signs and symptoms (physiologic and biologic); b) physical and/or cognitive functioning; c) well-being and emotional functioning; d) social functioning; e) satisfaction with care and other personal constructs (life satisfaction, spirituality, etc.); f) health-related quality of life (HRQOL). Over the past 20 years, there has been a better recognition of the patient’s point of view as an important component in the assessment of health care outcomes, and an increasing interest in HRQOL as an important area of research, due to the rising burden of chronic diseases, longer expectation of life, the growing number of health intervention alternatives, and greater emphasis on humanising health care. In addition, decision-making on issues of cost-effectiveness across health inputs and resource allocation across health programs is likely to be more sound if informed by HRQOL evidence. This paper reviews the literature and discusses the major issues regarding mainly measures of physical function (e.g., mobility or daily activities) and health status, including some so called HRQOL instruments.

The aim of the study was to compare the responsiveness of disease-specific (Arthritis Impact Measurement Scale 2, AIMS2), generic (Medical Outcome Study Short Form Health Survey, SF-36) and preference-based instruments (rating scale, RS and time tradeoff, TTO) to changes in articular status and perceived health in patients with rheumatoid arthritis (RA). Seventy-eight consecutive patients with RA, attending the care facilities of the Department of Rheumatology of Ancona, were recruited in this longitudinal study. In order to assess the responsiveness three strategies were used: effect size (ES), standardised response mean (SRM) and receiver operating characteristic (ROC). There were 55 women and 23 men with a mean age of 56 years (range 19-78) and arthritis duration of 7.1 years (range 6 months to 24 years). Using three-category EULAR criteria as external indicators of improvement/response, 21 patients (27%) reported a significant improvement, 23 (29.5%) moderate improvement, and 34 (43.5%) no change over the 12-month period. The mean change scores in generic and specific health status instruments and utility measures were significantly related to response category. The AIMS2 subscales (physical function, pain, psychological function and social interaction) were slightly more responsive than those of SF-36. The physical and pain dimensions were most sensitive for measuring change over a 12-month period, followed by psychological and social dimensions. For the utility measurement, RS scores were found to be significantly more responsive in detecting changes in preferences than TTO scores. These results may have implications for the application of the health status and utility measures in clinical trials in patients with RA.

Health-related quality of life (HRQOL) assessment is receiving increasing attention as an outcome measure in osteoarthritis (OA). The aims of this study were to compare HRQOL among older adults aged 55 to 78 years with hip and/or knee OA with those without OA, and to assess the influence of selected variables (sex, body mass index, radiographic OA severity, educational level, comorbidities) on HRQOL. The generic Medical Outcome Study Short Form-36 item health status questionnaire (SF-36) was administered to a cohort of 264 OA patients (105 with hip OA alone, 108 with knee OA alone, and 51 with both hip and knee OA) and 112 healthy controls. Compared with the healthy controls, OA of the lower extremities has a detrimental effect on the eight-scale profile score, as well as on physical and mental summary measures of the SF-36. The most striking impact was seen in the physical measures \"physical functioning\", \"physical role\" and \"pain\" (p<0.0001). No statistically significant differences in SF-36 scores were found among the three groups of OA patients. The physical and mental summary scales of the SF-36 were closely correlated (p<0.0001). One hundred and forty-five patients (54.9%) reported at least one chronic coexisting disease. There was a significant inverse association with measures of comorbidity (number of comorbidities and comorbidity index score) and both physical and mental summary scores of the SF-36 questionnaire. In patients with OA of the knee alone (but not in hip OA alone or hip and knee OA), the SF-36 pain score was inversely correlated with years of formal education (p=0.016). In addition, the impact of hip and knee SF-36 dimensions was not influenced by the degree of radiographic severity. Older adults with OA of the lower extremities undergo a significant impact on multiple dimensions of HRQOL, compared with healthy controls. The use of a generic measure of HRQOL such as the SF-36, in studies of OA where comorbidity is common, should be useful in characterizing the global burden of this disease.

Osteoporosis and its consequent increase in fracture risk is a major health concern for postmenopausal women and older men and has the potential to reach epidemic proportions. The \"gold standard\" for osteoporosis diagnosis is bone densitometry. However, economic issues or availability of the technology may prevent the possibility of mass screening. The goal of this study was to develop and validate a clinical scoring index designed as a prescreening tool to help clinicians identify which women are at increased risk of osteoporosis [bone mineral density (BMD) T-score -2.5 or less] and should therefore undergo further testing with bone densitometry. Records were analyzed for 1522 postmenopausal females over 50 years of age who had undergone testing with dual-energy X-ray absorptiometry (DXA). Osteoporosis risk index scores were compared to bone density T-scores. Hologic QDR 4500 technology was used to measure BMD at the femoral neck and lumbar spine (L1-L4). Participants who had a previous diagnosis of osteoporosis or were taking bone-active medication were excluded. Receiver-operating characteristic (ROC) analysis was used to identify the specific cutpoint value that would identify women at increased risk of low BMD. A simple algorithm based on age, weight, history of previous low impact fracture, early menopause, and corticosteroid therapy was developed. Validation of this five-item osteoporosis prescreening risk assessment (OPERA) index showed that the tool, at the recommended threshold (or cutoff value) of two, had a sensitivity that ranged from 88.1 [95% confidence interval (CI) for the mean: 86.2-91.9%] at the femoral neck to 90% (95% CI for the mean: 86.1-93.1%) at the lumbar spine area. Corresponding specificity values were 60.6 (95% CI for the mean: 57.9-63.3%) and 64.2% (95% CI for the mean: 61.4-66.9%), respectively. The positive predictive value (PPV) ranged from 29 at the femoral neck to 39.2% at the lumbar spine, while the corresponding negative predictive values (NPVs) reached 96.5 and 96.2%, respectively. Based on this cutoff value, the area under the ROC curve was 0.866 (95% CI for the mean: 0.847-0.882) for the lumbar spine and 0.814 (95% CI for the mean: 0.793-0.833) for the femoral neck. We conclude that the OPERA is a free and effective method for identifying Italian postmenopausal women at increased risk of osteoporosis. Its use could facilitate the appropriate and more cost-effective use of bone densitometry in developing countries.

Osteoarthritis (OA) is one of the most prevalent and disabling chronic conditions affecting older adults, and is a significant public health problem among adults of working age. The knee is the most frequently involved joint site associated with disability in OA. Diagnosis of OA is primarily based on history and physical examination, but radiographic findings, including asymmetric joint space narrowing (JSN), subchondral sclerosis, osteophyte formation, subluxation, and distribution patterns of osteoarthritic changes are all helpful when diagnosis is uncertain. Structural morphological changes on X-rays are also considered the primary outcome variables for assessing the progression of OA. The development of new methods for prevention and treatment of OA requires improved understanding of the factors that influence its progression. The ability to assess progression quantitatively is a necessary first step in understanding factors that influence the disease process. Depending on the joint studied, several indices are currently used for assessing radiological progression of OA, including individual radiographic features (e.g., marginal osteophytes), composite indices (e.g., Kellgren and Lawrence scoring systems), and quantitative measures (e.g., joint space width measurement). Unfortunately, the review of studies evaluating the longitudinal rate of JSN indicates that the yearly change may be very small and of doubtful clinical significance. This emphasizes the need for further refinement in the definition of radiographic outcomes in prospective clinical trials. This review focuses on the available scoring methods used for the sites most frequently involved in OA (hand, knee, hip) and their various advantages and disadvantages.

Troops from the semiautonomous Kurdish region and Iran-backed Shiite militias are playing important roles in the campaign against Islamic State . Kurdish and U.S. forces had to intervene in May to repel Islamic State militants who attacked a town north of Mosul that the militia was holding, in a battle that left one U.S. Navy SEAL dead .