The association of subchondral and systemic bone mineral density with osteoarthritis-related joint replacements in older adults.

OBJECTIVE: To describe the association of subchondral and systemic bone mineral density (BMD) with knee and hip replacements (KR and HR, respectively) due to osteoarthritis. DESIGN: 1,095 participants (mean age 63 years, 51% female) were included. At baseline, subchondral BMD of the medial and lateral tibia in three regions of interest (ROI) for the right knee, and systemic BMD of the lumbar spine, femoral neck, total hip and whole-body, were measured using dual-energy X-ray absorptiometry. Subchondral BMD of the hip was not measured. Competing risk regression models were used to estimate sub-distribution hazard ratios (SHRs) of KR/HR per one standard deviation (SD) higher in BMD measures, with adjustment of potential confounders. RESULTS: Over 12.2 years, 79 (7.2%) participants underwent a KR and 56 (5.1%) an HR due to osteoarthritis. For the right side, medial subchondral BMD in ROI-3 was associated with an increased risk of KR (SHR 1.95 per SD; 95% Confidence Interval [CI], 1.57 to 2.43). In contrast, systemic BMD was not associated with the risk of KR, but higher BMD at the lumbar spine (1.42, 1.07 to 1.88) and whole-body (1.29, 1.00 to 1.66) were associated with an increased risk of HR at both sides. CONCLUSIONS: Subchondral BMD is positively associated with an increased risk of KR and systemic BMD with an increased risk of HR, suggesting a role of BMD in the progression of osteoarthritis.

A randomised double-blind placebo-controlled crossover trial of HUMira (adalimumab) for erosive hand OsteoaRthritis - the HUMOR trial.

OBJECTIVE: To assess the efficacy of adalimumab in patients with erosive hand osteoarthritis (OA). METHOD: Patients >50 years old, meeting the American College of Rheumatology (ACR) criteria for hand OA, with pain >50 on 100 mm visual analogue scale (VAS), morning stiffness >30 min and ≥1 erosive joint on X-ray with synovitis present on magnetic resonance imaging (MRI) were included in a randomised double-blind placebo-controlled crossover trial. Patients were randomised to adalimumab (40 mg subcutaneous injections every other week) or identical placebo injections for 12 weeks followed by an 8-week washout and then crossed over treatment groups for another 12 weeks. The primary outcome was change in VAS hand pain over 12 weeks. Secondary outcomes included change in Australian/Canadian Hand OA Index (AUSCAN) pain, function and stiffness subscales from baseline to 4, 8 and 12 weeks, change in MRI-detected synovitis and bone marrow lesions (BMLs) from baseline to 12 weeks and change in VAS from baseline to 4 and 8 weeks. RESULTS: We recruited 51 patients and 43 were randomised to either Group 1 (N = 18, active then placebo) or Group 2 (N = 25, placebo then active). At 12 weeks there was no difference between the groups on the primary outcome measure (mean decrease in VAS pain of 3.2 mm standard deviation (SD 16.7) for adalimumab vs 0.8 mm (SD 29.6) for placebo). The adjusted treatment effect was -0.7 mm (95% confidence interval (CI) -9.3 to 8.0), P = 0.87. No statistically significant differences were found for any secondary outcomes. CONCLUSION: Adalimumab did not show any effect on pain, synovitis or BMLs in patients with erosive hand OA with MRI-detected synovitis as compared to placebo after 12 weeks. CLINICAL TRIAL REGISTRATION NUMBER: ACTRN12612000791831.

Cross-sectional and longitudinal associations between serum inflammatory cytokines and knee bone marrow lesions in patients with knee osteoarthritis.

OBJECTIVE: To describe cross-sectional and longitudinal associations between serum levels of interleukin (IL) - 6, IL-17A, IL-17F, IL-23 and knee bone marrow lesions (BMLs) in patients with knee osteoarthritis (OA). DESIGN: Patients (n = 192) with symptomatic knee OA (mean 63 years, range 50-79, female 53%) were assessed at baseline and after 24 months. At each time point, serum IL-6, IL-17A, IL-17F and IL-23 were measured using Bio-Plex® Multiplex Immunoassays with Luminex xMAP technology. Knee BMLs were scored using the modified whole organ MRI score (WORMS) from T2 weighted fat-suppressed fast spin echo magnetic resonance imaging (MRI). Multivariable linear regression and log binominal regression were used to determine the associations between cytokines and BMLs. RESULTS: Baseline IL-6 (quarters) were significantly associated with total knee BMLs (P < 0.01 for the trend) as well as associated with an increase in BML score (P = 0.05 for the trend), after adjustment for confounders. Baseline IL-17F and IL-23 (highest quarters vs others) was associated with an increase in BML score in females (P = 0.04 for IL-17F; P = 0.01 for IL-23), but not in males, in multivariable analyses. In contrast, IL-17A was not significantly associated with BMLs in either females or males. CONCLUSION: IL-6 is associated with increased knee BMLs in both females and males with OA. Serum IL-17F and IL-23 predicted increased knee BML scores in females only, suggesting that inflammation is involved in BML pathogenesis in knee OA, especially in women. TRAIL REGISTRATION: ClinicalTrials.gov identifier: NCT01176344; Australian New Zealand Clinical Trials Registry: ACTRN12610000495022.

Associations between serum ghrelin and knee symptoms, joint structures and cartilage or bone biomarkers in patients with knee osteoarthritis.

OBJECTIVE: The roles of ghrelin in knee osteoarthritis (OA) are unclear. This study aimed to examine cross-sectional associations of ghrelin with knee symptoms, joint structures and cartilage or bone biomarkers in patients with knee OA. METHODS: This study included 146 patients with symptomatic knee OA. Serum levels of ghrelin and cartilage or bone biomarkers including cartilage oligomeric matrix protein (COMP), cross linked C-telopeptide of type I collagen (CTXI), cross linked N-telopeptide of type I collagen (NTXI), N-terminal procollagen III propeptide (PIIINP), and matrix metalloproteinase (MMP)-3, 10, 13 were measured using Enzyme-linked immunosorbent assay (ELISA). Knee symptoms were assessed using the Western Ontario and McMaster Universities Arthritis Index (WOMAC). Infrapatellar fat pad (IPFP) volume, IPFP signal intensity alternation, cartilage defects, bone marrow lesions (BMLs) and effusion-synovitis were assessed using the (MRI). Osteophytes and joint space narrowing (JSN) were assessed using the Osteoarthritis Research Society International atlas. RESULTS: After adjustment for potential confounders, ghrelin quartiles were positively associated with knee symptoms including pain, stiffness, dysfunction and total score (quartile 4 vs 1: ß 24.19, 95% CI 8.13-40.25). Ghrelin quartiles were also significantly associated with increased IPFP signal intensity alteration (quartile 4 vs 1: OR 3.57, 95% CI 1.55-8.25) and NTXI, PIIINP, MMP3 and MMP13. Ghrelin was not significantly associated with other joint structures and biomarkers. CONCLUSIONS: Serum levels of ghrelin were significantly associated with increased knee symptoms, IPFP signal intensity alteration and serum levels of MMP3, MMP13, NTXI and PIIINP, suggesting that ghrelin may have a role to play in knee OA.

Temporal trends in thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (ATPO) testing across two phases of iodine fortification in Tasmania (1995-2013).

CONTEXT: Tasmania is an island state of the Australian Commonwealth with a well-documented history of mild iodine deficiency. Between 2001 and 2009, Tasmania experienced two incremental phases of iodine fortification. OBJECTIVE: To examine trends in thyroid-stimulating hormone (TSH) and thyroid peroxidase antibody (ATPO) testing and their relationship to different phases of iodine nutrition in the Tasmanian population between 1995 and 2013. DESIGN: Retrospective longitudinal study. SETTING AND PARTICIPANTS: The major primary care and largest public hospital pathology providers in Tasmania submitted data for all TSH and ATPO tests performed between 1995 and 2013. Data linkage methodology was used to determine trends in TSH and ATPO testing. RESULTS: A total of 1.66 million TSH assessments, involving 389,910 individual patients, were performed in Tasmania between 1995 and 2013. There was approximately a fourfold increase in the overall rate of TSH testing during this period with the rate of incident TSH assessment remaining relatively stable over the study period. The incidence of overt suppression and elevation of TSH (TSH≤0.1 mIU/L and ≥10 mIU/L) declined 62.3% and 59.7%, respectively, with a trend for increased incidence of borderline TSH elevation ≥4.0 mIU/L. The incidence of thyroid autoimmunity as determined by the proportion of abnormal ATPO results remained stable, with the absolute number of positive test results increasing during the study period. CONCLUSION: Iodine supplementation of this mildly iodine-deficient population was not associated with an obvious increase in incidence of overt thyroid dysfunction or autoimmunity. Whilst the volume of TSH testing increased over the study period, the increase was driven by patients undergoing follow-up TSH assessments.

The relationship between cumulative lifetime ultraviolet radiation exposure, bone mineral density, falls risk and fractures in older adults.

Data linking cumulative lifetime vitamin D status with skeletal outcomes are lacking. We show that increasing cumulative sun exposure was associated with higher bone mineral density in younger males and protective against fractures in females independent of current vitamin D. This supports the concept that cumulative sun exposure is an important contributor to skeletal health. INTRODUCTION: While low 25-hydroxyvitamin D levels are associated with increased fracture risk, this reflects only recent sun exposure. The Beagley-Gibson (BG) method utilises microtopographical skin changes to quantify cumulative lifetime ultraviolet radiation (sun) exposure. This study aimed to describe the relationship between BG grade, BMD, falls risk and fractures in older adults. METHODS: Eight hundred thirty-five community-dwelling adults aged 53-83 years had silicone casts from the dorsum of both hands graded by the BG method. BMD was measured using DXA and falls risk using the short form of the Physiological Profile Assessment. Vertebral deformities and symptomatic fractures were assessed by DXA and questionnaire, respectively. RESULTS: The relationship between BG grade, spine BMD and vertebral fracture varied depending upon sex. In females, increasing grade was associated with lower vertebral fracture prevalence (OR = 0.44/grade, p = 0.018) and fewer fractures (OR = 0.82/grade, p = 0.021), particularly major fractures (OR = 0.75/grade, p = 0.03). In males, increasing grade was associated with more DXA-detected vertebral deformities (RR = 1.28/grade, p = 0.001), but not symptomatic fractures. These relationships were independent of BMD, falls risk, smoking and current 25-hydroxyvitamin D. BG grade was not associated with falls risk. For BMD, there were interactions between BG grade and both age and sex and a positive trend with hip BMD in younger males. CONCLUSIONS: BG grade demonstrated beneficial associations with fracture outcomes in females and BMD in younger males independent of current 25-hydroxyvitamin D. These data support the concept that cumulative ultraviolet radiation exposure is an important determinant of skeletal health. The association with vertebral deformities in males may reflect outdoor physical trauma in younger life.

Predictors of Beagley-Gibson skin cast grade in older adults.

BACKGROUND AND PURPOSE: The Beagley-Gibson (BG) grading system utilizes microtopographical skin changes to generate an individualized, objective estimate of cumulative, lifetime ultraviolet radiation (UVR) exposure. However, predictors of BG grade are ill-defined, particularly in older populations. The aim of this cross-sectional study was to describe the factors associated with skin damage as measured by the BG method in 835 community-dwelling older adults. METHODS: Study participants aged 53-83 years had silicone casts taken from the dorsum of both hands and graded by the BG method. Lifetime sun exposure, skin phenotypic traits and smoking status were assessed by questionnaire. 25-hydroxyvitamin D and melanin density were measured using radioimmunoassay and spectrophotometry, respectively. Ordered logistic regression was used to compute a single odds ratio (OR) by taking BG grade as the outcome variable. RESULTS: Higher 25-hydroxyvitamin D was associated with increasing BG grade (OR = 1.39, P = 0.02) in adjusted analysis. Age (OR = 1.14, P < 0.001), occupational sun exposure (OR = 1.62, P < 0.001), ability to tan (OR = 1.40, P < 0.001), melanin density (OR=0.79, P = 0.001), lifetime leisure time sun exposure (OR = 1.21, P = 0.004), current smoking (OR = 1.82, P = 0.007), propensity to sunburn (OR = 1.18, P = 0.016), and waist-hip ratio (OR = 1.10, P = 0.02) were independent predictors of BG grade. Hair colour, number of sunburns, body mass index and gender were not independent predictors of BG grade. CONCLUSIONS: Beagley-Gibson skin cast grade is a biologically relevant marker of UVR exposure in older adults influenced by both intrinsic and extrinsic factors.

Population attributable fractions and joint effects of key risk factors for multiple sclerosis.

AIM: We examined the combined effect of having multiple key risk factors and the interactions between the key risk factors of multiple sclerosis (MS). METHODS: We performed an incident case-control study including cases with a first clinical diagnosis of central nervous system demyelination (FCD) and population-based controls. RESULTS: Compared to those without any risk factors, those with one, two, three, and four or five risk factors had increased odds of being an FCD case of 2.12 (95% confidence interval (CI), 1.11-4.03), 4.31 (95% CI, 2.24-8.31), 7.96 (95% CI, 3.84-16.49), and 21.24 (95% CI, 5.48-82.40), respectively. Only HLA-DR15 and history of infectious mononucleosis interacted significantly on the additive scale (Synergy index, 3.78; p = 0.03). The five key risk factors jointly accounted for 63.8% (95% CI, 43.9-91.4) of FCD onset. High anti-EBNA IgG was another important contributor. CONCLUSIONS: A high proportion of FCD onset can be explained by the currently known risk factors, with HLA-DR15, ever smoking and low cumulative sun exposure explaining most. We identified a significant interaction between HLA-DR15 and history of IM in predicting an FCD of CNS demyelination, which together with previous observations suggests that this is a true interaction.

Anxiety, depression and fatigue at 5-year review following CNS demyelination.

BACKGROUND: Anxiety and depression are common in multiple sclerosis (MS). We evaluated the prevalence and factors associated with anxiety, depression and fatigue at the 5-year review of a longitudinal cohort study following a first clinical diagnosis of CNS demyelination (FCD). METHODS: Cases with a FCD were recruited soon after diagnosis and followed annually thereafter. A variety of environmental, behavioural and clinical covariates were measured at five-year review. Anxiety and depression were measured using the Hospital Anxiety & Depression Scale (HADS), and fatigue by the Fatigue Severity Scale (FSS). RESULTS: Of the 236 cases, 40.2% had clinical anxiety (median HADS-A: 6.0), 16.0% had clinical depression (median HADS-D: 3.0), and 41.3% had clinical fatigue (median FSS: 4.56). The co-occurrence of all three symptoms was 3.76 times greater than expectation. Younger age, higher disability, concussion or other disease diagnosis were independently associated with a higher anxiety score; male sex, higher disability, being unemployed, less physical activity, and antidepressant and/or anxiolytic-sedative medication use were independently associated with a higher depression score. Higher disability, immunomodulatory medication use, other disease diagnosis and anxiolytic-sedative medication use were independently associated with having fatigue, while female sex, higher BMI, having had a concussion, being unemployed and higher disability were associated with a higher fatigue score. CONCLUSION: These results support previous findings of the commonality of anxiety, depression and fatigue in established MS and extend this to post-FCD and early MS cases. The clustering of the three symptoms indicates that they may share common antecedents.

Australian insurance costs of jockeys injured in a race-day fall.

BACKGROUND: The risk of falls and injuries in horseracing varies with sex and experience of the jockey. AIMS: To determine whether the incidence and costs of insurance claims also differ by such factors. METHODS: A retrospective analysis of compensation claims by flat racing and jumps jockeys injured in a race-day fall in Australia between 2002 and 2009. Claim incidence, costs, absentee days and location, cause and type of injury sustained were described, stratified by jockey sex, age and experience. RESULTS: The incidence of claims by flat and jumps racing was 0.6 and 6.5 per 1000 rides, respectively. The mean cost of a claim was 43374 Australian dollars (AUD) (SD 249612) in flat racing and AUD 52589 (SD 157808) in jumps racing. The incidence of claims was greater for experienced flat racing jockeys than apprentices but mean costs were higher for apprentices. After adjustment for experience, there were no sex differences in the average cost or incidence of flat racing jockeys' claims. In general, the fall incidence declined, but the claim incidence and median cost of a claim increased, with age. On average, jockeys were absent from work for 9 weeks following a substantive injury. Limb fractures (33%), muscular or soft tissue injuries (28%) and contusions (17%) were the most commonly reported injuries. CONCLUSIONS: The economic costs of jockey injuries sustained in race-day falls are considerable. Identification of differences in incidence and costs of insurance claims between jockey characteristics will assist decision makers in the development and assessment of targeted safety strategies.

Growth and geographical variation in the use of cardiac imaging in Australia.

BACKGROUND AND AIM: Growth rates and regional differences in the use of cardiac imaging are potential metrics of quality of care. This study sought to define growth and regional variation in outpatient cardiac imaging in Australia. METHODS: Analyses are based on the rate of outpatient transthoracic echocardiography (TTE), transoesophageal echocardiography (TOE) and stress echocardiography (SE) and single-photon emission computed tomography (SPECT) per 100 000 people in each geographic insurance region in Australia (Medicare local, ML). Numbers of tests from 2002 to 2013 were obtained from Medicare Australia Statistics, and the number of doctors was obtained from the Health Workforce data. Demographic data (total population, rural areas and quintiles of disadvantage) were obtained from census data. RESULTS: Over the past 11 years, TTE reimbursements/100 000 people increased from 1780 to 3497 (8.8% annualised growth), TOE from 33 to 61, SE from 181 to 947 and SPECT from 287 to 337. SE had the biggest increment, an average growth rate of 38.5%/year. The relationships between the use of each cardiac imaging techniques and demographic, medical and illness factors were analysed in outpatient tests reimbursed in 2012. For each additional medical practitioner per 1000 people, there was an increase in the rate of TTE (ß = 1.25 (95% confidence interval CI: 1.17-1.33), P < 0.001), and TOE use (ß = 1.13 (1.04-1.24), P = 0.005), independent of regional burden of cardiovascular disease and social determinants. For SPECT the largest independent correlate for testing was the percentage of women within the ML; each additional percentage increase resulted in doubling of the rate of testing (ß = 2.25 (1.72-2.94), P < 0.001). CONCLUSION: Variation in the use of TTE in Australia does not appear illness related and may be evidence of under- and overutilisation. An appropriate use process may contain this variation.

[Current Approaches in Cancer Immunotherapy]. / Soucasné moznosti imunoterapie nádorových onemocnení.

Methods of cancer immunotherapy have finally entered clinical medicine after years of preclinical research. Currently, there are several methods, which have proven to be very effective even in cases of incurable cancer. Antitumor monoclonal antibodies are among major therapeutic anti-cancer drugs and have been successfully used for many ears. Novel group of antibodies are immunomodulatory antibodies which can break tumor -specific immune tolerance and induce regression of tumors by nonspecific activation of immune system. Bispecific antibodies represent a novel class of anticancer agents which can induce expansion of T cells in vivo, blinatumomab is an example of such agents and is currently available for the treatment of acute B -cell leukemia. Cellular immunotherapy is also very effective, especially the use of Chimeric receptor modified T-cells for the therapy of B- cell lymphoproliferative diseases. Although it is a very complicated and expensive method, it is highly effective approach which can induce remission even in previously hopeless conditions. The goal of this article is to explain the basic principles of cancer immunotherapy and summarize the newest findings in this field.

Meta-analyses to investigate gene-environment interactions in neuroepidemiology.

BACKGROUND: Most chronic neurological diseases are caused by a combination of multiple genetic and environmental factors. Increasingly, gene-environment interactions (GxE) are being examined, providing opportunities to combine studies systematically using meta-analysis. METHODS: Systematic review of the literature on how to examine GxE using observational study designs, and how to conduct a meta-analysis of studies on GxE. RESULTS: Most methods and challenges related to a standard meta-analysis apply to a GxE meta-analysis. There are, however, some substantive differences. With GxE, there is the capability of using a case-only design. Research on GxE interactions may be more prone to publication bias, since interactions are usually not the primary hypothesis and only 'exciting' significant GxE findings are reported out of a range of secondary analyses. In disease aetiology research, there has been debate whether to measure interaction on a multiplicative or additive scale. There are some significant challenges associated with measuring interaction on an additive scale, and thus the uptake of the measures of additive interaction has been limited. As a result, the methods of analysing interaction have been less consistent and reporting has been highly variable. We suggest using the STROBE/STREGA reporting guidelines to allow evaluation of interaction on both scales. CONCLUSIONS: We identified a number of differences of a GxE meta-analysis over a standard meta-analysis. Awareness of these issues is important. Using established reporting guidelines for GxE studies is recommended. The development of consortia for neurological disorders that include both genetic and environmental data might offer benefits for GxE meta-analyses in the future.

Pre-exercise and acute movement-evoked pain trajectories during a 24-week outdoor walking program for knee osteoarthritis (WALK).

Objectives: Exploring (1) pre-exercise and acute movement-evoked pain (AMEP) during an outdoor walking program in individuals with knee osteoarthritis (OA); and (2) comparing baseline physical performance and AMEP flares initiated by walking between participants with either a higher or lower attendance rate. Methods: Individuals with knee OA were prescribed a 24-week walking program, including one unsupervised walk and two supervised walk classes per week. Participants self-reported knee pain on a numerical rating scale (NRS; 0-10) before and after each supervised class. Mixed-effects models were used to investigate trajectories over time for pre-exercise pain and AMEP change (post-minus pre-exercise pain; positive value indicates flare-up). Baseline physical performance (6 tests) and AMEP flares were compared between participants with higher (attending ≥70% of supervised classes) and lower attendance rates. Results: Of 24 participants commencing the program, 7 (29%) withdrew. Over 24 weeks, pre-exercise pain improved by 1.20 NRS (95% CI -1.41 to -0.99), with estimated largest per class improvements during the first 8 weeks (-0.05 (-0.06 to -0.03) and plateauing around 20-weeks. The AMEP was estimated to improve by 0.19 NRS (95% CI -0.38 to -0.004) over 24-weeks, with improvements plateauing around 12-weeks. Participants with lower attendance (n â€‹= â€‹11) scored poorer on all physical performance tests and experienced a slight increase in AMEP during the first two weeks of the program. Conclusions: Participants improved in pre-exercise pain and AMEP in the first 20 and 12 weeks, respectively. Despite supervision, physical performance and AMEP flares may have contributed to lower attendance. Trial registration number: 12618001097235.

A pilot randomized controlled trial evaluating outdoor community walking for knee osteoarthritis: walk.

OBJECTIVES: To determine the feasibility of a randomized controlled trial (RCT) examining outdoor walking on knee osteoarthritis (KOA) clinical outcomes and magnetic resonance imaging (MRI) structural changes. METHOD: This was a 24-week parallel two-arm pilot RCT in Tasmania, Australia. KOA participants were randomized to either a walking plus usual care group or a usual care control group. The walking group trained 3 days/week. The primary outcome was feasibility assessed by changes being required to the study design, recruitment, randomization, program adherence, safety, and retention. Exploratory outcomes were changes in symptoms, physical performance/activity, and MRI measures. RESULTS: Forty participants (mean age 66 years (SD 1.4) and 60% female) were randomized to walking (n = 24) or usual care (n = 16). Simple randomization resulted in a difference in numbers randomized to the two groups. During the study, class sizes were reduced from 10 to 8 participants to improve supervision, and exclusion criteria were added to facilitate program adherence. In the walking group, total program adherence was 70.0% and retention 70.8% at 24 weeks. The walking group had a higher number of mild adverse events and experienced clinically important improvements in symptoms (e.g., visual analogue scale (VAS) knee pain change in the walking group: - 38.7 mm [95% CI - 47.1 to - 30.3] versus usual care group: 4.3 mm [- 4.9 to 13.4]). CONCLUSIONS: This study supports the feasibility of a full-scale RCT given acceptable adherence, retention, randomization, and safety, and recruitment challenges have been identified. Large symptomatic benefits support the clinical usefulness of a subsequent trial. TRIAL REGISTRATION NUMBER: 12618001097235. Key Points • This pilot study is the first to investigate the effects of an outdoor walking program on knee osteoarthritis clinical outcomes and MRI joint structure, and it indicates that a full-scale RCT is feasible. • The outdoor walking program (plus usual care) resulted in large improvements in self-reported knee osteoarthritis symptoms compared to usual care alone. • The study identified recruitment challenges, and the manuscript explores these in more details and provides recommendations for future studies.

KARAOKE: Krill oil versus placebo in the treatment of knee osteoarthritis: protocol for a randomised controlled trial.

BACKGROUND: Knee osteoarthritis (OA) is a common and important cause of pain and disability, but interventions aimed at modifying structures visible on imaging have been disappointing. While OA affects the whole joint, synovitis and effusion have been recognised as having a role in the pathogenesis of OA. Krill oil reduces knee pain and systemic inflammation and could be used for targeting inflammatory mechanisms of OA. METHODS/DESIGN: We will recruit 260 patients with clinical knee OA, significant knee pain and effusion-synovitis present on MRI in five Australian cities (Hobart, Melbourne, Sydney, Adelaide and Perth). These patients will be randomly allocated to the two arms of the study, receiving 2 g/day krill oil or inert placebo daily for 6 months. MRI of the study knee will be performed at screening and after 6 months. Knee symptoms, function and MRI structural abnormalities will be assessed using validated methods. Safety data will be recorded. Primary outcomes are absolute change in knee pain (assessed by visual analog score) and change in size of knee effusion-synovitis over 24 weeks. Secondary outcomes include improvement in knee pain over 4, 8, 12, 16 and 20 weeks. The primary analyses will be intention-to-treat analyses of primary and secondary outcomes. Per protocol analyses adjusting for missing data and for treatment compliance will be performed as the secondary analyses. DISCUSSION: This study will provide high-quality evidence to assess whether krill oil 2 g/day reduces pain and effusion-synovitis size in older adults with clinical knee OA and knee effusion-synovitis. If krill oil is effective and confirmed to be safe, we will provide compelling evidence that krill oil improves pain and function, changes disease trajectory and slows disease progression in OA. Given the lack of approved therapies for slowing disease progression in OA, and moderate cost of krill oil, these findings will be readily translated into clinical practice. TRIAL REGISTRATION: Australian New Zealand Clinical Trials Registry, ACTRN12616000726459. Registered on 02 June 2016. Universal Trial Number (UTN) U1111-1181-7087.

The expression of the soluble isoform of hFlt3 ligand by recombinant vaccinia virus enhances immunogenicity of the vector.

Recombinant vaccinia viruses (rVACV) expressing various tumor-associated antigens have been shown to elicit anti-tumor effect in numerous experimental models and clinical trials. We tested the hypotheses that rVACV expressing biologically active fms-like tyrosine kinase 3 ligand (Flt3L) would show higher immunogenicity than control viruses expressing only model antigen and that coexpression of Flt3L would influence anti-tumor activity of rVACV in the preventive and therapeutic arrangements of the in vivo experiment. To answer these questions, we took advantage of the well-described model of transplanted tumor cells expressing HPV16 E6 and E7 oncoproteins. To determine the effects of hFlt3L on the induction of anti-tumor immunity, we generated live vaccinia viruses that express human Flt3L regulated by the early H5 or strong synthetic E/L promoter together with fusion protein SigE7LAMP, which is a highly immunogenic form of HPV E7 oncoprotein. We tested Flt3L production in vitro and in vivo. Despite higher expression of Flt3L from the synthetic E/L promoter in vitro, the P13-E/L-FL-SigE7LAMP induced lower levels of Flt3L in the serum of mice than P13-H5-FL-SigE7LAMP. The Flt3L expression under the strong early VACV H5 promoter is able to inhibit expansion of CD11b+Gr-1+ myeloid suppressor cells (MSC) and increase the amount of CD11b+ CD11c+ dendritic cells in the spleen of mice immunized with vaccinia virus. Determination of viral DNA isolated from the ovaries of infected animals did not reveal differences in replication between rVACVs in this organ. Coexpression of Flt3L by replication-competent virus P13-FL-SigE7LAMP induced enhancement of the cellular immune response against HPV16 E7 and VACV E3 proteins as well as increased anti-tumor efficacy in both the protective and therapeutic immunization schemes. On the other hand, the short-time Flt3L coexpression by MVA-H5-FL-SigE7LAMP was not sufficient to enhance anti-tumor effect of immunization.

Factors associated with prevalent and incident foot pain: data from the Tasmanian Older Adult Cohort Study.

OBJECTIVES: To describe factors associated with prevalent and incident foot pain in a population-based cohort of older adults (n = 1092). STUDY DESIGN: Longitudinal observational study. MAIN OUTCOME MEASURES: Prevalent foot pain, incident foot pain after 5 years. METHODS: Potential correlates included demographic factors, anthropometry, leg strength, metabolic factors, steps per day (using pedometer), pain at 6 other sites, and psychological wellbeing. Data were analysed using log binomial models. RESULTS: Participants were aged 50-80 years (mean 63 years), 49% male, mean body mass index (BMI) 27.8 ± 4.7 at baseline. The prevalence of foot pain at baseline was 38% and the incidence of new pain over 5 years was 20%. BMI, pain at other sites (neck, hands, knees, pain at three or more sites), and poorer psychological wellbeing were independently associated with baseline foot pain. Baseline BMI and pain in the neck, hands, and knees were independently associated with incident foot pain; but change in weight or BMI, total number of painful joints and psychological wellbeing were not. Self-reported diabetes and cigarette smoking were not associated with prevalent or incident foot pain. CONCLUSIONS: This study demonstrates that greater body weight and joint pain at multiple sites were consistently associated with prevalent foot pain and predict incident foot pain. Addressing excess body mass and taking a global approach to the treatment of pain may reduce the prevalence and incidence of foot pain in older adults.

CONCENTRATION OF NATURAL RADIONUCLIDES IN PRIVATE DRINKING WATER WELLS.

Water is one of the most important resources for a human being; therefore, its quality should be properly tested. According to Council Directive No. 2013/51/EUROATOM, there shall be established requirements for the general public health protection with regard to radioactive substances in water intended for human consumption. This article summarises measurement results of selected water samples at 444 private drinking water wells, which are not subject to regular inspection in terms of the Czech legislation.