Search

Background/Purpose Disordered osteoclast activity has been implicated in the pathogenesis of gouty bone erosion. We sought to determine if the addition of denosumab (a monoclonal antibody targeting the receptor activator of nuclear factor kappa-B ligand - RANKL) to intensive urate-lowering therapy (ULT) improves gouty bone erosion. Methods Open-label, parallel-group pilot randomized controlled trial in which 20 participants with gout with at least one confirmed conventional radiographic foot bone erosion were assigned in a 1:1 allocation to receive denosumab (60 mg subcutaneous every 6 months) added to intensive ULT (serum urate ≤5 mg/dL or 300 µmol/L at the time of randomization and continued for the duration of the study), or intensive ULT alone. The primary outcome was the change in the bilateral foot and ankle computed tomography (CT) bone erosion score from baseline to 12 months, assessed by an experienced musculoskeletal radiologist blinded to study assignment. Secondary outcomes included change in serum C-terminal telopeptide (CTX), and patient reported outcomes of pain and function. Results Although serum CTX declined markedly in the denosumab/ULT group compared with the ULT alone group, there was no interval change in CT erosion score in either the denosumab/ULT or ULT alone group after one year of follow-up. Other secondary outcomes did not differ between groups. There were two severe adverse events: One patient developed atrial fibrillation (on denosumab/ULT) and another atrial flutter (on ULT alone). Conclusions In this pilot study, denosumab did not offer additional benefit to intensive urate lowering therapy for gouty bone erosion.

Serum urate levels have been shown to be correlated with risk for incident cardiovascular disease (CVD) events among middle-aged or older adults. However, serum urate trajectory during young adulthood and its association with CVD events has been understudied. Using serum urate measurements collected at baseline and 10, 15, 20 years after baseline from 3563 Coronary Artery Risk Development in Young Adults (CARDIA) participants [mean age 25.1±3.6 (18–30) years at baseline (Year 0, 1985–86); 46.3% African American; 56.1% female], we determined sex-specific serum urate trajectories using SAS PROC TRAJ. We estimated hazard ratios (HR) for incident CVD events (coronary heart disease, heart failure, and stroke) occurring after the Year 20 exam through 2017. We identified 3 serum urate trajectories by sex, including low-stable (n=1251), moderate-stable (n=1761), and high-increasing (n=551). Over a median 10.6 years of follow-up, 157 incident CVD events occurred. Participants among the high-increasing trajectory group had 2.89 (95% confidence interval, 1.88–4.43) times greater risk for CVD compared to the low-stable trajectory group. The association was attenuated after adjustment for blood pressure levels during young adulthood. In conclusion, high-increasing serum urate trajectory during young adulthood was associated with incident CVD by middle age, and the association may be explained by blood pressure levels during the exposure period.

Background Previous studies have noted significant variation in serum urate (sUA) levels, and it is unknown how this influences the accuracy of hyperuricemia classification based on single data points. Despite this known variability, hyperuricemic patients are often used as a control group in gout studies. Our objective was to determine the accuracy of hyperuricemia classifications based on single data points versus multiple data points given the degree of variability observed with serial measurements of sUA. Methods Data was analyzed from a cross-over clinical trial of urate-lowering therapy in young adults without a gout diagnosis. In the control phase, sUA levels used for this analysis were collected at 2–4 week intervals. Mean coefficient of variation for sUA was determined, as were rates of conversion between normouricemia (sUA ≤6.8 mg/dL) and hyperuricemia (sUA > 6.8 mg/dL). Results Mean study participant (n = 85) age was 27.8 ± 7.0 years, with 39% female participants and 41% African-American participants. Mean sUA coefficient of variation was 8.5% ± 4.9% (1 to 23%). There was no significant difference in variation between men and women, or between participants initially normouricemic and those who were initially hyperuricemic. Among those initially normouricemic (n = 72), 21% converted to hyperuricemia during at least one subsequent measurement. The subgroup with initial sUA n = 54) was much less likely to have future values in the range of hyperuricemia compared to the group with screening sUA values between 6.0–6.8 (n = 18) (7% vs 39%, p = 0.0037). Of the participants initially hyperuricemic (n = 13), 46% were later normouricemic during at least one measurement. Conclusion Single sUA measurements were unreliable in hyperuricemia classification due to spontaneous variation. Knowing this, if a single measurement must be used in classification, it is worth noting that those with an sUA of Trial registration Data from parent study ClinicalTrials.gov Identifier: NCT02038179.

Gout and chronic kidney disease (CKD) frequently coexist, but quality evidence to guide gout management in people with CKD is lacking. Use of urate-lowering therapy (ULT) in the context of advanced CKD varies greatly, and professional bodies have issued conflicting recommendations regarding the treatment of gout in people with concomitant CKD. As a result, confusion exists among medical professionals about the appropriate management of people with gout and CKD. This Consensus Statement from the Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN) discusses the evidence and/or lack thereof for the management of gout in people with CKD and identifies key areas for research to address the challenges faced in the management of gout and CKD. These discussions, which address areas for research both in general as well as related to specific medications used to treat gout flares or as ULT, are supported by separately published G-CAN systematic literature reviews. This Consensus Statement is not intended as a guideline for the management of gout in CKD; rather, it analyses the available literature on the safety and efficacy of drugs used in gout management to identify important gaps in knowledge and associated areas for research., In this Consensus Statement, members of the Gout, Hyperuricemia and Crystal-Associated Disease Network (G-CAN) highlight gaps in knowledge about the management of gout in people with chronic kidney disease, and identify important areas for future research to address challenges in the treatment of this patient population.

Objective.To determine the association of serum urate (SU) levels with sudden cardiac death and incident coronary heart disease (CHD), separately, among adults without a history of CHD.Methods.We conducted a case-cohort analysis of Black and White participants aged ≥ 45 years enrolled in the REason for Geographic And Racial Differences in Stroke (REGARDS) study without a history of CHD at baseline between 2003 and 2007. Participants were followed for sudden cardiac death or incident CHD (i.e., myocardial infarction [MI] or death from CHD excluding sudden cardiac death) through December 31, 2013. Baseline SU was measured in a random sample of participants (n = 840) and among participants who experienced sudden cardiac death (n = 235) or incident CHD (n = 851) during follow-up.Results.Participants with higher SU levels were older and more likely to be male or Black. The crude HR (95% CI) per 1 mg/dL higher SU level was 1.26 (1.14–1.40) for sudden cardiac death and 1.17 (1.09–1.26) for incident CHD. After adjustment for age, sex, race, and cardiovascular risk factors, the HR (95% CI) per 1 mg/dL higher SU level was 1.19 (1.03–1.37) for sudden cardiac death and 1.05 (0.96–1.15) for incident CHD. HRs for sudden cardiac death were numerically higher among participants aged 45–64 vs ≥ 65 years, without vs with diabetes, and among those of White vs Black race, although P values for effect modification were all ≥ 0.05.Conclusion.Higher SU levels were associated with an increased risk for sudden cardiac death but not with incident CHD.

OBJECTIVE To determine whether serum urate reduction with allopurinol lowers blood pressure (BP) in young adults and the mechanisms mediating this hypothesized effect. METHODS We conducted a single-center, randomized, double-blind, crossover clinical trial. Adults ages 18-40 years with baseline systolic BP ≥120 and

Gout flare prophylaxis and therapy use in people with underlying chronic kidney disease (CKD) is challenging, given limited treatment options and risk of worsening renal function with inappropriate treatment dosing. This literature review aimed to describe the current literature on the efficacy and safety of gout flare prophylaxis and therapy use in people with CKD stages 3–5. A literature search via PubMed, the Cochrane Library, and EMBASE was performed from 1 January 1959 to 31 January 2018. Inclusion criteria were studies with people with gout and renal impairment (i.e. estimated glomerular filtration rate (eGFR) or creatinine clearance (CrCl) 2), and with exposure to colchicine, interleukin-1 inhibitors, non-steroidal anti-inflammatory drugs (NSAIDs), and glucocorticoids. All study designs were included. A total of 33 studies with efficacy and/or safety analysis stratified by renal function were reviewed—colchicine (n = 20), anakinra (n = 7), canakinumab (n = 1), NSAIDs (n = 3), and glucocorticoids (n = 2). A total of 58 studies reported these primary outcomes without renal function stratification—colchicine (n = 29), anakinra (n = 10), canakinumab (n = 6), rilonacept (n = 2), NSAIDs (n = 1), and glucocorticoids (n = 10). Most clinical trials excluded study participants with severe CKD (i.e. eGFR or CrCl of 2). Information on the efficacy and safety outcomes of gout flare prophylaxis and therapy use stratified by renal function is lacking. Clinical trial results cannot be extrapolated for those with advanced CKD. Where possible, current and future gout flare studies should include patients with CKD and with study outcomes reported based on renal function and using standardised gout flare definition.

OBJECTIVE. To determine the association of inhalant exposures with rheumatoid arthritis (RA)–related autoantibodies and severity in US veterans. METHODS. Participants in the Veterans Affairs Rheumatoid Arthritis (VARA) registry were mailed surveys assessing occupational, agricultural, and military inhalant exposures. Demographic characteristics, disease activity, functional status, and extraarticular features were obtained from the VARA registry, while HLA–DRB1 shared epitope (SE) status, anti–cyclic citrullinated peptide (anti-CCP) antibodies, and rheumatoid factor (RF) were measured using banked DNA/serum from enrollment. Associations between inhalant exposures and RA-related factors (autoantibodies, severity, and extraarticular features) were assessed using multivariable linear and logistic regression models adjusted for age, sex, race, and tobacco use and stratified by SE status. Adjusted odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. RESULTS. Questionnaires were returned by 797 of 1,566 participants (50.9%). Survey respondents were older, more often White or male, and less frequently smokers, and had lower disease activity compared to nonrespondents. Anti-CCP positivity was more common among veterans exposed to burn pits (OR 1.66 [95% CI 1.02, 2.69]) and military waste disposal (OR 1.74 [95% CI 1.04, 2.93]) independent of other factors. Among participants who were positive for SE alleles, burn pit exposure (OR 5.69 [95% CI 2.73, 11.87]) and military waste disposal exposure (OR 5.05 [95% CI 2.42, 10.54]) were numerically more strongly associated with anti-CCP positivity. Several inhalant exposures were associated with the presence of chronic lung disease, but not with the presence of RF or the level of disease activity. CONCLUSION. Military burn pit exposure and military waste disposal exposure were independently associated with the presence of anti-CCP antibodies in RA patients. These findings are consistent with emerging evidence that various inhalant exposures influence autoantibody expression and RA risk.

Objective This ancillary study examined the impact of depressive symptoms on the effectiveness of a urate‐lowering therapy in the context of a clinical trial. Methods Participants included 67 adults (ages 18–40) with elevated blood pressure who were enrolled in a double‐blind, randomized, crossover clinical trial evaluating the effectiveness of allopurinol (300 mg/d) versus placebo to decrease blood pressure. Depressive symptoms were measured at the beginning of each 4‐week phase with the Center for Epidemiological Studies Depression scale (CESD‐10). Serum urate (sUA) was assessed at the beginning and end of each treatment phase. Compliance to treatment was measured by having detectable oxypurinol levels. Linear regressions tested associations between depressive symptoms and change in sUA in each phase, adjusting for sex and race. Logistic regression predicted compliance from depressive symptoms. Results Participants had a mean age of 27 years and were 64% male and 39% African American. sUA levels decreased during the allopurinol treatment period but did not change during the placebo period. Higher depressive symptoms at pretreatment were associated with an attenuated urate‐lowering response during the allopurinol phase (β = 0.24, p < 0.05), but had no effect on sUA changes during the placebo phase. Depressive symptoms were not associated with treatment compliance assessed by oxypurinol levels. Conclusion Depressive symptoms were associated with reduced efficacy of allopurinol treatment for hyperuricemia in a clinical trial targeting hypertension. Studies evaluating the efficacy of urate‐lowering therapies may benefit from screening for depressive symptoms.

Objective To investigate the factors associated with discordance between patient and physician on the presence of a gout flare. Methods Patients’ self-reports of current gout flares were assessed with the question, ‘Are you having a gout flare today?’ which was then compared with a concurrent, blinded, physician’s assessment. Based on agreement or disagreement with physicians on the presence of a gout flare, flares were divided into concordant and discordant groups, respectively. Within the discordant group, two subgroups—patient-reported flare but the physician disagreed and physician-reported flare but the patient disagreed—were identified. The factors associated with discordance were analysed with multivariable logistic regression analysis. Results Of 268 gout flares, 81 (30.2%) flares were discordant, with either patient or physician disagreeing on the presence of a flare. Of the discordant flares, in 57 (70.4%) the patient reported a flare but the physician disagreed. In multivariable logistic regression analysis adjusted for demographics, disagreement among patients and physicians on the presence of a gout flare was associated with lower pain scores at rest [odds ratio (OR) for each point increase on 0–10 point pain scale 0.81 (95% Wald CI 0.73, 0.90), P < 0.0001] and less presence of joint swelling [OR 0.24 (95% CI 0.10, 0.61), P = 0.003] or joint warmth [OR 0.39 (95% CI 0.20, 0.75), P = 0.005]. Conclusion Although patients and physicians generally agree about the presence of gout flare, discordance may occur in the setting of low pain scores and in the absence of swollen or warm joints.

Uric acid is the final byproduct of purine metabolism. The loss of the enzyme that hydrolyzes uric acid to allantoin was lost, leading to a decrease in uric acid excretion and its further accumulation. The buildup of uric acid leads to damage in different organ systems, including the cardiovascular system. With the increasing burden of cardiovascular disease worldwide, a growing body of evidence has addressed the relationship between urate, cardiovascular outcomes, and gout medication cardiovascular safety.The treatment of gout reduces joint damage and it can also lessen CV morbidity. Allopurinol shows CV safety profile when compared to other ULTs. Evidence supporting CV safety with the use of colchicine and IL-1 agents is promising and research needs to be conducted to further assess this outcome.

Objective To review the epidemiology of gout and associated comorbidities. Methods We review the key published studies of the epidemiology of gout and associated comorbidities. Results The prevalence of gout ranged 1–4% worldwide and incidence ranged 0.1–0.3%. Gout is more common in men vs. women by 3:1 to 10:1. Gout incidence and prevalence increased by each decade of life, with prevalence increasing to 11–13% and incidence increasing to 0.4% in people older than 80 years. Racial minorities in the U.S., New Zealand Māori, Han Chinese and some ethnic groups in Asia have a higher prevalence of gout. Comorbidities are common in people with gout and complicate its management and disease outcomes. Hypertension is present in up to three-quarters of gout patients and could be in the causal pathway of its association with cardiovascular disease and stroke. Chronic kidney disease of stage 3 or greater severity is present in many patients with gout. Appropriate management can improve both gout and stabilize chronic kidney disease. Whether the association of gout with metabolic syndrome and diabetes is causal is still controversial. Given the biological anti-oxidant effect of serum urate, the association of gout with neurodegenerative disorders is being actively explored. Conclusions Gout is the most common inflammatory arthritis in adults worldwide, with a disproportionate burden of disease in men, the elderly and racial/ethnic minorities. Comorbidities in gout are very common and add further to the disease morbidity and make its management challenging.

Objective.To determine the relationship between gout flare rate and self-categorization into remission, low disease activity (LDA), and patient acceptable symptom state (PASS).Methods.Patients with gout self-categorized as remission, LDA, and PASS, and reported number of flares over the preceding 6 and 12 months. Multinomial logistic regression was used to determine the association between being in each disease state (LDA and PASS were combined) and flare count, and self-reported current flare. A distribution-based approach and extended Youden index identified possible flare count thresholds for each state.Results.Investigators from 17 countries recruited 512 participants. Remission was associated with a median recalled flare count of zero over both 6 and 12 months. Each recalled flare reduced the likelihood of self-perceived remission compared with being in higher disease activity than LDA/PASS, by 52% for 6 months and 23% for 12 months, and the likelihood of self-perceived LDA/PASS by 15% and 5% for 6 and 12 months, respectively. A threshold of 0 flares in preceding 6 and 12 months was associated with correct classification of self-perceived remission in 58% and 56% of cases, respectively.Conclusion.Flares are significantly associated with perceptions of disease activity in gout, and no flares over the prior 6 or 12 months is necessary for most people to self-categorize as being in remission. However, recalled flare counts alone do not correctly classify all patients into self-categorized disease activity states, suggesting that other factors may also contribute to self-perceived gout disease activity.

Objectives There are many potential ways that gout flares could be reported in clinical trials. The aim of this study was to describe the methods used to measure and report gout flare prevention outcomes in randomized controlled trials (RCTs). Methods A systematic search of electronic databases was conducted. Articles published between 2008 and 2018 were included if they were RCTs or articles reporting on analyses of RCT data (i.e. open label extension studies) and reported the impact of an intervention on the prevention of flares in people with gout. The modified-Jadad scale was used to assess study quality. Methods used to measure and report gout flare outcomes were extracted and synthesised separately for studies of anti-inflammatory prophylaxis and urate lowering/other long term therapy. Results A total of 38 articles were included, with 10 reporting outcomes for anti-inflammatory prophylaxis and 28 for urate lowering/other long term therapies. The overall quality score of all articles was good. There was marked heterogeneity across trials in gout flare definitions, data capture methods, reporting methods and time periods used to report flares. Anti-inflammatory prophylaxis studies used multiple methods to report gout flare outcomes (mean (SD) 4.3 (2.5) methods/article), while the majority of urate lowering/other long term therapy studies used a single method to report gout flare outcomes. The most common reporting method in anti-inflammatory prophylaxis studies was the mean number of gout flares per patient (n = =9 articles), and in urate lowering/other long term therapy studies was the proportion of patients with at least one gout flare (n = =22 articles). Only studies of anti-inflammatory prophylaxis therapy reported flare duration or pain during flare. Conclusion There is wide variation in methods used to measure and report gout flare prevention outcomes in long-term RCTs. These findings highlight the need for standardized methods for studies in which gout flare prevention is an outcome of interest.

Background Gout has been associated with a higher risk for coronary heart disease (CHD) and stroke in some prior studies. Few studies have assessed the association of gout with incident heart failure (HF). Methods We analyzed data from 5713 black and white men and women ≥ 65.5 years of age in the population-based REasons for Geographic And Racial Differences in Stroke (REGARDS) cohort study who had Medicare coverage without a history of HF, CHD, or stroke at baseline between 2003 and 2007. Gout was defined by ≥ 1 hospitalization or ≥ 2 outpatient visits with a diagnosis code for gout in Medicare claims prior to each participant’s baseline study examination. REGARDS study participants were followed for HF hospitalization, CHD, stroke, and all-cause mortality as separate outcomes through December 31, 2016. Analyses were replicated in a random sample of 839,059 patients ≥ 65.5 years of age with Medicare coverage between January 1, 2008, and June 30, 2015, who were followed through December 31, 2017. Results Among REGARDS study participants included in the current analysis, the mean age at baseline was 72.6 years, 44.9% were men, 31.4% were black, and 3.3% had gout. Over a median follow-up of 10.0 years, incidence rates per 1000 person-years among participants with and without gout were 13.1 and 4.4 for HF hospitalization, 16.0 and 9.3 for CHD, 9.3 and 8.2 for stroke, and 55.0 and 37.1 for all-cause mortality, respectively. After multivariable adjustment for sociodemographic variables and cardiovascular risk factors, hazard ratios (95% CI) comparing participants with versus without gout were 1.97 (1.22, 3.19) for HF hospitalization, 1.21 (0.79, 1.84) for CHD, 0.83 (0.48, 1.43) for stroke, and 1.08 (0.86, 1.35) for all-cause mortality. The multivariable-adjusted hazard ratio for HF hospitalization with reduced and preserved left ventricular ejection fraction among participants with versus without gout was 1.77 (95% CI 0.83, 3.79) and 2.32 (95% CI 1.12, 4.79), respectively. The multivariable-adjusted hazard ratio for heart failure hospitalization associated with gout among the 839,059 Medicare beneficiaries was 1.32 (95% CI 1.25, 1.39). Conclusion Among older adults, gout was associated with an increased risk for incident HF but not for incident CHD, incident stroke, or all-cause mortality.

The pathogenetic process of spontaneous CerebroSpinal Fluid (CSF) leaks in the middle cranial fossa has not been clearly identified yet. It is related to a tegmen defect associated to the presence of a simultaneous encephalocele or meningoencephalocele. The main complication of a CSF leak is meningitis, whose occurrence rate ranges from 4% to 50% according to different causes and conditions of the leak [1]. Surgical approaches to temporal bone reconstruction include middle cranial fossa (MCF) craniotomy, transmastoid (TM), or a combined (MCF/TM) approach. In our experience, we describe 2 cases of patients who presented with CSF rhinorrhea and meningoencephaloceles correlated with conductive hearing loss and meningitis. The MCF approach is a considerable way to successful repair CSF leaks and encephaloceles due to tegmen tympani and dural defects.

Previous studies do not widely support hyperuricemia as a risk factor for stroke and other cardiovascular diseases. We assessed the relationship between hyperuricemia and ischemic stroke (≈900 cases) using a large data set from the REGARDS study (Reasons for Geographic and Racial Differences in Stroke). We employed a case-cohort design (incident stroke cases and randomly selected cohort participants) and weighted Cox-proportional hazard models to estimate the association of serum urate level ≥6.8 mg/dL (ie, hyperuricemia) and 6.0 to

Gout flares are central to the patient experience of gout and are included in the Outcome Measures in Rheumatology (OMERACT) core outcome domain set for long-term gout studies. Although a valid definition for gout flare has been developed, there is no consensus around how flare outcomes are measured and reported in long-term clinical studies. Current methods of flare measurement, which are centered on measuring flares as a binary outcome (i.e., present vs absent), do not reflect the variable pattern of flares over time, nor the multidimensional patient experience of gout flares which include factors related to pain severity, functional disability, impact on family and social life, and psychological wellbeing. This review will discuss the importance and challenges of gout flare measurement.

BackgroundData on outcomes for people with gout and COVID-19 are extremely few. Our primary objective was to assess whether gout is a risk factor for diagnosis of COVID-19 and death related to COVID-19. The secondary objectives were to test for sex- and drug-specific differences in risk.MethodsWe used data from the UK Biobank that included 15,560 people with gout. Multivariable-adjusted logistic regression was employed in the following analyses using a case-control study design: Analysis A, to test for association between gout and COVID-19 diagnosis (n=459,837); Analysis B, to test for association between gout and death related to COVID-19 in a case-control cohort of people who died or survived with COVID-19 (n=16,336); Analysis C, to test for association between gout and death related to COVID-19 in the entire UK Biobank cohort (n=459,837); Analysis D, to stratify by prescription of urate-lowering therapy (ULT) and colchicine on the risk of death related to COVID-19 in a subset of the UK Biobank cohort with medication data (n=341,398).FindingsGout was associated with diagnosis of COVID-19 in analysis A (OR=1.2 [1.1 ; 1.3]) but not with risk of death in the COVID-19-diagnosed group in analysis B. In analysis C gout associated with risk of death related to COVID-19 in the unadjusted model (OR=3.9 [3.3 ; 4.7]), in Model 1 adjusted for demographic factors (OR=1.8 [1.5 ; 2.1]) and in the fully adjusted Model 2 (OR=1.3 [1.1 ; 1.6]). In Analysis C risk was higher in women than men in Model 1 adjusted for demographic factors (OR=3.5 [2.4 ; 5.0] and OR=1.5 [1.2 ; 1.8], respectively) with the difference maintained after additional adjustment for eight metabolic co-morbidities (ORMen=1.2 [0.9 ; 1.5], ORWomen=1.9 [1.3 ; 2.9]). There were no statistically significant differences in risk of death related to COVID-19 according to prescription of ULT or colchicine.InterpretationGout is a risk factor for death related to COVID-19 using the UK Biobank cohort with an increased risk in women with gout that was also driven by risk factors outside metabolic co-morbidities of gout.Research in contextEvidence before this studyThere are no studies investigating the risk of COVID-19 diagnosis and risk of death with COVID-19 in people with gout.Added value of this studyThe findings provide evidence that gout is a risk factor for diagnosis of COVID-19 and that gout is a risk factor for death with COVID-19, independent of included co-morbidities. Women with gout are at a higher risk of death with COVID-19 than men with gout.Implications of the available evidenceThe new evidence demonstrate that gout is a risk factor for death from COVID-19, particularly in women. This information will inform clinical decision-making in people with gout diagnosed with COVID-19. Future research should focus on replicating these findings, including a focus on understanding key factor(s) explaining the increased risk of death with COVID-19 in women with gout.

Serum urate (SU) is the most common primary efficacy outcome in trials of urate-lowering therapies for gout. Despite this, it is not formally considered a validated surrogate outcome. In this paper we will outline the definitions of biomarkers and surrogate outcome measures, respectively as well as the available frameworks and challenges in the assessment of the validity of serum urate as a surrogate in gout (i.e. a reasonable replacement for gout symptoms).

ObjectiveThe patient experience of gout flares is multidimensional, with several contributing factors including pain intensity, duration, and frequency. There is currently no consistent method for reporting gout flare burden in long-term studies. This study aimed to determine which factors contribute to patient perceptions of treatment efficacy in long-term studies of gout flare prevention.MethodsThis study involved face-to-face interviews with people with gout using visual representations of gout flare patterns. Participants were shown different flare scenarios over a hypothetical 6-month treatment period that portrayed varying flare frequency, pain intensity, and flare duration. The participants were asked to indicate and discuss which scenario they believed was most indicative of successful treatment over time. Quantitative data relating to the proportion of participants selecting each scenario were reported using descriptive statistics. A qualitative descriptive approach was used to code and categorize the data from the interview transcripts.ResultsTwenty-two people with gout participated in the semistructured interviews. All 3 factors of pain intensity, flare duration, and flare frequency influenced participants’ perception of treatment efficacy. However, a shorter flare duration was the most common indicator of successful treatment, with half of participants (n = 11, 50%) selecting the scenario with a shorter flare duration over those with less painful flares.ConclusionFlare duration, flare frequency, and pain severity are all taken into account by patients with gout when considering treatment efficacy over time. Long-term studies of gout should ideally capture all these factors to better represent patients’ experience of treatment success.

Objectives The aim was to evaluate the efficacy, defined as achieving target serum urate Methods PubMed, The Cochrane Library and EMBASE were searched from 1 January 1959 to 31 January 2018 for studies that enrolled people with gout, who had an estimated glomerular filtration rate (eGFR) or creatinine clearance (CrCl) of Results There were 36 reports with an analysis of efficacy and/or safety based upon renal function: allopurinol (n = 12), febuxostat (n = 10), probenecid (n = 3), benzbromarone (n = 5), lesinurad (n = 5) and pegloticase (n = 1). There were 108 reports that involved people with gout and renal impairment but did not contain any analysis on efficacy and/or safety based upon renal function: allopurinol (n = 84), febuxostat (n = 14), benzbromarone (n = 1), lesinurad (n = 3) and pegloticase (n = 6). Most studies excluded people with more severe degrees of renal impairment (eGFR or CrCl of Conclusion There is a lack of evidence regarding the efficacy and/or safety of currently used ULTs according to different levels of renal function. Future studies should include patients with CKD and should report study outcomes stratified by renal function.

Background: Previous studies have noted significant variation in serum urate (sUA) levels, and it is unknown how this influences the accuracy of hyperuricemia classification based on single data points. Despite this known variability, hyperuricemic patients are often used as a control group in gout studies. Our objective was to determine the accuracy of hyperuricemia classifications based on single data points versus multiple data points given the degree of variability observed with serial measurements of sUA.Methods: Data was analyzed from a cross-over clinical trial of urate-lowering therapy in young adults without a gout diagnosis. In the control phase, sUA levels used for this analysis were collected at 2-4 week intervals. Mean coefficient of variation for sUA was determined, as were rates of conversion between normouricemia (sUA ≤6.8 mg/dL) and hyperuricemia (sUA >6.8 mg/dL). Results: Mean study participant (n = 85) age was 27.8 ± 7.0 years, with 39% female participants and 41% African-American participants. Mean sUA coefficient of variation was 8.5% ± 4.9% (1% to 23%). There was no significant difference in variation between men and women, or between participants initially normouricemic and those who were initially hyperuricemic.Among those initially normouricemic (n=72), 15% converted to hyperuricemia during at least one subsequent measurement. The subgroup with initial sUA Conclusion: Single sUA measurements were unreliable in hyperuricemia classification due to spontaneous variation. Those with an sUA of Trial registration: Data from parent study ClinicalTrials.gov Identifier: NCT02038179

Background Colorectal cancer (CRC) harboring BRAFV600E mutation exhibits low response to conventional therapy and poorest prognosis. Due to the emerging correlation between gut microbiota and CRC carcinogenesis, we investigated in serrated BRAFV600E cases the existence of a peculiar fecal microbial fingerprint and specific bacterial markers, which might represent a tool for the development of more effective clinical strategies. Methods By injecting human CRC stem-like cells isolated from BRAFV600E patients in immunocompromised mice, we described a new xenogeneic model of this subtype of CRC. By performing bacterial 16S rRNA sequencing, the fecal microbiota profile was then investigated either in CRC-carrying mice or in a cohort of human CRC subjects. The microbial communities’ functional profile was also predicted. Data were compared with Mann-Whitney U, Welch’s t-test for unequal variances and Kruskal-Wallis test with Benjamini–Hochberg false discovery rate (FDR) correction, extracted as potential BRAF class biomarkers and selected as model features. The obtained mean test prediction scores were subjected to Receiver Operating characteristic (ROC) analysis. To discriminate the BRAF status, a Random Forest classifier (RF) was employed. Results A specific microbial signature distinctive for BRAF status emerged, being the BRAF-mutated cases closer to healthy controls than BRAF wild-type counterpart. In agreement, a considerable score of correlation was also pointed out between bacteria abundance from BRAF-mutated cases and the level of markers distinctive of BRAFV600E pathway, including those involved in inflammation, innate immune response and epithelial-mesenchymal transition. We provide evidence that two candidate bacterial markers, Prevotella enoeca and Ruthenibacterium lactatiformans, more abundant in BRAFV600E and BRAF wild-type subjects respectively, emerged as single factors with the best performance in distinguishing BRAF status (AUROC = 0.72 and 0.74, respectively, 95% confidence interval). Furthermore, the combination of the 10 differentially represented microorganisms between the two groups improved performance in discriminating serrated CRC driven by BRAF mutation from BRAF wild-type CRC cases (AUROC = 0.85, 95% confidence interval, 0.69–1.01). Conclusion Overall, our results suggest that BRAFV600E mutation itself drives a distinctive gut microbiota signature and provide predictive CRC-associated bacterial biomarkers able to discriminate BRAF status in CRC patients and, thus, useful to devise non-invasive patient-selective diagnostic strategies and patient-tailored optimized therapies.

Gout is common in people with chronic kidney disease (CKD) and its treatment is frequently suboptimal in this special population due to concerns over adverse events and/or efficacy of medications. There is controversy about the use of urate-lowering therapy (ULT) in those with CKD and lack of agreement about the dosing of allopurinol, the recommended first-line ULT1,2.

Background: Higher serum urate (SU) levels were shown to causally increase the risk for sudden cardiac death (SCD) in a Mendelian randomization analysis of white adults, most of whom had coronary heart disease (CHD). It is unclear if these results are generalizable to more racially diverse adults without CHD. Objective: To assess the risk for SCD and incident CHD associated with SU levels in adults without a history of CHD using data from a large, population-based cohort of US black and white men and women ≥45 years of age, the REason for Geographic And Racial Differences in Stroke (REGARDS) study. Methods: We conducted a case-cohort analysis of REGARDS study participants without a history of CHD at baseline between 2003 and 2007. Participants were followed for SCD or incident CHD (i.e., myocardial infarction or CHD death excluding SCD) from baseline through December 31, 2013. Baseline SU levels were measured in a random sample of participants (n=840) and among 235 participants with SCD and 851 participants with incident CHD. Results: Participants with higher SU levels were older and more likely to be black and male. The crude hazard ratio (95%CI) per 1 mg/dL higher SU level was 1.26 (1.14, 1.40) for SCD and 1.17 (1.09, 1.26) for incident CHD. Analyses modeling SU levels using splines supported that these associations were linear. After multivariable adjustment, higher SU levels remained associated with an increased risk for SCD, but not for incident CHD ( Table ). There was no effect modification in the association of SU levels with SCD or incident CHD by either age, gender, race or chronic kidney disease. However, the increased risk for SCD associated with higher SU levels was present in whites but not among blacks. Limitations: The study has limited statistical power for subgroup comparisons. Race differences in the association between SU levels and SCD require further investigation. Conclusions: In adults without a history of CHD, higher SU levels appear to be an independent risk factor for SCD, but no association was detected with incident CHD.

Introduction: Higher levels of serum urate (UA) obtained on a single occasion have been shown to be associated with a higher risk of cardiovascular disease (CVD) events among middle-aged or older adults. However, little is known regarding UA trajectory patterns during young adulthood and their associations with CVD outcomes by middle age. Hypothesis: We hypothesize that higher UA trajectory is associated with a higher risk for CVD events compared to lower UA trajectories. Methods: We included data from 4845 CARDIA Study participants (mean age at the Year 20 exam 44.8±3.7 (37-55) years; 50.8% African American; 55.6% female). Sex-specific UA trajectories were assessed using group-based trajectory modeling (PROC TRAJ in SAS version 9.4) based on UA levels obtained at baseline (Year 0) and 10, 15, 20 years later. Covariates included age, sex, race, and clinical characteristics at Year 20 (body mass index, diabetes and creatinine). We estimated hazard ratios (HR) for CVD events (coronary heart disease, heart failure, and stroke) from Year 20 (2005-06) through 2017. Results: We identified 3 UA trajectories in men and 3 similar but lower UA trajectories in women, characterized by low-increasing (men: 30%; n=652, mean UA 5.1; women 43%, n=1191, mean UA 3.9), moderate-increasing (men: 52%; n=1290, mean UA 6.4; women 45%, n=1284, mean UA 5.0), and high-increasing UA (men: 17%; n=377, mean UA 8.0; women 12%, n=305, mean UA 6.4) (Figure 1). Sex-specific trajectories were pooled. Over a median follow-up of 10.9 years, 203 incident CVD events occurred. The adjusted HRs for CVD events were 0.98 (95%CI, 0.66-1.45) for the pooled moderate-increasing group and 1.77 (95%CI, 1.10-2.84) for the pooled high-increasing group compared to the pooled low-increasing group. Conclusions: High-increasing UA trajectory during young adulthood was associated with an greater risk of CVD events by middle age. Modeling UA trajectories may help identify young adults at higher risk for CVD events.

Background Many gout comorbidities (e.g., hypertension) are correlated with serum urate. In this investigation, we identified risk factors (e.g., systolic blood pressure [SBP]), that (1) are associated with incident gout, (2) have effects on gout risk that cannot be fully explained by correlated differences in serum urate, and (3) may modulate the relationship between gout and serum urate. Methods Using data from the Atherosclerosis Risk in Communities (ARIC) study, we estimated the unadjusted associations between gout and risk factors by calculating ORs and using chi-square tests. The adjusted associations were analyzed using logistic regression by sequentially adding (1) one risk factor at a time or (2) all risk factors, to a baseline model that includes serum urate only. Stepwise selection was used to select main effects. Two-way interactions of variables from the main effects model were also analyzed. Results Average gout incidence was 2.7 per 1000 people per year. Serum urate was highly associated with incident gout, with odd ratios of 3.16 [95% CI 2.11, 4.76] and 25.9 [95% CI 17.2, 38.4] for moderately high (6–8 mg/dl) and high serum urate (> 8 mg/dl), relative to normal serum urate (

Dentato-Rubral-pallidoluysian atrophy (DRPLA) is a rare autosomal, dominant, progressive neurodegenerative disease that causes involuntary movements, mental and emotional problems. DRPLA is caused by a mutation in the ATN1 gene that encodes for an abnormal polyglutamine stretch in the atrophin-1 protein. DRPLA is most common in the Japanese population, where it has an estimated incidence of 2 to 7 per million people. This condition has also been seen in families from North America and Europe. We obtained a reprogrammed iPSC line from a Caucasian patient with a juvenile onset of the disease, carrying 64 CAG repeat expansion in the ATN1 gene.

Background Elevated levels of serum urate (sUA) is the known precursor of gout and urate lowering therapies (ULT) are the backbone of successful gout treatment. However, less is known about factors that influence the effectiveness of ULTs. Depression has shown strong relationships with treatment noncompliance, which may translate into reduced effectiveness of treatment with allopurinol. Little is known about any effects depression may produce on the observed serum urate lowering efficacy of ULTs (e.g.; allopurinol). Objectives To evaluate the role of depressive symptoms in the efficacy of allopurinol for lowering sUA in the context of a clinical trial. Methods Within a larger cross-over clinical trial of 300 daily mg of allopurinol vs. placebo for urate lowering and its effect in ambulatory blood pressure (1), 67 patients had complete data for depressive symptoms at the beginning of each treatment period, as well as sUA before and after a 4-week treatment period with allopurinol and a 4-week placebo period (order of conditions was randomized). Depressive symptoms were assessed with the Center for Epidemiologic Studies Depression Scale-10 (CESD-10) (2). Paired samples t-test evaluated change in sUA from pre- to post-treatment during active treatment and placebo. Then, linear regressions predicted change in sUA over each treatment period from pre-treatment depressive symptoms, adjusting for sex and race which were associated with baseline sUA levels. Results The 67 patients had average age 27.01 years (SD=6.5, range 18-40), 39% were African-American, and 64% were males. Over the 4-week active treatment period, sUA levels decreased from average 5.8 mg/dL (SD=1.2) (345.7 µmol/L) to 4.4 mg/dL (SD=1.2) (261.7 µmol/L), p Conclusion Even in the absence of clinical diagnosis of depression, depressive symptoms are associated with reduced efficacy of urate-lowering with allopurinol. This could have important implications for gout treatment, as it would suggest that screening for depressive symptoms might be indicated for treatment success. Additional analyses will address whether this effect can be explained by treatment noncompliance. References [1] Saddekni MB, Saag KG, Dudenbostel T, et al. Contemp Clin Trials. 2016:238-44. [2] Bjorgvinsson, T., Kertz, S.J., Bigda-Peyton, J.S., McCoy, K.L., Aderka, I.M. Assessment. 2013. 20, 429-436. Disclosure of Interests Sylvie Mrug: None declared, Catheryn Orihuela: None declared, Elizabeth Rahn: None declared, Kenneth Saag Grant/research support from: Amgen, Ironwood/AstraZeneca, Horizon, SOBI, Takeda, Consultant for: Abbvie, Amgen, Ironwood/AstraZeneca, Bayer, Gilead, Horizon, Kowa, Radius, Roche/Genentech, SOBI, Takeda, Teijin, Angelo Gaffo: None declared

Background The Veterans Affairs (VA) Rheumatoid Arthritis (RA) (VARA) registry is an observational cohort study of US Veterans with RA at 11 VA Medical Centers. VARA investigators capture clinical and laboratory disease activity measures (DAMs) during clinic visits via standardized templates in the electronic health record (EHR). Six clinical (tender/swollen joints, patient/provider global, MD-HAQ, pain) and 2 laboratory (ESR, CRP) DAMs are extracted post-visit using natural language processing (NLP). Objectives This analysis determined the impact of an audit, feedback and data correction system on the quantity and quality of DAMs collected in the VARA registry. Methods After September 2017, VARA site investigators were provided monthly feedback reports of incomplete/missing DAMs for the prior month to allow sites to correct data entry errors. Updated and/or corrected data were entered into the EHR via note addendums and then automatically re-extracted by NLP to complete the capture of DAM data. DAMs from October 1, 2016 to September 30, 2017 (pre-feedback implementation – Pre-IMP) was compared to October 1, 2017 to September 30, 2018 (post-feedback implementation – Post-IMP). Results During the pre-IMP period, there were 2,411 notes with DAMs collected on 1,116 unique patients compared to 2,873 notes on 1,208 unique patients in the post-IMP period - an increase of 92 (8.2%) unique patients and 460 (19.1%) notes. Enrollment in the VARA registry only increased by 121 (6.5%) during post-IMP period. During post-IMP period, there were 541 notes identified with deficiencies in clinical DAMs and monthly audit and feedback reports were provided to VARA sites to allow corrections. Individual site review resulted in 376 additional DAMs in 225 notes, with complete resolution of all error in 137 (25.3%) notes. The quantity of DAMs collected increased from 15,709 to 21,064, a 34.1% increase with the average number of DAMs collected per note rising from 4.9 to 5.6. The quality of data improved as demonstrated by the proportion of notes with all 6 clinical DAMs increasing from 52.5% to 81.1% and other improvements in quality/completeness as noted in table. Conclusion An audit, feedback, and efficient data collection system improved both the quantity and quality of DAMs collected. The improvement in the collection of DAMs in RA patients will further enhance epidemiologic and outcomes studies of RA and provide higher quality longitudinal data to enhance the care of RA patients. References [1] Fed Pract 2015; 32(5):24-29 Acknowledgement Work Support in Part by VA HSR&D and VA Specialty Care Centers of Innovation Disclosure of Interests Grant Cannon Grant/research support from: Amgen Inc., Jorge Rojas: None declared, Neill Bell: None declared, Namrata Singh: None declared, Ted Mikuls: None declared, Liron Caplan: None declared, Gail Kerr: None declared, Joshua Baker: None declared, Angelo Gaffo: None declared, Jennifer Barton: None declared, Deana Lazaro: None declared, J Steuart Richards: None declared, Brian Sauer Grant/research support from: Amgen Inc.

Background The association between serum urate and hypertension continues to be controversial. Animal models and studies in adolescents provided strong support of urate- lowering therapy (ULT) efficacy to improve early hypertension (1), while one recent randomized-controlled study in adults failed to find benefit (2). Objectives To test the hypothesis that serum urate reduction with allopurinol would lead to blood pressure reductions in young adults with pre-hypertension. Methods Single center, double-blinded, crossover trial in which participants were randomly assigned to allopurinol (300 daily mg) or placebo for a period of one month each. Adults ages 18-40, with baseline systolic blood pressure (SBP) ≥ 120 and 297.4 µmol/L) or ≥ 4.0 mg/dL (237.9 µmol/L) (men or women, respectively) were enrolled. Main exclusion criteria included chronic kidney disease, gout, or use of ULTs. The primary outcome was change from baseline in SBP assessed by 24 hour ambulatory blood pressure monitoring. Safety assessments were also conducted. Results 99 participants were randomized, and 82 completed study participation (Table 1). Serum urate decreased by -1.33 ± 1.21 mg/dL (-79.1 ± 72.0 µmol/L) during the allopurinol period (p 6.5 mg/dL (> 386.7 µmol/L) at baseline visit. No allopurinol hypersensitivity events or other serious adverse events were observed. Conclusion In the intention-to-treat analysis, urate -lowering therapy with allopurinol in young adults did not lead to reductions in blood pressure when compared with placebo. Blood pressure reductions with allopurinol may be limited only to participants with higher baseline serum urate levels. References [1] Feig DI, Soletsky B, Johnson RJ. JAMA. 2008;300:924-32. [2] McMullan CJ, Borgi L, Fisher N, et al. Clin J Am Soc Nephrol. 2017;12:807-16. Disclosure of Interests Angelo Gaffo: None declared, David Calhoun: None declared, Elizabeth Rahn: None declared, Suzanne Oparil: None declared, Paul Muntner Grant/research support from: Dr. Muntner declares research grant from Amgen, Peng Li: None declared, David Redden: None declared, Tanja Dudenbostel: None declared, Jeff Foster: None declared, Stephanie Biggers: None declared, Daniel Feig: None declared, Kenneth Saag Grant/research support from: Amgen, Ironwood/AstraZeneca, Horizon, SOBI, Takeda, Consultant for: Abbvie, Amgen, Ironwood/AstraZeneca, Bayer, Gilead, Horizon, Kowa, Radius, Roche/Genentech, SOBI, Takeda, Teijin

Stem cells are emerging as a therapeutic option for incurable diseases, such as Amyotrophic Lateral Sclerosis (ALS). However, critical issues are related to their origin as well as to the need to deepen our knowledge of the therapeutic actions exerted by these cells. Here, we investigate the therapeutic potential of clinical-grade human neural stem cells (hNSCs) that have been successfully used in a recently concluded phase I clinical trial for ALS patients (NCT01640067). The hNSCs were transplanted bilaterally into the anterior horns of the lumbar spinal cord (four grafts each, segments L3–L4) of superoxide dismutase 1 G93A transgenic rats (SOD1 rats) at the symptomatic stage. Controls included untreated SOD1 rats (CTRL) and those treated with HBSS (HBSS). Motor symptoms and histological hallmarks of the disease were evaluated at three progressive time points: 15 and 40 days after transplant (DAT), and end stage. Animals were treated by transient immunosuppression (for 15 days, starting at time of transplantation). Under these conditions, hNSCs integrated extensively within the cord, differentiated into neural phenotypes and migrated rostro-caudally, up to 3.77 ± 0.63 cm from the injection site. The transplanted cells delayed decreases in body weight and deterioration of motor performance in the SOD1 rats. At 40DAT, the anterior horns at L3–L4 revealed a higher density of motoneurons and fewer activated astroglial and microglial cells. Accordingly, the overall survival of transplanted rats was significantly enhanced with no rejection of hNSCs observed. We demonstrated that the beneficial effects observed after stem cell transplantation arises from multiple events that counteract several aspects of the disease, a crucial feature for multifactorial diseases, such as ALS. The combination of therapeutic approaches that target different pathogenic mechanisms of the disorder, including pharmacology, molecular therapy and cell transplantation, will increase the chances of a clinically successful therapy for ALS.

OBJECTIVE: School-based vaccination programs can be a source of distress for many students due to the pain from the needle injection and related fears. We created a multifaceted Knowledge Translation (KT) intervention to address vaccination and pain, fear, and fainting called The CARD™ System. The objectives were to document acceptability of key tools included in the multifaceted KT intervention and their effectiveness in improving knowledge and attitudes about vaccination pain and fear. METHODS: Quantitative and qualitative methods were used. Students, school staff, public health nurses, and parents participated in separate focus groups whereby they independently completed a knowledge and attitudes survey and provided structured and qualitative feedback on key KT tools of the multifaceted KT intervention. They then repeated the knowledge and attitudes survey. RESULTS: Altogether, 22 students (grade 6 and 7), 16 school staff (principals, grade 7 and 8 teachers, resource teachers, secretaries), 10 nurses (injecting, charge, and school nurses), and 3 parents participated. Knowledge test scores increased post-KT tool review: 8.5 (2.1) versus 7.3 (1.9); P

Background: Gout has been associated with a higher risk for coronary heart disease (CHD) and stroke in some but not all prior studies. There are few data available on the risk for incident heart failure associated with gout. Objective: To compare the incidence of heart failure, CHD and stroke among adults with versus without gout. Methods: We used data from 5,499 black and white REasons for Geographic and Racial Differences in Stroke (REGARDS) study participants >65 years of age with Medicare coverage without a history of heart failure, CHD or stroke at baseline in 2003-2007. Gout was defined by (1) ≥1 inpatient claim or ≥2 outpatient or carrier claims on separate days with an ICD-9 diagnosis code for gout (274.x) in Medicare prior to each participant’s baseline study visit, or (2) use of allopurinol, colchicine or probenecid based on a baseline medication inventory. REGARDS study participants were followed through December 31, 2015 for heart failure, CHD, and stroke events, which were adjudicated. Results: Among participants included in the current analysis (mean age 72 years, 45% male, 31% black), 223 (4%) had gout. The incidence of heart failure and CHD was higher, while the incidence of stroke was similar, among participants with versus without gout ( Figure ). After adjustment for sociodemographic and cardiovascular risk factors, hazard ratios comparing participants with versus without gout were 2.41 (95%CI 1.60, 3.64) for heart failure, 1.41 (0.96, 2.07) for CHD and 0.96 (0.58, 1.59) for stroke. There was no statistically significant effect modification by race or gender. In a sensitivity analysis defining gout only based on Medicare diagnosis codes, multivariable-adjusted hazard ratios for heart failure, CHD and stroke associated with gout were 2.25 (95%CI 1.41, 3.59), 1.26 (0.79, 1.99) and 0.83 (0.45, 1.52), respectively. Conclusion: After accounting for sociodemographic and cardiovascular risk factors, gout remains strongly associated with incident heart failure but not with incident CHD or stroke.

Introduction: The association between hyperuricemia and stroke has been inconsistent especially after adjustment for cardiovascular risk factors. Previous studies were limited in the number of events and did not measure these associations in subgroups. Methods: We used a stratified case-cohort design within the REasons for Geographic and Racial Differences in Stroke study. Clinically adjudicated stroke events (n=903) were defined as focal neurologic deficit lasting >24 hours or non-focal neurological symptoms with brain imaging consistent with stroke. Controls (n=951) were a random stratified sample selected from baseline to ensure representation of high-risk groups. Uric acid was assayed using the baseline sample and categorized into three groups: < 6 (referent), 6-6.8, ≥ 6.8 mg/dl (hyperuricemia). Cox-proportional-hazard-models adjusted for demographic and clinical variables were fit to examine the association between uric acid levels and stroke. We repeated the analysis stratified by race, gender, and age ( Results: Hyperuricemic individuals were more likely to be male and black. Hyperuricemia versus the referent category was significantly associated with stroke after adjustment for race, sex, age, and age*race interaction [model 1 HR(95%CI)= 1.42(1.12-1.80)], and after further adjustment for systolic and diastolic blood pressure [HR (95%CI)= 1.42(1.12-1.80)]. The associations was attenuated after full adjustment [HR (95%CI)= 1.22(0.91-1.63)]. Incremental adjustment by clinical variables suggested nHTN attenuated the association between hyperuricemia and stroke. Results were similar for hyperuricemia within subgroups defined by age, gender and race, except among men Conclusion: We observed a significant association between hyperuricemia and stroke that was partially dependent upon hypertension severity (count of antihypertensive treatment classes). The association was strongest among males aged

The main objective of this phase I trial was to assess the feasibility and safety of microtransplanting human neural stem cell (hNSC) lines into the spinal cord of patients with amyotrophic lateral sclerosis (ALS). Eighteen patients with a definite diagnosis of ALS received microinjections of hNSCs into the gray matter tracts of the lumbar or cervical spinal cord. Patients were monitored before and after transplantation by clinical, psychological, neuroradiological, and neurophysiological assessment. For up to 60 months after surgery, none of the patients manifested severe adverse effects or increased disease progression because of the treatment. Eleven patients died, and two underwent tracheotomy as a result of the natural history of the disease. We detected a transitory decrease in progression of ALS Functional Rating Scale Revised, starting within the first month after surgery and up to 4 months after transplantation. Our results show that transplantation of hNSC is a safe procedure that causes no major deleterious effects over the short or long term. This study is the first example of medical transplantation of a highly standardized cell drug product, which can be reproducibly and stably expanded ex vivo, comprising hNSC that are not immortalized, and are derived from the forebrain of the same two donors throughout this entire study as well as across future trials. Our experimental design provides benefits in terms of enhancing both intra- and interstudy reproducibility and homogeneity. Given the potential therapeutic effects of the hNSCs, our observations support undertaking future phase II clinical studies in which increased cell dosages are studied in larger cohorts of patients. Stem Cells Translational Medicine 2019;8:887–897

ObjectiveThere is a lack of standardisation in the terminology used to describe gout. The aim of this project was to develop a consensus statement describing the recommended nomenclature for disease states of gout.MethodsA content analysis of gout-related articles from rheumatology and general internal medicine journals published over a 5-year period identified potential disease states and the labels commonly assigned to them. Based on these findings, experts in gout were invited to participate in a Delphi exercise and face-to-face consensus meeting to reach agreement on disease state labels and definitions.ResultsThe content analysis identified 13 unique disease states and a total of 63 unique labels. The Delphi exercise (n=76 respondents) and face-to-face meeting (n=35 attendees) established consensus agreement for eight disease state labels and definitions. The agreed labels were as follows: ‘asymptomatic hyperuricaemia’, ‘asymptomatic monosodium urate crystal deposition’, ‘asymptomatic hyperuricaemia with monosodium urate crystal deposition’, ‘gout’, ‘tophaceous gout’, ‘erosive gout’, ‘first gout flare’ and ‘recurrent gout flares’. There was consensus agreement that the label ‘gout’ should be restricted to current or prior clinically evident disease caused by monosodium urate crystal deposition (gout flare, chronic gouty arthritis or subcutaneous tophus).ConclusionConsensus agreement has been established for the labels and definitions of eight gout disease states, including ‘gout’ itself. The Gout, Hyperuricaemia and Crystal-Associated Disease Network recommends the use of these labels when describing disease states of gout in research and clinical practice.

// Alessio D’Alessio 1 , Gabriella Proietti 1 , Gina Lama 1 , Filippo Biamonte 1 , Libero Lauriola 2 , Umberto Moscato 3 , Angelo Vescovi 4 , Annunziato Mangiola 5 , Cristiana Angelucci 1 , Gigliola Sica 1 1 Institute of Histology and Embryology, “A. Gemelli” Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy 2 Institute of Pathology, “A. Gemelli” Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy 3 Institute of Public Health, Hygiene Division,“A. Gemelli” Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy 4 IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo, Italy 5 Institute of Neurosurgery, "A. Gemelli" Faculty of Medicine, Catholic University of the Sacred Heart, Rome, Italy Correspondence to: Alessio D’Alessio, email: alessio.dalessio@unicatt.it Keywords: angiogenesis, glioblastoma, peritumoral tissue, cancer stem cells, hypoxia Received: April 22, 2016 Accepted: September 25, 2016 Published: October 01, 2016 ABSTRACT The formation of new blood vessels represents a crucial event under both physiological and pathological circumstances. In this study, we evaluated by immunohistochemistry, and/or Western blotting and/or quantitative real time-PCR the expression of HIF1α, HIF2α, VEGF, VEGFR1 and VEGFR2 in surgical glioblastoma multiforme (GBM) and peritumoral tissue samples obtained from 50 patients as well as in cancer stem cells (CSCs) isolated from GBM (GCSCs) and peritumoral tissue (PCSCs) of 5 patients. We also investigated the contribution of both GCSCs and PCSCs on the behavior of endothelial cells (ECs) in vitro . Immunohistochemistry demonstrated the expression of angiogenesis markers in both GBM and peritumoral tissue. In addition, in vitro tube formation assay indicated that both GCSCs and PCSCs stimulate EC proliferation as well as tube-like vessel formation. An increased migration aptitude was mainly observed when ECs were cultured in the presence of GCSCs rather than in the presence of PCSCs. These findings suggest that relevant neoangiogenetic events may occur in GBM. In particular, VEGF/VEGFR co-expression in PCSCs leads to hypothesize the involvement of an autocrine signaling. Moreover, our results suggest that both GCSCs and PCSCs own the skill of activating the “angiogenic switch” and the capability of modulating EC behavior, indicating that both cell types are either responsive to angiogenic stimuli or able to trigger angiogenic response. Together with our previous findings, this study adds a further piece to the challenging puzzle of the characterization of peritumoral tissue and of the definition of its real role in GBM pathophysiology.

The association between hyperuricemia and hypertension is controversial. Animal models, epidemiological data, and small clinical trials have favored a causative role for hyperuricemia in hypertension but more studies are necessary to elucidate putative mechanisms, population susceptibility, and potential for urate-lowering therapies (ULT) to decrease blood pressure (BP).To describe the background and design of the Serum Urate Reduction to Prevent Hypertension (SURPHER) study.SURPHER is a single center, double-blinded, crossover trial in which participants are randomly assigned to allopurinol (300mg) or placebo. Enrollment focused on adults 18-40years old with baseline systolic blood pressure≥120 and160mmHg or diastolic blood pressure≥80 and100mmHg, and serum urate ≥5.0mg/dL or ≥4.0mg/dL for men or women, respectively. SURPHER recruitment targets participants without chronic kidney disease (estimated glomerular filtration rate60mL/min/1.73m2), and without prior diagnosis of gout or use of ULT to treat gout. The primary outcome is change from baseline in blood pressure assessed by 24hour ambulatory blood pressure monitoring and mechanistic outcomes include changes in endothelial function as measured by flow-mediated dilation, as well as C-reactive protein levels.Since June 16, 2014 until present, SURPHER is recruiting participants in the city of Birmingham, Alabama.The study aims to enroll otherwise healthy young adults for a pharmacological intervention study with multiple study-related procedures. Challenges related to recruitment are anticipated and multiple strategies for increasing recruitment and retention are planned if necessary.

Despite being the most common type of inflammatory arthritis, gout is often poorly managed. Except for febuxostat and pegloticase, research in new therapeutic agents for the management of hyperuricemia in gout remained insufficient for several decades. With emerging evidence of possible roles of hyperuricemia in cardiometabolic comorbidities, as well as more convincing evidence regarding poor outcomes (e.g. disability, recurrent hospital admissions) in patients with uncontrolled gout, several agents are current under development. Increasing knowledge regarding renal urate transporters has resulted in the development of new generation uricosurics such as lesinurad and arhalofenate. This review aims at discussing current therapeutic strategies for gout, as well as their limitations and the possible role of emerging agents in the chronic management of hyperuricemia in gout. Drugs in phases I and II of development will be discussed, along with new agents and therapeutic classes, such as purine nucleoside phosphorylase inhibitors and dual-action drugs. These new developments are encouraging, and will hopefully contribute to a more adequate management of hyperuricemia in gout.

Background:Gout flares are considered a key clinical and research outcome in gout. Early treatment of gout flares increases patient well-being and warrants timely notification of the treating clinician.Objectives:To test the feasibility of a smartphone app to home-monitor gout flares real-time for both patients with a suspicion of and established gout.Methods:Thirty patients were recruited during their visit at the outpatient rheumatology clinic. Inclusion criteria were age ≥ 18 years, smartphone possession, established gout (crystal proven) or a clinical suspicion of gout and at least one flare reported in the last three months.A straight-forward query app was used to incorporate an adapted version of the 2017 four-criteria gout flare definition.[1] For 90 consecutive days the app asked patients to report their current pain score on an 11-points scale as screening question. Scoring pain below 4 terminated the query, otherwise the app posed the remaining criteria: does the patient experience warm and/or swollen joints and are symptoms regarded as a gout flare. Responses were transmitted in real-time to the dashboard and the clinician was alerted via email if predefined conditions were met. End of study evaluation consisted of the number of generated alerts, duration of (possible) flares and actions taken. Patient feasibility was assessed by measuring app attrition and using a questionnaire based on the Technology Acceptance Model. [2] All constructs were analysed using descriptive statistics.Results:All 30 recruited patients finished the trial. Three minor, resolvable technical issues were reported. Seventeen participants never missed a question. In total 110 responses (4.1%) were missed with three participants responsible for 66 missings. 90% of the participants rated app usability good to excellent and 70% would recommend the app to other patients.Twelve out of thirty patients generated a total amount of 174 alerts where four patients with a suspicion of gout were responsible for 148 alerts (85%). These patients scored three out of four criteria as they had warm, swollen and painful joints but, after consultation with the clinician, their symptoms were not regarded as a gout flare.The 174 alerts belonged to 23 (possible) flares with a median duration of 5 days [IQR 3,5 – 7,5]. Twenty-one pro-active telephone calls were made which resulted in four visits to the clinic within 48 hours. Clinical guidance over the phone consisted of checking in on patient’s symptoms, giving advice and ten medication adjustments.Conclusion:This prospective study shows feasibility of a smartphone app for home-monitoring gout flares for patients because of high usability scores and low attrition rates. The app has added value for gout care because it enables clinicians to act on flares as they occur. The next step is to further implement the app whilst perpetuating investigation into the added value for patients and clinical practice alike.References:[1]Gaffo AL, Dalbeth N, Saag KG, et al. Brief Report: Validation of a Definition of Flare in Patients With Established Gout. Arthritis Rheumatol. 2018;70(3):462-467.[2]Davis Jr. FD. A Technology Acceptance Model for empirically testing new end-user information systems: theory and results. MIT PhD thesis. 1985[3]Stoyanov SR, Hides L, Kavanagh DJ, Wilson H. Development and Validation of the User Version of the Mobile Application Rating Scale (uMARS). JMIR Mhealth Uhealth. 2016;4(2):e72.Acknowledgements:This study was funded by AbbVie and Menarini.Disclosure of Interests: :Bart Pouls: None declared, Charlotte Bekker: None declared, Bart van den Bemt Grant/research support from: UCB, Pfizer and Abbvie, Consultant of: Delivered consultancy work for UCB, Novartis and Pfizer, Speakers bureau: Pfizer, AbbVie, UCB, Biogen and Sandoz., Angelo Gaffo Grant/research support from: Received a research grant from AMGEN, Marcel Flendrie Grant/research support from: M. Flendrie has received grants from Menarini and Grunenthal., Consultant of: M. Flendrie has received consultancy fees from Menarini and Grunenthal.

Grade IV gliomas, also known as glioblastoma multiforme (GBM), are incurable, lethal brain tumors, whose average life expectancy is around 15 months. There is a desperate need for a better understanding of the basic biology of these tumors, in order to devise novel, more specific and effective therapeutics. The handling of GBM represents a daunting challenge to clinicians, also considering the few therapeutic options available, none of which can significantly alter the inevitable lethal outcome of these tumors. Hence, the development of effective therapies would greatly benefit from the availability of in vivo GBM models that can reliably mimic the characteristics of malignant cells and the features of the human disease. Candidate new drugs have to be tested in these in vivo models by adopting settings concerning direct intra-brain delivery in order to define their overall therapeutic efficacy under clinical-like conditions. Here, we describe local intracranial delivery of drugs by osmotic mini-pumps.

Introduction Amyotrophic Lateral Sclerosis (ALS) is a progressive, incurable neurodegenerative disease that targets motoneurons. Cell-based therapies have generated widespread interest as a potential therapeutic approach but no conclusive results have yet been reported either from pre-clinical or clinical studies. Areas covered This is an integrated review of pre-clinical and clinical studies focused on the development of cell-based therapies for ALS. We analyze the biology of stem cell treatments and results obtained from pre-clinical models of ALS and examine the methods and the results obtained to date from clinical trials. We discuss scientific, clinical, and ethical issues and propose some directions for future studies. Expert opinion While data from individual studies are encouraging, stem-cell-based therapies do not yet represent a satisfactory, reliable clinical option. The field will critically benefit from the introduction of well-designed, randomized and reproducible, powered clinical trials. Comparative studies addressing key issues such as the nature, properties, and number of donor cells, the delivery mode and the selection of proper patient populations that may benefit the most from cell-based therapies are now of the essence. Multidisciplinary networks of experts should be established to empower effective translation of research into the clinic.

Juvenile Onset Huntington's Disease (JOHD) is a rare variant of HD withage of onset ≤20 years, accounting for 3–10% of all HD patients. The rarity occurrence of JOHD cases, who severely progress towards mental and physical disability with atypical clinical manifestations compared to classical HD, are responsible of general lack of knowledge about this variant. We obtained a fully reprogrammed iPS cell line from fibroblasts of a JOHD patient carrying 65 CAG repeats and age at onset at age 15. At the biopsy time, the patient showed an advanced stage after 10 years of disease.

Aim: To develop age-, sex-, and ethnic-Appropriate normative reference ranges for standard echocardiographic measurements of the left heart by combining echocardiographic measurements obtained from adult volunteers without clinical cardiovascular disease or significant cardiovascular risk factors, from multiple studies around the world.Methods and results: The Echocardiographic Normal Ranges Meta-Analysis of the Left heart (EchoNoRMAL) collaboration was established and population-based data sets of echocardiographic measurements combined to perform an individual person data meta-Analysis. Data from 43 studies were received, representing 51 222 subjects, of which 22 404 adults aged 18-80 years were without clinical cardiovascular or renal disease, hypertension or diabetes. Quantile regression or an appropriate parametric regression method will be used to derive reference values at the 5th and 95th centile of each measurement against age. Conclusion: This unique data set represents a large, multi-ethnic cohort of subjects resident in a wide range of countries. The resultant reference ranges will have wide applicability for normative data based on age, sex, and ethnicity. © The Author 2013.

OBJECTIVE: To perform external validation of a provisional definition of disease flare in patients with gout. METHODS: Five hundred nine patients with gout were enrolled in a cross-sectional study during a routine clinical care visit at 17 international sites. Data were collected to classify patients as experiencing or not experiencing a gout flare, according to a provisional definition. A local expert rheumatologist performed the final independent adjudication of gout flare status. Sensitivity, specificity, predictive values, and receiver operating characteristic (ROC) curves were used to determine the diagnostic performance of gout flare definitions. RESULTS: The mean ± SD age of the patients was 57.5 ± 13.9 years, and 89% were male. The definition requiring fulfillment of at least 3 of 4 criteria (patient-defined gout flare, pain at rest score of >3 on a 0-10-point numerical rating scale, presence of at least 1 swollen joint, and presence of at least 1 warm joint) was 85% sensitive and 95% specific in confirming the presence of a gout flare, with an accuracy of 92%. The ROC area under the curve was 0.97. The definition based on a classification and regression tree algorithm (entry point, pain at rest score >3, followed by patient-defined flare "yes") was 73% sensitive and 96% specific. CONCLUSION: The definition of gout flare that requires fulfillment of at least 3 of 4 patient-reported criteria is now validated to be sensitive, specific, and accurate for gout flares, as demonstrated using an independent large international patient sample. The availability of a validated gout flare definition will improve the ascertainment of an important clinical outcome in studies of gout.