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Background and Purpose Experimental approach Key Results Conclusions and Implications Prolonged survival of neutrophils is essential for determining the progression and severity of inflammatory and immune‐mediated disorders, including gouty arthritis. Survivin, an anti‐apoptotic molecule, has been described as a regulator of cell survival. This study aims to examine the effects of YM155 treatment, a survivin selective suppressant, in maintaining neutrophil survival in vitro and in vivo experimental settings of neutrophilic inflammation.BALB/c mice were injected with monosodium urate (MSU) crystals and treated with YM155 (intra‐articularly) at the peak of inflammatory response. Leukocyte recruitment, apoptosis neutrophil and efferocytosis were determined by knee joint wash cell morphology counting and flow cytometry. Resolution interval (Ri) was quantified by neutrophil infiltration, monitoring the amplitude and duration of the inflammation. Cytokine production was measured by ELISA. Mechanical hypernociception was assessed using an electronic von Frey aesthesiometer. Efferocytosis was evaluated in zymosan‐induced neutrophilic peritonitis. Survivin and cleaved caspase‐3 expression was determined in human neutrophils by flow cytometry.Survivin was expressed in neutrophils during MSU‐induced gout, and the treatment with YM155 reduced survivin expression and shortened Ri from ∼8 h observed in vehicle‐treated mice to ∼5.5 h, effect accompanied by increased neutrophil apoptosis and efferocytosis, both crucial for the inflammation resolution. Reduced IL‐1β and CXCL1 levels were also observed in periarticular tissue. YM155 reduced histopathological score and hypernociceptive response. In human neutrophils, lipopolysaccharide (LPS) increased survivin expression, whereas survivin inhibition with YM155 induced neutrophil apoptosis, with activation of caspase‐3.Survivin may be a promising therapeutic target to control neutrophilic inflammation. [ABSTRACT FROM AUTHOR]

Objective Methods Results Conclusion The pregnancy, delivery, and neonatal outcomes of pregnancies complicated by gout have yet to be evaluated in a population‐based study. We sought to evaluate the obstetric and neonatal outcomes in pregnant patients with gout using a national population database.This is a retrospective population‐based cohort study utilizing the Healthcare Cost and Utilization Project, Nationwide Inpatient Sample (HCUP‐NIS). All women who delivered or had a maternal death in the USA (2004–2014) were included in the study. Pregnancy, delivery, and neonatal outcomes were compared between women with an ICD‐9 diagnosis of gout to those without.Overall, 9 096 788 women met the inclusion criteria. Of these, 168 women (1.8/100000) had gout. Patients with gout, compared to those without, were more likely to be older and obese and to have chronic hypertension, pregestational diabetes mellitus, and thyroid disease. Pregnant women with gout were more likely to develop gestational diabetes mellitus (aOR 1.78 [95% CI 1.17–2.72], P = 0.008), to require operative vaginal delivery (aOR 3.26 [95% CI 2.03–5.22], P = 0.0001), and to experience venous thromboembolism (aOR 8.47 [95% CI 2.06–34.82], P = 0.003) compared to pregnant patients without gout. Patients with gout were more likely to deliver a neonate with congenital anomalies compared to those without gout (aOR 3.38 [95% CI 1.24–9.20], P = 0.02).Gout in pregnancy, or pregnancies complicated by a history of gout, are associated with increased risk of gestational diabetes mellitus, pulmonary embolism, and neonatal anomalies. [ABSTRACT FROM AUTHOR]

Introduction: Oxidative stress plays a crucial role in the development and progression of hyperuricemia/gout. This study aims to explore the relationship between the Oxidative Balance Score (OBS) and hyperuricemia/gout. Methods: The study utilized complete data from adult participants in the National Health and Nutrition Examination Survey (NHANES) spanning from 2009 to 2018. OBS, composed of scores for 20 dietary and lifestyle factors, served as the exposure variable. Multivariable linear regression model was applied to evaluate the association between OBS and uric acid (UA). Multivariable logistic regression, subgroup analyses, and restricted cubic spline (RCS) regression were conducted to explore the relationship between OBS and hyperuricemia/gout. Results: A total of 18,998 participants were included. In the fully adjusted model, compared to the lowest quartile, the highest quartiles of OBS, dietary OBS, and lifestyle OBS were negatively correlated with UA (β=-0.31 (-0.36,-0.25), β=-0.18 (-0.24,-0.12), and β=-0.64 (-0.69,-0.59), respectively) and hyperuricemia (OR=0.63 (0.55,0.71), OR=0.76 (0.67,0.86), OR=0.37 (0.33,0.42), respectively). Moreover, the highest quartiles of OBS and lifestyle OBS exhibited a negative correlation with gout (OR=0.72(0.58,0.91), OR=0.54 (0.43,0.67), respectively). Subgroup analyses revealed differences in the negative association between OBS and hyperuricemia concerning hypertension (p for interaction =0.002) and diabetes (p for interaction= 0.004), while gender-related disparities were observed in the negative association between OBS and gout (p for interaction =0.008). RCS analysis demonstrated a linear negative association between hyperuricemia and OBS (p for non-linearity >0.05), while gout exhibited a non-linear negative association (p for non-linearity<0.05). Conclusion: The study found that a higher OBS was associated with a decreased risk of developing hyperuricemia/gout, underscoring its potential in the prevention and management of these conditions. [ABSTRACT FROM AUTHOR]

Background: Numerous observational studies consistently highlight a strong association between serum uric acid (sUA) levels and atrial fibrillation (AF). However, the causal relationship and the direction of this association remain elusive, despite extensive research efforts. Objective: This study aimed to investigate the bidirectional causal relationships between sUA, gout, and the risk of AF using the two-sample Mendelian randomization (MR) approach. Methods: We conducted a comprehensive analysis utilizing publicly available genome-wide association studies (GWAS) summary statistics, employing stringent criteria to meticulously select genetic variants associated with sUA, gout, and AF. Our primary analytical approach was the inverse-variance weighted (IVW) method, complemented by some sensitivity analyses, including MR-Egger, weighted median, simple mode, and weighted mode, to estimate the causal effects. To identify potential violations, we conducted Egger regression and leave-one-SNP-out analyses. We assessed the strength of instrumental variables using F values to evaluate weak instruments. Additionally, we referenced the Phenoscanner database to exclude single nucleotide polymorphisms (SNPs) associated with confounding factors or outcomes. Results: Our forward Mendelian randomization analysis suggests that there is no causal relationship between UA levels/gout from different populations and the risk of AF [IVW OR 1.03, 95% CI: 0.97–1.08; p = 0.335; IVW OR 0.99, 95% CI: 0.97–1.02; p = 0.583; and IVW OR 1.07, 95% CI: 0.84–1.37; p = 0.575], respectively. We did not detect significant heterogeneity or potential pleiotropy, and we also excluded the possibility of weak instrumental variables. Furthermore, we did not find any reverse causal effects of AF on sUA levels and gout risk. Conclusion: Our findings challenge the widely held belief that lowering urate levels is uniformly effective in reducing the risk of atrial fibrillation (AF). Our study fails to substantiate the existence of a causal link between uric acid (UA) levels or gout and the development of AF, regardless of direction. [ABSTRACT FROM AUTHOR]

Background: Gout stands as a prevailing manifestation of inflammatory arthritis. While it is linked to several well-established risk factors, the associations between lipid profiles and the risk of gout remain unclear. Methods: This research involved National Health and Nutrition Examination Survey data (2007–2018). The cardiometabolic index, which incorporates the Triglycerides (TG)/High-density lipoprotein cholesterol (HDL) ratio and waist to height ratio (WHtR), was used to assess lipid profiles and metabolic health. Multivariate logistic regression analysis, propensity score matching, and mediation analyses were utilized to evaluate the associations of lipid profiles and the cardiometabolic index with the risk of developing gout. Results: Among 11,032 participants, each 1-unit increase in TG levels was associated with a 65% increase in the odds of developing gout before matching [1.65 (1.15–2.38), P = 0.007] and a 155% increase in the odds of developing gout after matching [2.55 (1.59–4.09), P = 0.007]. Each 1-unit increase in the cardiometabolic index was linked to an 81% increase in the odds of developing gout before matching [1.81 (1.22–2.70), P = 0.004] and a 215% increase in the odds of developing gout after matching [3.15 (1.84–5.40), P < 0.001]. The participants with HDL levels in the third quartile presented a 35% reduction in gout risk relative to those with HDL levels in the first quartile before matching [0.65 (0.46–0.92), P = 0.014] and a 51% reduction in gout risk after matching [0.49 (0.32–0.75), P < 0.001]. Mediation analyses revealed that BMI, WHtR, and homeostatic model assessment for insulin resistance (HOMA-IR) mediated the relationships between TG levels and the risk of developing gout at 18.75%, 24.28%, and 5.35%, respectively. For the association between HDL levels and the risk of developing gout, the mediating effects of BMI, WHtR, leukocytes, γ-glutamyltransferase (in those with HDL < 56 mmol/L), and HOMA-IR were 57.98%, 69.03%, 8.77%, 5.18%, and 11.14%, respectively. Conclusion: This study reveals the relationship between lipid profiles and the risk of developing gout. Regularly checking TG and HDL levels and actively managing obesity, insulin resistance, oxidative stress and inflammation are important for lowering the risk of developing gout. [ABSTRACT FROM AUTHOR]

Background: Kidney stones are a common urologic disease with an increasing incidence year by year, and there are similar influences between gout status and kidney stone incidence. Therefore the contribution of gout status to the incidence of kidney stones is unclear. The aim of this study was to investigate the relationship between gout status and kidney stones and to further explore the causal relationship by Mendelian randomization (MR) analysis. Method: An epidemiologic study of 49,693 participants in the 2009–2018 National Health and Nutrition Examination Survey (NHANES) was conducted to examine the association between the two. The causal relationship between gout status and kidney stones was assessed by Mendelian randomization analysis of data from the GWAS database. Result: A total of 28,742 participants were included in the NHANES analysis. We found that gout status was associated with an increased risk of kidney stones [odds ratio (OR) = 1.45 (95%CI, 1.243–1.692); p < 0.001]. In the MR analysis, we found a causal relationship between gout status and the risk of developing kidney stones (OR = 1.047, 95%CI, 1.011–1.085, p = 0.009). Conclusion: There may be an association between gout status and kidney stone risk. This finding requires further large-sample studies and adequate follow-up. [ABSTRACT FROM AUTHOR]

Objectives Despite the well-established association between prediabetes and hyperuricaemia, knowledge about serum urate (SU) trends during the prediabetic phase is limited. Therefore, we aimed to assess the longitudinal changes of SU in individuals with prediabetes. Methods Individuals with prediabetes, defined by initial haemoglobin A1c (HbA1c) levels between 5.7% and 6.4%, were identified using electronic health records from an academic health system (2007–2022). We required at least one SU test before and after the prediabetes diagnosis. The primary outcome was the longitudinal SU trends during the follow-up period, estimated with a multivariable mixed-effects model. Patients were censored at diabetes onset. Marginal effects of covariates on SU changes were estimated. Subsequent analyses examined SU variations in subgroups stratified by age, sex, BMI, HbA1c, estimated glomerular filtration rate and metformin use. Results Out of 25 526 individuals with prediabetes, 1521 met the SU cohort requirements, contributing to 6832 SU observations. At baseline, median age was 63 years and 40% were female. Median values were SU 6.3 mg/dl, HbA1c 5.9% and BMI 30 kg/m2. Median follow-up was 7.4 years. Older age, male sex, greater BMI and higher HbA1c were significant predictors of increased longitudinal SU levels. Individuals with a BMI ≥30 kg/m2 exhibited higher SU levels compared with those with lower BMI values. Conclusion Among individuals with prediabetes, several baseline variables were significant predictors of increased SU levels over time. These longitudinal trends in SU, support the potential for early intervention during the prediabetic phase, possibly reducing the risk of gout. [ABSTRACT FROM AUTHOR]

Objectives The minor allele of the common rs2231142 ABCG2 variant predicts inadequate response to allopurinol urate lowering therapy. We hypothesize that additional variants in genes encoding urate transporters and allopurinol-to-oxypurinol metabolic enzymes also predict allopurinol response. Methods This study included a subset of participants with gout from the Long-term Allopurinol Safety Study Evaluating Outcomes in Gout Patients (LASSO), whose whole genome was sequenced (n  = 563). Good responders had a 4:1 or 5:1 ratio of good [serum urate (SU) <0.36 mmol/l on allopurinol ≤300 mg/day] to poor (SU ≥0.36 mmol/l despite allopurinol >300 mg/day) responses over five to six time points, while inadequate responders had a 1:4 or 1:5 ratio of good to poor responses. Adherence to allopurinol was determined by pill counts, and for a subgroup (n  = 303), by plasma oxypurinol >20μmol/l. Using the sequence kernel association test (SKAT), we estimated the combined effect of rare and common variants in urate secretory (ABCC4 , ABCC5 , ABCG2 , SLC17A1 , SLC17A3 , SLC22A6 , SLC22A8) and reuptake genes (SLC2A9 , SLC22A11) and in allopurinol-to-oxypurinol metabolic genes (AOX1 , MOCOS , XDH) on allopurinol response. Results There was an association of rare and common variants in the allopurinol-to-oxypurinol gene group (P SKAT-C = 0.019), and in MOCOS , encoding molybdenum cofactor sulfurase, with allopurinol response (P SKAT-C = 0.011). Evidence for genetic association with allopurinol response in the allopurinol-to-oxypurinol gene group (P SKAT-C = 0.002) and MOCOS (P SKAT-C < 0.001) was stronger when adherence to allopurinol therapy was confirmed by plasma oxypurinol. Conclusion We provide evidence for common and rare genetic variation in MOCOS associating with allopurinol response. [ABSTRACT FROM AUTHOR]

Background: Mavacamten is a first-in-class cardiac myosin inhibitor approved by the US Food and Drug Administration (FDA) for symptomatic obstructive hypertrophic cardiomyopathy (HCM). This pharmacovigilance study aimed to assess mavacamten-related adverse drug reactions (ADRs) in the real world as reported in the FDA Adverse Event Reporting System (FAERS). Methods: We conducted disproportionality analyses with four signal detection algorithms—reporting odds ratio (ROR), proportional reporting ratio (PRR), Bayesian confidence propagation neural network, and the multi-item gamma Poisson shrinker to identify mavacamten-related ADRs. Results: Out of 4,500,131 reports from the FAERS database, 1004 mavacamten-related ADRs were identified from 1 January 2022 to 30 September 2023. A total of 26 significant disproportionality preferred terms (PTs) conforming to the four signal detection algorithms were noted. Some of the statistically significant cardiac ADRs at PT level include decreased ejection fraction (EF) [ROR 33.60 (95% confidence interval, CI 21.79–51.82), PRR 32.86 (χ2 615.96), information component (IC) 5.03, IC025 4.61, empirical Bayesian geometric mean (EBGM) 32.77, EBGM05 21.25], cardiac failure [ROR 9.39 (95% CI 6.49–13.60), PRR 9.13 (χ2 202.42), IC 3.19, IC025 2.83, EBGM 9.12, EBGM05 6.30], and atrial fibrillation [ROR 16.63 (95% CI 12.72–21.75), PRR 15.66 (χ2 769.93), IC 3.97, IC025 3.71, EBGM 15.64, EBGM05 11.96]. Conclusions: The results of our study were consistent with the safety data of clinical trials, including reduced ejection fraction, atrial fibrillation, dyspnea, and syncope. We also found potential new and unexpected ADR signals, such as urinary tract infection, gout, and peripheral edema. [ABSTRACT FROM AUTHOR]

Hearing loss(HL) represents a significant public health concern. This study aimed to determine the association between hearing loss and gout and to elucidate the underlying causative mechanisms. Data for this study were obtained from the National Health and Nutrition Examination Survey (NHANES) and Mendelian randomization (MR) basic databases. Initially, baseline characteristics of individuals with and without gout were compared. A nonlinear relationship between pure tone audiometry (PTA) values and gout prevalence was confirmed through restricted cubic spline (RCS) curve analysis. Subsequently, hearing loss was categorized into different levels based on PTA values, and multiple logistic regression analysis was employed to calculate the impact of varying degrees of hearing loss on the risk of gout. Finally, MR analysis was conducted to further elucidate the causal relationship between hearing loss and gout. A total of 3,258 individuals were included in this study, with a gout prevalence of 3.7%. Significant differences were observed between the gout group and the non-gout group in variables such as age, gender, blood uric acid level, BMI, hypertension, and diabetes. RCS curve analysis revealed a significant nonlinear relationship between PTA values and gout risk, particularly when PTA values exceed a specific threshold, where the curve flattens. Based on different levels of hearing loss derived from PTA values, multiple logistic regression analysis demonstrated that mild and moderate hearing loss significantly increased the risk of gout, remaining statistically significant after adjusting for covariates (odds ratio (OR) = 2.10–3.48, P < 0.05). MR analysis further confirmed the causal relationship between hearing loss and gout. Inverse variance weighting (IVW) was employed as the primary method, revealing that both individuals with hearing difficulties (OR = 0.98, 95% confidence interval (CI) 0.96–0.999, P = 0.012) and those without hearing impairment (OR = 1.02, 95% CI 1.01–1.04, P = 0.012) exhibited a significant causal relationship with gout. Goodness-of-fit tests and sensitivity analyses were used to verify the reliability of the results. Hearing loss has a significant causal relationship with an increased risk of gout, providing a new perspective for the prevention and management of gout. Focused attention and prompt treatment of hearing loss, particularly mild and moderate hearing loss, may significantly reduce the risk of developing gout. [ABSTRACT FROM AUTHOR]