Autofluorescence (AF) imaging enables label-free visualization of tissue metabolism and microenvironmental alterations, while deep learning (DL) provides powerful tools to decode its complex optical signatures. Their integration has emerged as a promising framework for functional and biologically informed disease assessment. Recent studies demonstrate that AF-DL approaches improve lesion detection, intraoperative guidance, and early therapeutic response evaluation across multiple organ systems. By leveraging multidimensional spectral, temporal, and spatial features, DL mitigates the intrinsic variability and limited specificity of standalone AF imaging. This review summarizes current diagnostic, prognostic, and surgical applications of AF-DL integration, with particular emphasis on model interpretability, generalizability, and biological relevance. Key challenges, including device dependence, dataset heterogeneity, annotation burden, and regulatory considerations, are critically discussed. Finally, future directions are proposed toward standardized acquisition, prospective multicenter validation, and clinically integrated workflows. By bridging intrinsic tissue biochemistry with data-driven intelligence, AF-DL integration offers a new class of functional imaging biomarkers with significant potential for precision diagnosis, surgery, and treatment monitoring.

Objectives:Sinonasal inverted papilloma is a locally aggressive epithelial lesion with a relatively high recurrence rate, yet the molecular basis of its proliferative behaviour remains incompletely understood. This study investigated the clinical relevance of secreted phosphoprotein 1 in sinonasal inverted papilloma and its association with epithelial cell proliferation and related signalling pathways. Methods:Differentially expressed genes were identified from the GSE193016 dataset, followed by gene set enrichment analysis. The expression of secreted phosphoprotein 1 and the cell cycle-related molecules cell division cycle 25C and cyclin A2 in clinical specimens was assessed using quantitative PCR, Western blotting, and immunohistochemistry. Associations between secreted phosphoprotein 1 expression and postoperative recurrence were assessed based on follow-up data. In vitro experiments using human nasal epithelial cells were conducted to examine the effects of altered secreted phosphoprotein 1 expression on cell proliferation-associated phenotypes, and pathway inhibition assays were performed to investigate the involvement of the PI3K/AKT signalling pathway. Results:Secreted phosphoprotein 1 expression was significantly upregulated in sinonasal inverted papilloma tissues, with higher levels observed in advanced-stage cases (T3-T4), and was associated with postoperative recurrence. The expression of the cell cycle-related molecules cell division cycle 25C and cyclin A2, positively correlated with secreted phosphoprotein 1 expression and increased with disease progression. In vitro epithelial cell models demonstrated that modulation of secreted phosphoprotein 1 expression was accompanied by corresponding changes in cellular proliferative capacity and cell cycle-related protein expression. Pathway inhibition assays further suggested that PI3K/AKT signalling may be involved in secreted phosphoprotein 1-associated alterations in cell cycle regulation. Conclusion:These findings indicate that secreted phosphoprotein 1 is highly expressed in sinonasal inverted papilloma and may be associated with epithelial cell proliferation and PI3K/AKT signalling. In addition, secreted phosphoprotein 1 expression correlates with disease recurrence, highlighting its potential research value as a biological marker, while the underlying mechanisms warrant further investigation.

People with gout and combined-type hyperuricemia, defined as renal urate overload and renal urate under-excretion, have diminished responsiveness to urate-lowering therapy. Emerging observational data suggest that urine alkalization might improve responsiveness to febuxostat. Hence, this prospective study evaluated the urate-lowering efficacy of citrate mixture added to febuxostat in people with gout and combined-type hyperuricemia. Patients with combined-type hyperuricemia and low urine pH (< 6.2) were prospectively enrolled from a gout clinic. All were treated with febuxostat (initially 20 mg daily, escalated to 40 mg daily if serum urate (SU) ≥360µmol/L). Citrate mixture (3.5 g twice daily, open label) was added according to shared decision of both physician and patient (alkalization vs. non-alkalization). Participants were followed for 12 weeks, with primary endpoint being achievement of SU < 360 µmol/L at final assessment. We enrolled 234 eligible patients, with 194 completing 12 weeks follow-up (98 non-alkalization and 96 with alkalization). At week 12, more patients in the alkalization group achieved SU < 360µmol/L (57.3

Purpose:To evaluate the effect of urine alkalization with citrate mixture on reducing flare incidence during initial urate-lowering therapy period in male gout patients with renal underexcretion-type. Patients and Methods:In this prospective cohort study, patients with renal underexcretion and urinary pH < 6.2 were enrolled. All participants received febuxostat 20 mg/day during weeks 0-4, later increased to 40 mg/day if serum urate (SU) levels > 360 μmol/L. According to group assignment, patients received either alkalization therapy (Alk group; citrate mixture, 3.5 g twice/day) or no alkalization (Control group). The primary outcome measure was gout flare incidence. Results:In total, 240 patients (Alk 114, Control 126) completed the 12-week follow-up. The Alk group had a significantly lower flare incidence (35.1%) than the Control group (59.5%, P < 0.001) and a lower recurrence of flares (14.0% vs. 31.0%, P = 0.002). At week 4, the proportion of participants with SU < 360 μmol/L was significantly higher in the Alk than in the Control group (P = 0.039). The Alk group had lower triglycerides and higher high-density lipoprotein cholesterol levels than the Control group at weeks 4, 8, and 12 (P < 0.05). The urinary albumin-to-creatinine ratio (UACR) decreased from 1.65 (0.36-7.01) to 1.08 (0.62-2.99) at week 12 in the Alk group, significantly lower than that in the Control group (P = 0.001). No significant difference was noted in the incidence of adverse events between groups. Conclusion:In patients with renal underexcretion gout, urine alkalization with febuxostat therapy prevented gout flares, improved lipid metabolism, and lowered UACR. Study Registration:ChiCTR, https://www.chictr.org.cn, ChiCTR2100043573.

OBJECTIVE:To evaluate the efficacy of posterior nasal neurectomy (PNN) in patients with eosinophilic chronic rhinosinusitis (eCRS) and moderate to severe persistent allergic rhinitis (AR). METHODS:A total of 42 patients with eCRS and AR were recruited from the Otorhinolaryngology Department of Qingdao University Affiliated Hospital between December 1, 2022, and January 1, 2024. All patients underwent functional endoscopic sinus surgery (FESS), with 20 receiving additional PNN (intervention group) and 22 undergoing FESS alone (control group). Subjective symptoms were assessed using the visual analog scale (VAS), sino-nasal outcome test-22 (SNOT-22), and rhinoconjunctivitis quality of life questionnaire (RQLQ). Objective assessments included the modified Lund-Kennedy endoscopic score and Lund-Mackay CT score. Postoperative nasal secretions were collected for cytokine analysis using enzyme-linked immunosorbent assay (ELISA). RESULTS:Preoperatively, the intervention group exhibited higher rates of excessive sneezing and emotional impact on RQLQ scores (p < 0.05). At 6-month follow-up, the intervention group showed significantly reduced subjective symptom scores (SNOT-22, p = 0.003; RQLQ activity, p < 0.001; nasal symptoms, p = 0.003; eye symptoms, p = 0.002; total RQLQ score, p = 0.007) and improved objective symptoms (Lund-Kennedy score, p < 0.001) compared to the control group. Greater reductions (Δ) were observed in eye symptoms (p = 0.002), emotional (p = 0.002), and Modified Lund-Kennedy score (p < 0.001). Postoperative IL-5 concentrations were lower in the intervention group (p = 0.023). CONCLUSIONS:Concurrent PNN with FESS is both safe and effective, leading to significant improvements in both subjective and objective symptoms in eCRS patients with AR. Cytokine analysis further supports the therapeutic benefits of this combined approach. LEVEL OF EVIDENCE: 3:

To develop and validate a model that integrates dual-energy computed tomography (DECT) and clinical features for the prediction of the risk of frequent gout flares (FrGF). This retrospective cohort study included 1204 patients with gout who were randomly divided into training and validation cohorts and followed for 12 months after DECT. The patients were categorized into an FrGF group (≥ 2 flares, n = 606) and an infrequent gout flares (InGF) group (< 2 flares, n = 598) based on flare frequency during follow-up. Clinicoradiological features that were significant in univariate analysis were dimensionally reduced via least absolute shrinkage and selection operator regression, followed by multivariate logistic regression to identify independent risk factors for FrGF. An integrated clinicoradiological model was constructed using a nomogram. Model performance was evaluated using the receiver-operating characteristic (ROC) curve and clinical utility by decision curve analysis. The integrated model was compared with the clinical model using the DeLong test to evaluate the incremental value of radiological features. Independent risk factors for FrGF were chronic arthritis, recurrent gout at baseline, intermittent medication, non-adherence to a low-purine diet, high monosodium urate burden, elevated Sharp/van der Heijde score, and tarsal bone erosion. The integrated model had an area under the ROC curve (AUC) of 0.95 (95

OBJECTIVES:Stage ≥3 chronic kidney disease (CKD) affects ∼25% of people with gout. The effects of urate-lowering therapy (ULT) on CKD incidence and progression have remained inconclusive. Here, we assessed the impact of a gout ULT clinic intervention using artificial intelligence (AI) on CKD incidence and achievement of serum urate (SU) target. METHODS:An observational study compared propensity score (PS)-matched gout cohorts from an AI-based Gout Intelligent Management System (GIMS) and a standard Electronic Medical Records system (EMRS) clinic database. The GIMS included a mobile application, data fusion interface and modules for expert consultation and laboratory results management. All patients had gout and a starting estimated glomerular filtration rate >60 ml/min. Using a 1:2 PS-matched cohort study design, we assessed the impact of the AI-based system on CKD outcomes and ULT effectiveness over 4 years of follow-up. RESULTS:Compared with EMRS, GIMS was associated with reduced incidence of CKD stage ≥3. Specifically, 169/4117 new-onset CKD stage ≥3 (incidence 4.1 per 100 person-years) with GIMS compared with 164/2128 with EMRS (incidence 7.7 per 100 person-years) during follow-up. More participants achieved SU <6.0 mg/dl with GIMS versus EMRS during follow-up (49.8% vs 25.9%, P < 0.001). CONCLUSION:Application of the artificial intelligence-based Gout Intelligent Management System was associated with lower incidence of chronic kidney disease stage ≥3 and superior target serum urate achievement in people with gout. The Gout Intelligent Management System represents a novel approach to improve real-world renal outcomes and urate-lowering therapy success in gout.

OBJECTIVES:Gout patients frequently have decreased urine pH, related to metabolic syndrome (MetS) and chronic kidney disease. Here, we aimed to investigate whether the addition of urine alkalization to urate-lowering therapy (ULT) is associated with improvements in albuminuria, gout flares or MetS outcomes in men with gout and low urinary pH (pH < 6.2). METHODS:A prospective cohort study enrolled 385 participants starting ULT with febuxostat (initially 20 mg daily, escalated to 40 mg daily if serum urate ≥360 µmol/l), with or without alkalization based on patient preference using a 3.5 g bid citrate mixture. Participants were followed every 4 weeks to week 12. The primary outcome was urine albumin-to-creatinine ratio (UACR) at week 12. RESULTS:In total, 343 participants completed the week 12 visit (137 alkalization, 206 controls). At week 12, compared with controls, participants receiving alkalization required a significantly lower febuxostat dose (by ∼20%) but had no significant difference in serum urate at target <360 µmol/l. Urine pH increased significantly in the alkalization group from week 4 (P < 0.001). At week 12, the alkalization group had a significantly lower UACR compared with control (P < 0.001), without significantly different eGFR. Participants in the alkalization group experienced fewer gout flares and had lower pain visual analogue scale scores (P < 0.001). There were lower serum triglyceride levels (P < 0.01) and higher HDL-C levels (P < 0.001) in the alkalization group. No other differences in metabolic outcomes were observed. CONCLUSION:Urine alkalization was associated with lower UACR, fewer gout flares, and improved serum lipid profile in febuxostat-treated men with gout and low urine pH. TRIAL REGISTRATION:ChiCTR, http://www.chictr.org.cn, ChiCTR2100043573.

OBJECTIVES:To identify specific metabolomic profiles associated with gout flares in people with gout. METHODS:Participants with gout were sequentially enrolled. In cross-sectional analysis, data were analysed according to the presence of gout flare (acute group) or absence of gout flare (intercritical group) at the time of enrolment. Participants in the intercritical group were prospectively followed and analysed according to the development of gout flares (recurrent flare group) or no gout flare (no flare group) over 1 year. Relative abundances of metabolites in serum obtained at the baseline visit were measured by untargeted liquid chromatography-mass spectrometry. Risk of incident flare was analysed using least absolute shrinkage and selection operator (LASSO)-Cox regression and time-receiver operating characteristic (ROC). Machine learning models were performed to identify biomarkers in cross-sectional and longitudinal analysis, which was further optimised using quantitative targeted metabolomics in an independent validation cohort. RESULTS:Participants in the acute and intercritical groups showed distinct metabolic profiles, including carbohydrate, lipid and nucleotide metabolism. Many metabolites were associated with recurrent gout flare in the prospective analysis. The metabolic risk score with six LASSO-derived metabolites, including 5-methoxytryptamine, differentiated well for gout flare risk, yielding an area under the ROC curve (AUC) of 0.82 (95% CI 0.74 to 0.90). Machine learning models achieved an AUC of 0.828 for comparison between the acute and intercritical groups. For the prediction of recurrent flare, AUC reached 0.807-0.867 with combined metabolites and clinical measurements. CONCLUSIONS:Metabolic reprogramming differentiates between the acute and intercritical stages of gout, and implicated metabolites may serve as biomarkers for future gout flares.

OBJECTIVE:The aim of this updated guideline is to provide comprehensive recommendations for the management of gout in patients with common comorbidities, such as chronic kidney disease (CKD), cardiovascular disease (CVD), diabetes, osteoarthritis (OA), and gastrointestinal disorders. METHODS:This guideline was developed by a multidisciplinary expert panel consisting of specialists in endocrinology, rheumatology, nephrology, cardiology, gastroenterology, and methodology. The development process adhered to standard methodologies, including PICO (population, intervention, comparator, and outcomes) question deconstruction, systematic literature review, the Grading of Recommendations Assessment, Development and Evaluation (GRADE) for evidence and recommendation evaluation, Delphi voting, and expert consensus. RESULTS:The guideline presents 26 evidence-based recommendations addressing seven clinical questions for patients with hyperuricemia and gout in the context of comorbidities. Key recommendations include the maintenance of strict serum urate targets, particularly for patients with CKD stage ≥ 3, chronic gouty arthritis, and OA, in order to prevent disease progression. In patients with CVD or diabetes, intra-articular triamcinolone is preferred over systemic glucocorticoids. Prioritized anti-inflammatory treatments for patients with CKD, gastrointestinal diseases, and OA are recommended. The guideline also introduces emerging therapies, such as interleukin-1 inhibitors and selective urate transport inhibitors, as potential treatment options for refractory cases. CONCLUSION:The update offers a comprehensive, patient-centered approach to managing gout, particularly in individuals with associated comorbidities. Multidisciplinary collaboration and emerging new treatments and evidence ensure the optimization of the recommendations.

OBJECTIVE:Mechanisms underlying the adolescent-onset and early-onset gout are unclear. This study aimed to discover variants associated with early-onset gout. METHODS:We conducted whole-genome sequencing in a discovery adolescent-onset gout cohort of 905 individuals (gout onset 12 to 19 years) to discover common and low-frequency single-nucleotide variants (SNVs) associated with gout. Candidate common SNVs were genotyped in an early-onset gout cohort of 2,834 individuals (gout onset ≤30 years old), and meta-analysis was performed with the discovery and replication cohorts to identify loci associated with early-onset gout. Transcriptome and epigenomic analyses, quantitative real-time polymerase chain reaction and RNA sequencing in human peripheral blood leukocytes, and knock-down experiments in human THP-1 macrophage cells investigated the regulation and function of candidate gene RCOR1. RESULTS:In addition to ABCG2, a urate transporter previously linked to pediatric-onset and early-onset gout, we identified two novel loci (Pmeta < 5.0 × 10-8): rs12887440 (RCOR1) and rs35213808 (FSTL5-MIR4454). Additionally, we found associations at ABCG2 and SLC22A12 that were driven by low-frequency SNVs. SNVs in RCOR1 were linked to elevated blood leukocyte messenger RNA levels. THP-1 macrophage culture studies revealed the potential of decreased RCOR1 to suppress gouty inflammation. CONCLUSION:This is the first comprehensive genetic characterization of adolescent-onset gout. The identified risk loci of early-onset gout mediate inflammatory responsiveness to crystals that could mediate gouty arthritis. This study will contribute to risk prediction and therapeutic interventions to prevent adolescent-onset gout.

Key points Spontaneous cerebrospinal fluid rhinorrhea (sCSFR) is often accompanied by an increase in intracranial pressure (ICP). The widening of optic nerve sheath diameter (ONSD) is an indicator of increased ICP. Using CT to measure ONSD is a simple and noninvasive auxiliary method for determining high ICP in sCSFR patients.

Objectives: To evaluate whether ultrasound findings of monosodium urate (MSU) crystal deposition predict frequent gout flares in index joints over 12 months. Methods: This single-center study enrolled people with at least one gout flare involving the MTP1, ankle or knee joint. The most painful or most frequently joint was identified as index joint for analysis. All participants were started on urate-lowering therapy and had an ultrasound scan of the index joints at the baseline visit. OMERACT scores (for tophus, double contour sign and aggregates) were used to analyze whether ultrasound scores predicted frequent (>= 2) gout flares in the index joint over 12 months. Results: Frequent flares were significantly higher in those with ultrasound findings in all index joints (MTP1: tophus: 85.0% vs 46.0%, P < 0.001, aggregates: 78.8% vs 59.0%, P < 0.01; ankle: tophus: 54.6% vs 20.8%, P < 0.001; aggregates: 60.0% vs 35.9%, P < 0.05; knee: tophus: 68.4% vs 28.6%, P < 0.05). For the MTP1, for each 1-point increase in tophus score, the odds of frequent gout flares increased by 5.19 [(95%CI: 1.26-21.41), 7.91 [(95%CI: 2.23-28.14), and 13.79 [(95%CI: 3.79-50.20)] fold respectively. For the ankle, a tophus score of 3 markedly improved the prediction of the frequent flares [OR= 9.24 (95%CI=2.85-29.91)]. Semi-quantitative sum scores were associated with frequent flares with an OR (95%CI) of 13.66 (3.44-54.18), P < 0.001 at the MTP1, 7.05 (1.98-25.12), P < 0.001 at the ankle. Conclusion: Ultrasound features of MSU crystal deposition at the MTP1 and knee predict subsequent risk of frequent gout flares in the same joints following initiation of urate-lowering therapy, with the highest risk in those with high tophus scores.

Objective:This study aimed to understand predictors of inadequate response (IR) to low-dose febuxostat treatment based on clinical variables.Methods:We pooled data from 340 patients of an observational cohort and two clinical trials who received febuxostat 20 mg/day for at least 3 months. IR was defined as failure to reach the target serum urate level (sUA<6 mg/dL) at any time point during 3 months treatment. The potential predictors associated with short- or mid-term febuxostat IR after pooling the three cohorts were explored using mixed-effect logistic analysis. Machine learning models were performed to evaluate the predictors for IR using the pooled data as the discovery set and validated in an external test set.Results:Of the 340 patients, 68.9% and 51.8% were non-responders to low-dose febuxostat during short- and mid-term follow-up, respectively. Serum urate and triglyceride (TG) levels were significantly associated with febuxostat IR, but were also selected as significant features by LASSO analysis combined with age, BMI, and C-reactive protein (CRP). These five features in combination, using the best-performing stochastic gradient descent classifier, achieved an area under the receiver operating characteristic curve of 0.873 (95% CI [0.763, 0.942]) and 0.706 (95% CI [0.636, 0.727]) in the internal and external test sets, respectively, to predict febuxostat IR.Conclusion:Response to low-dose febuxostat is associated with early sUA improvement in individual patients, as well as patient age, BMI, and levels of TG and CRP.

There is a current lack of data pertaining to the potential link between gout flares and dual-energy computed tomography radiomic features. This study aimed to construct and validate a comprehensive dual-energy computed tomography-based radiomics model for differentiating patients with and without gout flares. The analysis included 200 patients, of whom 150 were confirmed to have experienced at least one flare in the past 12 months; the remaining 50 patients did not experience flares. The radiomic features of the tophi at the bilateral first metatarsophalangeal joints were extracted and analyzed. Optimal radiomic features were selected using the least absolute shrinkage and selection operator method, and logistic regression analysis was used to screen clinical characteristics and establish a clinical model. The optimal radiomic features were then combined with the identified independent clinical variables to develop a comprehensive model. The performances of the radiomic, clinical, and comprehensive models were evaluated using receiver operating characteristic curve analysis, calibration curves, and decision curve analysis. Four radiomic features distinguished patients with at least one flare from those without flares and were used to establish the radiomic model. Disease duration and hypertension were independent factors that differentiated flare occurrences. The radiomic, clinical, and comprehensive models showed favorable discrimination, with areas under the receiver operating characteristic curves of 0.76 (95

Objective: Adolescent-onset gout has a greater impact on the lives and health of patients than adult-onset gout. However, there is a relative lack of clinical information on adolescent-onset gout. Hence, we analyzed a Chinese cohort. Methods: We studied clinical features of 9,003 Chinese patients. Gout onset age of 12 - 19 years is defined as adolescent-onset group (AG), 20 - 40 years as early-onset group (EG), and 41 - 64 years as late-onset group (LG). Multivariable regression analysis evaluated factors associated with recurrent flares, serum urate (SU) levels, and underexcretion type in AG. Results: Compared with EG and LG, the AG had higher SU levels [AG: 9.5 (2.2) mg/dL, EG: 8.6 (2.1) mg/dL, LG: 7.73 (2.0) mg/dL, P < 0.001], higher percentage of positive family history of gout (AG: 41.8 %, EG: 29.6 %, LG: 24.6 %, P < 0.001), underexcretion type (AG: 62.4 %, EG: 62.5 %, LG: 58.8 %, P = 0.04), recurrent flares (AG: 78.1 %, EG: 70.3 %, LG: 68.9 %, P = 0.01). Urate-lowering therapy (ULT) initiated [OR 6.58 (95 % CI 1.35 - 32.00)] and hypercholesterolemia [OR 4.16 (95 % CI 1.28 - 13.53)] were associated with recurrent flares. eGFR was identified to be a significant variable of increasing SU levels [beta -0.24 (95 % CI -0.04 to -0.01)]. Hypertriglyceridemia [OR 0.35 (95 % CI 0.17 - 0.71)] was related to underexcretion type. Conclusion: Adolescent-onset gout patients had clinically distinctive features with higher SU levels, BMI, positive gout family history, underexcretion type and recurrent flares. These specific populations were less likely to achieve ULT target, requiring more clinical attention.

BACKGROUND:Epithelial-mesenchymal transition (EMT) is a key process of chronic rhinosinusitis with nasal polyps (CRSwNP). The molecular mechanism of EMT in CRSwNP remains unknown. In this study, we aimed to investigate the role of FERMT1 during the EMT process in CRSwNP. METHODS:Western blotting, qRT-PCR, and immunohistochemistry (IHC) were performed to examine the expression of related proteins and mRNAs. The migration ability of human nasal epithelial cells (HNEpCs) was evaluated with wound scratch assay. RNA sequencing was performed to investigate the downstream genes of FERMT1. The CRSwNP mouse model was established to study the effect of FERMT1 in vivo. RESULTS:We found that FERMT1 was increased in nasal polyp tissues and correlated with the symptom scores of CRSwNP patients. Knockdown of FERMT1 inhibited the EMT process and cell migration induced by TGF-β1 through the PI3K/Akt pathway, and Akt inhibitor partially blocked the EMT induced by FERMT1 overexpression. In the CRSwNP mouse model, FERMT1 knockdown reduced nasal polyp formation and reversed the EMT process. CONCLUSIONS:Our data indicate that knockdown of FERMT1 inhibits migration and EMT process of HNEpCs via PI3K/Akt signaling pathway, suggesting that FERMT1 may be a novel and potential therapeutic target for CRSwNP treatment.

Purpose: Higher baseline serum urate or higher initial urate-lowering medication dose increased risk of gout flares during uratelowering therapy (ULT) initiation. The decrease in serum urate may play a crucial role in this process. Therefore, we aim to explore the relationship between decrease in serum urate and the risk of gout flares during ULT initiation.Patients and Methods: A 12-week prospective cohort study of Chinese male gout patients was conducted at Shandong Provincial Clinical Research Center for Immune Diseases and Gout in China. Patients were grouped by baseline serum urate (7-7.9 mg/dL, 8- 8.9 mg/dL and =9 mg/dL). All patients received febuxostat 20 mg daily during weeks 0-4, then escalated to 40mg during weeks 4-12 if serum urate >6mg/dL. The main outcomes were the number of gout flares and the decrease in serum urate. Poisson regression was performed.Results: A total of 282 participants were enrolled, of whom 260 completed (84, 87 and 89 in each group) from March 2021 to December 2021. A 44.2% of all participants experienced at least one gout flare. In the multivariate Poisson regression 1, ? serum urate 0-12 weeks (IRR 1.184, 95% CI, 1.062-1.320; P=0.002), the number of gout flares before treatment 1 year (1.017, 1.010-1.024; P<0.001) and tophus (1.580, 1.023-2.440; P=0.039) were independently associated with the number of gout flares. While in the multivariate Poisson regression 2, baseline serum urate (1.256, 1.050-1.503; P=0.013) and the number of gout flares before treatment 1 year (1.014, 1.007-1.022; P<0.001) were independently associated with the number of gout flares, ? serum urate 0-12 weeks (1.055, 0.923-1.207; P=0.433) was no longer a risk factor.Conclusion: ULT-induced gout flares depend on the degree of decrease in serum urate, which is affected by baseline serum urate. Higher baseline serum urate and greater decrease in serum urate lead to higher risk of gout flares.

The deposition of monosodium urate (MSU) crystals within synovial joints and tissues is the initiating factor for gout arthritis. Thus, MSU crystals are a vital tool for studying gout's molecular mechanism in animal and cellular models. This study mainly compared the excellence and worseness of MSU crystals prepared by different processes and the degree of inflammation induced by MSU crystals.MSU crystals were prepared using neutralization, alkali titration, and acid titration methods. The crystals' shape, length, quality, and uniformity were observed by polarized light microscopy and calculated by the software Image J. The foot pad and air pouch models were used to assess the different degrees of inflammation induced by the MSU crystals prepared by the three different methods at different time points. Paw swelling was evaluated by caliper. In air pouch lavage fluid, inflammatory cell recruitment was measured by hemocytometer, and the level of IL-1β, TNF-α, and IL-18 by ELISA. Inflammatory cell infiltration was assayed by immunohistochemistry of air pouch synovial slices.For the preparation of MSU crystals with the same uric acid, the quantity acquired by the alkalization method was highest, followed by neutralization, with the acid titration method being the lowest. The crystals prepared by neutralization were the longest. The swelling index of the foot pad induced by MSU crystals prepared by acid titration was significantly lower than that of the other methods at 24 h. The inflammatory cell recruitment and level of IL-1β, TNF-α, and IL-18 in air pouch lavage fluid were lowest in animals with crystals prepared by acid titration. IL-1β secretion induced by MSU crystals prepared by acid titration was significantly lower than that of the other two groups, but there was no significant difference in IL-18 secretion between the three groups in THP-1 macrophages and BMDMs.All three methods can successfully prepare MSU crystals, but the levels of inflammation induced by the crystals prepared by the three methods were not identical. The degree of inflammation induced by MSU crystals prepared by neutralization and alkalization is greater than by acid titration, but the quantity of MSU crystals obtained by the alkalization method is higher and less time-consuming. Apparently, the window of inflammation triggered by acid titration preparation is shorter compared to other forms of crystal preparation. Overall, MSU crystals prepared by the alkaline method should be recommended for studying the molecular mechanisms of gout in animal and cellular models.

Summary Background Gout is a polygenetic inflammatory disease. Although hundreds of genetic variants associated with gout and serum urate levels have been identified in studies of adults, the pathogenesis of adolescent-onset gout remains unclear. To better characterize the genetic landscape of adolescent-onset gout, a whole genome sequencing study was done in a large Chinese adolescent-onset gout cohort. Methods We conducted whole genome sequencing in a discovery adolescent-onset gout cohort of 905 individuals (gout onset 12-19 years) to discover common SNVs, uncommon SNVs, and indels associated with gout. Candidate common SNVs were replicated in an early-onset gout cohort of 2834 individuals (gout onset ≤ 30 years old). Loci associated with early-onset gout ( P < 5.0 × 10 −8 ) were identified after meta-analysis with the discovery and replication cohorts. Transcriptome and epigenomic analyses, RT-qPCR and RNA-seq in human peripheral blood leukocytes, and knock-down experiments in human THP-1 macrophage cells investigated regulation and functions of candidate gene RCOR1 . Findings In addition to ABCG2 , a urate transporter previously linked to pediatric-onset and early-onset gout, we identified four novel loci: VPRBP (rs868933181, P meta = 6.27 × 10 −9 ; OR meta = 1.66), NKILA-MIR4532 (rs72626599, P meta = 6.48 × 10 −9 ; OR meta = 1.58), RCOR1 (rs12887440, P meta = 3.37 × 10 −8 ; OR meta = 1.48), and FSTL5 - MIR4454 (rs35213808, P meta = 4.02 × 10 −8 ; OR meta = 1.49). Additionally, we found association at ABCG2 and SLC22A12 that was driven by low frequency SNVs. Furthermore, eight uncommon SNVs and three indels in the exome were predicted to be harmful. SNVs in RCOR1 were linked to heightened blood leukocyte mRNA levels. THP-1 macrophage culture studies revealed the potential of decreased RCOR1 to suppress gouty inflammation. Interpretation Performing the first comprehensive characterization of adolescent-onset gout genomes identified risk loci of early-onset gout. Loci mediate inflammatory responsiveness to crystals that could mediate gouty arthritis. This study will contribute to risk prediction and therapeutic interventions to prevent adolescent-onset gout. Funding The National Natural Science Foundation of China and the National Key R&D Program of China. Research in context Evidence before this study Gout is a polygenic disease and can present in adolescents and young adults. We searched PubMed for studies published as of Dec 31, 2021, without starting date or language restrictions and with the terms “adolescent-onset gout”, “early-onset gout”, “whole genome sequencing”, and “GWAS”, and no reports were found. Although GWAS have identified hundreds of genetic variants associated with gout and serum urate levels, they are all identified in adults (mean age 37.6-76.4 years old). The mechanism of early-onset gout is still unclear. The variants previously associated with early-onset gout are only in ABCG2 . Due to the lack of large-scale genetic studies of the adolescent gout population, the mechanism of the early-onset gout is unknown. Added value of this study To the best of our knowledge, this is the first report of the comprehensive characterization of adolescent gout genomes. We identified common and uncommon risk loci of early-onset gout, most of which implicated in inflammation response, including RCOR1 . SNVs in candidate risk gene RCOR1 displayed expression regulation function. Knockdown of RCOR1 decreased IL-1β levels in THP-1 cells after MSU treatment. These immune-related genetic variants leading to heightened inflammatory responses to monosodium urate (MSU) crystals may contribute to early onset of gout in adolescents. Implications of all the available evidence This is the first report of the genetic landscape of adolescent-onset gout and increases our knowledge of the biological mechanisms underlying early-onset gout. The immune-related loci associated with early-onset gout discovered in this study are potential drug targets. Reducing inflammatory MSU crystal inflammatory responses to MSU crystals is a central objective in the prevention and treatment of adolescent-onset gout.