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Lin-Feng Yan,1,* Ying-Zhi Sun,1,* Sha-Sha Zhao,1,* Yu-Chuan Hu,1,* Yu Han,1 Gang Li,2 Xin Zhang,1 Qiang Tian,1 Zhi-Cheng Liu,1 Yang Yang,1 Hai-Yan Nan,1 Ying Yu,1 Qian Sun,1 Jin Zhang,1 Ping Chen,1 Bo Hu,1 Fei Li,3 Teng-Hui Han,3 Wen Wang,1 Guang-Bin Cui1 1Department of Radiology & Functional and Molecular Imaging Key Laboratory of Shaanxi Province, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710038, People’s Republic of China; 2Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi 710038, People’s Republic of China; 3Student Brigade, Fourth Military Medical University, Xi’an, Shaanxi 710032, People’s Republic of China*These authors contributed equally to this workCorrespondence: Wen Wang; Guang-Bin CuiDepartment of Radiology & Functional and Molecular Imaging Laboratory of Shaanxi Province, Tangdu Hospital, Fourth Military Medical University, 569 Xinsi Road, Xi’an 710038, People’s Republic of ChinaTel +86-29-84778689; 86-29-84777863Email wangwen@fmmu.edu.cn; cuigbtd@fmmu.edu.cnPurpose: This study aims to incorporate informative histogram indicator analyses and advanced multimodal MRI parameters to differentiate low-grade gliomas (LGGs) from high-grade gliomas (HGGs) and to explore the features associated with patients’ survival.Patients and methods: A total of 120 patients with pathologically confirmed LGGs or HGGs receiving conventional and advanced MRI such as three-dimensional arterial spin labeling (3D-ASL), intravoxel incoherent motion-diffusion weighted imaging (IVIM-DWI), and dynamic contrast-enhanced MRI (DCE-MRI) were included. The mean and histogram indicators from advanced MRI were calculated from the entire tumor. The efficacies of a single indicator or multiple parameters were tested in distinguishing HGGs from LGGs and predicting patients’ survival. Receiver operating characteristic (ROC) curve and multivariable stepwise logistic regression were used to evaluate the diagnostic efficacies. Leave-one-out cross-validation was further used to validate the accuracy of the parameter sets in glioma grading. Log-rank test using the Kaplan–Meier curve was utilized to predict patients’ survival.Results: Overall, parameters from DCE-MRI performed better than those from 3D-ASL or IVIM-DWI in both glioma grading and survival prediction. The histogram metrics of Ve were demonstrated to have higher accuracies (the accuracies for Extended Tofts_Vemean and Extended Tofts_Vemedian were 68.33% and 71.67%, respectively, while those for the Incremental_Vemean and Incremental_Ve75th were 68.33% and 72.50%, respectively) in grading LGGs from HGGs. The combination of Tofts_Ve histogram metrics was the one with the highest accuracy (81.67%) and area under ROC curve (AUC = 0.840). On the other hand, Patlak_Ktrans95th (AUC = 0.9265) and Extended Tofts_Ve95th (AUC = 0.9154) performed better than their corresponding means (Patlak_Ktransmean: AUC = 0.9118 and Extended Tofts_Vemean: AUC = 0.9044) in predicting patients’ overall survival (OS) at 18-month follow-up.Conclusion: DCE-MRI-derived histogram features from the entire tumor were promising metrics for glioma grading and OS prediction. Combining single modal histogram features improved glioma grading.Trial registration: NCT 02622620.Keywords: multi-modal MRI, histogram features, receiver operating curve, glioma grading, survival analysis

Bao-Ding Chen,1,* Zheng Zhang,1,* Ke-Ke Wang,1 Meng-Yuan Shang,1 Shuang-Shuang Zhao,1 Wen-Bo Ding,2 Rui Du,1 Zhuan Yu,1 Xi-Ming Xu31Department of Medical Ultrasound, Affiliated Hospital of Jiangsu University, Zhenjiang 212000, People’s Republic of China; 2Department of Medical Ultrasound, Jiangsu Province Hospital on Integration of Chinese and Western Medicine, Nanjing 210028, People’s Republic of China; 3Department of Pharmaceutics, School of Pharmacy and Center for Drug/Gene Delivery and Tissue Engineering, Jiangsu University, Zhenjiang, Jiangsu 212001, People’s Republic of China*These authors contributed equally to this workBackground: Prophylactic central lymph node dissection (CLND) in papillary thyroid microcarcinoma (PTMC) patients without clinical evidence of central lymph node metastasis (CLNM) remains controversial. The purpose of our study is to identify preoperative predictive factors for finding CLNM in Chinese PTMC patients, which may allow tailored CLND.Methods: We retrospectively reviewed 182 consecutive Chinese PMTC patients with negative central lymph nodes who underwent total thyroidectomy plus central neck dissection from October 2015 to December 2017. Chi-squared and multivariate analysis were performed to evaluate the association of CLNM with ultrasonographic and clinicopathologic characteristics. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the utility of markers in predicting CLNM.Results: The CLNM was found in 39.0% (71 of 182) of cN0 PTMC patients. In multivariate analysis, tumor size>7 mm (OR: 3.636, 95% CI: 1.671–7.914), marked hypoechogenicity (OR: 2.686, 95% CI: 1.080–6.678), multifocality (OR: 4.184, 95% CI: 1.707–10.258) and BRAFV600E mutation (OR: 5.339, 95% CI: 2.529–11.272) were independent predictors of CLNM. In ROC analysis integrating these predictors, the sensitivity was 63.4% and specificity was 80.2%, and the area under the ROC (AUC) was 0.755.Conclusion: In conclusion, we found tumor size>7 mm, marked hypoechogenicity, multifocality, and BRAFV600E mutation were risk factors for CLNM. In term of these preoperative risk factors for CLNM, prophylactic CLND should be cautiously performed in cN0 PTMC patients.Keywords: central lymph node metastasis, prophylactic central lymph node dissection, papillary thyroid microcarcinoma, risk factor

BACKGROUND: Antrodia camphorata (AC) is an important fungus native to Taiwanese forested regions. Scientific studies have demonstrated that extracts of AC possess a variety of pharmacological functions. This study aims to identify the full profile fingerprint of nucleosides and nucleobases in mycelial AC and to assess the quality of two commercial mycelial AC products. METHODS: High-performance liquid chromatography coupled with diode array detector and mass spectrometry was employed to identify the major components in mycelial AC. The chemical separation was carried out using a gradient program on a reverse phase Alltima C18 AQ analytical column (250 x 4.6 mm, 5 mum) with the mobile phase consisting of deionized water and methanol. RESULTS: Ten nucleosides and nucleobases, two maleimide derivatives, and a sterol were identified as the major constituents in mycelial AC. These groups of chemical compounds constitute the first chromatographic fingerprint as an index for quality assessment of this medicinal fungus. CONCLUSIONS: This study provides the first chromatographic fingerprint to assess the quality of mycelial AC. [ABSTRACT FROM AUTHOR]

Background: Hepatocellular carcinoma (HCC) is one of the most prevalent and lethal cancers worldwide, with death rates increasing by approximately 2-3% per year. The high mortality and poor prognosis of HCC are primarily due to inaccurate early diagnosis and lack of monitoring when liver transplantation is not feasible. Fatty acid (FA) metabolism is a critical metabolic pathway that provides energy and signaling factors in cancer, particularly in HCC, and promotes malignancy. Therefore, it is essential to explore specific FA metabolism-related diagnostic and prognostic signatures that can enable the effective early diagnosis and monitoring of HCC., Methods: In this study, we used genes associated with FA metabolism pathway and weighted gene co-expression network analysis (WGCNA) to establish a gene co-expression network and identify hub genes related to HCC (disease WGCNA) and FA clusters (cluster WGCNA). A diagnostic model was constructed using data downloaded from the Gene Expression Omnibus database (GSE25097), and a prognostic model was established using The Cancer Genome Atlas cohort, in which Univariate Cox regression analysis, multivariate Cox risk model, and LASSO Cox regression analysis were applied. The immune infiltration of HCC cells was evaluated using CIBERSORT. The function of the key SLC22A1 gene was experimentally verified in vitro and in vivo., Results: Twelve overlapping genes (CPEB3, ASPDH, DEPDC7, ETFDH, UGT2B7, GYS2, F11, ANXA10, CYP2C8, GLYATL1, C6, and SLC22A1) from disease and cluster WGCNA were identified as key genes and used in the construction of the diagnostic and prognostic models. The RF model had the highest area under the ROC curve (AUC) of 0.994 was identified as the most effective for distinguishing patients with HCC with different features. The top five important genes (C6, UGT2B7, SLC22A1, F11, and CYP2C8) from the RF model were selected as diagnostic genes for further analysis (ROC curves: AUC value = 0.986, 95% confidence interval [95% CI] = 0.967-0.999). Moreover, a risk score formula consisting of four genes (GYS2, F11, ANXA10 and SLC22A1) was established and its independent prognostic ability was further demonstrated (univariate Cox regression analysis: hazard ratio [HR] = 3.664%, 95% CI = 2.033-6.605, P < 0.001; multivariate Cox regression analysis: HR = 2.801%, 95% CI = 1.553-5.049, P < 0.001). Additionally, in vitro and in vivo experiments demonstrated that SLC22A1 inhibits HCC tumor development, suggesting it may be a potential therapeutic target for HCC., Conclusions: These findings indicate a considerable value of specific FA metabolism-related genes in the diagnostic and prognostic evaluation of HCC, which provide novel insights into the disease's management, as well as has potential implications for personalized treatment strategies. However, further investigation of the effects of these model genes on HCC is required., Competing Interests: Declarations Ethics approval and consent to participate All participants signed informed consent forms. This study was reviewed and approved by the Institutional Review Board (Approval Number: 21K196) of Shanghai Tenth People’s Hospital, Tongji University School of Medicine, Shanghai. The animal study also approved under declaration with the approval number of SHDSYY-2021-4709. Consent for publication Not applicable. Competing interests The authors declare no competing interests., (© 2024. The Author(s).)

Porcine reproductive and respiratory syndrome virus (PRRSV) has led to significant economic losses in the global swine industry. Type I interferon (IFN-I) plays a crucial role in the host's resistance to PRRSV infection. Despite extensive research showing that PRRSV employs multiple strategies to antagonise IFN-I induction, the underlying mechanisms remain to be fully elucidated. In this study, we have discovered that PRRSV inhibits the production of IFN-I by degrading TANK-binding kinase 1 (TBK1) through chaperon-mediated autophagy (CMA). From a mechanistic standpoint, PRRSV nonstructural protein 2 (Nsp2) increases the interaction between the heat shock protein member 8 (HSPA8) and TBK1. This interaction leads to the translocation of TBK1 into lysosomes for degradation, mediated by lysosomal-associated membrane protein 2A (LAMP2A). As a result, the downstream activation of IFN regulatory factor 3 (IRF3) and the production of IFN-I are hindered. Together, these results reveal a new mechanism by which PRRSV suppresses host innate immunity and contribute to the development of new antiviral strategies against the virus., Competing Interests: Declarations Competing interests The authors declare that they have no competing interests., (© 2024. The Author(s).)

Aim: A bidirectional relationship exists between obstructive sleep apnoea (OSA) and type 2 diabetes (T2D). We aimed to examine the cumulative impact of having both OSA and T2D on patient outcomes, relative to having either condition alone., Materials and Methods: Using TriNetX, a global federated research network (n = 128 million), we undertook two retrospective cohort studies, using time-to-event analysis. Analysis 1 compared OSA with T2D versus OSA alone; analysis 2 compared T2D with OSA versus T2D alone. Propensity score matching using greedy nearest neighbour (calliper 0.1) balanced the cohorts (1:1) for significant covariates. Primary outcomes were cardiovascular, liver, diabetes-related (microvascular) and cancer events over 1-5 years., Results: Analysis 1 (n = 179 688): A codiagnosis of T2D/OSA significantly increased risk of all-cause mortality (hazard ratio [HR] 1.52; confidence interval [CI]: 1.48, 1.57), dementia (HR 1.19; CI: 1.12, 1.26), liver (HR 2.20; CI: 1.77, 2.73), pancreatic (HR 1.62; CI: 1.35, 1.93), colon, renal and endometrial cancers; all cardiovascular, microvascular and liver related outcomes versus OSA alone over 1-5 5 years following OSA diagnosis. Analysis 2 (n = 240 094): A codiagnosis of OSA/T2D significantly increased the risk of peripheral (HR 1.39; CI: 1.36, 1.43) and autonomic (HR 1.63; CI: 1.51, 1.75) neuropathy; retinopathy (HR 1.13; CI: 1.09, 1.18), CKD (HR 1.21; CI: 1.18, 1.23); all cardiovascular and liver outcomes; all-cause mortality and several obesity related cancers versus T2D alone., Conclusions: T2D significantly potentiates risk of cardiovascular, malignancy and liver-related outcomes in individuals with OSA. OSA, in individuals with T2D, significantly potentiates risk of cardiovascular disease, malignancy, death and several microvascular complications (retinopathy, CKD, peripheral/autonomic neuropathy)., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Introduction: The cumulative impact of metabolic syndrome (MetS) components on micro- and macrovascular disease in metabolic dysfunction-associated steatotic liver disease (MASLD) is unclear. We aimed to determine whether the number of the MetS components increases the risk of micro- and macrovascular disease in patients with MASLD., Methods: We performed a retrospective cohort study of electronic medical records using the TriNetX network, a global federated database. The exposure arm was patients with hepatic steatosis (defined via International Classification of Diseases, 10th Revision coding, or modified hepatic steatosis index), and ≥1 MetS components (obesity/central adiposity, insulin resistance, hypertension, or dyslipidaemia), compared with a reference arm of adults without any MetS components or hepatic steatosis. Our propensity score matched (1:1) for confounders with 5 years of follow-up. Primary outcomes included microvascular (peripheral neuropathy, retinopathy, and nephropathy) and macrovascular (cardiovascular events, cerebrovascular accidents, and peripheral vascular disease) disease. Secondary analyses assessed the impact of additional MetS components on these outcomes, as well as the impact of sex., Results: MASLD, defined by hepatic steatosis and insulin resistance (n = 15 937), carried the highest risk of microvascular disease (HR 13.93 (95% CI 8.55-22.68)), whilst MASLD, defined by hepatic steatosis and hypertension (n = 53 028), carried the highest risk of macrovascular disease (7.23 (6.45-8.13)). MASLD with all MetS components carried greatest risk of both micro- (31.20 (28.88-33.70) (n = 462 789)) and macrovascular (8.04 (7.33-8.82) (n = 336 010)) disease., Conclusion: We demonstrate a differential effect of MetS components on micro- and macrovascular disease risk in patients with MASLD, with a cumulative impact of multiple MetS on overall risk. The impact of MetS components was most pronounced in women. Aggressive metabolic risk factor management is critical for prevention of micro- and macrovascular complications., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Objective: Inhibitors of the interleukin 13 (IL-13) pathway, such as dupilumab, are licensed for atopic dermatitis and asthma. Adverse events resembling psoriatic disease after dupilumab initiation have been reported, but evidence is limited to case reports with uncertain causality. We aimed to investigate whether genetically mimicked IL-13 inhibition (IL-13i) is associated with risk of psoriatic arthritis (PsA) and psoriasis., Methods: We instrumented IL-13i using a protein-coding variant in the IL13 gene, rs20541, that is associated with circulating eosinophil count (biomarker of IL-13i) at genome-wide significance in a study of 563,946 individuals. Outcome genetic data were taken from studies of PsA, psoriasis, and related spondyloarthritis traits in up to 10,588 cases and 209,287 controls. Colocalization analysis was performed to examine genetic confounding. We additionally used circulating IgE as a biomarker to test whether associations were replicated, both in the test and in an independent genetic dataset. We also replicated analyses using individual-level data from the UK Biobank., Results: Genetically proxied IL-13i was associated with increased risk of PsA (odds ratio [OR] 37.39; 95% confidence interval [95% CI] 11.52-121.34; P = 1.64 × 10 -9 ) and psoriasis (OR 20.08; 95% CI 4.38-92.01; P = 1.12 × 10 -4 ). No consistent associations were found for Crohn disease, ulcerative colitis, ankylosing spondylitis, or iritis. Colocalization showed no strong evidence of genetic confounding for psoriatic disease. Results were replicated using circulating IgE for the exposure, using independent outcome data and using individual-level data., Conclusion: We provide supportive genetic evidence that IL-13i is linked to increased risk of PsA and psoriasis. Physicians prescribing IL-13 inhibitors should be vigilant for these adverse events., (© 2024 The Author(s). Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Objectives: The aim of our study was to identify the potential distinct phenotypes within a broad SpA population., Methods: We conducted a cross-sectional study using the REGISPONSER registry, which has data from 31 specialist centres in Spain, including patients with SpA who have fulfilled the ESSG criteria. A latent class analysis (LCA) was performed to identify the latent classes underlying SpA according to a set of predefined clinical and radiographic features, independently of expert opinion., Results: In a population of 2319 SpA patients, a five-classes LCA model yielded the best fit. Classes named 'Axial with spine involvement' and 'Axial with isolated SI joint involvement' showed a primarily axial SpA phenotype defined by inflammatory back pain and high HLA-B27 prevalence. Patients in class 'Axial + peripheral' showed a similar distribution of manifest variables to previous classes but also had a higher likelihood of peripheral involvement (peripheral arthritis/dactylitis) and enthesitis, therefore representing a mixed (axial and peripheral) subtype. Classes 'Peripheral + psoriasis' and 'Axial + peripheral + psoriasis' were indicative of peripheral SpA (and/or PsA) with high likelihood of psoriasis, peripheral involvement, dactylitis, nail disease, and low HLA-B27 prevalence, while class 'Axial + peripheral + psoriasis' also exhibited increased probability of axial involvement both clinically and radiologically., Conclusion: The identification of five latent classes in the REGISPONSER registry with significant overlap between axial and peripheral phenotypes is concordant with a unifying concept of SpA. Psoriasis and related features (nail disease and dactylitis) influenced the phenotype of both axial and peripheral manifestations., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Discovery of highly efficient and thermal stable phosphors is the focus of the studies in phosphor-converted white light-emitting diodes (LEDs). Herein, a tetraphenylethylene-based cerium metal-organic framework ( SYNU-2 ) was synthesized and characterized. The intricate architecture of SYNU-2 shows an overall 3D → 3D 2-fold interpenetration framework. SYNU-2 exhibited good luminescence properties, and its latent fingerprint developer was prepared, which showed good fluorescence and stability under ultraviolet (UV) radiation. It is worth noting that a prototype WLED device can be designed using SYNU-2 and red phosphors (Ca,Sr)AlSiN 3 :Eu 2+ with CIE coordinates of (0.33, 0.33) at an applied 3 V bias.

Background and Aims: We examined the impact of a co-diagnosis of metabolic dysfunction-associated steatotic liver disease (MASLD) and type 2 diabetes (T2D) on patient outcomes., Methods: Using TriNetX, a global federated research network (n = 114 million), we undertook two retrospective cohort studies, using time-to-event analysis. Analysis 1 compared MASLD with T2D to MASLD alone; analysis 2 compared T2D with MASLD to T2D alone. Propensity score matching using greedy nearest neighbour (calliper .1) balanced the cohorts (1:1) for significant covariates. Primary outcomes were cardiovascular, liver, diabetes-related, and cancer events over 5 years., Results: Analysis 1 (n = 95 275): a co-diagnosis of T2D significantly increased the risk of ischaemic heart disease (IHD) (HR 1.39; CI: 1.34, 1.44), ischaemic stroke (HR 1.45; CI: 1.35, 1.56), heart failure (HR 1.42; CI: 1.36, 1.49), atrial fibrillation (HR 1.09; CI: 1.03, 1.16), hepatocellular carcinoma (HR 1.96; CI: 1.69, 2.27), pancreatic cancer (HR 1.25; CI: 1.06, 1.48) and liver-related complications over 5 years from MASLD diagnosis. Analysis 2 (n = 15 208): a co-diagnosis of MASLD significantly increased risk of all-cause mortality (HR 1.11; CI: 1.02, 1.22), IHD (HR 1.181; CI: 1.08, 1.29), hepatocellular (HR 50.31; CI: 6.94, 364.72), pancreatic (HR 1.78; CI: 1.12, 2.84), breast (HR 1.43; CI: 1.09, 1.88) and renal cancer (HR 2.01; CI: 1.24, 3.26), and diabetic neuropathy (HR 1.17; CI: 1.09, 1.27) over 5 years from metformin initiation., Conclusions: T2D significantly potentiates the risk of cardiovascular, malignancy and liver-related outcomes in people with MASLD. The effect of MASLD on people with T2D, although less dramatic, still potentiated risk of death, IHD, malignancy and peripheral neuropathy., (© 2024 The Author(s). Liver International published by John Wiley & Sons Ltd.)

Background: Post-stroke depression (PSD) is a common and debilitating condition affecting stroke survivors, significantly impacting their recovery and overall quality of life., Aim: To assess the effects of early PSD screening on functional outcomes, quality of life, and mortality., Methods: From an initial pool of 1065 articles, 6 studies met the inclusion criteria and were selected for analysis. Functional outcomes were measured using the functional independence measure (FIM)., Results: The analysis revealed a significant improvement in FIM scores for a PSD screening group compared to controls [standardized mean difference (SMD) = 8.90, 95% confidence interval (CI): 4.65-13.15, P < 0.01]. Quality of life was assessed using the Stroke-Specific Quality of Life Scale, with the screening group showing significantly higher scores (SMD = 20.83, 95%CI: 15.27-26.38, P < 0.01). Mortality analysis indicated a reduction in five-year mortality rates for the PSD screening group., Conclusion: Early PSD screening enhances functional recovery, improves quality of life, and reduces mortality rates in stroke survivors. Thus, integrating PSD screening into routine stroke care improves long-term outcomes for patients., Competing Interests: Conflict-of-interest statement: The authors deny any conflict of interest., (©The Author(s) 2024. Published by Baishideng Publishing Group Inc. All rights reserved.)

Objectives: Interleukin-12 (IL-12) signalling was proposed in the immunopathogenesis of primary Sjögren's disease. The efficacy of therapies targeting this pathway is currently unclear. Herein, we investigated the associations between circulating proteins involved in the IL-12 and IL-23 signalling pathways on primary Sjögren's disease using mendelian randomization., Methods: We selected SNPs from protein quantitative trait loci of IL12A, IL12B, IL12Rβ1, IL12Rβ2, and IL23R to examine the association between alterations in their levels and risk of primary Sjögren's disease. Genetic association data for proteins were taken from studies ranging from 3,301-54 306 in sample size, and from 3,232 cases of primary Sjögren's disease and 17 481 controls. The Wald ratio or inverse variance weighted methods estimated causal effects. We applied colocalization and pleiotropy-robust methods as sensitivity analyses for confounding., Results: There was a negative association between genetically predicted IL-12p40 (encoded by IL12B) and primary Sjögren's disease. In the two independent exposure datasets odds ratio (OR) 0.79 (95% confidence interval [CI] 0.68-0.93; P-value = 0.004) and OR 0.86 (95% CI 0.78-0.95; P-value = 0.003) per standard deviation decrease in genetically predicted IL-12p40. Neither IL-12Rβ2 and IL-23R met the threshold P-value after MR analyses (P-value < 0.01) for colocalization assessment. No variants for the IL12A gene met prerequisite thresholds for weak instrument bias., Conclusion: This study provides genetic evidence that IL-12p40 has a causal role in primary Sjögren's disease pathogenesis. Our data suggest that decreasing levels of IL-12p40 may be deleterious. We would not suggest selecting this drug target as a therapeutic option., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: There have been only few reports on Rhupus syndrome with severe visceral involvement. Moreover, there was little consensus regarding its treatment. Belimumab is one of the options for treating this disease. For patients with clinical symptoms and elevated levels of anti CCP antibodies and anti-double stranded DNA antibodies, and it suggests Rhupus syndrome. After effective treatment, the decrease in levels of anti CCP antibodies and anti-double stranded DNA (ds-DNA) antibodies can effectively delay the progression of the disease and protect target organs., Methods: We used a chemiluminescence instrument, (Yahuilong; Shenzhen, China), to measure the changes in CCP and dsDNA before and after treatment., Results: Prior to treatment, the patient presented with symptoms of rheumatoid arthritis and systemic lupus erythematosus. Her laboratory tests showed dsDNA (214 IU/mL) and CCP level of ˃ 3,000 U/mL. After treatment with belimumab, the clinical symptoms were significantly relieved, and the patient's CCP IgG level decreased to 263.5 U/mL. A blood test found that her anti-dsDNA was negative., Conclusions: CCP and dsDNA can serve as indicators for the diagnosis and treatment of Rhupus syndrome.

Spondyloarthropathies (SpA), including ankylosing spondylitis (AS) and psoriatic arthritis (PsA), have been shown to have a substantial genetic predisposition based on heritability estimates derived from family studies and genome-wide association studies (GWAS). GWAS have uncovered numerous genetic loci associated with susceptibility to SpA, with significant associations to human leukocyte antigen (HLA) genes, which are major genetic risk factors for both AS and PsA. Specific loci differentiating PsA from cutaneous-only psoriasis have been identified, though these remain limited. Further research with larger sample sizes is necessary to identify more PsA-specific genetic markers. Current research focuses on translating these genetic insights into clinical applications. For example, polygenic risk scores are showing promise for the classification of disease risk and diagnosis and future research should focus on refining these risk assessment tools to improve clinical outcomes for individuals with SpA. Addressing these challenges will help integrate genetic testing into patients care and impact clinical practice., Competing Interests: Declaration of competing interest None., (Copyright © 2024. Published by Elsevier Ltd.)

Purpose: Antiplatelet therapy is used for the primary and secondary prevention of thrombotic diseases such as acute coronary syndrome (ACS). These patients are more vulnerable to infections, as such, strategies are required to mitigate these risks., Methods: We conducted a retrospective cohort study using TriNetX, a global federated health research network that includes both inpatient and outpatient electronic medical records from health care organizations worldwide. Patients ≥18 years old, after ACS, who were placed on aspirin and ticagrelor were compared with patients placed on aspirin and clopidogrel or prasugrel. Patients were identified using International Statistical Classification of Diseases and Related Health Problems terminology codes. After propensity score matching (1:1), a total of 239,358 patients were identified in each cohort. The primary outcomes of interest investigated were rates of (1) acute and subacute infective endocarditis, (2) sepsis of unknown origin, (3) staphylococcus arthritis, (4) cellulitis and acute lymphangitis, (5) Staphylococcus aureus bacteremia, and (6) staphylococcal pneumonia after initiation of treatment. Outcomes were analyzed at 1, 3, and 5 years., Findings: At 5 years, a combination of aspirin and ticagrelor, compared with a combination of aspirin and clopidogrel or prasugrel, was associated with significantly reduced rates of (1) acute and subacute endocarditis (hazard ratio [HR] plus 95% CI) (HR = 0.85; 0.77-0.945; P = 0.030), (2) sepsis of unknown origin (HR = 0.89; 95% CI, 0.86-0.91; P < 0.0001), (3) cellulitis and acute lymphangitis (HR = 0.89; 95% CI, 0.87-0.92; P < 0.0001, and (4) Staphylococcus aureus bacteremia (HR = 0.72; 95% CI, 0.61-0.85; P = 0.0007). However, a combination of aspirin and clopidogrel was associated with a marinally lower risk of staphylococcal pneumonia (HR = 1.04; 95% CI, 1.01-1.062; P < 0.0001)., Implications: A combination of aspirin and ticagrelor is associated with a lower rate of a variety of bacterial infections. This combination warrants further investigation in in-vitro studies to tease out mechanisms and through clinical randomized trials in groups who have ACS and are at high infection risk., Competing Interests: Declaration of competing interest U. Alam has received honoraria from Procter & Gamble, Eli Lilly, Viatris, Grunenthal, and Sanofi for educational meetings. U. Alam has also received investigator-led research funding from Procter & Gamble and attendance at an educational meeting by Daiichi-Sankyo. G.Y.H. Lip has received consultancy and speaker fees from Bayer, Bayer/Janssen, Bristol Myers Squibb/Pfizer, Biotronik, Medtronic, Boehringer Ingelheim, Microlife, Roche, and Daiichi-Sankyo outside the submitted work. The other authors have indicated that they have no other conflicts of interest regarding the content of this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aim: To evaluate the impact of denosumab on (i) the incidence of type 2 diabetes (T2D), and (ii) long-term health outcomes (microvascular [neuropathy, retinopathy, nephropathy] and macrovascular [cardiovascular disease, cerebrovascular accident] complications, and all-cause mortality) in patients with T2D, before (iii) combining results with prior studies using meta-analysis., Methods: A retrospective analysis of data in a large global federated database (TriNetX; Cambridge, MA) was conducted from 331 375 patients, without baseline T2D or cancer, prescribed either denosumab (treatment, n = 45 854) or bisphosphonates (control, n = 285 521), across 83 healthcare organizations. Propensity score matching (1:1) of confounders was undertaken that resulted in 45 851 in each cohort. Secondary analysis further evaluated the impact of denosumab on long-term health outcomes in patients with T2D. Additionally, we systematically searched prior literature that assessed the association between denosumab and T2D. Estimates were pooled using random-effects meta-analysis. Risk of bias and evidence quality were assessed using Cochrane-endorsed tools., Results: Denosumab (vs. bisphosphonates) was associated with a lower risk of incident T2D over 5 years (hazard ratio 0.83 [95% confidence interval {CI} 0.78-0.88]). Secondary analysis showed significant risk reduction in all-cause mortality (0.79 [0.72-0.87]) and foot ulceration (0.67 [0.53-0.86]). Also, pooled results from four studies (three observational, one randomized controlled trial) following meta-analysis showed a reduced relative risk (RR [95% CI]) for incident T2D in patients prescribed denosumab (0.83 [0.79-0.87]) (I 2  = 10.76%)., Conclusions: This is the largest cohort study to show that denosumab treatment is associated with a reduced RR of incident T2D, as well as an associated reduced RR of all-cause mortality and microvascular complications, findings that may influence guideline development in the treatment of osteoporosis, particularly in patients who are at a high risk of T2D., (© 2024 The Author(s). Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Background: Dermatitis has been reported after initiation of IL-6 receptor (IL-6R) inhibitors (IL-6Ri), while genetic association studies of atopic dermatitis (AD) have implicated IL-6R pathway signaling. However, causality remains unclear. As the indications for IL-6Ri expand, so do the clinical importance of determining whether there is mechanistic evidence linking it to AD., Objective: Our aim was to examine the association between IL-6Ri and risk of AD., Methods: To genetically mimic IL-6Ri, we selected single-nucleotide polymorphisms within or near the IL6R gene associated with C-reactive protein at genome-wide significance among 343,524 individuals. Genetic data were obtained from 10,788 individuals with AD and 30,047 controls of European ancestry. We used inverse variance-weighted and pleiotropy-robust methods and examined genetic confounding using colocalization. Analyses were replicated by using 13,473 Finnish and 2,385 East Asian individuals with AD. The results from 3 independent analyses were pooled by meta-analysis., Results: Genetically proxied IL-6Ri was associated with increased risk of AD (odds ratio [OR] = 1.78 per 4.4-mg/L reduction in C-reactive protein level [95% CI = 1.28-2.48] [P = 6.5 × 10 -4 ]). The results were replicated using Finnish outcome data (OR = 2.07 [95% CI = 1.58-2.72] [P = 1.57 × 10 -7 ]) and Eastern Asian data (OR = 1.68 [95% CI = 1.12-2.54] [P = .013]). Meta-analysis of 3 independent populations (OR = 1.89 [95% CI = 1.57-2.28] [P = 2.68 × 10 -11 ]) showed no evidence of heterogeneity (P = .65). We found no statistical evidence for pleiotropy or genetic confounding., Conclusion: This genetic investigation provides consistent evidence (across independent multiancestry populations) that IL-6R signaling is causally implicated in AD susceptibility. Clinicians should remain vigilant for adverse effects resembling AD when using IL-6R inhibitors for immune-mediated inflammatory diseases., Competing Interests: Disclosure statement Supported by the National Institute for Health and Care Research (NIHR) Manchester Biomedical Research Centre (grant NIHR203308), as well as by an NIHR Clinical Lectureship (to S.S.Z.) and Versus Arthritis (grants 21173, 21754, and 21755). The views expressed are those of the author(s) and not necessarily those of the NIHR or the Department of Health and Social Care. Disclosure of potential conflict of interest: The authors declare that they have no relevant conflicts of interest., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Psoriatic arthritis (PsA) is an inflammatory joint and entheseal disease associated with significant personal and public health burden. PsA has a prevalence of up to 1%, affecting ~20% of people suffering with psoriasis. PsA is frequently accompanied by metabolic syndrome (MetS), and both conditions are characterised by a chronic pro-inflammatory state, with several key cytokines in PsA (interleukin (IL)-17 and IL-23) also elevated in those with MetS. This narrative review aims to provide an update on MetS in PsA, focusing on its prevalence, pathogenesis, prognosis, treatment interactions and future therapeutic options. MetS is particularly prevalent in PsA compared to other inflammatory arthritides. Cohort studies indicate a higher risk of PsA in individuals with obesity, while Mendelian randomization studies link childhood obesity, insulin resistance, and dyslipidaemia to PsA. Weight loss interventions have been shown to reduce disease activity in PsA. Additionally, MetS negatively impacts the efficacy of tumour necrosis factor inhibitor (TNFi) drugs in treating PsA. Drugs given for PsA may also affect the conditions constituting MetS. Leflunomide has been shown to reduce body weight but also increase blood pressure. TNFi drugs lead to weight gain but reduce cardiovascular risk. Janus kinase inhibitors increase lipid levels and cardiovascular risk among high-risk groups. Anti-IL-17 and anti-IL-12/IL-23 drugs may cause a short-term increase in cardiovascular risk, although the long-term effects have yet to be established. Weight loss represents an unexplored avenue for disease modification in PsA, alongside a plethora of general health benefits. Dietary and exercise modifications are the cornerstone of weight management but vary substantially across individuals. Novel therapies to treat weight loss, such as glucagon-like peptide 1 agonists and sodium-glucose cotransporter 2 inhibitors, may prove useful alongside disease-modifying therapies for those with PsA and MetS and should be investigated as potential therapeutic adjuncts., Competing Interests: The authors declare that there is no conflict of interest., (© The Author(s), 2024.)

Background: Tirzepatide, a novel dual agonist of glucagon-like-peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP), has demonstrated greater magnitude of weight loss compared to semaglutide in a phase 3 clinical trial. However, the effect of tirzepatide on incidence of type 2 diabetes (T2D) in individuals with overweight and obesity, and the effect on major adverse cardiovascular outcomes in individuals with pre-existing T2D, remains unknown., Methods: We performed a retrospective cohort study of anonymised electronic medical records using the TriNetX network (TriNetX LLC, Cambridge, MA, USA) a global federated database. The data used in this study was collected on 5th June 2024. Two cohorts of individuals were generated: 1) without pre-existing T2D and, 2) with T2D. We adopted an active comparator new user design on new initiations of either tirzepatide or semaglutide therapy. Analysis began from the index event which was defined as individuals on respective therapy for 6 months only. Analysis of outcomes was conducted off-drug, in individuals without a pre-existing history of the disease of interest. Individuals were followed up for 12 months post the index event. Primary outcome for cohort 1 was incidence of T2D, and for cohort 2 was composite: all-cause mortality, cerebral infarction, acute coronary syndrome, and heart failure. Secondary outcomes for cohort 1 were change in HbA1c and body weight and for cohort 2 : incidence of micro- and macrovascular complications, suicidal ideation and/or attempt, and all-cause mortality. We propensity score matched (1:1) for potential confounders: baseline demographics, socioeconomic circumstances, HbA1c, weight, relevant co-morbidities, and anti-obesity, hypoglycaemic and cardioprotective agents., Findings: The study population without T2D consisted of 13,846 individuals, equally split between tirzepatide and semaglutide users. Tirzepatide was associated with both lower risk for incident T2D (HR 0.73, 95% CI 0.58-0.92, p < 0.001) and greater weight loss (-7.7 kg, [95% CI -6.8, -8.5 kg], p < 0.001), compared to semaglutide (-4.8 kg, [95% CI -3.9, -5.6 kg], p < 0.001). In individuals with pre-existing T2D (n = 8446), tirzepatide was associated with lower risk of the composite outcome (HR 0.54, 95% CI 0.38-0.76, p < 0.001), cerebral infarction (HR 0.45, 95% CI 0.24-0.84, p = 0.010) and all-cause mortality (HR 0.33, 95% CI 0.15-0.73, p = 0.004) compared to semaglutide., Interpretation: Tirzepatide is associated with significantly reduced risk of developing T2D and major adverse cardiovascular events in individuals living with obesity and T2D respectively. Randomised controlled trials investigating the utility of dual incretin agonists in the primary prevention of T2D and cardiovascular disease in higher risk populations are now required., Funding: Nil., Competing Interests: MA receives a fellowship from the Novo Nordisk UK research foundation and JDRF. DJC has received investigator-initiated grants from Astra Zeneca and Novo Nordisk, support for education from Perspectum with any financial remuneration from pharmaceutical company consultation made to the University of Liverpool. GHI is an employee of TriNetX LLC. UA has received honoraria from Eli Lilly, Procter & Gamble, Viatris, Grunenthal and Sanofi for educational meetings and funding for attendance to an educational meeting from Diiachi Sankyo. UA has also received investigator-led funding by Procter & Gamble and is a council member of the Royal Society of Medicine's Vascular, Lipid & Metabolic Medicine Section. JPHW consults widely for pharmaceutical companies in relation to obesity and diabetes (fees paid to the University of Liverpool via his institution) and has received research grants from industry. He has received lecture fees from commercial organisations including the pharmaceutical industry while providing unpaid support to various charities in relation to his interest in obesity and diabetes. All other authors declare that there are no financial relationships or activities that might bias, or be perceived to bias, their contribution to this manuscript., (© 2024 The Author(s).)

Under the long-term pressure overload stimulation, the heart experiences embryonic gene activation, leading to myocardial hypertrophy and ventricular remodelling, which can ultimately result in the development of heart failure. Identifying effective therapeutic targets is crucial for the prevention and treatment of myocardial hypertrophy. Histone lysine lactylation (HKla) is a novel post-translational modification that connects cellular metabolism with epigenetic regulation. However, the specific role of HKla in pathological cardiac hypertrophy remains unclear. Our study aims to investigate whether HKla modification plays a pathogenic role in the development of cardiac hypertrophy. The results demonstrate significant expression of HKla in cardiomyocytes derived from an animal model of cardiac hypertrophy induced by transverse aortic constriction surgery, and in neonatal mouse cardiomyocytes stimulated by Ang II. Furthermore, research indicates that HKla is influenced by glucose metabolism and lactate generation, exhibiting significant phenotypic variability in response to various environmental stimuli. In vitro experiments reveal that exogenous lactate and glucose can upregulate the expression of HKla and promote cardiac hypertrophy. Conversely, inhibition of lactate production using glycolysis inhibitor (2-DG), LDH inhibitor (oxamate) and LDHA inhibitor (GNE-140) reduces HKla levels and inhibits the development of cardiac hypertrophy. Collectively, these findings establish a pivotal role for H3K18la in pathological cardiac hypertrophy, offering a novel target for the treatment of this condition., (© 2024 The Author(s). Journal of Cellular and Molecular Medicine published by Foundation for Cellular and Molecular Medicine and John Wiley & Sons Ltd.)

Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Dipender Gill reports a relationship with Novo Nordisk that includes: employment. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Abstract: Our aim was to investigate relative contributions of central and peripheral mechanisms to knee osteoarthritis (OA) diagnosis and their independent causal association with knee OA. We performed longitudinal analysis using data from UK-Biobank participants. Knee OA was defined using International Classification of Diseases manual 10 codes from participants' hospital records. Central mechanisms were proxied using multisite chronic pain (MCP) and peripheral mechanisms using body mass index (BMI). Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated, and proportional risk contribution (PRC) was estimated from receiver-operator-characteristic (ROC) analysis. To estimate the causal effects, we performed 2-sample multivariable Mendelian Randomisation (MR) analysis. We selected genetic instruments from the largest Genome Wide Association Study of BMI (N = 806,834) and MCP (N = 387,649) and estimated the instruments genetic associations with knee OA in the largest available dataset (62,497 cases and 333,557 control subjects). The multivariable MR was performed using modified inverse-variance weighting methods. Of the 203,410 participants, 6% developed knee OA. Both MCP (OR 1.23, 95% CI; 1.21-1.24) and BMI (1.10, 95% CI; 1.10-1.11) were associated with knee OA diagnosis. The PRC was 6.9% (95% CI; 6.7%-7.1%) for MCP and 21.9% (95% CI; 21.4%-22.5%) for BMI; the combined PRC was 38.8% (95% CI; 37.9%-39.8%). Body mass index and MCP had independent causal effects on knee OA (OR 1.76 [95% CI, 1.64-1.88] and 1.83 [95% CI, 1.54-2.16] per unit change, respectively). In conclusion, peripheral risk factors (eg, BMI) contribute more to the development of knee OA than central risk factors (eg, MCP). Peripheral and central factors are independently causal on knee OA., (Copyright © 2024 International Association for the Study of Pain.)

Objectives: Adults with RA are being switched from etanercept originator to biosimilar in non-medical/cost-saving switching. This analysis aims to investigate outcomes in these patients, including (i) drug survival and (ii) disease activity at 6 months and 12 months, compared with those who remain on the originator., Methods: Using BSRBR-RA, those who switched directly from etanercept originator to biosimilar were identified and matched to patients receiving the originator, based on gender, age, disease duration and originator start year. Drug survival was calculated; Cox-proportional hazard models assessed differences in drug persistence between those who switched vs remaining on originator. Change in DAS28 after 6 months and 12 months was compared between cohorts. Multiple imputation was used., Results: A total of 1024 adults with RA switching from etanercept originator to biosimilar were included, with a matched cohort of patients remaining on the originator. Patients who switched onto a biosimilar product were no more likely to discontinue etanercept treatment vs those who remained on the originator; hazard ratio 1.06 (95%CI 0.89-1.26), with 65% of patients remaining on treatment at three years. Ninety-five (9%) patients switched back to the originator within the first year. After 6 months and 12 months, biosimilar patients were no more likely to have a worsening of DAS28 (>0.6 units) compared with those who remained on the originator., Conclusions: This is the largest matched comparative effectiveness analysis showing patients switching from etanercept originator to biosimilar appearing to do just as well with regard to disease activity and drug persistence compared with those who remained on the originator. These data will be reassuring to clinicians and patients regarding non-medical switching., (© The Author(s) 2023. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Objectives: Timely diagnosis remains a challenge in axial SpA (axSpA). In addition, data are scarce on the impact of diagnostic delay and disease progression in affected individuals. The British Axial Spondyloarthritis Inception Cohort (BAxSIC) study aims to investigate the impact of newly diagnosed axSpA, the natural history of the disease and the effect of diagnostic delay on disease outcomes., Methods: BAxSIC is a prospective, multicentre, observational study. Eligible participants are adults (≥16 years of age), with a physician-confirmed diagnosis of axSpA in the 6 months prior to study entry, recruited from secondary and tertiary rheumatology centres in the UK. Participants will be followed up for 3 years, with in-person visits at baseline and 24 months. In addition, patient self-reported assessments will be recorded remotely via the online electronic case report form (eCRF) at 6, 12, 18, 30 and 36 months., Results: The first patient was enrolled in BAxSIC in June 2023. Recruitment is currently ongoing and is planned to end in June 2026. Initial results will be available in 2027. Since opening, the trial has undergone two protocol amendments., Conclusion: The BAxSIC study is the first inception cohort designed to investigate the impact of diagnostic delay on clinical presentation and long-term functional outcomes in patients with axSpA in the UK. With an innovative, patient-led virtual longitudinal data collection model, data generated from this study will help inform and improve the care of people newly diagnosed with axSpA., Trial Registration: ClinicalTrials.gov (http://clinicaltrials.gov), NCT05676775., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology.)

Purpose: This study aimed to evaluate the relative association between sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1Ra) with the incidence of gout in patients with type 2 diabetes (T2D) using real-world data., Methods: We conducted a cohort study using data from TriNetX (an international federated database). We included patients commenced on metformin or insulin, either alone or with an SGLT2i or GLP-1Ra, at least 2 years prior to date of analysis. We propensity score matched (PSM) (1:1) for 26 relevant characteristics. Time to event analysis was performed to assess the incidence of gout, all-cause mortality (positive control), and herpes zoster infection (negative control) at 5 years following drug initiation., Findings: Prior to PSM, the cohort numbers were as follows: metformin control, 1,111,449; SGLT2i with metformin, 101,706; GLP-1Ra with metformin, 110,180, insulin control, 1,398,066; SGLT2i with insulin, 68,697; and GLP-1Ra with insulin, 99,693. SGLT2i with metformin demonstrated a statistically significant decreased incidence of gout at 5 years compared to the metformin control cohort (HR 0.75 [95% CI 0.69-0.82], P < 0.0001). Similarly, SGLT2i with insulin demonstrated a statistically significant decreased incidence of gout at 5 years compared to the insulin control cohort (HR 0.83 [95% CI 0.74-0.92], P < 0.0001). Conversely, no significant disparity in gout incidence was observed between the use of GLP-1Ra and matched controls. Subgroup analysis showed an associated reduced incidence of gout with SGLT2i use compared to GLP-1Ra, in groups using metformin (HR 0.77 [95% CI 0.70-0.86], P < 0.0001) or insulin (HR 0.82 [95% CI 0.73-0.91)], P < 0.0001)., Implications: In this large-scale real-world study, SGLT2i use was associated with a lower incidence of gout in patients with T2D compared to both insulin and metformin controls. These findings suggest the potential of SGLT2i as a promising therapeutic option for treating gout in this population., Competing Interests: Declaration of competing interest UA has received honoraria from Procter & Gamble, Viatris, Grunenthal and Sanofi for educational meetings. UA has also received investigator-led funding by Procter & Gamble. DJC has received investigator-led funding and conference support from Astra Zeneca, NovoNordisk and Perspectum. All other authors declare that there are no relationships or activities that might bias, or be perceived to bias, their contribution to this manuscript., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: The beneficial effects of fibroblast growth factor 21 (FGF21) and sodium butyrate (NaB) on protection against cholestasis-induced liver fibrosis are not well known. This study aimed to explore the effects of FGF21 and NaB on bile duct ligation (BDL)-induced liver fibrosis., Methods: Wild-type (WT) and FGF21 knockout (KO) mice received BDL surgery for 14 days. Liver fibrosis was assessed by Masson's staining for fibrosis marker expressions at the mRNA or protein levels. Adenovirus-mediated FGF21 overexpression in the WT mice was assessed against BDL damage. BDL surgeries were performed in WT and FGF21 KO mice that were administered either phosphate-buffered saline or NaB. The effects of NaB on the energy metabolism and gut microbiota were assessed using stable metabolism detection and 16S rRNA gene sequencing., Results: BDL-induced liver fibrosis in the WT mice was accompanied by high induction of FGF21. Compared to the WT mice, the FGF21 KO mice showed more severe liver fibrosis induced by BDL. FGF21 overexpression protected against BDL-induced liver fibrosis, as proved by the decreasing α-SMA at both the mRNA and protein levels. NaB administration enhanced the glucose and energy metabolisms as well as remodeled the gut microbiota. NaB alleviated BDL-induced liver fibrosis in the WT mice but aggravated the same in FGF21 KO mice., Conclusion: FGF21 plays a key role in alleviating cholestasis-induced liver damage and fibrosis. NaB has beneficial effects on cholestasis in an FGF21-dependent manner. NaB administration can thus be a novel nutritional therapy for treating cholestasis via boosting FGF21 signaling and regulating the gut microbiota., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. The author(s) declared that they were an editorial board member of Frontiers at the time of submission. This had no impact on the peer review process and the final decision., (Copyright © 2024 Yang, Chen, Zhao, Du, Fan, Liu, Li and Li.)

Vitamin D deficiency has been linked to various chronic pain conditions. However, randomized trials of vitamin D supplementation have had mixed results. In contrast, systematic reviews of randomized trials indicate a protective effect of vitamin D supplementation on depression. We undertake a Mendelian randomization investigation in UK Biobank, a study of UK residents aged 40-65 at recruitment. We perform linear and non-linear Mendelian randomization analyses for four outcomes: fibromyalgia, clinical fatigue, chronic widespread pain, and probable lifetime major depression. We use genetic variants from four gene regions with known links to vitamin D biology as instruments. In linear analyses, genetically-predicted levels of 25-hydroxyvitamin D [25(OH)D], a clinical marker of vitamin D status, were not associated with fibromyalgia (odds ratio [OR] per 10 nmol/L higher 25(OH)D 1.02, 95% confidence interval [CI] 0.93, 1.12), clinical fatigue (OR 0.99, 95% CI 0.94, 1.05), chronic widespread pain (OR 0.95, 95% CI 0.89, 1.02), or probable lifetime major depression (OR 0.97, 95% CI 0.93, 1.01). In non-linear analyses, an association was observed between genetically-predicted 25(OH)D levels and depression in the quintile of the population with the lowest 25(OH)D levels (OR 0.75, 95% CI 0.59, 0.94); associations were null in other strata. Our findings suggest that population-wide vitamin D supplementation will not substantially reduce pain or depression; however, targeted supplementation of deficient individuals may reduce risk of depression., (© 2024. The Author(s).)

Purpose: Psoriatic arthritis (PsA) is a chronic inflammatory condition with complex and heterogenous manifestations. Although a myriad of treatment options including biologic medications are available to alleviate symptoms and slow disease progression, there is currently no cure for this condition. There has been a recent emergence of understanding about the relationship between the gut microbiome and immune-mediated inflammatory diseases. This has generated interest in the potential role of dietary interventions, particularly anti-inflammatory diets, and fecal microbiota transplant (FMT) as novel therapeutic approaches. The purpose of this narrative review is to examine the role of an anti-inflammatory diet and FMT in turn and whether their combination may offer alternate approaches for the management of PsA., Methods: Our non-systematic narrative review was informed by a literature search using PubMed and Google Scholar using the terms anti-inflammatory diet, FMT, nutrition supplements, and PsA. Preclinical studies and non-English language articles were excluded when synthesizing the narrative review., Findings: Current randomized controlled trials (RCTs) and observational evidence suggest that a hypocaloric diet or Mediterranean diet can help achieve weight loss among PsA patients who are overweight or obese, which in turn reduces inflammation and improves disease activity. However, there is no strong data to support the beneficial effects of intermittent fasting, vitamin supplements, turmeric supplements, probiotics, or omega-3 fatty acid supplements in PsA. Current evidence on the use of FMT in PsA is limited as only one small RCT has been conducted which did not demonstrate efficacy for improving clinical symptoms., Implications: Clinicians can consider recommending hypocaloric or Mediterranean diets as an adjunct to standard management of PsA, possibly under the guidance of a dietician. Further research is needed to explore the beneficial effects of the synergistic role of combining an anti-inflammatory diet with FMT in PsA., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Sizheng Stevn Zhao: consulting editor—Rheumatology, Clinical Therapeutics journal. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this article., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Aims: To evaluate the efficacy and cardiovascular outcomes of combination pioglitazone with either a glucagon-like peptide-1 receptor agonist (GLP-1RA) or a sodium-glucose cotransporter-2 (SGLT2) inhibitor in individuals with type 2 diabetes (T2D) by conducting a systematic review, meta-analysis, and analysis of a large international real-world database., Methods: We searched MEDLINE, SCOPUS and Web of Science to identify relevant articles for inclusion (PROSPERO [CRD: 42023483126]). Nineteen studies assessing pioglitazone + SGLT2 inhibitors or GLP-1RAs versus controls were identified, 16 of which were randomized controlled trials. Risk of bias was assessed using Cochrane-endorsed tools and quality of evidence was assessed using GRADE. We additionally performed a retrospective cohort study of all individuals aged 18 years or over with T2D, using the TriNetX platform. We included propensity-score-matched individuals who were treated for at least 1 year with pioglitazone and a GLP-1RA or pioglitazone and an SGLT2 inhibitor, compared against GLP-1RA and SGLT2 inhibitor monotherapy. Outcomes were all-cause mortality, heart failure, chronic kidney disease and composite stroke and transient ischaemic attack., Results: The average follow-up in the included studies ranged from 24 to 52 weeks. Combination of pioglitazone with a GLP-1RA reduced glycated haemoglobin (HbA1c) and weight greater than in controls: mean differences -1% (95% confidence interval [CI] -1.27, -0.74) and -1.19 kg (95% CI -1.80, -0.58), respectively. There was no statistically significant difference in systolic blood pressure (SBP) or mortality between groups: mean difference - 1.56 mmHg (95% CI -4.48, 1.35; p = 0.30) and relative risk (RR) 0.29 (95% CI 0.07-1.15; p = 0.08), respectively. Combination of pioglitazone with SGLT2 inhibitors reduced HbA1c, weight and SBP to a greater extent than control treatment: mean differences -0.48% (95% CI -0.67, -0.28), -2.3 kg (95% CI -2.72, -1.88) and -2.4 mmHg (95% CI -4.1, -0.7; p = 0.01), respectively. There was no statistically significant difference in mortality between groups (RR 1.81, 95% CI 0.30-10.97; p = 0.52). The included trials demonstrated a reduction in risk of heart failure with combination treatment. Similarly, from the real-world database (n = 25 230 identified), pioglitazone and SGLT2 inhibitor combination therapy was associated with reduced risk of heart failure compared to monotherapy alone (hazard ratio 0.50, 95% CI 0.38-0.65; p < 0.001)., Conclusion: Both our systematic review/meta-analysis and the real-world dataset show that combination of pioglitazone with either GLP-1RAs or SGLT2 inhibitors is associated with increased weight loss and reduced risk of heart failure compared with monotherapy., (© 2024 The Authors. Diabetes, Obesity and Metabolism published by John Wiley & Sons Ltd.)

Aims/hypothesis: A protective role of sodium-glucose cotransporter 2 inhibitors (SGLT2is) and glucagon-like peptide 1 receptor agonists (GLP1-ra) in the development of diabetic retinopathy and diabetic macular oedema has been described in some recent studies, which may extend beyond glycaemic control. We aimed to review the clinical impact of SGLT2i and GLP1-ra therapy on the risk of diabetic retinopathy and diabetic macular oedema in individuals with type 2 diabetes taking insulin., Methods: This is a retrospective cohort analysis of approximately two million people with type 2 diabetes receiving insulin across 97 healthcare organisations using a global federated health research network (TriNetX, Cambridge, USA). Two intervention cohorts (SGLT2i + insulin, n=176,409; GLP1-ra + insulin, n=207,034) were compared against a control cohort (insulin with no SGLT2i/GLP1-ra, n=1,922,312). Kaplan-Meier survival analysis was performed and estimated HRs were reported for each outcome. Propensity score was used to 1:1 match for age, sex, ischaemic heart disease, hypertension, microvascular complications, chronic kidney disease, HbA 1c , BMI and use of pioglitazone, lipid modifying agents, antilipemic agents, ACE inhibitors, angiotensin II inhibitors and metformin. A sub-analysis comparing the two intervention cohorts was also performed., Results: SGLT2i with insulin was associated with a reduced HR (95% CI) for diabetic macular oedema compared with the control cohort (0.835; 0.780, 0.893), while GLP1-ra with insulin demonstrated a lack of signal with no statistical significance to the HR (1.013; 0.960, 1.069). SGLT2i with insulin was not associated with a clinically significant increase in the risk of developing diabetic retinopathy (1.076; 1.027, 1.127), while GLP1-ra with insulin increased diabetic retinopathy risk (1.308; 1.261, 1.357). Compared with SGLT2i with insulin, GLP1-ra with insulin was associated with higher risk of diabetic retinopathy (1.205; 1.153, 1.259) and diabetic macular oedema (1.130; 1.056, 1.208)., Conclusions/interpretation: Our study suggests that the combination of SGLT2i and insulin is associated with lower risk of developing diabetic macular oedema. However, the use of GLP1-ra was associated with an increased risk of diabetic retinopathy in individuals with type 2 diabetes also taking insulin. A comparative analysis showed favourable outcomes with SGLT2i and insulin in the development of diabetic macular oedema and diabetic retinopathy. RCTs using dedicated  retinal imaging are required to determine the causal relationship with these therapies., (© 2024. The Author(s).)

The explosion in Mendelian randomization (MR) publications is hard to ignore and shows no signs of slowing. Clinician readers, who may not be familiar with jargon-ridden methods, are expected to discern the good from the many low-quality studies that make overconfident claims of causality or stretch the plausibility of what MR can investigate. We aim to equip readers with foundational concepts, contextualized using examples in rheumatology, to appraise the many MR papers that are or will appear in their journals. We highlight the importance of assessing whether exposures are under plausibly specific genetic influence, whether the hypothesized causal pathways make biological sense, and whether results stand up to replication and use of control outcomes. Quality of research can vary substantially using MR as with any design, and all methods have inherent limitations. MR studies have provided and can still contribute valuable insights in the context of evidence triangulation., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Objectives: Sleep disturbance has been associated with chronic widespread pain (CWP), but their causal relationship remains unclear. We aimed to examine the causal relationship and direction between CWP and sleep traits, namely insomnia, sleep duration and chronotype, using Mendelian Randomization., Method: We used genetic association data from ~0.5 million individuals and up to 1.8 million controls from the UK Biobank (UKB). All traits were defined predominantly by self-report. Short sleep duration was defined as average ≤6 hours per 24 hours. Chronotype refers to the inclination to sleep at certain times where some wake and go to bed early ('morning' person), and others wake and go to sleep later ('evening' person). To permit use of the largest available genetic association data, we used the Causal Analysis Using Summary Effect estimates (CAUSE) method, which allows for sample overlap., Results: Insomnia (OR 1.009, 95% credible interval 1.005, 1.014; p = 0.018 that the causal model is a better fit than non-causal model) and short sleep duration (OR 1.060, 95%CrI 1.038, 1.083; p = 0.040) were causally associated with increased risk of CWP, with limited evidence for reverse causation. There was no evidence in support of long sleep duration or chronotype being associated with CWP., Conclusions: This study suggest that insomnia and short sleep duration (≤6 hours) are associated with an increased risk of CWP. Improving short sleep duration and insomnia, rather than chronotype, may be effective in reducing the risk of CWP, although these results should be replicated in epidemiological and interventional studies., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Aims: We compared the glycaemic and cardiorenal effects of combination therapy involving metformin, pioglitazone, sodium-glucose-linked-cotransporter-2 inhibitor (SGLT2i), and glucagon-like peptide-1 receptor agonist (GLP-1RA) versus a more conventional glucocentric treatment approach combining sulphonylureas (SU) and insulin from the point of type 2 diabetes (T2D) diagnosis. Methods: We performed a retrospective cohort study using the Global Collaborative Network in TriNetX. We included individuals prescribed metformin, pioglitazone, an SGLT2i, and a GLP-1 RA for at least 1-year duration, within 3 years of a T2D diagnosis, and compared with individuals prescribed insulin and a SU within the same temporal pattern. Individuals were followed up for 3 years. Results: We propensity score-matched (PSM) for 26 variables. A total of 1762 individuals were included in the final analysis ( n = 881 per cohort). At 3-years, compared to the insulin/SU group, the metformin/pioglitazone/SGLT2i/GLP-1 RA group had a lower risk of heart failure (HR 0.34, 95% CI 0.13-0.87, p = 0.018), acute coronary syndrome (HR 0.29, 95% CI 0.12-0.67, p = 0.002), stroke (HR 0.17, 95% CI 0.06-0.49, p < 0.001), chronic kidney disease (HR 0.50, 95% CI 0.25-0.99, p = 0.042), and hospitalisation (HR 0.59, 95% CI 0.46-0.77, p < 0.001). Conclusions: In this real-world study, early, intensive polytherapy, targeting the distinct pathophysiological defects in T2D, is associated with significantly more favourable cardiorenal outcomes, compared to insulin and SU therapy., Competing Interests: M. A. receives a salary from the Pain Relief Foundation. P. A. and G. H. I. are employees of TriNetX LLC. D. J. C. has received investigator-initiated grants from AstraZeneca and Novo Nordisk and support for education from Perspectum. U. A. has received honoraria from Procter & Gamble, Viatris, Grunenthal, and Sanofi for educational meetings. U. A. has also received investigator-led funding from Procter & Gamble. All other authors declare no conflicts of interest., (Copyright © 2024 Matthew Anson et al.)

Objective: Polymyalgia rheumatica (PMR) is an age-related inflammatory disease of unknown cause. We aimed to identify potentially modifiable risk factors and therapeutic targets for preventing or treating PMR., Methods: We meta-analysed genetic association data from 8,156 cases of PMR (defined using diagnostic codes and self-report) and 416,495 controls of European ancestry from the UK Biobank and FinnGen. We then performed Mendelian randomization analyses to estimate the association between eight modifiable risk factors (using data from up to 1.2 million individuals) and 65 inflammation-related circulating proteins (up to 55,792 individuals), using the inverse variance weighted and pleiotropy robust methods., Results: We identified three novel genome-wide significant loci in the IL1R1, NEK6 and CCDC88B genes and confirmation of previously described associations with HLA-DRB1 and ANKRD55. Genetically predicted smoking intensity (OR 1.32; 95%CI 1.08-1.60; p = 0.006) and visceral adiposity (OR 1.22; 95%CI 1.10-1.37; p = 3.10x10-4) were associated with PMR susceptibility. Multiple circulating proteins related to IL-1 family signaling were associated with PMR. IL-1 receptor-like 2, also known as IL-36 receptor (OR 1.25; p = 1.89x10-32), serum amyloid A2 (OR 1.06, 9.91x10-10) and CXCL6 (OR 1.09, p = 4.85x10-7) retained significance after correction for multiple testing., Conclusion: Reducing smoking and visceral adiposity at a population level might reduce incidence of PMR. We identified proteins that may play causal roles in PMR, potentially suggesting new therapeutic opportunities. Further research is needed before these findings are applied to clinical practice., (© The Author(s) 2024. Published by Oxford University Press on behalf of the British Society for Rheumatology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Ionic liquids (ILs) have attracted considerable interest in the last two decades owing to their unique fluorescent properties. Herein, N-octylpyridine hydrogen sulphate ([OP]HSO 4 ) was synthesised and characterised using 1 H NMR and infrared spectroscopies. In addition, the fluorescence spectra of [OP]HSO 4 in water, methanol, ethanol and acetonitrile were studied. In a single solvent, as the concentration of the solvent (methanol, ethanol or acetonitrile) increases, the fluorescence intensity of the IL first increases and then decreases. A similar trend was observed in their mixed solvents with water. Moreover, the fluorescence intensity of [OP]HSO 4 decreases with increasing temperature. A fluorescence intensity reduction of only 4.46% for [OP]HSO 4 after continuous scanning for 40 cycles under the maximum excitation state was analysed. The lack of photobleaching observed in [OP]HSO 4 indicates its good photobleaching resistance., Competing Interests: The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (© 2024 Published by Elsevier Ltd.)