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BACKGROUND: While numerous allergy-related biomarkers and targeted treatment strategies have been developed and employed, there are still signifcant limitations and challenges in the early diagnosis and targeted treatment for allegic diseases. Our study aims to identify circulating proteins causally associated with allergic disease-related traits through Mendelian randomization (MR)-based analytical framework. METHODS: Large-scale cis-MR was employed to estimate the effects of thousands of plasma proteins on five main allergic diseases. Additional analyses including MR Steiger analyzing and Bayesian colocalisation, were performed to test the robustness of the associations; These findings were further validated utilizing meta-analytical methods in the replication analysis. Both proteome- and transcriptome-wide association studies approach was applied, and then, a protein-protein interaction was conducted to examine the interplay between the identified proteins and the targets of existing medications. RESULTS: Eleven plasma proteins were identified with links to atopic asthma (AA), atopic dermatitis (AD), and allergic rhinitis (AR). Subsequently, these proteins were classified into four distinct target groups, with a focus on tier 1 and 2 targets due to their higher potential to become drug targets. MR analysis and extra validation revealed STAT6 and TNFRSF6B to be Tier 1 and IL1RL2 and IL6R to be Tier 2 proteins with the potential for AA treatment. Two Tier 1 proteins, CRAT and TNFRSF6B, and five Tier 2 proteins, ERBB3, IL6R, MMP12, ICAM1, and IL1RL2, were linked to AD, and three Tier 2 proteins, MANF, STAT6, and TNFSF8, to AR. CONCLUSION: Eleven Tier 1 and 2 protein targets that are promising drug target candidates were identified for AA, AD, and AR, which influence the development of allergic diseases and expose new diagnostic and therapeutic targets.
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Biomarcadores , Proteínas Sanguíneas , Hipersensibilidade , Análise da Randomização Mendeliana , Proteômica , Humanos , Proteômica/métodos , Biomarcadores/sangue , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Proteínas Sanguíneas/análise , Hipersensibilidade/genética , Hipersensibilidade/sangue , Teorema de Bayes , Estudo de Associação Genômica AmplaRESUMO
BACKGROUND: Severe heart failure (HF) has a higher mortality during vulnerable period while targeted predictive tools, especially based on drug exposures, to accurately assess its prognoses remain largely unexplored. Therefore, this study aimed to utilize drug information as the main predictor to develop and validate survival models for severe HF patients during this period. METHODS: We extracted severe HF patients from the MIMIC-IV database (as training and internal validation cohorts) as well as from the MIMIC-III database and local hospital (as external validation cohorts). Three algorithms, including Cox proportional hazards model (CoxPH), random survival forest (RSF), and deep learning survival prediction (DeepSurv), were applied to incorporate the parameters (partial hospitalization information and exposure durations of drugs) for constructing survival prediction models. The model performance was assessed mainly using area under the receiver operator characteristic curve (AUC), brier score (BS), and decision curve analysis (DCA). The model interpretability was determined by the permutation importance and Shapley additive explanations values. RESULTS: A total of 11,590 patients were included in this study. Among the 3 models, the CoxPH model ultimately included 10 variables, while RSF and DeepSurv models incorporated 24 variables, respectively. All of the 3 models achieved respectable performance metrics while the DeepSurv model exhibited the highest AUC values and relatively lower BS among these models. The DCA also verified that the DeepSurv model had the best clinical practicality. CONCLUSIONS: The survival prediction tools established in this study can be applied to severe HF patients during vulnerable period by mainly inputting drug treatment duration, thus contributing to optimal clinical decisions prospectively.
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Insuficiência Cardíaca , Modelos de Riscos Proporcionais , Humanos , Insuficiência Cardíaca/mortalidade , Insuficiência Cardíaca/tratamento farmacológico , Feminino , Masculino , Idoso , Reprodutibilidade dos Testes , Prognóstico , Análise de Sobrevida , Pessoa de Meia-Idade , Curva ROC , Algoritmos , Área Sob a Curva , Bases de Dados Factuais , Aprendizado Profundo , Índice de Gravidade de DoençaRESUMO
PURPOSE: To investigate the association between proton pump inhibitors (PPIs) administration during hospitalization and mortality and length of stay in critically ill pediatric patients. MATERIALS AND METHODS: This is a retrospective observational cohort study on pediatric ICU patients (0 to 18 years). Propensity score matching (PSM), Kaplan-Meier curves, Cox proportional hazards model and Linear regression model was applied for assessing the effects of PPIs on mortality and other outcomes during hospitalization. RESULTS: A total of 2269 pediatric ICU patients were included, involving 1378 omeprazole (OME) users and 891 non-OME users. The results showed significant association between OME exposure and decreased ICU stay (ß -0.042; 95% CI -0.073--0.011; P = 0.008) but prolonged non-ICU hospital stay (ß 0.121; 95% CI 0.097-0.155; P = 0.040). No statistical significance was observed between OME exposure and reduced mortality, but the OME group had a slightly decreased tendency in 28-day mortality (HR 0.701; 95% CI 0.418-1.176) and in-hospital mortality (HR 0.726; 95% CI 0.419-1.257). Furthermore, subgroup analyses revealed that the decreased tendency of mortality were more obvious in patients less than 1 year old compared with older pediatric patients, although not statistically significant. In addition, we also observed that OME exposure was significantly associated with reduced mortality of general ICU subgroup. CONCLUSIONS: This study provided a sign that PPIs used only in the ICU, rather than throughout hospital stay, might provide more benefit for critically ill pediatric patients. Additionally, younger pediatric patients might gain relatively more benefit than older children when receiving PPIs.
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Estado Terminal , Omeprazol , Humanos , Criança , Adolescente , Lactente , Tempo de Internação , Estudos de Coortes , Omeprazol/uso terapêutico , Estado Terminal/terapia , Mortalidade Hospitalar , Inibidores da Bomba de Prótons/uso terapêutico , Unidades de Terapia Intensiva , Estudos RetrospectivosRESUMO
BACKGROUND: The potential effects of insulin therapy on osteoarthritis (OA) risk are poorly understood. This study aimed to explore the causal relationship between insulin therapy and OA. METHODS: Mendelian randomization (MR) analysis was performed to examine the association between genetically proxied inhibition of insulin targets and the risk of overall, hip (HOA) and knee OA (KOA). We then performed univariable MR using summary statistics regarding insulin target genes derived from the DrugBank database. Data related to blood glucose reduction levels were used as a proxy for insulin levels. Two phenotypes, type 2 diabetes, and glycosylated hemoglobin levels, were selected as positive controls to confirm the direction and validity of the proxies. The OA datasets were derived from the UK Biobank cohort. Multivariable MR was adjusted for body mass index, sedentary behavior, cigarette smoking, frequency of alcohol intake, age, and genetic sex. RESULTS: Genetically proxied insulin therapy was associated with an increased risk of overall OA [odds ratio (OR):1.2595; 95% confidence interval (CI):1.0810-1.4675] and HOA (OR:1.4218; 95%CI:1.1240-1.7985), which remained consistent across multiple MR methods. After adjusting for confounders, we found evidence supporting a significant causal link with a higher risk of overall OA and HOA. A further two-step MR analysis revealed no significant mediation effects from the six mediators in the associations. CONCLUSION: There was a causal association between genetically proxied insulin therapy and a higher risk of OA, especially HOA.
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BACKGROUND Previous studies have shown that primary repair (PR) and anterior cruciate ligament reconstruction (ACLR) can effectively treat ACL injuries. Our study aimed to compare different treatments of ACL tears, including autograft, allograft, hybrid graft ACLR, and PR, by assessing clinical outcomes and adverse events. MATERIAL AND METHODS PubMed, Cochrane Library, Embase, and CNKI databases were searched and a frequentist-framework network meta-analysis was used. RESULTS Overall, PR with augmentation was superior to ACLR only for activity recovery (WMD 0.28 95%CI [0.07 to 0.49]), and there was no significant difference shown between PR without augmentation and ACLR. ACLR with irradiated allograft was a poor option for the treatment of ACL rupture, showing the weakest subjective evaluations and functional outcomes and worst safety profile. PR with or without augmentation provided fairly good postoperative efficacy results and produced less postoperative knee laxity than irradiated allograft ACLR (PR: standardized mean difference [SMD] -1.27 [-1.80 to -0.74]; ACLR: SMD -1.36 [-1.88 to -0.83]). However, PR without augmentation showed a high failure rate compared with autograft ACLR (autograft vs PR without augmentation: risk ratio 0.29 [0.10 to 0.85]). CONCLUSIONS For surgical treatment of ACL rupture, irradiated allograft ACLR had the worst efficacy and safety and is not recommended. PR may be an ideal treatment method in terms of efficacy but it is related to a significantly higher revision risk if without augmentation. Autograft ACLR may be the preferred method currently available for most patients requiring surgical treatment of ACL rupture.
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Lesões do Ligamento Cruzado Anterior , Reconstrução do Ligamento Cruzado Anterior , Ligamento Cruzado Anterior/cirurgia , Lesões do Ligamento Cruzado Anterior/cirurgia , Reconstrução do Ligamento Cruzado Anterior/métodos , Autoenxertos , Humanos , Articulação do Joelho/cirurgia , Metanálise em Rede , Ruptura/cirurgiaAssuntos
Psoríase , Serotonina , Ansiedade/diagnóstico , Ansiedade/epidemiologia , Transtornos de Ansiedade/diagnóstico , Transtornos de Ansiedade/epidemiologia , Depressão/diagnóstico , Depressão/epidemiologia , Humanos , Psoríase/diagnóstico , Psoríase/epidemiologia , Índice de Gravidade de DoençaRESUMO
OBJECTIVE: To explore whether there is a genetic causal relationship between sleep traits and the risk of autoimmune arthritis (AA). METHODS: Univariable and multivariable Mendelian randomization was employed using genome-wide association studies data to assess sleep traits' associations with AAs, including rheumatoid arthritis (RA), ankylosing spondylitis, and psoriatic arthritis. The inverse-variance weighted method served as the primary analysis, supplemented by the CAUSE method to improve power and mitigate false positives. Mediation Mendelian randomization was used to quantify direct and indirect effects. RESULTS: Significant associations were shown between insomnia symptoms and increased risk of overall RA (odds ratio = 2.75, 95% confidence interval 1.45-5.22) and seronegative RA (odds ratio = 6.95, 95% confidence interval 2.47-19.56). CAUSE results revealed an association of insomnia symptoms with overall RA and seronegative RA, as well as the sleep duration with overall RA. After the adjustment for body mass index, alcohol status, smoking status, and physical activity levels, multivariable analyses revealed that genetic predisposition to insomnia symptoms and prolonged sleep duration showed independent negative associations with the risk of overall RA and seropositive RA. In the reversed multivariable analyses, a borderline negative association was shown in the overall RA-sleep duration and a positive association of seropositive RA with the risk of insomnia symptoms. CONCLUSION: This study demonstrated a potential bidirectional causal relationship that genetic predisposition to insomnia symptoms and shorter sleep duration was associated with the risk of AA, especially RA. Genetic predisposition to RA was also associated with decreased sleep duration, as well as increased insomnia symptom risk.
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Artrite , Distúrbios do Início e da Manutenção do Sono , Humanos , Distúrbios do Início e da Manutenção do Sono/epidemiologia , Distúrbios do Início e da Manutenção do Sono/genética , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Sono/genética , Predisposição Genética para DoençaRESUMO
This study addresses the diagnostic and therapeutic challenges in malignant melanoma (MM) and non-melanoma skin cancers (NMSC). We aim to identify circulating proteins causally linked to MM and NMSC traits using a multicenter Mendelian randomization (MR) framework. We utilized large-scale cis-MR to estimate the impact of numerous plasma proteins on MM, NMSC, squamous cell carcinoma (SCC), and basal cell carcinoma (BCC). To ensure robustness, additional analyses like MR Steiger and Bayesian colocalization are conducted, followed by replication through meta-analytical methods. The associations between identified proteins and outcomes are also validated at the tissue level using Transcriptome-Wide Association Study methods. Furthermore, a protein-protein interaction analysis is conducted to explore the relationship between identified proteins and existing cancer medication targets. The MR analysis has identified associations of 13 plasma proteins with BCC, 2 with SCC, and 1 with MM. Specifically, ASIP and KRT5 are associated with BCC, with ASIP also potentially targeting MM. CTSS and TNFSF8 are identified as promising druggability candidates for BCC. This multidimensional approach nominates ASIP, KRT5, CTSS, and TNFSF8 as potential diagnostic and therapeutic targets for skin cancers.
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Proteínas Sanguíneas , Melanoma , Análise da Randomização Mendeliana , Proteoma , Neoplasias Cutâneas , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/sangue , Neoplasias Cutâneas/metabolismo , Humanos , Melanoma/genética , Melanoma/metabolismo , Proteínas Sanguíneas/genética , Proteínas Sanguíneas/metabolismo , Biomarcadores Tumorais/genética , Biomarcadores Tumorais/metabolismo , Biomarcadores Tumorais/sangue , Carcinoma Basocelular/genética , Carcinoma Basocelular/metabolismo , Estudo de Associação Genômica AmplaRESUMO
BACKGROUND: The relationship between local epicardial adipose tissue (EAT) macrophages and atrial fibrillation (AF) remains unclear. The purpose of this study was to investigate the role of KCa3.1 in the migration of macrophages from EAT to adjacent atrial tissue during rapid pacing. METHODS: Part 1: Eighteen beagles were randomly divided into the sham group, pacing group, and pacing + clodronate liposome (CL) group. Part 2: Eighteen beagles were randomly divided into the sham group, pacing group, and pacing + TRAM-34 group. HL-1 cells and RAW264.7 cells were cocultured to explore the specific migratory mechanism of macrophages. RESULTS: Depleting EAT macrophages significantly reduced macrophage infiltration in the adjacent atrium and the induction of AF in canines with rapid atrial pacing. TRAM-34 significantly inhibited the migration of macrophages from EAT to the adjacent atrium and electrical remodeling in canines with rapid atrial pacing. Compared with those of the control HL-1 cells, the secretion of CCL2 and the number of migrating macrophages in pacing HL-1 cells were significantly increased, which could be reversed by TRAM-34. Further in vitro experiments showed that KCa3.1 regulated CCL2 secretion through the p65/STAT3 signaling pathway. CONCLUSION: Inhibiting myocardial KCa3.1 reduced the migration of EAT macrophages to adjacent atrial muscles caused by rapid atrial pacing, thereby decreasing vulnerability to AF. The mechanism by which KCa3.1 regulates CCL2 may be related to the p65/STAT3 signaling pathway.
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Previous evidence has suggested that childhood sunburn could be a risk factor for cutaneous malignant melanoma (MM) and non-melanoma skin cancer (NMSC). However, existing observational studies could not reveal the causal associations genetically. This study aimed to investigate whether there was a genetic causal relationship between childhood sunburn and skin cancers. Univariable Mendelian randomization (MR) and Causal Analysis Using Summary Effect analysis was carried out for causal estimates and evaluation for the horizontal pleiotropy. Multivariable MR and the mediation effects analysis were used to test whether the causal associations were mediated by potential confounders. A suggestively significant causal association between childhood sunburn and MM was indicated (OR = 4.74; 95% CI: 1.31-17.19; p = 1.79E-02). Genetically predicted childhood sunburn was significantly associated with increased risk of overall melanoma in situ (MIS) (OR = 4.02; 95% CI: 2.00-8.08; p = 9.40E-05), MIS of face (OR = 18.28; 95% CI: 5.28-63.35; p = 4.59E-06), and MIS of trunk (OR = 7.05; 95% CI: 2.06-24.13; p = 1.88E-03). Similar trends were found for childhood sunburn and NMSC (OR = 8.16; 95% CI: 6.07-10.99; p = 1.53E-20), including both basal cell carcinoma (BCC) (OR = 3.76; 95% CI:2.96-4.77; p = 2.19E-08) and squamous cell carcinoma (SCC) (OR = 7.44; 95% CI: 5.09-10.87; p = 2.19E-08). After adjustment for hair and skin color, facial ageing, vitamin D levels, body mass index, alcohol consumption, and smoking status, childhood sunburn showed an independent association with MIS, MIS of face, MIS of trunk, as well as NMSC, including both BCC and SCC. Mediation analysis showed no significant mediation effect. This study demonstrated a causal relationship between childhood sunburn and the risk of both MM and NMSC, which suggested that enhanced screening and prevention for childhood sunburn could contribute to the early detection and decreased risk of MM and NMSC.
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Carcinoma Basocelular , Carcinoma de Células Escamosas , Melanoma , Neoplasias Cutâneas , Queimadura Solar , Criança , Humanos , Melanoma/epidemiologia , Melanoma/complicações , Queimadura Solar/epidemiologia , Queimadura Solar/complicações , Análise da Randomização Mendeliana , Neoplasias Cutâneas/epidemiologia , Carcinoma Basocelular/complicações , Fatores de RiscoRESUMO
Atrial fibrillation (AF) poses a serious healthcare burden on society due to its high morbidity and the resulting serious complications such as thrombosis and heart failure. The principle of catheter ablation is to achieve electrical isolation by linear destruction of cardiac tissue, which makes AF a curable disease. Currently, catheter ablation does not have a high long-term success rate. The current academic consensus is that inflammation and fibrosis are central mechanisms in the progression of AF. However, artificially caused inflammatory cell death by catheter ablation may have a significant impact on structural and electrical remodeling, which may affect the long-term prognosis. This review first focused on the inflammatory response induced by apoptosis, necrosis, necroptosis, pyroptosis, ferroptosis and their interaction with arrhythmia. Then, we compared the differences in cell death induced by radiofrequency ablation, cryoballoon ablation and pulsed-field ablation. Finally, we discussed the structural and electrical remodeling caused by inflammation and the association between inflammation and the recurrence of AF after catheter ablation. Collectively, pulsed-field ablation will be a revolutionary innovation with faster, safer, better tissue selectivity and less inflammatory response induced by apoptosis-dominated cell death.
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OBJECTIVES: This study aimed at exploring the potential causal effects of leisure sedentary behavior (LSB) on common types of arthritis. METHOD: Two-sample Mendelian randomization (MR), including both univariable MR (UVMR) and multivariable MR (MVMR) analysis, was performed to explore the effects of LSB on the risk of several common types of arthritis, including osteoarthritis, rheumatoid arthritis (RA), and psoriatic arthritis (PsA). Genetic variants from genome-wide association studies (GWAS) of LSBs for time spent on television watching, computer use, and driving were obtained from the UK Biobank. Summarized GWAS data of OA [overall, OA of the hip (HOA), and OA of the knee (KOA)], RA [overall, seronegative RA (nRA) and seropositive RA], and PsA was also acquired from the FinnGen Biobank Analysis. Causal Analysis Using Summary Effect Estimates (CAUSE) were further applied to verify the causality. RESULTS: UVMR results provided evidence for the causal relationship of time spent on watching TV with overall OA [odds ratio (OR) = 1.80, 95% confidence interval (CI) = 1.45-2.23], KOA (OR = 1.86, 95% CI = 1.45-2.39) and HOA (IVW-fixed: OR = 1.65, 95% CI =1.20-2.26). Similar associations were observed in the TV-overall RA and TV-pRA, and TV-PsA, but the CAUSE method results only supported the causal association of time spent TV watching with OA and KOA. Moreover, MVMR results showed indicated an independent causal effect of TV watching on OA (overall, KOA, and HOA). CONCLUSION: This study demonstrated the genetic causal association of prolonged TV watching time with overall OA and KOA risks.
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Artrite Psoriásica , Artrite Reumatoide , Osteoartrite , Humanos , Análise da Randomização Mendeliana , Estudo de Associação Genômica Ampla , Comportamento Sedentário , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Observational research reported the underlying correlation of metabolic syndrome (MetS) and its components with rotator cuff tendinopathy (RCT), but their causality remained unclear. This study aimed to investigate whether genetically predicted MetS was related to the risk of RCT. METHODS: Both univariable and multivariable Mendelian randomization (MR) analysis was applied using summary-level data from the most comprehensive genome-wide association studies to estimate the associations of MetS and its component with RCT, with the inverse variance weighted (IVW) as the primary method, and the method of Causal Analysis Using Summary Effect Estimates (CAUSE) as a supplement for false positives detection. The mediation analysis was furtherly used for the assessment of direct and indirect effects. RESULTS: Univariable analysis revealed that genetically predicted MetS (OR: 1.0793; 95% CI 1.0311 to 1.1297), body mass index (BMI) (OR 1.2239; 95% CI 1.1357 to 1.3189), and waist circumference (WAC) (OR 1.3177; 95% CI 1.2015 to 1.4451) had a significant positive association with the risk of RCT. Triglycerides and systolic blood pressure were suggestively associated with RCT risk. These associations were also identified by CAUSE. There was independent causality of BMI (OR: 1.1806; 95% CI 1.0788 to 1.2920) and WAC (OR 1.3716; 95% CI 1.2076 to 1.5580) on RCT after adjustment for confounders. No mediator was found in the causal associations. CONCLUSION: Our study revealed the genetic causality of MetS and its components, especially BMI and WAC, with RCT risk. Early prevention and diagnosis of excess central adiposity contributing to MetS are significant in the RCT risk management.
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BACKGROUND: Observational studies have found an association between rheumatoid arthritis (RA) and risk of obstructive lung disease (ORDs). However, whether RA plays a role in ORDs development remains unclear. OBJECTIVES: This study aimed to explore the causal association of RA with ORDs. METHODS: Both univariable and multivariable Mendelian randomization (MR) analyses were employed. Summary statistics for RA were obtained from the genome-wide association study (GWAS) meta-analysis, and the GWAS data source of ORDs, including the chronic obstructive pulmonary disease (COPD) and asthma, was accessed from the FinnGen Biobank. Causal Analysis Using Summary Effect Estimates (CAUSE) method was used to improve statistical power. multivariable and two-step mediation MR was applied to calculate the independent and mediated effects. RESULTS: The causal estimates by univariable and CAUSE results indicated genetic predisposition to RA had an effect on the increased risk of asthma/COPD (A/C) (ORCAUSE = 1.03; 95% CI: 1.02-1.04), COPD/asthma related infections (ACI) (ORCAUSE = 1.02; 95% CI: 1.01-1.03) and COPD/asthma related pneumonia or pneumonia derived septicemia (ACP) (ORCAUSE = 1.02; 95% CI: 1.01-1.03). Genetic predisposition to RA was significantly associated with early onset COPD (ORCAUSE = 1.02; 95% CI: 1.01-1.03) and asthma (ORCAUSE = 1.02; 95% CI: 1.01-1.03) risk and suggestively associated with non-allergic asthma (nAA) risk. After adjustment for confounders, independent causal effects remained for the associations of RA with risk of A/C, ACI, and ACP, as well as COPD, early-onset COPD, and asthma [total, nAA and allergic asthma (AA)] risk. Mediation analyses revealed no potential mediator. CONCLUSION: This study indicates a causal effect of increased genetic predisposition to RA on an increased risk of ORDs, including COPD and asthma, especially early-onset COPD and nAA, and on asthma/COPD related infections, pneumonia or pneumonia derived septicemia.
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Artrite Reumatoide , Asma , Pneumonia , Doença Pulmonar Obstrutiva Crônica , Sepse , Humanos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Análise da Randomização Mendeliana , Doença Pulmonar Obstrutiva Crônica/epidemiologia , Doença Pulmonar Obstrutiva Crônica/genética , Asma/epidemiologia , Asma/genética , Artrite Reumatoide/complicações , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/genéticaRESUMO
OBJECTIVES: The current world witnesses a greatly increased prevalence and incidence of hyperuricemia and gout with unfortunately the comparative efficacy and safety of present available uricosuric agents remaining uncertain. We herein aimed to investigate the most appropriate uricosuric agent for gout or hyperuricemia patients. METHOD: PubMed, Embase, Cochrane Library databases, and ClinicalTrials.gov from inception to 2 July 2022 were searched to retrieve eligible studies assessing efficacy and safety of uricosuric drugs in hyperuricemia or gout patients. Network meta-analysis was carried out using the Stata 16.0 software. RESULTS: Twelve randomized controlled trials comprising 1851 patients were eventually included. Network meta-analysis showed that dotinurad 4 mg once daily, verinurad, dotinurad 2 mg once daily, dotinurad 1 mg once daily, and benzbromarone were the top 5 effective treatments to achieve target serum uric acid. Furthermore, dotinurad 4 mg once daily was more effective at achieving urate-lowering targets (RR of dotinurad 4 mg once daily vs. probenecid: 1.68, 95% CI [1.13; 2.50]) and safer (RR of probenecid vs. dotinurad 4 mg once daily: 1.77, 95% CI [0.69; 4.56]) than probenecid. CONCLUSIONS: This network meta-analysis demonstrated an important absolute benefit of dotinurad 4 mg once daily to achieve target serum uric acid and low risk of adverse events for drug treatment of gout or hyperuricemia patients. Additionally, verinurad might be used as an alternative uricosuric therapeutic option to dotinurad. These findings provided further comprehensive insight into the treatment value of current uricosuric agents for gout or hyperuricemia. Key Points 1. This is the first systematic review and network meta-analysis examining the efficacy and safety of currently available uricosuric agents in gout or hyperuricemia patients. 2. Recommended doses of dotinurad 4mg once daily used for the treatment of gout or hyperuricemia patients can significantly decrease serum uric acid levels. 3. The present findings will provide further comprehensive insight into the treatment value of certain uricosuric agents for gout or hyperuricemia.
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Gota , Hiperuricemia , Uricosúricos , Humanos , Gota/tratamento farmacológico , Supressores da Gota/efeitos adversos , Hiperuricemia/tratamento farmacológico , Metanálise em Rede , Probenecid , Ensaios Clínicos Controlados Aleatórios como Assunto , Ácido Úrico , Uricosúricos/efeitos adversosRESUMO
Objectives: Previous studies have reported a potential association of polyunsaturated fatty acids (PUFAs) levels with allergic disease risk and the possible benefit of PUFAs supplementation on allergic disease prevention. This study was performed to estimate the genetic association between PUFAs and allergic diseases using the method of both univariable and multivariable two-sample Mendelian randomization (MR). Methods: As indicators of the PUFAs levels, we included the omega-3, omega-6, docosahexaenoic acid (DHA), eicosapentaenoic acid (EPA), linoleic acid (LA), and the ratio of omega-6 to omega-3 (omega-6:3). Summarized statistics of genome-wide association studies (GWASs) for these PUFAs were obtained from the United Kingdom Biobank and the Twins United Kingdom cohort. Genetic data relating to allergic diseases, including atopic dermatitis (AD), allergic rhinitis (AR), allergic conjunctivitis (AC), allergic urticaria (AU) and asthma, were accessed from the FinnGen biobank analysis. Odds ratios and 95% CIs were used to express the impact. Results: The MR results denoted a genetic association between the genetically determined increase in omega-3 levels and the decreased risk of some allergic diseases including AD (OR: 0.863; 95% CI: 0.785 to 0.949; p = 3.86E-03), AC (OR:0.720; 95% CI: 0.547 to 0.947; p = 1.87E-02) and AU (OR:0.821; 95% CI: 0.684 to 0.985; p = 3.42E-02), while omega-6 and DHA level was only found to have negatively correlation with risk of AC with ORs of 0.655 (95% CI: 0.445 to 0.964; p = 3.18E-02) and 0.671 (95% CI 0.490 to 0.918; p = 1.25E-02), respectively. Omega-6:3 were causally significantly associated with the increased risk of AD (OR:1.171; 95% CI: 1.045 to 1.312; p = 6.46E-03) and AC (IVW: OR:1.341; 95% CI: 1.032 to 1.743; p = 2.83E-02). After adjustment of age, economic level, BMI, smoking and alcohol behaviors in the multivariable MR analysis, a direct causal protective effect of omega-3 on AD and AC, as well as a direct causal association between DHA and AD were observed. Omega-6:3 was also found to be directly associated with an increased risk of AD and AC. No association was found of EPA or LA with allergic diseases. Conclusion: Higher PUFA concentrations (omega-3, omega-6, DHA) and lower omega-6:3 ratios were genetically associated with a lower risk of some allergic diseases.
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Background: Previous observational studies have found an association between inflammatory bowel disease (IBD) and psoriasis. Using the mendelian randomization (MR) approach, we aim to determine whether there was a causal association between IBD and psoriasis. Methods: We performed a two-sample MR with the genetic instruments identified for IBD and its main subtypes, Crohn's disease (CD) and ulcerative colitis (UC), from a genome-wide association study (GWAS) involving 25,042 cases with an IBD diagnosis and 34,915 controls. Summarized data for psoriasis were obtained from different GWAS studies which included 4510 cases and 212,242 controls without psoriasis. Causal estimates are presented as odds ratios (ORs) with 95% confidence intervals (CIs). Results: The overall outcome of MR analysis was to demonstrate that genetic predisposition to IBD was associated with an increased risk of psoriasis (OR: 1.1271; 95% CI: 1.0708 to 1.1864). Psoriatic arthritis (PsA) had a significant association with total IBD (OR: 1.1202; 95% CI: 1.0491 to 1.1961). Casual relationship was also identified for CD-psoriasis (OR: 1.1552; 95% CI: 1.0955 to 1.2182) and CD-PsA (OR: 1.1407; 95% CI: 1.0535 to 1.2350). The bidirectional analysis did not demonstrate that a genetic predisposition to psoriasis was associated with total IBD, although psoriasis showed association with CD (OR: 1.2224; 95% CI: 1.1710 to 1.2760) but not with UC. A genetic predisposition to PsA had a borderline association with IBD (OR: 1.0716; 95% CI: 1.0292 to 1.1157) and a suggestive association with CD (OR: 1.0667; 95% CI: 1.0194 to 1.1162). Conclusion: There appears to be a causal relationship between IBD and psoriasis, especially for PsA, but for psoriasis and IBD, only total psoriasis and PsA were associated with CD. Understanding that specific types of psoriasis and IBD constitute mutual risk factors facilitates the clinical management of two diseases.
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Artrite Psoriásica , Colite Ulcerativa , Doença de Crohn , Doenças Inflamatórias Intestinais , Psoríase , Artrite Psoriásica/complicações , Colite Ulcerativa/complicações , Colite Ulcerativa/genética , Doença de Crohn/complicações , Doença de Crohn/genética , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Doenças Inflamatórias Intestinais/complicações , Doenças Inflamatórias Intestinais/genética , Análise da Randomização Mendeliana , Psoríase/complicações , Psoríase/epidemiologia , Psoríase/genéticaRESUMO
Background: Ankylosing spondylitis (AS) is a common immune-related systemic chronic inflammatory osteoarthropathy. Previous studies have proven that biologic agents, including IL-17A inhibitors (IL17Ai), TNF-α inhibitor FC fusion protein (TNFiFCP), or fully human monoclonal antibody (TNFiNMA) and JAK inhibitor (JAKi), are effective for AS treatment. Our study is aimed at comparing the clinical efficacy, tolerability, and safety of different biological agents, including novel IL-6 inhibitor (IL6i), IL-23 inhibitor (IL23i), and IL-17 A/F dual variable domain inhibitor (IL17AFi) in AS. Method: PubMed, Scopus, Embase, CNKI, and the Cochrane Library were systematically searched. A frequentist framework network meta-analysis with a random-effects model was performed. Ranking effects were calculated by surface under the cumulative ranking analysis (SUCRA) and cluster-rank analysis. Results: IL17AFi reported both the highest ASAS40 (SUCRA = 91.4%) and ASAS20 (SUCRA = 92.5%) response, while IL6i and IL23i reported the lowest responses (SUCRA = 6.6% and 19.9%, respectively). With the exceptions of IL6i (RR 0.60, 95% CI (0.22 to 1.67) for ASAS40 and 1.36 (0.71 to 2.58) for ASAS20) and IL23i (0.98 (0.68 to 1.40) for ASAS40 and 0.91 (0.70 to 1.19) for ASAS20), all biological drugs demonstrated statistically superior ASAS responses than placebo. TNFiFMA performed best in the suppression of disease activity (SUCRA = 77.4%, SMD 2.35, and 95% CI (1.11 to 3.59)) and functional improvement (SUCRA = 68.8%, SMD 1.67, and 95% CI (0.59 to 2.74)). There were no significant differences in tolerability or safety between biologic drugs and placebo. Conclusions: The novel IL-17 A/F dual variable domain inhibitor, bimekizumab, may be an ideal future treatment choice for AS, while IL-23 and IL-6 inhibitors demonstrate little potential in the treatment of AS. For patients with rapid disease progression and severe functional limitation, TNF-α inhibitors, especially infliximab, are safe and effective and could be a first-line treatment choice.
Assuntos
Produtos Biológicos , Espondilite Anquilosante , Fatores Biológicos/uso terapêutico , Produtos Biológicos/uso terapêutico , Humanos , Interleucina-17/uso terapêutico , Interleucina-23 , Interleucina-6 , Metanálise em Rede , Espondilite Anquilosante/tratamento farmacológico , Resultado do Tratamento , Fator de Necrose Tumoral alfaRESUMO
PURPOSE: It has been found that childhood obesity (CO) may play an important role in the onset and progression of osteoarthritis (OA). Thus we conducted this mendelian randomisation analysis (MR) to evaluate the causal association between childhood obesity and osteoarthritis. METHODS: Instrumental variables (IVs) were obtained from publicly available genome-wide association study datasets. The leave-one-out sensitivity test, MR Pleiotropy RESidual Sum and Outlier test (MR-PRESSO), and Cochran's Q test were used to confirm the heterogeneity and pleiotropy of identified IVs, then five different models, including the inverse variance weighted model (IVW), weighted median estimator model (WME), weighted model-based method (WM), MR-Egger regression model (MER), and MR-Robust Adjusted Profile Score (MRAPS) were applied in this MR analysis. RESULTS: After excluding all outliers identified by the MR-PRESSO test, no evident directional pleiotropy was found. Significant heterogeneity was found in the secondary MR and as a result, the multiplicative random-effect model was used. Significant causal association between CO and OA (OR 1.0075, 95% CI [1.0054, 1.0010], p = 8.12 × 10-13). The secondary MR also revealed that CO was causally associated with knee OA (OR 1.1067, 95% CI [1.0769, 1.1373], p = 3.30 × 10-13) and hip OA (OR 1.1272, 95% CI [1.0610, 1.1976], p = 1.07 × 10-4). The accuracy and robustness of these findings were confirmed by sensitivity tests. CONCLUSION: There appears to be a causal relationship between childhood obesity and OA. Our results indicate that individuals with a history of childhood obesity require specific clinical attention to prevent the development of knee and hip OA.
Assuntos
Osteoartrite do Quadril , Obesidade Infantil , Criança , Estudo de Associação Genômica Ampla , Humanos , Análise da Randomização Mendeliana , Osteoartrite do Quadril/etiologia , Osteoartrite do Quadril/genética , Obesidade Infantil/complicações , Obesidade Infantil/epidemiologia , Obesidade Infantil/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
BACKGROUND: Tranexamic acid (TXA) has been widely used for bleeding reduction in spinal surgery. Available evidence is insufficient to inform clinical decisions making and there remains a lack of comprehensive comparisons of dose regimens and delivery routes. This study is aimed to assess and compare different strategies regarding the involvement of TXA in spinal surgery for the optimal pathway of efficacy and safety. MATERIALS AND METHODS: Cochrane Library, PubMed, Embase, Scopus and CNKI were searched for the period from January 1990 to October 2021. A random-effect model was built in the Bayesian network meta-analysis. The surface under the cumulative ranking analysis (SUCRA) and clustering rank analysis was performed for ranking the effects. RESULTS: The current network meta-analysis incorporated data from 33 studies with 3302 patients. Combination administration showed superior effects on reducing intraoperative bleeding (SUCRA 78.78%, MD -129.67, 95% CI [(-222.33, -40.58)]) than placebo, and was ranked as top in reducing postoperative bleeding (SUCRA 86.91%, MD -169.92, 95% CI [(-262.71, -83.52)]), changes in haemoglobin (SUCRA 97.21%, MD -1.28, 95% CI [(-1.84, -0.73)]), and perioperative blood transfusion (SUCRA 93.23%, RR 0.10, 95% CI [(0.03, 0.25)]) simultaneously, and was shown as the best effectiveness and safety (cluster-rank value for IBL and VTE: 4057.99 and for TRF and VTE: 4802.26). CONCLUSIONS: Intravenous (IV) plus topical administration of TXA appears optimal in the reduction of perioperative bleeding and blood transfusion, while the local infiltration administration is not effective for blood conservation. Further studies are required to verify the current findings.