Risk of gout flare after medication: prescription symmetry sequence analysis.

OBJECTIVES: The research aimed to study the following questions: (1) five well-known gout-related medications were selected to test the validity of the prescription symmetry sequence analysis in Taiwan; (2) four exploratory medications were selected to test their relation to gout flares. METHODS: We utilized the 2003-2017 dataset of the Taiwan National Health Insurance Program containing all claims data with 2 million beneficiaries as a data source. In order to explore the temporal association, we designed a scenario of medication-induced gout flares. Nine medications were selected as the index agent, including aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol, pyrazinamide, metformin, pioglitazone, fenofibrate, and losartan. The gout flare was defined as subjects with use of the marker agent for treatment of gout flares. The observation-window period between initiation of the index agent and initiation of the marker agent was 1 year. Subjects who used an index agent and a marker agent on the same day were excluded. The prescription symmetry sequence analysis was carried out to compare the observed number of persons who took an index agent prior to starting a marker agent with the observed number of persons who took a marker agent before starting an index agent. The adjusted sequence ratio (adjusted SR) with 95% confidence interval was applied to estimate the relation between an index agent and the marker agent. RESULTS: Among five medications including aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol, and pyrazinamide, the adjusted sequence ratio ranged from 1.15 to 3.35 and all reached statistical significance. Fenofibrate use and losartan use were associated with a lower probability of gout flares, with reaching statistical significance (adjusted SR = 0.60 for fenofibrate and adjusted SR = 0.92 for losartan). Metformin use was associated with a greater probability of gout flares, with reaching statistical significance (adjusted SR = 1.14). Pioglitazone use did not reach statistical significance. CONCLUSION: Based on the confirmatory analysis including five well-known gout-related medications, this study supports that the prescription symmetry sequence analysis can be used to detect an adverse drug event associated with one potential offending agent. The exposure to fenofibrate or losartan might be a protective factor against gout flares. Metformin use could be associated with a greater probability of gout flares, but this finding should be validated by other studies. KEY POINTS: • What is already known about this subject? 1. The prescription symmetry sequence analysis is a useful method for detecting an adverse drug reaction associated with one potential offending drug. 2. Numerous medications are found to induce gout flares. • What does this study add? 1. The prescription symmetry sequence analysis supports the evidence that aspirin (low-dose), thiazide diuretics, loop diuretics, ethambutol and pyrazinamide are associated with a greater probability of gout flares. 2. The exposure to fenofibrate or losartan might be a protective factor against gout flares. 3. Metformin use could be associated with a greater probability of gout flares. • How might this impact on clinical practice or future developments? 1. Clinicians should always consider the possibility of medication-induced gout flares. If gout flares develop, discontinuation of risky medications is the first step. Then prescribing cascades can be eliminated.

Prenatal and postnatal exposure to heavy metals in PM2.5 and autism spectrum disorder.

Autism spectrum disorder (ASD) is a group of neurodevelopmental disorders, and its incidence is increasing over time. Although several environmental factors have been suspected to be risk factors for ASD, studies on the effects of airborne heavy metals on newly developed ASD are still limited. We conducted a large birth cohort study of 168,062 live term births in Taichung during 2004-2011 to assess the association of heavy metals in particulate matter with an aerodynamic diameter less than 2.5 µm (PM2.5) with ASD, and identify sensitive time windows during prenatal and postnatal periods. Heavy metals, including arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) in PM2.5, were estimated using the Weather Research and Forecasting/Chem (WRF/Chem), inserted from the top 75 emission sources for the module. The association between childhood ASD and 4 metals were analyzed from pregnancy to 9 months after birth. The Cox proportional hazard model with a distributed lag nonlinear model (DLNM) was used to estimate the association between heavy metals in PM2.5 and ASD. We identified 666 incident ASD cases in 168,062 participants. A positive association between Hg and ASD was found at 9 months after birth (Hazard Ratio: 1.63; 95% CI: 1.13-2.36). According to the DLNM, there was an increased risk of exposure to Hg during 10-25 weeks after birth, and decreased risk of exposure to Hg during gestational weeks 4-6. Exposure to As and Hg on the risk of ASD were significantly stronger in low birth weight infants (<2500 g) than in those of birth weight ≥2500 g during postnatal period. Postnatal exposure to Hg in PM2.5 may associate with increased ASD incidence. Infants with low birth weight and exposure to As and Hg in PM2.5 are more likely to develop ASD.

Sodium-glucose cotransporter-2 inhibitors use and the risk of gout: a systematic review and meta-analysis.

Objective: To assess the relationship between use of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and the risk of gout among patients with type 2 diabetes mellitus (T2DM). Methods: A systemic review and meta-analysis were designed by reviewing articles published between 2000 January 1 and 2022 December 31 using PubMed system and Web of Science system based on the PRISMA 2020 guidelines. The end point of interest was gout (including gout flares, gout events, starting uric-acid lowering therapy and starting anti-gout drugs use) among patients with T2DM using SGLT2i versus not using SGLT2i. A random-effects model was utilized to measure the pooled hazard ratio (HR) with 95% confidence interval (CI) for the risk of gout associated with SGLT2i use. Results: Two prospective post-hoc analyses of randomized controlled trials and 5 retrospective electronic medical record-linkage cohort studies met the inclusion criteria. The meta-analysis demonstrated that there was a decreased risk of developing gout for SGLT2i use as comparing with non-use of SGLT2i among patients with T2DM (pooled HR=0.66 and 95%CI=0.57-0.76). Conclusions: This meta-analysis demonstrates that SGLT2i use is associated with a 34% decreased risk of developing gout among patients with T2DM. SGLT2i may be the treatment options for patients with T2DM who are at high risk of gout. More randomized controlled trials and real-world data are needed to confirm whether there is a class effect of SGLT2i for the risk reduction of gout among patients with T2DM.

Comparison of benzbromarone and allopurinol on the risk of chronic kidney disease in people with asymptomatic hyperuricemia.

OBJECTIVE: The objective of the study was to compare the relative effects of benzbromarone and allopurinol on the risk of developing chronic kidney disease in persons with asymptomatic hyperuricemia. METHODS: A retrospective cohort study was conducted to analyze a 2003-2015 national database including all claims data of 2 million beneficiaries in Taiwan. Asymptomatic hyperuricemia was defined as follows: persons using urate-lowering drugs who never developed gout flares. The benzbromarone group included persons ages 20-84 that had asymptomatic hyperuricemia and received benzbromarone alone. The allopurinol group included persons ages 20-84 that had asymptomatic hyperuricemia and received allopurinol alone. The maximum follow-up time was set as 5 years in this study. The main outcome was defined as follows: persons were newly diagnosed with chronic kidney disease. A Cox proportional hazards regression analysis was performed to test the association between variables and the risk of chronic kidney disease. RESULTS: After propensity score matching, 9107 persons in the benzbromarone group and 4554 persons in the allopurinol group were eligible for the study. Approximately 71% of the study subjects were males. The mean age was 56 years old. The incidence rate of chronic kidney disease was lower in the benzbromarone group than in the allopurinol group (1.18 versus 1.99/per 100 person-years, incidence ratio = 0.60, and 95% confidence interval = 0.52-0.68).The Cox proportional hazards regression analysis disclosed that after adjusting for co-variables, there was a decreased risk of developing chronic kidney disease in the benzbromarone group as compared with the allopurinol group (hazard ratio = 0.59, 95% confidence interval = 0.52-0.67 and P<0.001). CONCLUSIONS: The use of benzbromarone is associated with a lower hazard of developing chronic kidney disease as compared to allopurinol use among persons ages 20-84 with asymptomatic hyperuricemia. More studies are needed to confirm our findings.

Maternal exposure to fine particulate matter and congenital heart defects during preconception and pregnancy period: A cohort-based case-control study in the Taiwan maternal and child health database.

BACKGROUND: Few studies have explored the association between maternal exposure to particulate matter with an aerodynamic diameter of ≤2.5 µm (PM2.5) and congenital heart defects occurring before and during pregnancy. We aimed to investigate the association and the critical time windows between the maternal exposure to PM2.5 and congenital heart defects. METHOD: We conducted a cohort-based case-control study of 507,960 participants obtained from the Taiwan Maternal and Child Health Database between 2004 and 2015. We applied satellite-based spatiotemporal models with 1-km resolution to calculate the average PM2.5 concentration during preconception and the specific periods of pregnancy. We also performed conditional logistic regression with distributed lag non-linear models (DLNMs) to assess the effects of weekly average PM2.5 on both congenital heart defects and their isolated subtypes, as well as the concentration-response relationships. RESULTS: In DLNMs, exposure to PM2.5 (per 10 µg/m3) during weeks 7-12 before conception and weeks 3-9 after conception was associated with congenital heart defects. The strongest association at 12 weeks before conception (odds ratio [OR] = 1.026, 95% confidence intervals [CI]: 1.012-1.040) and 7 weeks after conception (OR = 1.024, 95% CI: 1.012-1.036) for every 10 µg/m3 increase in PM2.5 concentration. In modification analysis, strongest associations were observed for low SES. CONCLUSIONS: Our study revealed that exposure to ambient PM2.5 raises the risk of congenital heart defects, particularly among individuals with lower socioeconomic status. Moreover, our findings suggest that preconception exposure to PM2.5 may be a crucial period for the development of congenital heart defects.

Monitoring ambient air pollution and pulmonary function in asthmatic children by mobile applications in COVID-19 pandemic.

BACKGROUND: Several public health measures were implemented during the COVID-19 pandemic. However, little is known about the real-time assessment of environmental exposure on the pulmonary function of asthmatic children. Therefore, we developed a mobile phone application for capturing real-time day-to-day dynamic changes in ambient air pollution during the pandemic. We aim to explore the change in ambient air pollutants between pre-lockdown, lockdowns, and lockdowns and analyze the association between pollutants and PEF mediated by mite sensitization and seasonal change. METHOD: A prospective cohort study was conducted among 511 asthmatic children from January 2016 to February 2022. Smartphone-app used to record daily ambient air pollution, particulate matter (PM2.5, PM10) Ozon (O3), nitrogen dioxide (NO2), Carbon Monoxide (CO), sulfur dioxide (SO2), average temperature, and relative humidity, which measured and connected from 77 nearby air monitoring stations by linking to Global Positioning System (GPS)-based software. The outcome of pollutants' effect on peak expiratory flow meter (PEF) and asthma is measured by a smart peak flow meter from each patient or caregiver's phone for real-time assessment. RESULTS: The lockdown (May 19th, 2021, to July 27th, 2021) was associated with decreased levels of all ambient air pollutants aside from SO2 after adjusting for 2021. NO2 and SO2 were constantly associated with decreased levels of PEF across lag 0 (same day when the PEF was measured), lag 1 (one day before PEF was measured), and lag 2 (two days prior when the PEF was measured. Concentrations of CO were associated with PEF only in children who were sensitized to mites in lag 0, lag 1, and lag 2 in the stratification analysis for a single air pollutant model. Based on the season, spring has a higher association with the decrease of PEF in all pollutant exposure than other seasons. CONCLUSION: Using our developed smartphone apps, we identified that NO2, CO, and PM10 were higher at the pre-and post-COVID-19 lockdowns than during the lockdown. Our smartphone apps may help collect personal air pollution data and lung function, especially for asthmatic patients, and may guide protection against asthma attacks. It provides a new model for individualized care in the COVID era and beyond.

The risk of ischemic cerebrovascular disease associated with benzbromarone use in gout people: A retrospective cohort study in Taiwan.

Epidemiological studies have shown that people having hyperuricemia are at increased risk of ischemic cerebrovascular disease. This research aimed to study the relation of ischemic cerebrovascular disease with benzbromarone use among persons with gout-related disorders. This was a retrospective cohort design utilizing a 2003 to 2015 national health insurance database in Taiwan. Subjects aged 20 to 99 years who already had suffered from gout-related disorders were included as eligible subjects. Eligible persons who had the benzbromarone prescription alone were selected into the benzbromarone group. Sex-matched and age-matched eligible persons who never used any urate-lowering agents were selected into the control group. An index date was set as a date of benzbromarone being prescribed. The end-point was defined as ischemic cerebrovascular disease being newly diagnosed. A hazard ratio was applied to measure the association strength between benzbromarone use and ischemic cerebrovascular disease. Totally, there were 13,398 persons in the benzbromarone group and 13,398 persons in the control group. The incidence rate of ischemic cerebrovascular disease seemed to be modestly higher in the benzbromarone group than the control group, but it did not achieve statistical significance (0.78 vs 0.75 every 100 person-years, incidence rate ratio = 1.05, 95% confidence interval = 0.94-1.16). A crude hazard ratio of ischemic cerebrovascular disease showed 1.05 in the benzbromarone group (95% confidence interval = 0.94-1.17, P = .373) comparing with the control group. No significant association can be detected between benzbromarone use and the probability of ischemic cerebrovascular disease among persons with gout-related disorders. We think that reduction of the serum uric acid by use of benzbromarone could not be related to the probability of ischemic cerebrovascular disease. Further research is suggested to clarify this issue.

Prenatal and postnatal exposure to PM2 .5 and the risk of tic disorders.

BACKGROUND: Tic disorders are common neurodevelopmental disorders during childhood. Whether prenatal and postnatal exposure to particulate matter with an aerodynamic diameter less than 2.5 µm (PM2.5 ) plays a role in the development of tic disorders remains unexplored. OBJECTIVES: To investigate the association of exposure between PM2.5 during the pregnancy and infancy periods and the risk of tic disorders. METHODS: This birth cohort study recruited singleton live births at term gestations in central Taiwan from the Taiwan Maternal and Child Health Database between 2004 and 2012 and followed up to the end of 2017. New cases of tic disorders were defined using the ICD-9-CM (307.2) and ICD-10-CM (F95), which include all tic spectrum disorders. We assigned daily PM2.5 concentrations derived from a satellite-based model to individuals based on maternal residential addresses at delivery. We fit Cox proportional hazard model and distributed lag non-linear model to estimate the associations between PM2.5 and tic disorders, with hazard ratio (HR) with 95% confidence interval (CI) as the effect measure. RESULTS: Of the 309,376 singleton live births at term gestations, we identified 5902 (1.9%) tic disorder cases. The HR of tic disorders was positively associated with a 10 µg/m3 increase in PM2.5 : during pregnancy HR 1.09, 95% CI 1.04, 1.15 and during infancy HR 1.12, 95% CI 1.06, 1.18. The vulnerable time window for infants with increased risk of tic disorders was 6-52 weeks after birth. We observed a nonlinear relationship between PM2.5 and the risk of tic disorders, with exposure to PM2.5 between 16 and 64 µg/m3 being associated with the risk of tic disorders. The association was restricted to Tourette's disorder group. Infant sex did not modify these associations. CONCLUSIONS: Infants delivered at term and exposed to PM2.5 are associated with an increased risk of tic disorders (6-52 weeks). Further studies are needed to confirm these associations.

Allopurinol Use and the Risk of Type 2 Diabetes Mellitus: A Meta-Analysis of Cohort Studies.

Objective: To assess whether there is a relation between allopurinol use and the probability of type 2 diabetes mellitus (T2DM) in persons with gout and/or hyperuricemia. Methods: According to the PRISMA 2020 guidelines, a meta-analysis was performed by searching literature published from 2000 to 2021 in two electronic databases (Ebscohost and PubMed). The end point was set as a new diagnosis ofT2DM between people with the use of allopurinol and people with non-use of allopurinol. The random-effects model was performed to evaluate the pooled hazard ratio (HR) with 95% confidence interval (CI) for T2DM associated with allopurinol use. Results: Three cohort studies could meet the inclusion criteria in the meta-analysis. There was a high heterogeneity of the outcome between studies (I2 = 99%). The research duration ranged from 13 to 16 years. The subject number in each work ranged from 1114 to 138,652. A meta-analysis disclosed that there was not an association between allopurinol use and the risk of developing T2DM (pooled HR = 1.01 and 95%CI = .55-1.84). Conclusions: The meta-analysis shows that no correlation is detected between allopurinol use and the risk of T2DM in individuals with gout and/or hyperuricemia. Because there are not enough eligible studies, the strength of evidence in our meta-analysis is weak. More cohort studies are needed to determine an association between use of allopurinol and the probability of T2DM for individuals with gout and/or hyperuricemia.

Identification of Genetic Variations in the NAD-Related Pathways for Patients with Major Depressive Disorder: A Case-Control Study in Taiwan.

Background and Objectives: Nicotinamide adenine dinucleotide (NAD) is an important coenzyme in various physiological processes, including sirtuins (SIRTs) and kynurenine pathway (KP). Previous studies have shown that lower NAD levels can be indicative of increased risks of cancer and psychiatric disorders. However, there has been no prior study exploring the link between NAD homeostasis and psychiatric disorders from a genetic perspective. Therefore, we aimed to investigate the association of genetic polymorphism in the pathways of NAD biosynthesis with major depressive disorder (MDD). Methods: A total of 317 patients were included in the case group and were compared with sex-matched control group of 1268 participants (1:4 ratio) from Taiwan Biobank (TWB). All subjects in the control group were over 65 years old, which is well past the average age of onset of MDD. Genomic DNA extracted from patients' blood buffy coat was analyzed using the Affymetrix TWB array. Full-model tests were conducted for the analysis of single nucleotide polymorphism (SNPs) in all candidate genes. We focused on genes within the NAD-related candidate pathways, including 15 in KP, 12 in nicotinate metabolism, 7 in SIRTs, and 19 in aldehyde dehydrogenases (ALDHs). A total of 508 SNPs were analyzed in this study. After significant SNPs were determined, 5000 genome-wide max(T) permutations were performed in Plink. Finally, we built a predictive model with logistic regression and assessed the interactions of SNPs with the haplotype association tests. Results: We found three SNPs that were significantly associated with MDD in our NAD-related candidate pathways, one within the KP (rs12622574 in ACMSD) and two within the nicotinate metabolism (rs28532698 in BST1 and rs3733593 in CD38). The observed association with MDD was significant in the dominant model of inheritance with marital status, education level, and body mass index (BMI) adjusted as covariates. Lastly, in haplotype analysis, the three associated SNPs consisted of one haploblock in ACMSD, four haploblocks in BST1, and two haploblocks in CD38. Conclusions: This study provides the first evidence that genetic variations involved in NAD homeostasis in the KP and nicotinate metabolism may be associated with the occurrence of MDD.