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PURPOSE: To assess the role of gene-environment interaction between interleukin (IL)-4 promoter and mold exposure on the development of asthma. METHODS: We conducted a cohort-based, incident, case-control study. The case group consisted of 188 children with new asthma and the control group (n = 376) was matched for age and gender. The outcome of interest was the development of asthma over the 6-year study period. The studied determinants were three polymorphisms of IL-4 promoter (TT, CT, and CC) and three indicators of exposure including histories of water damage, presence of visible molds, and perceived mold odor in the home. RESULTS: Apparent joint effects between IL-4 promoter and mold exposure were observed on both additive and multiplicative scales. Specially, the risk of asthma was significantly associated with children carrying the CT genotype and visible mold exposure comparing with those carrying the TT genotype without any exposure indicator (adjusted odds ratio [OR], 2.14; 95% confidence interval [CI], 1.05-4.34; modified Rothman synergy index for directly use of odds and OR [s] = 1.41; P for interaction = .03). A similar tendency was found (s = 1.30; P for interaction = .04) for children who were exposed to mold odor and carried CT genotype (adjusted OR, 1.99; 95% CI, 1.03-4.41). CONCLUSIONS: The results of this study suggest that gene-environment interactions between the IL-4 promoter and an indoor mold problem may play an important role in childhood asthma. [ABSTRACT FROM AUTHOR]

Objectives Previous studies on the effects of angiotensinogen (AGT) gene polymorphisms and chronic exposure to occupational noise on the risk of hypertension have mainly been cross-sectional or prevalent case-control studies, where temporality constitutes problems. The present study was to assess longitudinally both independent and joint effects of AGT gene polymorphisms and chronic exposure to occupational noise on occurrence of hypertension. Methods The authors conducted a 20-year prospective cohort study of 1301 aviation workers in Taiwan. The study population included 912 workers without hypertension at baseline. The outcome of interest was the development of hypertension during the study period. The studied determinants were three AGT genotypes (TT, TM and MM) and four exposure categories according to the levels of noise representing high (>80 dBA), medium (80-65 dBA), low exposure (64-50 dBA) and the reference level (49-40 dBA). Results In Poisson regression adjusting for confounders, AGT (TT vs MM adjusted incidence rate ratio (IRR) 1.77, 95% CI 1.24 to 2.51) and noise exposure (high and medium combined) during 3-15 years (adjusted IRR 2.35, 95% CI 1.42 to 3.88) were independent determinants of hypertension. Furthermore, the risk of hypertension increased with noise exposure (adjusted IRR 3.73, 95% CI 1.84 to 7.56) among TT homozygotes but not among those with at least one M allele (Rothman synergy index=1.05). Conclusions The results evidence further the independent effects of AGT gene polymorphisms and exposure to occupational noise. Our finding also suggests that workers carrying TT variant allele have higher risk of hypertension under chronic exposure to occupational noise. [ABSTRACT FROM AUTHOR]

Background: Recent findings suggest that exposure to disinfection by-products may increase the risk of birth defects. Previous studies have focused mainly on birth defects in general or groups of defects. The objective of the present study was to assess the effect of water disinfection byproducts on the risk of most common specific birth defects. Methods: We conducted a population-based cross-sectional study of 396,049 Taiwanese births in 2001-2003 using information from the Birth Registry and Waterworks Registry. We compared the risk of eleven most common specific defects in four disinfection by-product exposure categories based on the levels of total trihalomethanes (TTHMs) representing high (TTHMs 20+ µg/L), medium (TTHMs 10-19 µg/L), low exposure (TTHMs 5-9 µg/L), and 0-4 µg/L as the reference category. In addition, we conducted a meta-analysis of the results from the present and previous studies focusing on the same birth defects. Results: In multivariate logistic regression analysis the risk of ventricular septal defects (adjusted odds ratio 1.81, 95% confidence interval: 0.98 3.35), cleft palate (1.56. 95% CI: 1.00, 2.41), and anencephalus (1.96, 95% CI: 0.94, 4.07) were elevated in the high exposure compared to the reference category. In the meta-analysis, the summary odds ratio for ventricular septal defects (1.59, 95% CI: 1.21, 2.07) was consistently elevated. Conclusion: The present study suggests that prenatal exposure to disinfection by-products increases the risk of ventricular septal defects, cleft palate, and anencephalus. The evidence on ventricular septal defects is consistent in the three available studies. [ABSTRACT FROM AUTHOR]

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., (© 2024. The Author(s), under exclusive licence to International League of Associations for Rheumatology (ILAR).)

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 (PM 2.5 ) 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 PM 2.5 , 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 PM 2.5 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 PM 2.5 may associate with increased ASD incidence. Infants with low birth weight and exposure to As and Hg in PM 2.5 are more likely to develop ASD., 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 © 2023. Published by Elsevier Inc.)

Background: Few studies have explored the association between maternal exposure to particulate matter with an aerodynamic diameter of ≤2.5 μm (PM 2.5 ) 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 PM 2.5 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 PM 2.5 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 PM 2.5 on both congenital heart defects and their isolated subtypes, as well as the concentration-response relationships., Results: In DLNMs, exposure to PM 2.5 (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/m 3 increase in PM 2.5 concentration. In modification analysis, strongest associations were observed for low SES., Conclusions: Our study revealed that exposure to ambient PM 2.5 raises the risk of congenital heart defects, particularly among individuals with lower socioeconomic status. Moreover, our findings suggest that preconception exposure to PM 2.5 may be a crucial period for the development of congenital heart defects., 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 © 2023 Elsevier Inc. All rights reserved.)

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., Competing Interests: Declaration of Competing Interest The authors declare that they have no conflict of interest., (Copyright © 2023 European Federation of Internal Medicine. Published by Elsevier B.V. All rights reserved.)

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 (O 3 ), nitrogen dioxide (NO 2 ), Carbon Monoxide (CO), sulfur dioxide (SO 2 ), 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 SO 2 after adjusting for 2021. NO 2 and SO 2 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 NO 2 , 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., (Copyright © 2023 Elsevier GmbH. All rights reserved.)

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 (PM 2.5 ) plays a role in the development of tic disorders remains unexplored., Objectives: To investigate the association of exposure between PM 2.5 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 PM 2.5 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 PM 2.5 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/m 3 increase in PM 2.5 : 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 PM 2.5 and the risk of tic disorders, with exposure to PM 2.5 between 16 and 64 μg/m 3 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., (© 2022 John Wiley & Sons Ltd.)

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., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 the Author(s). Published by Wolters Kluwer Health, Inc.)

Background: Human immunodeficiency virus and acquired immune deficiency syndrome (HIV/AIDS) is still among the leading causes of disease burden and mortality in sub-Saharan Africa (SSA), and the world is not on track to meet targets set for ending the epidemic by the Joint United Nations Programme on HIV/AIDS (UNAIDS) and the United Nations Sustainable Development Goals (SDGs). Precise HIV burden information is critical for effective geographic and epidemiological targeting of prevention and treatment interventions. Age- and sex-specific HIV prevalence estimates are widely available at the national level, and region-wide local estimates were recently published for adults overall. We add further dimensionality to previous analyses by estimating HIV prevalence at local scales, stratified into sex-specific 5-year age groups for adults ages 15-59 years across SSA., Methods: We analyzed data from 91 seroprevalence surveys and sentinel surveillance among antenatal care clinic (ANC) attendees using model-based geostatistical methods to produce estimates of HIV prevalence across 43 countries in SSA, from years 2000 to 2018, at a 5 × 5-km resolution and presented among second administrative level (typically districts or counties) units., Results: We found substantial variation in HIV prevalence across localities, ages, and sexes that have been masked in earlier analyses. Within-country variation in prevalence in 2018 was a median 3.5 times greater across ages and sexes, compared to for all adults combined. We note large within-district prevalence differences between age groups: for men, 50% of districts displayed at least a 14-fold difference between age groups with the highest and lowest prevalence, and at least a 9-fold difference for women. Prevalence trends also varied over time; between 2000 and 2018, 70% of all districts saw a reduction in prevalence greater than five percentage points in at least one sex and age group. Meanwhile, over 30% of all districts saw at least a five percentage point prevalence increase in one or more sex and age group., Conclusions: As the HIV epidemic persists and evolves in SSA, geographic and demographic shifts in prevention and treatment efforts are necessary. These estimates offer epidemiologically informative detail to better guide more targeted interventions, vital for combating HIV in SSA., (© 2022. The Author(s).)

Only a few studies have assessed the effects of fine particulate matter (PM 2.5 ) exposure during the prenatal and postnatal periods on the development of attention-deficit/hyperactivity disorder (ADHD). We investigated the association of exposure to PM 2.5 during pregnancy and early life with ADHD. This birth cohort consisted of 425,736 singleton live-term births between 2004 and 2015 in Taiwan. Daily PM 2.5 concentrations were derived from a 1-km satellite-based estimation model. A time-dependent Cox model was used to assess the effects of PM 2.5 on ADHD during the first, second, and third trimesters and from age 1-5 years after birth. The distributed lag nonlinear model was utilized to explore the dose-response relationship. Total 9,294 children were diagnosed with ADHD during the study period. The hazard ratio (HR) of ADHD was significantly associated with a 10 μg/m 3 increase in PM 2.5 during the first trimester (HR = 1.26; 95% confidence interval [CI]: 1.13-1.40) and increased at PM 2.5 over 16 μg/m 3 . For postnatal periods, the HR of ADHD was significantly associated with increased PM 2.5 at the first to third year of life (HR ranged between 1.40 and 1.87). According to the dose-response relationship of exposure to PM 2.5 at the third year of life, the HR of ADHD was significantly associated with PM 2.5 above 16 μg/m 3 and sharply increased as PM 2.5 >50 μg/m 3 . We did not observe a significant modification of sex on the relation between PM 2.5 and ADHD. Exposure of pregnant women to PM 2.5 above 16 μg/m 3 from conception to the early life of their children may increase the risk of ADHD. The government should improve the criteria for air quality control and meet the WHO air quality guidelines to protect pregnant women and children from developing ADHD in the future., (Copyright © 2022 Elsevier Inc. All rights reserved.)

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 (I 2 = 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., Competing Interests: Declaration of Conflicting Interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© The Author(s) 2022.)

Although studies have revealed that ambient particulate matter (PM) has detrimental effects on the ocular surface, there have been limited reports detailing the effect of ambient PM on the posterior segment of the eye. A large-scale longitudinal cohort study evaluating the association between fine PM, especially PM2.5, and the retina could elucidate the risk of ambient pollutants for retinal diseases. We investigated the association between PM2.5 and the development of age-related macular degeneration (AMD). We conducted a population-based cohort study of 4,284,128 participants in Taiwan between 2001 and 2011. PM2.5 was continuously measured by satellites and subsequently assigned to each geographic district along with its postcode. A time-dependent Cox proportional-hazard model was used to assess the overall effects of average PM2.5. We used distributed lag non-linear models to evaluate the dose-response relationship between PM2.5 and AMD development. The annual mean of PM2.5 exposure was 34.23 ± 7.17 μg/m3. The PM2.5 concentrations were highest in spring, followed by those in winter, autumn, and summer. Twelve thousand ninety-five new AMD cases were reported during the study period. After adjusting for covariates, the AMD risk increased by 19% (95% confidence interval 1.13-1.25) for a 10 μg/m3 PM2.5 increase. The present study demonstrated that chronic exposure to PM2.5 increases the risk of AMD. Almost half of the Taiwanese live in a polluted area where the PM2.5 levels are higher than the World Health Organization recommended air quality guideline of 10 μg/m3 had a 1.4-fold risk, which significantly increases concern about their visual health and social burden., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: This study aimed to compare the risk of dementia between exposed to allopurinol and not exposed to allopurinol in persons who had gout and/or hyperuricemia., Methods: The meta-analysis was conducted to select case-control research written in English through the help of PubMed and Web of Science. The pooled odds ratio (OR) with 95% confidence interval based on the fixed-effect model was applied to compare the allopurinol exposure among cases (subjects with dementia) and controls (subjects without dementia)., Results: A total of 4 case-control studies relating the allopurinol exposure to the risk of dementia were identified. The study duration was from 9 to 14 years. The number of study persons was from 3148 to 137,640. The male percentage of study subjects was from 36.9 to 62.5. The mean age of study persons was from 72.3 to 78.7 years. Overall, the odds of the allopurinol exposure among cases were lower than the odds of the allopurinol exposure among control subjects (OR = 0.91, 95% confidence interval = 0.87-0.95, P < .001). The heterogeneity between these eligible studies was low (I² = 0%). The sensitivity analysis revealed that after excluding the studies with concern, the pooled OR did not achieve statistical significance., Conclusions: This is the first meta-analysis to report that there is a negative relationship between the allopurinol exposure and the risk of dementia. Although the results favor the hypothesis, currently it is unable to draw strong conclusions about the protective effect of allopurinol against dementia due to inclusion of only a few eligible studies. Randomized controlled trials are needed to explore the relationship between allopurinol exposure and the probability of dementia., Competing Interests: The authors have no funding and conflicts of interest to disclose., (Copyright © 2022 the Author(s). Published by Wolters Kluwer Health, Inc.)

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.

Objectives. Whether uric acid-lowering agent use in asymptomatic hyperuricemia can reduce the development of the first gout flare remains unsettled. The goal of the present research was to test the efficacy of benzbromarone and allopurinol on primary prevention of the first gout flare in persons with asymptomatic hyperuricemia in Taiwan. Methods. One observational cohort study was constructed to examine the 2001−2015 dataset adapted from the National Health Insurance Program of Taiwan containing the claims data of 2 million beneficiaries. Asymptomatic hyperuricemia was considered as individuals on uric acid-lowering therapy who did not have gout flares. Individuals aged 20−84 without gout flares who had the use of benzbromarone alone were assigned into a benzbromarone group. Individuals ages 20−84 without gout flares who had the use of allopurinol alone were assigned into an allopurinol group. The final study included 6111 pairs of 1:1 propensity score-matched individuals from both benzbromarone and allopurinol groups. The end point was assigned as individuals who were newly diagnosed with their first gout flare. The incidence rate of the first gout flare was estimated between the benzbromarone and allopurinol groups. A Cox proportional hazards regression model was applied to explore the hazard ratio and 95% confidence interval of the first gout flare related to benzbromarone use and allopurinol use. Results. The incidence rate of the first gout flare was lower in the benzbromarone group compared with an allopurinol group (3.29 versus 5.46 per 1000 person-months, incidence rate ratio = 0.60 and 95% confidence interval = 0.56−0.64). After adjustment for co-variables, the adjusted hazard ratio of the first gout flare was 0.63 (95% confidence interval = 0.59−0.68, p < 0.001) for the benzbromarone group when compared with the allopurinol group. Conclusion. People with asymptomatic hyperuricemia taking benzbromarone have a lower hazard of developing their first gout flare when compared with those taking allopurinol. Based on the medication safety, the therapeutic effects and the low price, with oral administration once daily, we suggest that benzbromarone should be the first drug of choice if clinicians are treating asymptomatic hyperuricemia.

Competing Interests: The authors have no funding and conflicts of interest to disclose.

Importance: The Global Burden of Diseases, Injuries, and Risk Factors Study 2019 (GBD 2019) provided systematic estimates of incidence, morbidity, and mortality to inform local and international efforts toward reducing cancer burden., Objective: To estimate cancer burden and trends globally for 204 countries and territories and by Sociodemographic Index (SDI) quintiles from 2010 to 2019., Evidence Review: The GBD 2019 estimation methods were used to describe cancer incidence, mortality, years lived with disability, years of life lost, and disability-adjusted life years (DALYs) in 2019 and over the past decade. Estimates are also provided by quintiles of the SDI, a composite measure of educational attainment, income per capita, and total fertility rate for those younger than 25 years. Estimates include 95% uncertainty intervals (UIs)., Findings: In 2019, there were an estimated 23.6 million (95% UI, 22.2-24.9 million) new cancer cases (17.2 million when excluding nonmelanoma skin cancer) and 10.0 million (95% UI, 9.36-10.6 million) cancer deaths globally, with an estimated 250 million (235-264 million) DALYs due to cancer. Since 2010, these represented a 26.3% (95% UI, 20.3%-32.3%) increase in new cases, a 20.9% (95% UI, 14.2%-27.6%) increase in deaths, and a 16.0% (95% UI, 9.3%-22.8%) increase in DALYs. Among 22 groups of diseases and injuries in the GBD 2019 study, cancer was second only to cardiovascular diseases for the number of deaths, years of life lost, and DALYs globally in 2019. Cancer burden differed across SDI quintiles. The proportion of years lived with disability that contributed to DALYs increased with SDI, ranging from 1.4% (1.1%-1.8%) in the low SDI quintile to 5.7% (4.2%-7.1%) in the high SDI quintile. While the high SDI quintile had the highest number of new cases in 2019, the middle SDI quintile had the highest number of cancer deaths and DALYs. From 2010 to 2019, the largest percentage increase in the numbers of cases and deaths occurred in the low and low-middle SDI quintiles., Conclusions and Relevance: The results of this systematic analysis suggest that the global burden of cancer is substantial and growing, with burden differing by SDI. These results provide comprehensive and comparable estimates that can potentially inform efforts toward equitable cancer control around the world.

Objectives: The aim of the study was to assess if an association exists between cirrhosis and herpes zoster in Taiwan., Methods: A retrospective cohort study was designed to analyse the 2000-2013 claim dataset of 1 million insured residents who were randomly sampled from the Taiwan National Health Insurance Program. In total, 16 190 subjects aged 20-84 years old with newly diagnosed cirrhosis since 2000 to 2012 were identified as the cirrhosis group and 16 190 sex- and age-matched subjects without cirrhosis were selected as the non-cirrhosis group. Both cirrhosis and non-cirrhosis groups were followed until a new diagnosis of herpes zoster was made or until the end of 2013. The multivariable Cox proportional hazard regression model was applied to calculate the hazard ratio (HR) and 95% confidence interval (CI) for herpes zoster associated with cirrhosis., Results: The incidence rate of herpes zoster was 1.08-fold greater in the cirrhosis group than the non-cirrhosis group (8.33 vs 7.69 per 1000 person-years, 95%CI 1.02-1.15). After adjusting for confounders, the adjusted HR of herpes zoster was 1.11 (95% CI 1.004-1.24) for the cirrhosis group compared with the non-cirrhosis group. The adjusted HR increased to 1.33 (95% CI 1.02-1.74) for the decompensated cirrhosis group compared with the non-cirrhosis group., Conclusions: Cirrhosis is associated with a small but significant increase in the risk of herpes zoster. Given that the risk of herpes zoster is small and the expense of herpes zoster vaccination is high, whether cirrhotic persons need to be vaccinated should assess the balance of cost and benefit., (© 2021 John Wiley & Sons Ltd.)

Objective: The study aimed to thoroughly address the influence of benzbromarone and allopurinol on the risk of the development of type 2 diabetes mellitus (T2DM) in people with asymptomatic hyperuricemia. Methods: We conducted a retrospective cohort study to examine the 2000-2015 national dataset containing all claims data of 23 million beneficiaries in Taiwan. Subjects who already had diabetes mellitus, gout-related diseases, and any cancer prior to the index date were excluded. Asymptomatic hyperuricemia was defined as subjects taking urate-lowering drugs who never had a gout flare. Subjects aged 20-84 with asymptomatic hyperuricemia who had benzbromarone prescriptions were selected as the benzbromarone group. Sex-matched and age-matched subjects with asymptomatic hyperuricemia who had allopurinol prescriptions were identified as the allopurinol group. The maximum follow-up duration was set as 5 years in our study. The outcome was set as subjects who had a new diagnosis of T2DM. The incidence density of T2DM was calculated in the benzbromarone and allopurinol groups. The hazard ratio (HR) and 95% confidence interval (CI) for T2DM was utilized to estimate the association between medications and the risk of T2DM. Results: The incidence of T2DM among benzbromarone users was significantly lower than that of allopurinol users (7.91 versus 8.48 per 100 person-years, incidence rate ratio = 0.93, and 95% CI = 0.87-0.99). After adjustment for co-variables, the adjusted HR of T2DM would be 0.91 (95% CI = 0.85-0.98 and p = 0.008) in benzbromarone users as compared to allopurinol users. Conclusion: There is a small but statistically significant risk reduction of developing T2DM in people with asymptomatic hyperuricemia taking benzbromarone as compared to those taking allopurinol during 5 years of follow-up. It indicates a future research direction for the use of individual urate-lowering drugs on the prevention of T2DM in the general population., 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., (Copyright © 2021 Lai, Liao, Kuo, Lin, Liu and Hwang.)

Abstract: Inflammatory bowel disease is associated with an increased risk of opportunistic infections. This study aimed to investigate the incidence rate of herpes zoster in patients with inflammatory bowel disease.A meta-analysis was conducted by searching PubMed literature published from January 2000 to July 2019. The main outcome was the incidence rate of a new diagnosis of herpes zoster in patients previously diagnosed with inflammatory bowel disease. The incidence rate ratio (IRR) and 95% confidence interval (95% CI) for herpes zoster associated with inflammatory bowel disease was measured.A total of 6 eligible cohort studies matching the entry criteria were included in the meta-analysis, providing 216,552 participants with inflammatory bowel disease and 790 events of herpes zoster among these participants with inflammatory bowel disease. The pooled incidence rate of developing herpes zoster was 10.41 per 1000 person-years in the inflammatory bowel disease group and 6.10 per 1000 person-years in the non-inflammatory bowel disease group, respectively. The meta-analysis demonstrated that patients with inflammatory bowel disease were associated with 1.68-fold increased risk of developing herpes zoster when compared to those without inflammatory bowel disease (IRR = 1.68, 95% CI = 1.53-1.84). Crohn disease and ulcerative colitis were associated with an increased risk of developing herpes zoster (IRR = 1.67, 95% CI = 1.40-1.98 for Crohn disease and IRR = 1.49, 95% CI = 1.34-1.65 for ulcerative colitis, respectively).Patients with inflammatory bowel disease are at increased risk of developing herpes zoster. We suggest that the vaccination should be considered at the time of inflammatory bowel disease being diagnosed., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

Purpose: Noise pollution in urban areas is increasing steadily, and the study of road traffic noises and their effects on the auditory system was rare. This study investigated the potential effects of road traffic noise on auditory systems and hearing., Methods: A case-control study recruited outpatients from the Otolaryngology department. The case group ( n  = 41) had binaural hearing loss (HL) of standard pure-tone average(PTA)  ≥ 25 dB or high frequency PTA ≥ 25 dB, while the control group ( n  = 39) had binaural hearing level of any frequency < 25 dB. Detailed otologic evaluations were performed. Between-group data were evaluated using logistic regression analysis. Case or control group was identified based on the audiogram., Results: A total of 80 subjects were recruited, including 41 with hearing impairment and 39 as control. The mean exposure level of road traffic noise was significantly higher in the case group than the control group ( p  = 0.005). A crude OR of 5.78 showed an increased risk of greater than 70 dB of road traffic noise on hearing impairment and tinnitus ( p  < 0.001). The aOR of 9.24 ( p  = 0.002) from a multiple variate analysis suggested that road traffic noise levels greater than 70 dB may have a damaging effect on hearing. Damaging effects on hearing persisted even after adjusting for confounders in the full multivariate model (aOR of 9.24 [95% CI: 2.198-38.869]; p  = 0.002)., Conclusions: Exposing to road traffic noise greater than 70 dB showed an increased risk of damage to the auditory system. These results might help public health administrators and physicians to develop programs that address the health dangers of noise., Competing Interests: Conflict of interestThe authors declare that they have no conflict of interest., (© Springer Nature Switzerland AG 2021.)

Background: Asthma is the most common chronic allergic disease in children; it affects more than 300 million people worldwide. Information on the association between exposure to ambient heavy metals and incidence of pediatric asthma is limited., Objective: We sought to evaluate the effects of heavy metals during pregnancy and infancy periods with asthma and identify a sensitive time window, clarifying the effect of ambient heavy metals on lung development., Methods: A total of 171,281 children, who were born from 2004 to 2011 in Taichung City, were followed until 2014. Concentrations of ambient heavy metals such as arsenic (As), cadmium (Cd), mercury (Hg), and lead (Pb) were obtained from the Weather Research and Forecasting/Chem model, considering the top 75 emission sources in Taiwan. The distributed lag nonlinear model was used to investigate the relationship between combined exposure to heavy metals in 2.5 μm particulate matter and asthma in pregnant women and 1-year-old infants., Results: We identified 31,277 new asthma cases from the birth cohort. After adjustment for socioeconomic status, maternal age, maternal atopy, maternal anemia, and maternal kidney disease, distributed lag nonlinear model results revealed positive associations of asthma with exposure to Pb during gestational weeks 1 to 14 and 21 to 40, and 1 to 3 weeks after birth. Regarding the sensitivity analyses, coexposure to Pb and As, coexposure to Pb and Cd, and coexposure to Pb and Hg were positively associated with asthma onset as well., Conclusions: Our study suggested that combined exposure to Pb with As, Cd, and Hg during early and late gestational weeks was associated with the incidence of pediatric asthma., (Copyright © 2020 American Academy of Allergy, Asthma & Immunology. Published by Elsevier Inc. All rights reserved.)

Background: The effect of prenatal and postnatal exposure to fine particulate matter (PM 2.5 ) on the development of allergic rhinitis (AR) is poorly understood. We further identified the vulnerable period for AR development to determine methods to decrease adverse effects., Methods: We used a large population-based birth cohort of 140 911 singleton live infants in Taichung, Taiwan with a highly temporal-resolution satellite-based hybrid model to evaluate the effects of prenatal and early postnatal exposure on the onset of AR., Results: Among 140 911 children, 47 276 (33.55%) were cases of incident AR. The mean age of the children with AR at initial diagnosis was 2.97±1.78 years. We identified a significant association of AR with an interquartile range (IQR 17.98 µg/m 3 ) increase in PM 2.5 from 30 gestational weeks to 52 weeks after birth. The exposure-response relationship revealed that AR had a significant positive association between PM 2.5 of 26-76 µg/m 3 (adjusted hazard ratios ranged from 1.00 to 1.05)., Conclusion: Our study provides evidence that both prenatal and postnatal exposures to PM 2.5 are associated with later development of AR. The vulnerable time window may be within late gestation and the first year of life. Further study is required to confirm the vulnerable time period of PM 2.5 on AR., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Few studies have explored the relationship between long-term exposure to particulate matter with an aerodynamic diameter of ≤2.5 μm (PM 2.5 ) and osteoporotic fracture, particularly in high PM 2.5 level areas. The aim of this study was to assess the association between long-term exposure to PM 2.5 and osteoporotic fracture. We performed a matched case-control study of 16,175 participants obtained from a hospital registry during 2005-2014 in Taiwan. A major osteoporotic fracture was defined as a fracture of the spine, hip, proximal humerus, and forearm. We applied satellite-based spatiotemporal models with 1-km resolution to individually calculate the 1-year average PM 2.5 concentration before the index date which was defined as the first visit date for the osteoporotic fracture. Logistic regression models with and without potential confounding factors were used to estimate odds ratios (OR) and 95% confidence intervals (CI) between PM 2.5 and osteoporotic fracture, whereas a restricted cubic spline model was used to estimate the dose-response relationship. The sample's median age was 44.7 years (interquartile range: 30.7, 63.1 years). We observed that long-term PM 2.5 exposure was associated with osteoporotic fracture, the OR was 1.12 (95% CI: 1.03, 1.22) per 10-μg/m 3 increase in PM 2.5 in women. In the dose-response association, the OR of osteoporotic fracture was significantly increased for PM 2.5 exposures more than 41 μg/m 3 . We did not find a significant association between PM 2.5 (per 10-μg/m 3 increase) and osteoporotic fracture among overall population (adjusted OR, 1.02 [95% CI, 0.97 to 1.08]) and men (adjusted OR, 0.94 [95% CI, 0.86 to 1.02]). The results of the stratified analysis showed that women were more sensitive to the adverse impact of PM2.5 that were men, and evidence was obtained of sex-based effect modification (P for interaction = 0.002). Our findings suggest that long-term exposure to PM 2.5 is associated with osteoporotic fracture, particularly among women., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Abstract: The research has correlated the risk factors of herpes zoster with some chronic diseases. This meta-analysis aimed to assess the incidence of herpes zoster in patients with diabetes mellitus.We conducted a literature search using Web of Science and PubMed for articles published from January 1, 2000 to December 31, 2019. The incidence rate ratio and 95% confidence interval for herpes zoster associated with diabetes mellitus was calculated.We included 5 cohort studies for a meta-analysis. The pooled incidences of herpes zoster in patients with diabetes mellitus and in patients without diabetes mellitus were 7.22 and 4.12 per 1000 person-years. The overall risk of developing herpes zoster was significantly higher in patients with diabetes mellitus when compared to those with no diabetes mellitus (incidence rate ratio = 1.60, 95% confidence interval = 1.33-1.93).Patients with diabetes mellitus are substantially at increased risk for the development of herpes zoster. Patients with diabetes mellitus should take into consideration the vaccination to prevent herpes zoster., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2021 the Author(s). Published by Wolters Kluwer Health, Inc.)

The aim of the study was to examine the relationship between ambient temperature, ultraviolet radiation, and the development of herpes zoster in Taiwan. An ecological study was conducted to analyse the database of the Taiwan National Health Insurance Programme. Participants aged ≥20 years with newly diagnosed herpes zoster between 2003 and 2012 were selected for analysis. The monthly incidence rate of herpes zoster was measured between 2003 and 2012. Monthly average ambient temperature in Celsius (°C) between 2003 and 2012 was measured according to the official database of the Central Weather Bureau in Taiwan. Monthly accumulated ultraviolet radiation (MJ m -2 ) between 2003 and 2012 was measured according to the official database of the Environmental Protection Administration in Taiwan. The overall incidence rates of herpes zoster ranged from 2.54 to 5.67 per 10 000 persons per month from 2003 to 2012.The monthly average ambient temperature was higher and the monthly accumulated ultraviolet radiation was stronger from May to October. The incidence rates of herpes zoster seemed to be high during the period of high ambient temperature and strong ultraviolet radiation (from May to October).Whenever ambient temperature increased 1°C per month, the incidence rate of herpes zoster increased by 0.072 per 10,000 persons per month. Whenever ultraviolet radiation increased 1 MJ m -2 per month, the incidence rate of herpes zoster increased by 0.313 per 10 000 persons per month. There is a significant association between ambient temperature, ultraviolet radiation, and the development of herpes zoster in Taiwan. The incidence rate of herpes zoster is high during the period of high ambient temperature and strong ultraviolet radiation. Low ambient temperature and weak ultraviolet radiation might be beneficial for the prevention of herpes zoster., (© 2020 John Wiley & Sons Ltd.)

Rationale & Objective: Limited evidence concerns fine particulate matter (with aerodynamic diameter ≤ 2.5μm [PM 2.5 ]) exposure and the risk for kidney failure with replacement therapy (KFRT). This study assessed whether PM 2.5 exposure was associated with progression of chronic kidney disease (CKD) to KFRT., Study Design: Prospective cohort study., Setting & Participants: 6,628 adult patients with CKD were recruited from the Advanced CKD Program in Taiwan between 2003 and 2015., Exposure: Satellite-based spatiotemporal models were used to calculate each individual's 1-year PM 2.5 exposure before the date of enrollment into the Advanced CKD Program., Outcomes: Time to KFRT (defined as initiation of maintenance hemodialysis, peritoneal dialysis, or kidney transplantation) and time to all-cause mortality., Analytical Approach: Multivariable proportional hazard regression analyses were used to estimate the association of PM 2.5 with KFRT and all-cause mortality. Restricted cubic splines were used to explore dose-response relationships., Results: The study population included 6,628 adult patients with CKD who were aged 20 to 90 years. 941 KFRT events and 1,653 deaths occurred during follow-up. The adjusted HR for progression to KFRT was 1.19 (95% CI, 1.08-1.31) per 7.8μg/m 3 greater PM 2.5 , an amount spanning the interquartile range. There was evidence of a dose-response relationship (adjusted HRs of 1.16 [95% CI, 0.90-1.51], 1.19 [95% CI, 0.94-1.52], and 1.42 [95% CI, 1.12-1.80] for low, medium, and high PM 2.5 levels). There was no significant association between PM 2.5 and all-cause mortality (adjusted HR, 1.01 [95% CI, 0.95-1.08])., Limitations: Misclassification of PM 2.5 exposure assessment and the potential for residual confounding., Conclusions: Our findings suggest that long-term exposure to PM 2.5 is associated with increased risk for progression to KFRT in patients with CKD., (Copyright © 2020 National Kidney Foundation, Inc. Published by Elsevier Inc. All rights reserved.)