Metalloradical Catalysis: General Approach for Controlling Reactivity and Selectivity of Homolytic Radical Reactions.

Since Friedrich Wöhler's groundbreaking synthesis of urea in 1828, organic synthesis over the past two centuries has predominantly relied on the exploration and utilization of chemical reactions rooted in two-electron heterolytic ionic chemistry. While one-electron homolytic radical chemistry is both rich in fundamental reactivities and attractive with practical advantages, the synthetic application of radical reactions has been long hampered by the formidable challenges associated with the control over reactivity and selectivity of high-energy radical intermediates. To fully harness the untapped potential of radical chemistry for organic synthesis, there is a pressing need to formulate radically different concepts and broadly applicable strategies to address these outstanding issues. In pursuit of this objective, researchers have been actively developing metalloradical catalysis (MRC) as a comprehensive framework to guide the design of general approaches for controlling over reactivity and stereoselectivity of homolytic radical reactions. Essentially, MRC exploits the metal-centered radicals present in open-shell metal complexes as one-electron catalysts for homolytic activation of substrates to generate metal-entangled organic radicals as the key intermediates to govern the reaction pathway and stereochemical course of subsequent catalytic radical processes. Different from the conventional two-electron catalysis by transition metal complexes, MRC operates through one-electron chemistry utilizing stepwise radical mechanisms.

Asymmetric Radical Bicyclization for Stereoselective Construction of Tricyclic Chromanones and Chromanes with Fused Cyclopropanes.

Asymmetric radical bicyclization processes have been developed via metalloradical catalysis (MRC) to stereoselectively construct chiral chromanones and chromanes bearing fused cyclopropanes. Through optimization of a versatile D2-symmetric chiral amidoporphyrin ligand platform, a Co(II)-metalloradical system can homolytically activate both diazomalonates and α-aryldiazomethanes containing different alkene functionalities under mild conditions for effective radical bicyclization, delivering cyclopropane-fused tricyclic chromanones and chromanes, respectively, in high yields with excellent control of both diastereoselectivities and enantioselectivities. Combined computational and experimental studies, including the electron paramagnetic resonance (EPR) detection and 2,2,6,6-tetramethyl-1-piperidinyloxy (TEMPO) trapping of key radical intermediates, shed light on the working details of the underlying stepwise radical mechanisms of the Co(II)-catalyzed bicyclization processes. The two catalytic radical processes provide effective synthetic tools for stereoselective construction of valuable cyclopropane-fused chromanones and chromanes with newly generated contiguous stereogenic centers. As a specific demonstration of synthetic application, the Co(II)-catalyzed radical bicyclization has been employed as a key step for the first asymmetric total synthesis of the natural product (+)-Radulanin J.

Healthcare utilization, psychiatric disorders, and physical illnesses shortly before suicide mortality in adolescents in Taiwan.

BACKGROUND: This study examined the pattern of medical utilization and the distribution of comorbidities shortly before death among adolescents who died from suicide and compared these data with those of living controls. METHODS: From Taiwan's National Health Insurance Research Database, this study identified adolescents aged 10-19 years who died from suicide (n = 935) between 1 January 2000, and 31 December 2016, by linking each patient with the national mortality database. The researchers conducted a nested case-control study through risk set sampling, and for each case, 20 age- and sex-matched controls (n = 18 700) were selected from the general population. The researchers applied conditional logistic regression to investigate differences in medical utilization and physical and psychiatric comorbidities between cases and controls. RESULTS: Cases had a higher proportion of contact with the psychiatric department but a similar proportion of contact with any non-psychiatric medical department within 1 year before suicide compared with controls. There were 18.6% of adolescent suicide victims who only had contacted with a psychiatric department 3 months before suicide. Moreover, cases had a higher proportion of contact with non-psychiatric services within 3 months before suicide, particularly with emergency, surgery, and internal medicine departments. Cases had higher risks of several psychiatric disorders and physical illnesses, including heart diseases, pneumonia, and ulcer disease, than did controls. CONCLUSIONS: The findings of increased medical utilization and higher risks of physical and psychiatric comorbidities in adolescent suicide victims are crucial for developing specific interventions to prevent suicide in this population.

Healthcare utilization and comorbidity shortly before suicide mortality in patients with attention-deficit/hyperactivity disorder: a nested case-control study.

BACKGROUND: Few studies have analyzed healthcare utilization before suicide among individuals with attention-deficit/hyperactivity disorder (ADHD). This study examined the pattern of healthcare utilization and comorbidities shortly before death among patients with ADHD who died by suicide and compared these data with those of living controls. This study used Taiwan's National Health Insurance Research Database to identify patients with ADHD (N = 379,440) between January 1, 2001, and December 31, 2016. Subsequently, the researchers identified 159 suicide decedents by linking each patient with the National Mortality Database. By conducting a nested case-control study with risk-set sampling from the ADHD cohort, the researchers selected 20 age- and sex-matched controls (n = 3180) for each patient who died by suicide (cases). The researchers then applied conditional logistic regression to investigate differences in healthcare utilization as well as psychiatric and physical comorbidities between case patients and controls. Case patients had higher healthcare utilization within 3 months before suicide, particularly in the psychiatry, emergency, internal medicine, neurosurgery, and plastic surgery departments. These patients also had higher risks of psychiatric comorbidities, including schizophrenia, bipolar disorder, depressive disorder, and sleep disorder, as well as physical comorbidities such as hypertension and other forms of heart disease. Among patients with ADHD, suicide decedents had increased healthcare utilization and higher risks of specific psychiatric and physical comorbidities than living controls. Thus, for suicide prevention among individuals with ADHD, suicide risk must be detected early and comorbidities should be adequately managed.

Metalloradical Activation of In Situ-Generated α-Alkynyldiazomethanes for Asymmetric Radical Cyclopropanation of Alkenes.

α-Alkynyldiazomethanes, generated in situ from the corresponding sulfonyl hydrazones in the presence of a base, can serve as effective metalloradicophiles in Co(II)-based metalloradical catalysis (MRC) for asymmetric cyclopropanation of alkenes. With D2-symmetric chiral amidoporphyrin 2,6-DiMeO-QingPhyrin as the optimal supporting ligand, the Co(II)-based metalloradical system can efficiently activate different α-alkynyldiazomethanes at room temperature for highly asymmetric cyclopropanation of a broad range of alkenes. This catalytic radical process provides a general synthetic tool for stereoselective construction of alkynyl cyclopropanes in high yields with high both diastereoselectivity and enantioselectivity. Combined computational and experimental studies offer several lines of evidence in support of the underlying stepwise radical mechanism for the Co(II)-catalyzed olefin cyclopropanation involving a unique α-metalloradical intermediate that is associated with two resonance forms of α-Co(III)-propargyl radical and γ-Co(III)-allenyl radical. The resulting enantioenriched alkynyl cyclopropanes, as showcased with several stereospecific transformations, may serve as valuable chiral building blocks for stereoselective organic synthesis.

Increased medical utilization and psychiatric comorbidity following a new diagnosis of methamphetamine use disorder.

Background: Evidence of patterns of medical utilization and distribution of comorbidities among individuals using methamphetamine remains limitedObjective: This study aims to investigate changes in medical utilization and comorbidities before and after a diagnosis of methamphetamine use disorder.Methods: A total of 3321 cases (79% were male) of methamphetamine use disorder between January 1, 1996, and December 31, 2012, were identified from Psychiatric Inpatient Medical Claims database in Taiwan. Information was collected on demographics, diagnoses, and medical utilizations. The date of newly diagnosed with methamphetamine use disorder was defined as the baseline. Mirror-image study design was used to compare changes in medical utilization and comorbidities between the pre-baseline period (within 1 year before diagnosis) and the post-baseline period (within 1 year after diagnosis). Conditional logistic regression was used to estimate changes in medical utilization and comorbidities.Results: Most cases (77%) were first identified in a psychiatric department. There is a significant increase (P < .001) in psychiatric admission (odds ratio[OR] = 2.19), psychiatric emergency visits (OR = 1.31), and psychiatric outpatient visits (OR = 1.15) after diagnosis. Multivariable analysis revealed significantly increased risks (P < .001) of non-methamphetamine drug induced mental disorders (adjusted OR[aOR] = 29.47), schizophrenia (aOR = 2.62), bipolar disorder (aOR = 2.14), organic mental disorder (aOR = 1.82), and upper respiratory tract infection (aOR = 2.03) after diagnosis.Conclusions: We found significant increases of medical utilization and psychiatric comorbidities after diagnosed with methamphetamine use disorder. These findings may reflect the problem of delayed diagnosis and treatment. Enhancement of early identification of methamphetamine use disorder in general practice is required for early intervention and decreased subsequent morbidities.

New Catalytic Radical Process Involving 1,4-Hydrogen Atom Abstraction: Asymmetric Construction of Cyclobutanones.

While alkyl radicals have been well demonstrated to undergo both 1,5- and 1,6-hydrogen atom abstraction (HAA) reactions, 1,4-HAA is typically a challenging process both entropically and enthalpically. Consequently, chemical transformations based on 1,4-HAA have been scarcely developed. Guided by the general mechanistic principles of metalloradical catalysis (MRC), 1,4-HAA has been successfully incorporated as a key step, followed by 4-exo-tet radical substitution (RS), for the development of a new catalytic radical process that enables asymmetric 1,4-C-H alkylation of diazoketones for stereoselective construction of cyclobutanone structures. The key to success is the optimization of the Co(II)-based metalloradical catalyst through judicious modulation of D2-symmetric chiral amidoporphyrin ligand to adopt proper steric, electronic, and chiral environments that can utilize a network of noncovalent attractive interactions for effective activation of the substrate and subsequent radical intermediates. Supported by an optimal chiral ligand, the Co(II)-based metalloradical system, which operates under mild conditions, is capable of 1,4-C-H alkylation of α-aryldiazoketones with varied electronic and steric properties to construct chiral α,ß-disubstituted cyclobutanones in good to high yields with high diastereoselectivities and enantioselectivities, generating dinitrogen as the only byproduct. Combined computational and experimental studies have shed light on the mechanistic details of the new catalytic radical process, including the revelation of facile 1,4-HAA and 4-exo-tet-RS steps. The resulting enantioenriched α,ß-disubstituted cyclobutanones, as showcased with several enantiospecific transformations to other types of cyclic structures, may find useful applications in stereoselective organic synthesis.

Controlling Enantioselectivity and Diastereoselectivity in Radical Cascade Cyclization for Construction of Bicyclic Structures.

Radical cascade cyclization reactions are highly attractive synthetic tools for the construction of polycyclic molecules in organic synthesis. While it has been successfully implemented in diastereoselective synthesis of natural products and other complex compounds, radical cascade cyclization faces a major challenge of controlling enantioselectivity. As the first application of metalloradical catalysis (MRC) for controlling enantioselectivity as well as diastereoselectivity in radical cascade cyclization, we herein report the development of a Co(II)-based catalytic system for asymmetric radical bicyclization of 1,6-enynes with diazo compounds. Through the fine-tuning of D2-symmetric chiral amidoporphyrins as the supporting ligands, the Co(II)-catalyzed radical cascade process, which proceeds in a single operation under mild conditions, enables asymmetric construction of multisubstituted cyclopropane-fused tetrahydrofurans bearing three contiguous stereogenic centers, including two all-carbon quaternary centers, in high yields with excellent stereoselectivities. Combined computational and experimental studies have shed light on the underlying stepwise radical mechanism for this new Co(II)-based cascade bicyclization that involves the relay of several Co-supported C-centered radical intermediates, including α-, ß-, γ-, and ε-metalloalkyl radicals. The resulting enantioenriched cyclopropane-fused tetrahydrofurans that contain a trisubstituted vinyl group at the bridgehead, as showcased in several stereospecific transformations, may serve as useful intermediates for stereoselective organic synthesis. The successful demonstration of this new asymmetric radical process via Co(II)-MRC points out a potentially general approach for controlling enantioselectivity as well as diastereoselectivity in synthetically attractive radical cascade reactions.

Estimating climate change-related impacts on outdoor air pollution infiltration.

BACKGROUND: Rising temperatures due to climate change are expected to impact human adaptive response, including changes to home cooling and ventilation patterns. These changes may affect air pollution exposures via alteration in residential air exchange rates, affecting indoor infiltration of outdoor particles. We conducted a field study examining associations between particle infiltration and temperature to inform future studies of air pollution health effects. METHODS: We measured indoor fine particulate matter (PM2.5) in Atlanta in 60 homes (810 sampling-days). Indoor-outdoor sulfur ratios were used to estimate particle infiltration, using central site outdoor sulfur concentrations. Linear and mixed-effects models were used to examine particle infiltration ratio-temperature relationships, based on which we incorporated projected meteorological values (Representative Concentration Pathways intermediate scenario RCP 4.5) to estimate particle infiltration ratios in 20-year future (2046-2065) and past (1981-2000) scenarios. RESULTS: The mean particle infiltration ratio in Atlanta was 0.70 ± 0.30, with a 0.21 lower ratio in summer compared to transition seasons (spring, fall). Particle infiltration ratios were 0.19 lower in houses using heating, ventilation, and air conditioning (HVAC) systems compared to those not using HVAC. We observed significant associations between particle infiltration ratios and both linear and quadratic models of ambient temperature for homes using natural ventilation and those using HVAC. Future temperature was projected to increase by 2.1 °C in Atlanta, which corresponds to an increase of 0.023 (3.9%) in particle infiltration ratios during cooler months and a decrease of 0.037 (6.2%) during warmer months. DISCUSSION: We estimated notable changes in particle infiltration ratio in Atlanta for different 20-year periods, with differential seasonal patterns. Moreover, when stratified by HVAC usage, increases in future ambient temperature due to climate change were projected to enhance seasonal differences in PM2.5 infiltration in Atlanta. These analyses can help minimize exposure misclassification in epidemiologic studies of PM2.5, and provide a better understanding of the potential influence of climate change on PM2.5 health effects.

Optimal collecting policy for apheresis platelets in a regional blood center.

BACKGROUND AND OBJECTIVES: Planning platelet collection and inventory must rely not only on adequate forecasts of transfusion demand but also sophisticated mathematical modeling techniques. This research aims to develop a better demand forecasting model of apheresis platelets and a mathematical programming model to determine the best target amounts of apheresis platelet collection. MATERIALS AND METHODS: Time series data of apheresis platelets collected from donors and platelets supplied to hospitals daily in Taipei Blood Center from January 2014 to December 2015 was used to fit a forecasting model which combines a regression-type model for formulating the deterministic trends and seasonal variation and an autoregressive moving average model (ARMA) for explaining remaining serial correlations. A seasonal autoregressive integrated moving average (SARIMA) model was also used for benchmarking the prediction performance. A linear programming model was then formulated to solve for the optimal daily target collection volumes that maximize the total social benefits. RESULTS: The time series model achieved good predictive power with a mean absolute percentage error less than 10%. The appropriateness of the proposed target collection volumes was also verified by using a simulation model, and the proportion of the total platelets requested by hospitals that can be filled by collected apheresis platelets can increase significantly by using the new policy. CONCLUSION: The methods proposed in this study can be easily implemented to enhance the management efficiency of blood collecting and supplying of a blood center, and to decrease the costs of the blood outdates and shortages.

Estimation in generalized linear models under censored covariates with an application to MIREC data.

In many biological experiments, certain values of a biomarker are often nondetectable due to low concentrations of an analyte or the limitations of a chemical analysis device, resulting in left-censored values. There is an increasing demand for the analysis of data subject to detection limits in clinical and environmental studies. In this paper, we develop a novel statistical method for the maximum likelihood estimation in generalized linear models with covariates subject to detection limits. Simulations are carried out to study the relative performance of the proposed estimators, as compared to other existing estimators. The proposed method is also applied to a real dataset from the Maternal-Infant Research on Environmental Chemicals cohort study, where we investigate how different chemical mixtures affect the health outcomes of infants and pregnant women.

Copper(II)-Mediated ortho-Selective C(sp2)-H Tandem Alkynylation/Annulation and ortho-Hydroxylation of Anilides with 2-Aminophenyl-1H-pyrazole as a Directing Group.

2-Aminophenyl-1H-pyrazole has been identified as a viable directing group to promote copper(II)-mediated ortho-selective sp2 C-H bond tandem alkynylation/annulation of anilides with terminal alkynes to offer arylmethylene isoindolinones. Meanwhile, copper(II)-mediated ortho-selective sp2 C-H hydroxylation of anilides has also been optimized as the major reaction pathway by using Cu(OAc)2 as the promoter and 1,1,3,3-tetramethylguanidine as an organic base. Recovery of the directing group was achieved by hydrazinolysis for arylmethylene isoindolinones and basic hydrolysis for the hydroxylation products.

Palladium-Catalyzed Direct C(sp2)-H ortho-Arylation of Anilides Using 2-Aminophenylpyrazole as the Directing Group.

Palladium-catalyzed ortho-arylation of anilides was achieved using 2-aminophenyl-1H-pyrazole (2-APP) as a new directing group. Using Pd(OAc)2 as the catalyst and AgO as the promoter, mono- and diarylation of anilides were realized in up to 89% isolated yield. Further manipulation of the arylation product may be accomplished by a 2-step sequence involving an acidic hydrolysis of the methylated amide. More interestingly, in the presence of K2CO3, tandem C-C/C-N cyclization products were obtained for a couple of substrates.

Characteristics of extended-spectrum ß-lactamase-producing Escherichia coli isolated from fecal samples of piglets with diarrhea in central and southern Taiwan in 2015.

BACKGROUND: The production of extended-spectrum ß-lactamases (ESBLs) confer resistance to the commonly used beta-lactam antimicrobials and ESBL-producing bacteria render treatment difficulty in human and veterinary medicine. ESBL-producing bacteria have emerged in livestock in recent years, which may raise concerns regarding possible transfer of such bacteria through the food chain. The swine industry is important in Taiwan, but investigations regarding the status of ESBL in swine are limited. RESULTS: We collected 275 fecal swab samples from piglets with diarrhea in 16 swine farms located in central and southern Taiwan from January to December 2015 and screened them for ESBL-producing Escherichia coli. ESBL producers were confirmed phenotypically by combination disc test and genotypically by polymerase chain reaction and DNA sequencing. The occurrence rate of ESBL-producing E. coli was 19.7% (54 of 275), and all were obtained in swine farms located in southern Taiwan. bla CTX-M-1-group and bla CTX-M-9-group were the two bla CTX-M groups found. bla CTX-M-55 (34 of 54; 63.0%) and bla CTX-M-15 (16 of 54; 29.6%), which belong to the bla CTX-M-1-group, were the two major bla gene types, whereas bla CTX-M-65 was the only type found in the bla CTX-M-9 group. Twenty-seven strains contained bla TEM-1, and the other 27 strains contained bla TEM-116. One strain found in Pingtung harbored three bla genes: bla TEM-116, bla CTX-M-55, and bla CTX-M-65. ESBL-producing E. coli exhibited a multidrug-resistant phenotype, and multilocus sequence typing revealed that the ST10 clonal complexes, including ST10, 167, 44, and 617 accounted for 35% (19 of 54) of these strains. CONCLUSIONS: ESBL-producing E. coli from piglets with diarrhea were isolated from swine farms located in southern Taiwan. The most commonly detected bla were bla CTX-M-15 and bla CTX-M-55. The ST10 clonal complexes comprised most of our ESBL-producing E. coli strains. Fecal shedding from swine may contaminate the environment, resulting in public health concerns; thus, continued surveillance of ESBL is essential in swine and in other food animals.

Using health games for rehabilitation of patients with infantile cerebral palsy.

[Purpose] The purposes of this study were to evaluate whether the therapeutic games developed by the study team are significantly effective for upper limb rehabilitation of patients with cerebral palsy and to assess the development of the games and the evolution of patients throughout the therapy sessions. [Subjects and Methods] This study demonstrates the results of using therapeutic games in patients with infantile cerebral palsy. The therapies were performed in 30-minute sessions for about 1 to 4 months. This study shows the progress of five children with cerebral palsy during the sessions. The time it took the children on each road and the times required to complete a task were measured. In addition, the level of difficulty of the games was gradually increased at each session. [Results] Results have shown good progress on the accuracy of the movements and an increase in concentration level during the execution of the games, showing an improvement in the patients' performance by 40-55% faster. [Conclusions] Health games encourage children to comply with therapy. The advantage of the game is that the patient can perform the therapy at home, which could help achieve further progress in patients.

Validation and Application of the Mass Balance Model To Determine the Effectiveness of Portable Air Purifiers in Removing Ultrafine and Submicrometer Particles in an Apartment.

We validated the use of the mass balance model to determine the effectiveness of portable air purifiers in removing ultrafine (<0.10 µm) and submicrometer particles (0.10-0.53 µm) in an apartment. We evaluated two identical portable air purifiers, equipped with high efficiency particulate air filters, for their performance under three different air flow settings and three target air exchange rates: 0.60, 0.90, and 1.20 h(-1). We subsequently used a mixed effects model to estimate the slope between the measured and modeled effectiveness by particle size. Our study showed that effectiveness was highly particle size-dependent. For example, at the lowest target air exchange rate, it ranged from 0.33 to 0.56, 0.51 to 0.75, and 0.60 to 0.81 for the three air purifier flow settings, respectively. Our findings suggested that filtration was the dominant removal mechanism for submicrometer particles, whereas deposition could play a more important role in ultrafine particle removal. We found reasonable agreement between measured and modeled effectiveness with size-resolved slopes ranging from 1.11 ± 0.06 to 1.25 ± 0.07 (mean ± SE), except for particles <35 nm. Our study design can be applied to investigate the performances of other portable air purifiers as well as the influences of various parameters on effectiveness in different residential settings.

Size-resolved deposition rates for ultrafine and submicrometer particles in a residential housing unit.

We estimated the size-resolved particle deposition rates for the ultrafine and submicrometer particles using a nonlinear regression method with unknown particle background concentrations during nonsourced period following a controlled sourced period in a well-mixed residential environment. A dynamic adjustment method in conjunction with the constant injection of tracer gas was used to maintain the air exchange rate at three target levels across the range of 0.61-1.24 air change per hour (ACH). Particle deposition was found to be highly size dependent with rates ranging from 0.68 ± 0.10 to 5.03 ± 0.20 h(-1) (mean ± s.e.). Our findings also suggest that the effect of air exchange on the particle deposition under enhanced air mixing was relatively small when compared to both the strong influence of size-dependent deposition mechanisms and the effects of mechanical air mixing by fans. Nonetheless, the significant association between air exchange and particle deposition rates for a few size categories indicated potential influence of air exchange on particle deposition. In the future, the proposed approach can be used to explore the separate or composite effects between air exchange and air mixing on particle deposition rates, which will contribute to improved assessment of human exposure to ultrafine and submicrometer particles.

Iron(III)-based metalloradical catalysis for asymmetric cyclopropanation via a stepwise radical mechanism.

Metalloradical catalysis (MRC) exploits the metal-centred radicals present in open-shell metal complexes as one-electron catalysts for the generation of metal-stabilized organic radicals-key intermediates that control subsequent one-electron homolytic reactions. Cobalt(II) complexes of porphyrins, as stable 15e-metalloradicals with a well-defined low-spin d7 configuration, have dominated the ongoing development of MRC. Here, to broaden MRC beyond the use of Co(II)-based metalloradical catalysts, we describe systematic studies that establish the operation of Fe(III)-based MRC and demonstrate an initial application for asymmetric radical transformations. Specifically, we report that five-coordinate iron(III) complexes of porphyrins with an axial ligand, which represent another family of stable 15e-metalloradicals with a d5 configuration, are potent metalloradical catalysts for olefin cyclopropanation with different classes of diazo compounds via a stepwise radical mechanism. This work lays a foundation and mechanistic blueprint for future exploration of Fe(III)-based MRC towards the discovery of diverse stereoselective radical reactions.

Wildfire exposure and academic performance in Brazil: A causal inference approach for spatiotemporal data.

As the frequency and intensity of wildfires are projected to globally amplify due to climate change, there is a growing need to quantify the impact of exposure to wildfires in vulnerable populations such as adolescents. In our study, we applied rigorous causal inference methods to estimate the effect of wildfire exposure on the academic performance of high school students in Brazil between 2009 and 2015. Using longitudinal data from 8,183 high schools across 1,571 municipalities in Brazil, we estimated that the average performance in most academic subjects decreases under interventions that increase wildfire exposure, e.g., a decrease of 1.8 % (p = 0.01) in the natural sciences when increasing the wildfire density from 0.0035 wildfires/km2 (first quantile in the sample) to 0.0222 wildfires/km2 (third quartile). Furthermore, these effects considerably worsened over time. Our findings highlight the adverse impact of wildfires on educational outcomes.

Quantifying the potential effects of air pollution reduction on population health and health expenditure in Taiwan.

Air pollution, particularly ambient fine particulate matter (PM2.5) pollution, poses a significant risk to public health, underscoring the importance of comprehending the long-term impact on health burden and expenditure at national and subnational levels. Therefore, this study aims to quantify the disease burden and healthcare expenditure associated with PM2.5 exposure in Taiwan and assess the potential benefits of reducing pollution levels. Using a comparative risk assessment framework that integrates an auto-aggressive integrated moving average model, we evaluated the avoidable burden of cardiopulmonary diseases (including ischemic heart disease, stroke, chronic obstructive pulmonary disease, lung cancer, and diabetes mellitus) and related healthcare expenditure under different air quality target scenarios, including status quo and target scenarios of 15, 10, and 5 µg/m3 reduction in PM2.5 concentration. Our findings indicate that reducing PM2.5 exposure has the potential to significantly alleviate the burden of multiple diseases. Comparing the estimated attributable disease burden and healthcare expenditure between reference and target scenarios from 2022 to 2050, the avoidable disability-adjusted life years were 0.61, 1.83, and 3.19 million for the 15, 10, and 5 µg/m3 target scenarios, respectively. Correspondingly, avoidable healthcare expenditure ranged from US$ 0.63 to 3.67 billion. We also highlighted the unequal allocation of resources and the need for policy interventions to address health disparities due to air pollution. Notably, in the 5 µg/m3 target scenario, Kaohsiung City stands to benefit the most, with 527,368 disability-adjusted life years avoided and US$ 0.53 billion saved from 2022 to 2050. Our findings suggest that adopting stricter emission targets can effectively reduce the health burden and associated healthcare expenditure in Taiwan. Overall, this study provides policymakers in Taiwan with valuable insights for mitigating the negative effects of air pollution by establishing a comprehensive framework for evaluating the co-benefits of air pollution reduction on healthcare expenditure and disease burden.