Real-World Treatment Patterns and Outcomes of First-Line Immunotherapy Among Patients With Advanced Nonsquamous NSCLC Harboring BRAF, MET, or HER2 Alterations.

Introduction: Data on utilization and clinical outcomes of programmed cell death protein or programmed death-ligand 1 (PD-[L]1) inhibitors in NSCLC with uncommon oncogenic alterations is limited. Methods: This retrospective study used a deidentified U.S. nationwide clinicogenomic database to select patients with advanced nonsquamous NSCLC without EGFR, ALK, or ROS1 alterations, diagnosed from January 1, 2016 to September 30, 2020, who initiated first-line therapy. Our objectives were to summarize characteristics and treatment patterns for patients with four little-studied genomic alterations or driver-negative NSCLC. We estimated Kaplan-Meier real-world time on treatment (rwTOT) and time to next treatment for patients receiving PD-(L)1 inhibitors. The data cutoff was September 30, 2021. Results: Of the 3971 eligible patients, 84 (2%) had NSCLC with BRAF V600E mutation, 117 (3%) had MET exon 14 skipping mutation, 130 (3%) had MET amplification, 91 (2%) had ERBB2 activation mutation, and 691 patients (17%) had driver-negative NSCLC. Patient characteristics differed among cohorts as expected. The most common first-line regimen in each cohort was a PD-(L)1 inhibitor as monotherapy or in combination with chemotherapy. The median rwTOT with anti-PD-(L)1 monotherapy was 4.6 months in the driver-negative cohort and ranged from 2.9 months (ERBB2 mutation) to 7.6 months (BRAF V600E mutation). The median rwTOT with anti-PD-(L)1-chemotherapy combination was 5.2 months in the driver-negative cohort and 6 months in all but the BRAF V600E cohort (17.5 mo). The patterns of real-world time to next treatment results were similar. Conclusions: Substantial use of anti-PD-(L)1 therapy and associated clinical outcomes are consistent with previous real-world findings and suggest no detriment from PD-(L)1 inhibitors for advanced nonsquamous NSCLC harboring one of these four genomic alterations relative to driver-negative NSCLC.

Real-world utilization of immune checkpoint inhibitors in extensive stage small-cell lung cancer in community settings.

Aim: This study examined real-world treatment patterns for extensive-stage small-cell lung cancer (ES-SCLC) after immune checkpoint inhibitors (ICIs) became available for frontline use. Methods: Adult patients with ES-SCLC initiating 1L systemic treatment were identified from electronic health records. Results: Among patients with recurrent/progressive ES-SCLC, the most common treatment classes were platinum-based chemotherapy (81.1% of 228) and ICI monotherapy (35.1% of 191) in 1L and 2L, respectively. Among patients with de novo ES-SCLC, the most common treatment classes were ICI + platinum-based chemotherapy (64.4% of 1268) and other chemotherapy (44.9% of 512) in 1L and 2L, respectively. Among patients who received no ICI in 1L, 62.6%-70.3% received it in 2L and 62.6-68.5% in 3L. Some who received 1L ICI were re-treated with ICI in subsequent lines (14.5-18.8% in 2L, 18.2-50.0% in 3L). Conclusion: Real-world ICI utilization in ES-SCLC, particularly ICI re-challenge, demonstrates high unmet needs in this patient population.

Small-cell lung cancer (SCLC) is a type of lung cancer that is highly lethal. About 70% of patients have advanced SCLC when they first get their diagnosis and most die within 5 years. This study focused on immune checkpoint inhibitors (ICIs), a type of treatments that can help the immune system to fight cancer and has only been approved to treat SCLC in the past 4­5 years. We studied 1496 patients with advanced SCLC treated at community cancer practices in USA between October 2018 and February 2020. Patients averaged about 68 years old when they started treatment. By looking at the types and sequences of treatments, we found that although ICI are often used to treat SCLC, patients with this aggressive cancer still need other effective treatment choices.

Risk factors for thromboembolic events in patients with paroxysmal nocturnal hemoglobinuria (PNH): a nested case-control study in the International PNH Registry.

The objective of this analysis was to identify risk factors for thromboembolic events (TE) in patients with paroxysmal nocturnal hemoglobinuria (PNH) who were not treated with C5 inhibitors. Patients with PNH and a history of ≥ 1 TE at enrollment in the International PNH Registry (NCT01374360; registration date, January 2011) were each matched with up to 5 patients without TE. Multivariable analysis was performed with the following variables: percentage glycosylphosphatidylinositol (GPI)-negative cells, high disease activity (HDA), non-TE major adverse vascular event history, and recent anticoagulation. Of 2541 eligible patients, 57 with TE and 189 matched controls were analyzed. Multivariable analysis (odds ratio [95% CI]) identified the following factors as being associated with increased thrombotic risk: patients with no history of TE (with recent anticoagulation, 9.30 [1.20-72.27]), patients with history of TE (with recent anticoagulation, 8.91 [0.86-92.62]; without recent anticoagulation, 5.33 [0.26-109.57]), patients with ≥ 30% GPI-negative granulocytes (≥ 30% to < 50%, 4.94 [0.54-45.32]; ≥ 50%, 1.97 [0.45-8.55]), or patients with lactate dehydrogenase (LDH) ratio ≥ 1.5 × upper limit of normal (ULN) plus ≥ 2 HDA criteria (2-3 criteria, 3.18 [0.44-23.20]; ≥ 4 criteria, 3.60 [0.38-33.95]). History of TE, ≥ 30% GPI-negative granulocytes, and LDH ratio ≥ 1.5 × ULN with ≥ 2 HDA criteria are TE risk factors for patients with PNH. These findings will aid physicians by providing important clinical and laboratory risk factors that can be used to identify and manage patients with PNH who are at risk of developing TE.

Relationship of paroxysmal nocturnal hemoglobinuria (PNH) granulocyte clone size to disease burden and risk of major vascular events in untreated patients: results from the International PNH Registry.

Paroxysmal nocturnal hemoglobinuria (PNH) is caused by acquired gene mutations resulting in deficiency of glycosylphosphatidylinositol (GPI)-anchored complement regulatory proteins on the surface of blood cells, leading to terminal complement-mediated intravascular hemolysis and increased risk of major adverse vascular events (MAVEs). Using data from the International PNH Registry, this study investigated the relationship between the proportion of GPI-deficient granulocytes at PNH onset and (1) the risk for MAVEs (including thrombotic events [TEs]) and (2) the following parameters at last follow-up: high disease activity (HDA); lactate dehydrogenase (LDH) ratio; fatigue; abdominal pain; and rates of overall MAVEs and TEs. A total of 2813 patients untreated at enrollment were included and stratified by clone size at PNH disease onset (baseline). At last follow-up, higher proportion of GPI-deficient granulocytes (≤ 5% vs. > 30% clone size) at baseline was associated with significantly increased HDA incidence (14% vs. 77%), mean LDH ratio (1.3 vs. 4.7 × upper limit of normal), and rates of MAVEs 1.5 vs. 2.9 per 100 person-years) and TEs (0.9 vs. 2.0 per 100 person-years). Fatigue was evident in 71 to 76% of patients regardless of clone size. Abdominal pain was more frequently reported with clone size > 30%. A larger clone size at baseline appears to indicate a greater disease burden and risk of TEs and MAVEs and may inform decision making among physicians managing PNH patients at risk of experiencing TEs or other MAVEs. ClinicalTrials.gov ID: NCT01374360.

Molecular epidemiology study of programmed death ligand 1 and ligand 2 protein expression assessed by immunohistochemistry in extensive-stage small-cell lung cancer.

Objectives: Prevalence of tumor PD-L1 expression in extensive-stage small-cell lung cancer (ES-SCLC) is variable, and data on PD-L2 expression are limited. The prognostic values of these biomarkers are not well understood. The current study was conducted to address these data gaps. Methods: A retrospective cohort study of Danish patients with histologically confirmed ES-SCLC and evaluable tumor samples who were receiving usual care before the introduction of immunotherapy was conducted. Protein expression of PD-L1 and PD-L2 was determined by immunohistochemistry (IHC) using the PD-L1 IHC 22C3 pharmDx assay and a PD-L2 IHC assay using a propriety mouse monoclonal antibody. A combined positive score (CPS) of ≥1 was used to define biomarker positivity. Kaplan-Meier plots and Cox proportional hazard models were employed to assess the relationship between PD-L1 and PD-L2 protein expression and OS. Results: Among 80 patients, 31% (n=25) and 36% (n=29) had disease positive for PD-L1 and PD-L2, respectively. Overall, 85% (n=68) of patients had concordant PD-L1/PD-L2 status; 26% (n=21) had double positive disease (both PD-L1 and PD-L2 CPS ≥1) and 59% (n=47) had double negative disease (both PD-L1 and PD-L2 CPS <1). PD-L1 and PD-L2 positivity were each associated with longer OS (unadjusted hazard ratios [HRs], 0.35 [95% CI, 0.21-0.61] and 0.50 [95% CI, 0.31-0.82]); the associations persisted after adjustment for several known prognostic factors (HRs, 0.41 [95% CI, 0.22-0.75] and 0.44 [95% CI, 0.25-0.79] for PD-L1 and PD-L2 positivity, respectively). When evaluating OS in patients with double positive disease, unadjusted and adjusted HRs for double positive compared with double negative were similar to those with only PD-L1 or PD-L2 positivity (unadjusted HR, 0.36 [95% CI, 0.20-0.64]; adjusted HR, 0.36 [0.18-0.73]). Conclusion: PD-L1 and PD-L2 positivity were observed in approximately one-third of assessed ES-SCLC tumor samples and were highly congruent. Patients with PD-L1 and PD-L2 positivity, alone or combined, were associated with longer OS, independent of other prognostic factors.

Incidence of Pneumonitis Among Limited Stage Small Cell Lung Cancer Patients Exposed to Concurrent Chemoradiation: A Systematic Literature Review and Meta-Analysis.

Severe pneumonitis (≥ grade 3 by Common Terminology Criteria for Adverse Events [CTCAE]) is a toxicity associated with concurrent chemoradiation therapy (CCRT), which is the standard first-line treatment for patients with limited-stage small cell lung cancer (LS-SCLC). We summarize and quantify the risk of pneumonitis in LS-SCLC patients receiving first-line CCRT. A systematic literature review (SLR) and meta-analysis were performed in accordance with Cochrane and PRISMA guidelines. Electronic databases were searched to identify relevant randomized controlled trials (RCTs), observational studies, and non-randomized trials between 2014 to July 16, 2020. The primary outcome was incidence of pneumonitis. Thirteen studies were included in the SLR and 1539 pooled patients from 10 studies were included in the base-case meta-analysis. The pooled incidence of ≥ grade 3 pneumonitis was 3.28% (95% confidence interval [CI]: 1.52%-5.04%) in RCTs, and 6.34% (95% CI: 3.64%-9.04%) in non-RCTs. The pooled incidence risk of grade 5 (fatal) pneumonitis was 0.29% (95% CI: 0.00%-0.62%) in RCTs and 0.88% (95% CI: 0.02%-1.74%) in non-RCT. Results from sensitivity analyses were consistent with the base-case analysis. The results from this analysis show that the incidence of ≥ grade 3 pneumonitis in patients with LS-SCLC was 3.28% to 6.34%. The incidence of pneumonitis was higher in studies conducted in non-RCTs compared to RCTs. These results can be used to understand the safety, with regard to pneumonitis, of novel therapeutic agents when administered with CCRT to treat patients with LS-SCLC. To summarize and quantify the risk of pneumonitis in LS-SCLC patients receiving first-line CCRT, a systematic literature review (SLR) and meta-analysis were performed in accordance with Cochrane and PRISMA guidelines.

Heat shock protein B8 promotes proliferation and migration in lung adenocarcinoma A549 cells by maintaining mitochondrial function.

Heat shock protein B8 (HSPB8) impacts on tumor proliferation and migration of malignancy. However, the role of HSPB8 in lung adenocarcinoma (LUAC) remains unclear. The aim of this study, therefore, was to clarify whether HSPB8 could bring benefits to proliferation and migration of LUAC and its underlying mechanisms. The expression of HSPB8 was first evaluated by immunohistochemistry in 35 LUAC samples. Then, A549 lung adenocarcinoma cells were transfected with pcDNA-HSPB8 or si-HSPB8 to induce HSPB8 overexpression and silence. Cellular activity was evaluated with a Cell Counting Kit-8 (CCK-8) assay. Cell proliferation and migration were observed by EdU assay and scratch assay. Mitochondria-specific reactive oxygen species (mtROS) and membrane potential were measured using MitoSOX Red probe and JC-1 staining. Superoxide dismutase (SOD) activities and malondialdehyde (MDA) level were measured using commercial kits, respectively. HSPB8 protein, mitochondrial fusion protein MFN2 and mitochondrial fission protein p-Drp1/Drp1 were measured using western blot. Compared with the normal tissues, the expression of HSPB8 protein was higher in LUAC tissues and upregulation of HSPB8 protein was related to tumor size and tumor location. Furthermore, HSPB8 overexpression aggravated cell proliferation and migration of A549 cells. Mechanistically, HSPB8 suppressed mitochondrial impairment, leading to promoting the progress of A549 lung adenocarcinoma cells. These data demonstrate that HSPB8 plays an important role in progression of LUAC and may be a new target to treat LUAC.

Critical review of long-term ozone exposure and asthma development.

Asthma, a chronic respiratory disorder with complex etiology and various phenotypes, is a considerable public health concern in the USA and worldwide. While there is evidence suggesting ambient ozone exposure may exacerbate asthma, information regarding the potential role of ozone in asthma development is more limited. Thus, we conducted a critical review of observational epidemiology studies to determine whether long-term ambient ozone exposure is a risk factor for asthma development. We identified 14 relevant studies; 11 evaluated asthma development in children, while three studies, based on a single cohort, assessed this outcome in adults. Studies of childhood asthma and long-term ozone exposure - including exposure in utero, during the first year of life and during early childhood - reported inconsistent findings, which were further weakened by critical methodological limitations in statistical analyses and in exposure and outcome assessments, such as exposure measurement error and a lack of adjustment for key confounders. For adult-onset asthma, long-term ozone exposure was associated with an increased risk in men but not women. In addition to considerable uncertainties due to potential exposure measurement error and a lack of adjustment for key confounders, this study has limited generalizability to the US general population. While experimental evidence indicates that it may be biologically plausible that long-term ozone exposure could contribute to asthma development, it does not provide insight regarding an established mode of action. Future research is needed to address the uncertainties regarding the role of long-term ambient ozone exposure in asthma development.

Short-term ozone exposure and asthma severity: Weight-of-evidence analysis.

To determine whether evidence indicates that short-term exposure to ambient concentrations of ozone in the United States can affect asthma severity, we systematically reviewed published controlled human exposure, epidemiology, and animal toxicity studies. The strongest evidence for a potential causal relationship came from epidemiology studies reporting increased emergency department visits and hospital admissions for asthma following elevated ambient ozone concentrations. However, while controlled exposure studies reported lung function decrements and increased asthma symptoms following high ozone exposures 160-400 parts per billion [ppb]), epidemiology studies evaluating similar outcomes reported less consistent results. Animal studies showed changes in pulmonary function at high ozone concentrations (> 500ppb), although there is substantial uncertainty regarding the relevance of these animal models to human asthma. Taken together, the weight of evidence indicates that there is at least an equal likelihood that either explanation is true, i.e., the strength of the evidence for a causal relationship between short-term exposure to ambient ozone concentrations and asthma severity is "equipoise and above."

Endobronchial hamartoma mimicking malignant lung tumor contralateral endobronchial metastasis: A case report.

RATIONALE: Endobronchial hamartoma, the most common benign lung tumor, is located in the bronchus, and it easily mimics lung cancer or bronchial metastasis. Endobronchial hamartoma can cause coughing, hemoptysis, and pulmonary infection; thus, it should be treated right away by surgery or fiberoptic bronchoscopy. PATIENT CONCERNS: We report a rare case of endobronchial hamartoma in which the clinical symptoms and imaging overlapped strongly with malignant lung tumor contralateral endobronchial metastasis. DIAGNOSES: Endobronchial hamartoma coexisting with a malignant lung tumor. INTERVENTIONS: Fiberoptic bronchoscopy was conducted, and the pathologic diagnosis was hamartoma. A second fiberoptic bronchoscopy was conducted, and fine-needle aspiration cytology of the enlarged lymph nodes indicated squamous cell carcinoma. OUTCOMES: The clinical symptoms were relieved, and the treatment options were docetaxel, cis-dichlorodiamineplatinum, and endostatin. LESSONS: Fiberoptic bronchoscopy needs to be guided by imaging and can be considered an effective method for the diagnosis of endobronchial hamartoma.

Dermal exposure to toluene diisocyanate and respiratory cancer risk.

Human exposure to toluene diisocyanate (TDI) occurs mainly through inhalation of vapors in occupational settings where TDI is produced or used, but dermal exposure to TDI is also possible during some operations. Because of a recent epidemiology study reporting a possible association with lung cancer risk in workers with potential dermal exposure to TDI, we evaluated the evidence from epidemiological, toxicological, and toxicokinetic studies to assess whether it is likely that dermal exposure to TDI can cause human respiratory cancers. We found that the reported associations with respiratory cancers in the epidemiology studies do not support TDI as a causal factor, as there are other explanations that are more likely than causation, such as confounding by smoking and low socioeconomic status. Experimental animal and genotoxicity studies indicate that the carcinogenic potential of TDI depends on its conversion to toluene diamine (TDA), and there is no evidence of systemic availability of TDA after dermal or inhalation exposure to TDI. Also, systemic uptake of TDI is very low after dermal exposure, and any absorbed TDI is more likely to react with biomolecules on or below the skin surface than to form TDA. Even if some TDA formation occurred after dermal exposure to TDI, TDA does not induce respiratory tract tumors in experimental animals after either dermal or oral exposure. We conclude that the available evidence indicates that dermal TDI exposure does not cause respiratory cancers in humans.

Applying Nonparametric Methods to Analyses of Short-Term Fine Particulate Matter Exposure and Hospital Admissions for Cardiovascular Diseases among Older Adults.

Short-term exposure to fine particulate matter (PM2.5) has been associated with increased risks of cardiovascular diseases (CVDs), but whether such associations are supportive of a causal relationship is unclear, and few studies have employed formal causal analysis methods to address this. We employed nonparametric methods to examine the associations between daily concentrations of PM2.5 and hospital admissions (HAs) for CVD among adults aged 75 years and older in Texas, USA. We first quantified the associations in partial dependence plots generated using the random forest approach. We next used a Bayesian network learning algorithm to identify conditional dependencies between CVD HAs of older men and women and several predictor variables. We found that geographic location (county), time (e.g., month and year), and temperature satisfied necessary information conditions for being causes of CVD HAs among older men and women, but daily PM2.5 concentrations did not. We also found that CVD HAs of disjoint subpopulations were strongly predictive of CVD HAs among older men and women, indicating the presence of unmeasured confounders. Our findings from nonparametric analyses do not support PM2.5 as a direct cause of CVD HAs among older adults.

Ambient ozone and asthma hospital admissions in Texas: a time-series analysis.

BACKGROUND: Many studies have evaluated associations between asthma emergency department (ED) visits, hospital admissions (HAs), and ambient ozone (O3) across the US, but not in Texas. We investigated the relationship between O3 and asthma HAs, and the potential impacts of outdoor pollen, respiratory infection HAs, and the start of the school year in Texas. METHODS: We obtained daily time-series data on asthma HAs and ambient O3 concentrations for Dallas, Houston, and Austin, Texas for the years 2003-2011. Relative risks (RRs) and 95% confidence intervals (CIs) of asthma HAs per 10-ppb increase in 8-h maximum O3 concentrations were estimated from Poisson generalized additive models and adjusted for temporal trends, meteorological factors, pollen, respiratory infection HAs, day of the week, and public holidays. We conducted a number of sensitivity analyses to assess model specification. RESULTS: We observed weak associations between total asthma HAs and O3 at lags of 1 day (RR10 ppb = 1.012, 95% CI: 1.004-1.021), 2 days (RR10 ppb = 1.011, 95% CI: 1.002-1.019), and 0-3 days (RR10 ppb = 1.017, 95% CI: 1.005-1.030). The associations were primarily observed in children aged 5-14 years (e.g., for O3 at lag 0-3 days, RR10 ppb = 1.037, 95% CI: 1.011-1.064), and null in individuals 15 years or older. The effect estimates did not change significantly with adjustment for pollen and respiratory infections, but they attenuated considerably and lost statistical significance when August and September data were excluded. A significant interaction between time around the start of the school year and O3 at lag 2 day was observed, with the associations with pediatric asthma HAs stronger in August and September (RR10 ppb = 1.040, 95% CI: 1.012-1.069) than in the rest of the year (October-July) (RR10 ppb = 1.006, 95% CI: 0.986-1.026). CONCLUSIONS: We observed small but statistically significant positive associations between total and pediatric asthma HAs and short-term O3 exposure in Texas, especially in August and September. Further research is needed to determine how the start of school could modify the observed association between O3 and pediatric asthma HAs.

Impact of respiratory infections, outdoor pollen, and socioeconomic status on associations between air pollutants and pediatric asthma hospital admissions.

BACKGROUND: Epidemiology studies have shown that ambient concentrations of ozone and fine particulate matter (PM2.5) are associated with increased emergency department (ED) visits and hospital admissions (HAs) for asthma. OBJECTIVE: Evaluate the impact of outdoor pollen, respiratory infections, and socioeconomic status (SES) on the associations between ambient ozone and PM2.5 and asthma HAs in New York City. METHODS: Daily ozone, PM2.5, meteorological factors, pollen, and hospitalization records during 1999 to 2009 were obtained for New York City residents. Daily counts of HAs for asthma and respiratory infections were calculated for all-age and specific age groups, and for high- and low-SES communities. Generalized additive models were used to examine ambient concentrations of ozone and PM2.5 and asthma HAs, potential confounding effects of outdoor pollen and HAs for respiratory infections, and potential effect modification by neighborhood SES. RESULTS: Both ozone and PM2.5 were statistically significantly associated with increased asthma HAs in children aged 6-18 years (per 10 ppb increase in ozone: RR = 1.0203, 95% CI: 1.0028-1.0382; per 10 µg/m3 increase in PM2.5: RR = 1.0218, 95% CI: 1.0007-1.0434), but not with total asthma HAs, or asthma HAs in other age groups. These associations were stronger for children living in the high-SES areas. Adjustment for respiratory infection HAs at various lags did not result in changes greater than 10% in the risk estimates for either ozone or PM2.5. In contrast, adjustment for outdoor pollen generally attenuated the estimated RRs for both ozone and PM2.5. CONCLUSIONS: Ambient ozone and PM2.5 are associated with asthma HAs in school-age children, and these associations are not modified by SES. HAs for respiratory infections do not appear to be a confounder for observed ozone- and PM2.5-asthma HAs associations, but pollen may be a weak confounder.

Quantitative assessment of lung and bladder cancer risk and oral exposure to inorganic arsenic: Meta-regression analyses of epidemiological data.

Inorganic arsenic (iAs) in drinking water varies geographically and is prevalent worldwide. While exposures in the US are generally low, there are some areas with higher levels of naturally occurring iAs (potentially >100µg/L) where residents rely on unregulated drinking water wells. Much of the evidence on the association between iAs and cancer comes from epidemiological studies conducted in South American and Asian populations. These populations have generally been exposed to much higher levels of iAs and have differing underlying characteristics, both of which make comparing them to Western populations difficult. A key question is whether and how one should extrapolate from these high exposure studies to estimate cancer risk at lower exposures. We conducted an independent analysis to determine the most appropriate cancer endpoints, studies, and models to support an oral carcinogenicity assessment of iAs, taking into consideration factors that affect the apparent potency of iAs across geographically and culturally distinct populations. We identified bladder and lung cancer as high-priority endpoints and used meta-regression to pool data across studies from different regions of the world to derive oral cancer slope factors (CSFs) and unit risks (excess risk per µg/L) for iAs based on the background risks of bladder and lung cancer in the US. We also calculated concentrations of iAs in water that are not likely to result in cancer risk above what is considered acceptable by the United States Environmental Protection Agency (US EPA). While we derived these factors assuming a linear, no-threshold relationship between iAs and cancer risk, we also evaluated the shape of the dose-response curves and assessed the evidence for overall nonlinearity. Overall, we found that the incremental risks of bladder and lung cancer associated with iAs were relatively low. The sensitivity analyses we conducted suggested that populations with relatively high iAs exposures appeared to drive the pooled cancer risk estimates, but many of our other tested assumptions did not substantially alter these estimates. Finally, we found that the mode of action evidence supports there being a threshold, but making a robust quantitative demonstration of a threshold using epidemiological data is difficult. When considered in the context of typical exposure levels in the US, our potency estimates indicate that iAs-induced cancer risk is much lower than observed bladder and lung cancer incidences. This suggests that the low iAs levels to which much of the general US population is exposed likely do not result in substantial additional cancer risk.

Concentration-response of short-term ozone exposure and hospital admissions for asthma in Texas.

BACKGROUND: Short-term exposure to ozone has been associated with asthma hospital admissions (HA) and emergency department (ED) visits, but the shape of the concentration-response (C-R) curve is unclear. METHODS: We conducted a time series analysis of asthma HAs and ambient ozone concentrations in six metropolitan areas in Texas from 2001 to 2013. Using generalized linear regression models, we estimated the effect of daily 8-hour maximum ozone concentrations on asthma HAs for all ages combined, and for those aged 5-14, 15-64, and 65+years. We fit penalized regression splines to evaluate the shape of the C-R curves. RESULTS: Using a log-linear model, estimated risk per 10ppb increase in average daily 8-hour maximum ozone concentrations was highest for children (relative risk [RR]=1.047, 95% confidence interval [CI]: 1.025-1.069), lower for younger adults (RR=1.018, 95% CI: 1.005-1.032), and null for older adults (RR=1.002, 95% CI: 0.981-1.023). However, penalized spline models demonstrated significant nonlinear C-R relationships for all ages combined, children, and younger adults, indicating the existence of thresholds. We did not observe an increased risk of asthma HAs until average daily 8-hour maximum ozone concentrations exceeded approximately 40ppb. CONCLUSION: Ozone and asthma HAs are significantly associated with each other; susceptibility to ozone is age-dependent, with children at highest risk. C-R relationships between average daily 8-hour maximum ozone concentrations and asthma HAs are significantly curvilinear for all ages combined, children, and younger adults. These nonlinear relationships, as well as the lack of relationship between average daily 8-hour maximum and peak ozone concentrations, have important implications for assessing risks to human health in regulatory settings.