Real-World Outcomes and Prognostic Factors Among Patients with Advanced Non-Small Cell Lung Cancer and High PD-L1 Expression Treated with Immune Checkpoint Inhibitors as First-Line Therapy.

Background: Immune checkpoint inhibitors (ICIs) are standard-of-care for patients with advanced non-small cell lung cancer (aNSCLC) and programmed cell death-ligand 1 (PD-L1) expression ≥50%. Methods: A retrospective cohort study was conducted using the US de-identified electronic health record-derived Flatiron Health aNSCLC database (January 1, 2018, to July 31, 2021) among patients with PD-L1 ≥50% initiating first-line ICIs with or without chemotherapy. A clinical trial-like sub-cohort was also identified with Eastern Cooperative Oncology Group performance status 0-1, adequate organ function, and no brain metastases or other primary cancers. Kaplan-Meier methods were used to estimate time to treatment discontinuation, time to next treatment, progression-free survival and overall survival (OS) by ICI regimen (ICI+chemotherapy, ICI monotherapy) and PD-L1 expression (50-69%, 70-89%, 90-100%). Cox proportional hazard models were used to examine associations between ICI regimen, PD-L1 level, and OS, adjusting for baseline demographic and clinical variables. Results: A total of 2631 patients with aNSCLC initiating ICI+chemotherapy (n = 992) or ICI monotherapy (n = 1639) were included; median (Q1, Q3) age was 71 (63-78) years and 51.6% were male. The trial-like sub-cohort (n = 1029) generally had better outcomes vs. the overall cohort. Patients receiving ICI+chemotherapy generally had longer median OS vs. ICI monotherapy. Multivariable analyses showed no association between ICI regimen and OS among patients with PD-L1 70-89% (hazard ratio [HR]: 0.90, 95% confidence interval [CI]: 0.73-1.09) or 90-100% (HR: 0.91, 95% CI: 0.77-1.08), but patients with PD-L1 50-69% receiving ICI+chemotherapy had longer OS (HR: 0.80, 95% CI: 0.64-0.99). Conclusion: Outcomes in real-world clinical trial-like patients with aNSCLC approached those reported in pivotal ICI trials in high PD-L1 expressers. ICI monotherapy offers a potential alternative in patients with PD-L1 ≥70% while avoiding potential chemotherapy toxicity exposure; the benefits are less clear in patients with PD-L1 50-69%. Future studies should confirm these findings.

Real-World Cost of Nasal Polyps Surgery and Risk of Major Complications in the United States: A Descriptive Retrospective Database Analysis.

Background: Endoscopic nasal polyp (NP) surgery is a treatment option for patients with chronic rhinosinusitis with nasal polyps (CRSwNP). Previous studies report NP surgery costs of $8000-13,000 and risk of major complications of NP surgery of ~0.1-1%. Limited contemporary data for costs and complications associated with NP surgery in US clinical practice are available. Methods: IQVIA PharMetrics Plus claims data were used to identify patients with NP surgery in 2019 with ≥3 years continuous baseline health-plan enrollment prior to index date (date of first eligible NP surgery) and ≥30 days continuous enrollment after index (follow-up). In this descriptive analysis, total costs of NP surgery were estimated as all medical costs on the index date (or during the entire hospital stay for patients who received surgery in the inpatient setting). Total medical costs (all-cause) were estimated for all medical services occurring from the index date to the index date +9 or +29 days (10-day and 30-day). Major complication was defined as cerebrospinal fluid (CSF) leak, orbital injury, or major hemorrhage within 30 days of index. Results: Of 6311 patients, median age was 46 years (interquartile range: 34-56); 59.7% were male; 88.2% had no NP surgery in the prior 3 years; 63.7% had allergic rhinitis, and 37.1% had asthma. Mean (SD) total medical cost of surgery was $14,697 (11,679) and mean (SD) 10-day total medical cost was $15,401 (11,968). Major complications occurred in 102 (1.7%) patients. Total medical costs and 10-day costs were higher in patients with major complications than those without ($23,605 [19,264] vs $15,251 [11,741]). Conclusion: In this descriptive analysis, NP surgery costs and rates of major surgical complications were updated using recent real-world data in the US. Results indicated that NP surgery complication rates were numerically higher than previously reported.

Machine learning models for identifying predictors of clinical outcomes with first-line immune checkpoint inhibitor therapy in advanced non-small cell lung cancer.

Immune checkpoint inhibitors (ICIs) are standard-of-care as first-line (1L) therapy for advanced non-small cell lung cancer (aNSCLC) without actionable oncogenic driver mutations. While clinical trials demonstrated benefits of ICIs over chemotherapy, variation in outcomes across patients has been observed and trial populations may not be representative of clinical practice. Predictive models can help understand heterogeneity of treatment effects, identify predictors of meaningful clinical outcomes, and may inform treatment decisions. We applied machine learning (ML)-based survival models to a real-world cohort of patients with aNSCLC who received 1L ICI therapy extracted from a US-based electronic health record database. Model performance was evaluated using metrics including concordance index (c-index), and we used explainability techniques to identify significant predictors of overall survival (OS) and progression-free survival (PFS). The ML model achieved c-indices of 0.672 and 0.612 for OS and PFS, respectively, and Kaplan-Meier survival curves showed significant differences between low- and high-risk groups for OS and PFS (both log-rank test p < 0.0001). Identified predictors were mostly consistent with the published literature and/or clinical expectations and largely overlapped for OS and PFS; Eastern Cooperative Oncology Group performance status, programmed cell death-ligand 1 expression levels, and serum albumin were among the top 5 predictors for both outcomes. Prospective and independent data set evaluation is required to confirm these results.

Low temperature and temperature decline increase acute aortic dissection risk and burden: A nationwide case crossover analysis at hourly level among 40,270 patients.

Background: Acute aortic dissection (AAD) is a life-threatening cardiovascular emergency with high mortality, so identifying modifiable risk factors of AAD is of great public health significance. The associations of non-optimal temperature and temperature variability with AAD onset and the disease burden have not been fully understood. Methods: We conducted a time-stratified case-crossover study using a nationwide registry dataset from 1,868 hospitals in 313 Chinese cities. Conditional logistic regression and distributed lag models were used to investigate associations of temperature and temperature changes between neighboring days (TCN) with the hourly AAD onset and calculate the attributable fractions. We also evaluated the heterogeneity of the associations. Findings: A total of 40,270 eligible AAD cases were included. The exposure-response curves for temperature and TCN with AAD onset risk were both inverse and approximately linear. The risks were present on the concurrent hour (for temperature) or day (for TCN) and lasted for almost 1 day. The cumulative relative risks of AAD were 1.027 and 1.026 per 1°C lower temperature and temperature decline between neighboring days, respectively. The associations were significant during the non-heating period, but were not present during the heating period in cities with central heating. 23.13% of AAD cases nationwide were attributable to low temperature and 1.58% were attributable to temperature decline from the previous day. Interpretation: This is the largest nationwide study demonstrating robust associations of low temperature and temperature decline with AAD onset. We, for the first time, calculated the corresponding disease burden and further showed that central heating may be a modifier for temperature-related AAD risk and burden. Funding: This work was supported by the National Natural Science Foundation of China (92043301 and 92143301), Shanghai International Science and Technology Partnership Project (No. 21230780200), the Medical Research Council-UK (MR/R013349/1), and the Natural Environment Research Council UK (NE/R009384/1).

Characterizing the Shifting Real-World Treatment Landscape by PD-L1 Testing Status and Expression Level in Advanced Non-Small Cell Lung Cancer.

INTRODUCTION: Contemporary real-world data on advanced non-small cell lung cancer (aNSCLC) treatment patterns across programmed cell death-ligand 1 (PD-L1) expression levels and testing status are limited. METHODS: A retrospective cohort was selected of adults newly diagnosed with aNSCLC between January 1, 2018, and July 31, 2021, who initiated first-line treatments, which were described by PD-L1 status and expression levels (≥ 50%, 1-49%, < 1%). Treatment received before and after PD-L1 test results were described for patients initiating first-line treatment before PD-L1 results. For patients who initiated chemotherapy alone before PD-L1 results, the probability of receiving immune checkpoint inhibitors (ICIs) after PD-L1 results was estimated by PD-L1 level and associated factors were explored. RESULTS: Among 12,202 patients with aNSCLC initiating first-line treatment [54.7% male, mean (standard deviation) age 69.2 (9.4) years], the most common therapies were ICI-based regimens across PD-L1 levels, and chemotherapy alone among PD-L1-untested patients. Use of chemotherapy alone decreased between 2018 and 2019 and stabilized thereafter, accounting for 21-29% of first-line treatments across PD-L1 levels and 48% of untested patients in 2021. Of 1468 patients initiating first-line treatment before PD-L1 results, treatments remained unchanged in most patients after PD-L1 results. Among patients initiating chemotherapy alone before PD-L1 results, the probability of receiving ICIs within 45 days after test results was 40.5% [95% confidence interval (CI) 31.6-48.3%], 28.6% (95% CI 20.3-36.0%), and 22.9% (95% CI 16.9-28.4%) at PD-L1 ≥ 50%, 1-49%, and < 1%, respectively. CONCLUSION: While ICI-based regimens accounted for most first-line treatments across PD-L1 levels, chemotherapy alone was initiated in > 20% of patients tested for PD-L1 and 48% of untested patients in 2021. Patients who initiated chemotherapy alone had a low probability of receiving ICIs after PD-L1 test results. These results highlight the need for understanding the role and timing of PD-L1 test results for informing treatment decisions for patients with aNSCLC.

Hedgehog pathway inhibitor real-world treatment patterns in patients with basal cell carcinoma: a claims-based analysis.

Aims: To examine real-world treatment patterns for Hedgehog pathway inhibitors (HHIs) for the treatment of advanced basal cell carcinoma. Patients & methods: HHI initiators between January 2013 and June 2019 were identified from IBM MarketScan® claims data. Time to treatment discontinuation and reinitiation were estimated using Kaplan-Meier methods using a 60-day grace period. Results: Among 526 patients with basal cell carcinoma who initiated an HHI, median time to first discontinuation was 144 days, and risk of discontinuation by 12 months was 88.0%. Probability of reinitiation within 12 months was 19.7%, and median time to second discontinuation was 118 days. Conclusion: HHI discontinuation was common and reinitiation uncommon in clinical practice. Future research should evaluate persistence with recently approved therapies.

This study examined patterns of discontinuation and reinitiation of Hedgehog pathway inhibitors (HHIs) such as vismodegib or sonidegib for patients with basal cell carcinoma, the most common form of skin cancer. Initiation of HHI treatment was identified from prescriptions filled by patients with commercial insurance or Medicare who had basal cell carcinoma. Discontinuation was defined as a gap of more than 60 days without treatment, after drug supply had run out. Among the 526 patients identified, one-half had discontinued HHI treatment within about 5 months and 88% had discontinued treatment within 1 year. Fewer than 20% of patients restarted treatment. Discontinuations are common but restarting treatment is uncommon among patients with basal cell carcinoma treated with HHIs.

Real-World Treatment Patterns After CD19-Directed CAR T Cell Therapy Among Patients with Diffuse Large B Cell Lymphoma.

INTRODUCTION: CD19-directed chimeric antigen receptor T cells (CAR T) are approved for treatment of adults with relapsed/refractory diffuse large B cell lymphoma (DLBCL) following at least two lines of therapy. METHODS: This study describes real-world treatment patterns after CAR T in adults with DLBCL. It includes adults diagnosed with DLBCL in IBM MarketScan Commercial and Medicare Supplemental healthcare claims databases administered CAR T between 2017 and 2019 (index event) and at least 6 months of continuous health plan enrollment pre-index. Kaplan-Meier methods were used to estimate risk and time to first subsequent treatment after CAR T, as a proxy for CAR T failure. RESULTS: Among 129 patients meeting study criteria, most (123; 95.4%) were hospitalized during CAR T therapy. Median length of stay was 17 (25th-75th percentile, 13-22) days. Estimated 6-month risk of subsequent treatment was 36.2% (95% confidence interval [CI] 27.1-45.8%). During median follow-up of 195 (25th-75th percentile, 102-362) days, median time to the first line of therapy after CAR T, accounting for censoring, was 378 days (95% CI 226, not reached). Among 48 patients who received another therapy after CAR T, 58.3% received immunotherapy, 50.0% radiation therapy, 25.0% chemotherapy, 25.0% targeted therapy, and 12.5% hematopoietic stem cell transplant. CONCLUSIONS: Among real-world patients with DLBCL treated with CAR T, the risk of not achieving a durable response is considerable; additional, effective options for DLBCL salvage treatment are needed.

Epidemiology of diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) in the United States and Western Europe: population-level projections for 2020-2025.

Diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL) treatments have been rapidly evolving for patients treated in later lines of therapy (LoT). Country-specific cancer registry data for the US and Western Europe (WE) were combined with physician survey results to project the incidence, prevalence, and number of DLBCL and FL patients eligible for and treated by LoT between 2020 and 2025. The total number of incidents and prevalent cases of DLBCL and FL is expected to increase between 2020 and 2025 in the US and WE. 56% and 53% of the third line plus (3L+) eligible DLBCL patients and 60% and 55% of eligible FL patients initiated treatment in the US and WE, respectively. Further research is warranted to understand the reasons behind the high proportion of treatment eligible patients who do not initiate treatment, and potential differences between countries, especially in the 3L + settings.

Trends in real-world biomarker testing and overall survival in US patients with advanced non-small-cell lung cancer.

Background: Trends/outcomes associated with National Comprehensive Cancer Network (NCCN)-recommended biomarker testing to guide advanced non-small-cell lung cancer (aNSCLC) treatment were assessed. Methods: Patients initiating first-line aNSCLC treatment were included using a nationwide electronic health record-derived database (1/1/2015-10/31/2021). Trends in pre-first-line biomarker testing (PD-L1, major genomic aberrations), factors associated with testing and associations between testing and outcomes were assessed. Results: PD-L1/genomic aberration testing rates increased from 33% (2016) to 81% (2018), then plateaued. Certain clinical and demographic factors were associated with a greater likelihood of PD-L1 testing. Patients tested for PD-L1 or genomic aberrations had longer overall survival (OS). Conclusion: Biomarker testing may be associated with improved OS in aNSCLC, though not all patients had equal access to testing.

Molecular diagnostics play a critical role in precision medicine. Treatment guidelines from the National Comprehensive Cancer Network (NCCN) recommend that patients newly diagnosed with advanced non-small-cell lung cancer (aNSCLC) undergo molecular testing for PD-L1 and genomic aberrations to guide treatment choices. Based on the results of such biomarker testing, physicians can select optimal treatments for individual patients. The aim of this study was to describe the latest trends and disparities in real-world biomarker testing with a focus on PD-L1 and to explore the impact of biomarker testing on outcomes in first-line treatment of aNSCLC in the United States. Patients initiating first-line aNSCLC treatment were identified in the Flatiron Health database (1/1/2015­10/31/2021; N = 30,631). Annual trends in pre-first-line biomarker testing (PD-L1, major genomic aberrations), demographic and clinical factors associated with PD-L1 testing, and associations between PD-L1 and/or ≥1 genomic aberration testing and outcomes (e.g., overall survival [OS], time-to-next treatment [TTNT]) were assessed. Biomarker testing in patients receiving first-line treatment for aNSCLC increased between 2015 and 2017 and plateaued between 2018 and 2021. By 2021, approximately 20% of patients did not receive PD-L1 testing before first-line treatment and not all patients had equal access to testing. Both PD-L1 and genomic aberration testing were associated with improved OS and TTNT. This is likely due to enhanced treatment decisions leading to optimal treatment selection. Future research is warranted to understand interventions to improve biomarker testing and reduce disparities between different patient populations to improve treatment outcomes.

The association of triglyceride levels with the incidence of initial and recurrent acute pancreatitis.

BACKGROUND: This retrospective cohort study assessed the annualized incidence rate (IR) of acute pancreatitis (AP) in a nationally representative US adult population, as well as the variation in the risk of AP events across strata of triglyceride (TG) levels. METHODS: Data were obtained from IQVIA's US Ambulatory Electronic Medical Records (EMR) database linked with its LRxDx Open Claims database. Inclusion criteria included ≥1 serum TG value during the overlapping study period of the EMR and claims databases, ≥1 claim in the 12-month baseline period, and ≥ 1 claim in the 12 months post index. All TG measurements were assigned to the highest category reached: < 2.26, ≥2.26 to ≤5.65, > 5.65 to ≤9.94, > 9.94, and > 11.29 mmol/L (< 200, ≥200 to ≤500, > 500 to ≤880, > 880, and > 1000 mg/dL, respectively). The outcome of interest was AP, defined as a hospitalization event with AP as the principal diagnosis. RESULTS: In total, 7,119,195 patients met the inclusion/exclusion criteria, of whom 4158 (0.058%) had ≥1 AP events in the prior 12 months. Most patients (83%) had TGs < 2.26 mmol/L (< 200 mg/dL), while < 1% had TGs > 9.94 mmol/L (> 880 mg/dL). Overall, the IR of AP was low (0.08%; 95% confidence internal [CI], 0.08-0.08%), but increased with increasing TGs (0.08% in TGs < 2.26 mmol/L [< 200 mg/dL] to 1.21% in TGs > 11.29 mmol/L [> 1000 mg/dL]). In patients with a prior history of AP, the IR of AP increased dramatically; patients with ≥2 AP events at baseline had an IR of 29.98% (95% CI, 25.1-34.9%). CONCLUSION: The risk of AP increases with increasing TG strata; however, the risk increases dramatically among patients with a recent history of AP.

Ambient fine particulate matter air pollution and the risk of preterm birth: A multicenter birth cohort study in China.

Preterm birth (PTB), defined as live birth before the 37th week of gestation, is believed to have profound impacts on the infant's health in later life. Air pollution has been suggested to be a potential risk factor of PTB, but the evidence was inconsistent. In this multicenter birth cohort study, we aimed to examine the association between fine particulate matter (PM2.5) exposure during pregnancy and PTB in China. A total of 5976 live births were identified between Jan. 2009 and Feb. 2011 from 8 provinces in China. Residential exposures to PM2.5 were assigned based on satellite remote sensing estimates. Cox proportional hazards regressions were employed to explore the correlation for each trimester as well as the entire pregnancy. A total of 443 (7.4%) preterm births were observed. The average PM2.5 during pregnancy was 57.2 ± 8.8 µg/m3. We found exposure to PM2.5 during the whole pregnancy (hazard ratio, HR = 1.262; 95% CI: 1.087-1.465) and in the first trimester (HR = 1.114; 95% CI: 1.007-1.232) was associated with higher risk of PTB. The associations of PM2.5 were stronger for subjects with older maternal or paternal age, lower maternal pre-pregnancy BMI, and lower family income. This study adds supports to the cumulating evidence linking PM2.5 exposure and elevated PTB risk. Measures of air pollution reduction are needed during pregnancy, especially at early stage of pregnancy to prevent adverse birth outcomes.

Breast Cancer Risk Factors and Circulating Anti-Müllerian Hormone Concentration in Healthy Premenopausal Women.

CONTEXT: We previously reported that anti-Müllerian hormone (AMH), a marker of ovarian reserve, is positively associated with breast cancer risk, consistent with other studies. OBJECTIVE: This study assessed whether risk factors for breast cancer are correlates of AMH concentration. METHODS: This cross-sectional study included 3831 healthy premenopausal women (aged 21-57, 87% aged 35-49) from 10 cohort studies among the general population. RESULTS: Adjusting for age and cohort, AMH positively associated with age at menarche (P < 0.0001) and parity (P = 0.0008) and inversely associated with hysterectomy/partial oophorectomy (P = 0.0008). Compared with women of normal weight, AMH was lower (relative geometric mean difference 27%, P < 0.0001) among women who were obese. Current oral contraceptive (OC) use and current/former smoking were associated with lower AMH concentration than never use (40% and 12% lower, respectively, P < 0.0001). We observed higher AMH concentrations among women who had had a benign breast biopsy (15% higher, P = 0.03), a surrogate for benign breast disease, an association that has not been reported. In analyses stratified by age (<40 vs ≥40), associations of AMH with body mass index and OCs were similar in younger and older women, while associations with the other factors (menarche, parity, hysterectomy/partial oophorectomy, smoking, and benign breast biopsy) were limited to women ≥40 (P-interaction < 0.05). CONCLUSION: This is the largest study of AMH and breast cancer risk factors among women from the general population (not presenting with infertility), and it suggests that most associations are limited to women over 40, who are approaching menopause and whose AMH concentration is declining.

Prenatal fine particulate matter exposure, placental DNA methylation changes, and fetal growth.

This study was designed to examine the impact of prenatal fine particulate matter (PM2.5) exposure on fetal growth and the underlying placental epigenetic mechanism in a cohort of Chinese women. Within the prospective Shanghai Mother-Child Pairs cohort (Shanghai MCPC), 329 women carrying singleton pregnancy with a due date in 2018 were recruited between 2017 and 2018. Maternal PM2.5 exposure levels were estimated using gestational exposure prediction model combining satellite-driven ambient concentrations and personal air sampling. Fetal growth characteristics were evaluated by prenatal ultrasound examinations and anthropometric measurements at birth. In a discovery phase, whole-genome DNA methylation analysis was performed using the Infinium 850 K array. In a validation phase, placental DNA methylation was measured using bisulfite pyrosequencing for five candidate genes that showed the most significant alterations and function relevance in our methylation array screen, including BID (BH3 interacting domain death agonist), FOXN3 (Forkhead box N3), FOXP1 (Forkhead box P1), IGF2 (Insulin-like growth factor 2) and HSD11B2 (Hydroxysteroid 11-beta dehydrogenase 2). Multivariate linear regression models were applied to examine the associations among PM2.5 exposure, fetal growth characteristics and DNA methylation on placental candidate genes. Sobel tests were used to evaluate the mediating role of DNA methylation in multivariable models. After excluding women who withdrew or failed to provide placenta, a total of 287 pregnant women with an average age of 30 entered the final analysis. Increased PM2.5 exposure was significantly associated with reduced biparietal diameter (BPD) (ß: -0.136 mm, 95% CI: -0.228 to -0.043), head circumference (HC) (ß: -0.462 mm, 95% CI: -0.782 to -0.142), femur length (FL) (ß: -0.113 mm, 95% CI: -0.185 to -0.041) and abdominal circumference (AC) (ß: -0.371 mm, 95% CI: -0.672 to -0.071) in the second trimester and birth length (ß: -0.013 cm, 95% CI: -0.025 to -0.001). Prenatal PM2.5 exposure could lead to aberrant changes in DNA methylation profile of placenta genome, which were mainly enriched in reproductive development, energy metabolism and immune response. DNA methylation of IGF2 and BID showed significant associations with PM2.5 exposures during all exposure windows. In addition, BID methylation was negatively correlated with HC (ß: -1.396 mm, 95% CI: -2.582 to -0.209) and BPD (ß: -0.330 mm, 95% CI: -0.635 to -0.026) in the second trimester. Further mediation analysis indicated that BID methylation mediated about 30% of the effects of PM2.5 exposure on HC. These findings collectively suggested that prenatal PM2.5 exposure may cause adverse effects on fetal growth by modifying placental DNA methylation.

Associations of long-term exposure to ambient nitrogen dioxide with indicators of diabetes and dyslipidemia in China: A nationwide analysis.

BACKGROUND: The associations between ambient NO2 and diabetes and dyslipidemia have been controversial, and data is especially lacking in developing countries. OBJECTIVE: This study aimed to assess the associations of long-term exposure to NO2 with diabetes and dyslipidemia in China. METHODS: We conducted a cross-sectional study including 13,013 participants from the China Health and Retirement Longitudinal Study (CHRLS). The annual average concentrations of NO2 were estimated based on the residential addresses of participants. We applied logistic regression models to evaluate the associations of NO2 with diabetes and dyslipidemia, and linear regression models to assess the associations with blood biomarkers. RESULTS: A total of 1933 diabetes cases (14.85%) and 1935 (14.87%) dyslipidemia cases were identified. Significant associations were observed between NO2 and risk of diabetes and dyslipidemia independent of PM2.5 and O3. For an interquartile range (IQR) increase in NO2 (12.39 µg/m3), we observed a 13% [odds ratio (OR): 1.13; 95% confidence interval (CI): 1.01, 1.26] increased risk of diabetes, 1.48% (95%CI: 0.51%, 2.46%) increase in glucose, 0.74% (95%CI: 0.19%, 1.29%) increase in glycosylated hemoglobin (HbA1c), 17% (OR: 1.17; 95% CI: 1.05, 1.31) increased risk of dyslipidemia, 4.62% (95%CI: 2.49%, 6.79%) increase in triglyceride, and a decrease of 2.96% (95%CI: 2.13%, 3.79%) in high-density lipoprotein. The associations of NO2 with glucose disorders were stronger among smokers. CONCLUSIONS: Our study indicated long-term exposure to NO2 might contribute to the development of diabetes and dyslipidemia, and the associations were potentially independent of O3 and PM2.5.

Ambient fine particulate matter induced the elevation of blood pressure through ACE2/Ang(1-7) pathway: The evidence from urine metabolites.

BACKGROUND: Exposure to ambient fine particulate matter (PM2.5) is associated with various adverse health outcomes. Although several mechanisms have been proposed including oxidative stress and inflammatory responses, the exact mechanism is still unknown. Few studies have investigated the mechanism linking PM2.5 and blood pressure (BP). In this study, we measured urinary metabolites and BP -related renin-angiotensin-aldosterone system (RAAS) to investigate the associations between ambient PM2.5 exposure and BP in healthy C57BL/6 mice. METHODS: The C57BL/6 mice were exposed to ambient concentrated PM2.5 or filtered air (FA) for 16 weeks. Systolic BP and diastolic BP were measured by noninvasive BP system. The urine metabolites were quantified using the untargeted metabolomics approach. The expression of RAAS-related proteins angiotensin-converting enzyme (ACE)2, angiotensin (Ang) II, Ang (1-7) and aldosterone (ALD) were measured using Western blot and ELISA kits. RESULTS: The metabolomics analysis demonstrated that PM2.5 exposure induced significant changes of some metabolites in urine, including stress hormones, amino acids, fatty acids, and lipids. Furthermore, there was an elevation of BP, increase of serous Ang II and ALD, along with the decrease of ACE2 and Ang (1-7) in kidney in the PM2.5-exposed mice compared with FA-exposed mice. CONCLUSIONS: The results demonstrated that PM2.5 exposure-induced BP elevation might be associated with RAAS activation. Meanwhile, PM2.5 exposure-induced changes of stress hormone and lipid metabolism might mediate the activation of RAAS. The results suggested that the systemic stress hormone and lipid metabolism was associated with the development of hypertension.

Necessity of personal sampling for exposure assessment on specific constituents of PM2.5: Results of a panel study in Shanghai, China.

Many epidemiological studies have evaluated the health risks of ambient fine particulate matter (PM2.5). However, few studies have investigated the potential exposure misclassification caused by using ambient PM2.5 concentrations as proxy for individual exposure to PM2.5 in regions with high-level of air pollution. This study aimed to compare the differences between personal and ambient PM2.5 constituent concentrations, and to predict the personal exposure of sixteen PM2.5 constituents. We collected 141 72-h personal exposure filter samples from a panel of 36 healthy non-smoking college students in Shanghai, China. We then used the liner mixed effects models to predict personal constituent-specific exposure using ambient observations and several possible influencing factors including time-activity patterns, temporal variables, and meteorological conditions. The final model of each component was further evaluated by determination coefficient (R2) and root mean square error (RMSE) from leave-one-out-cross-validation (LOOCV). We observed ambient concentrations were higher than personal concentrations for all PM2.5 components except for Mn, Fe, Ca, and V. Especially, ambient NH4+, As, and NO3- concentrations were 3.65, 5.65 and 7.33-fold higher than their corresponding personal concentrations, respectively. The ambient level was the strongest predictor of their corresponding personal PM2.5 components with the highest marginal R2 (RM2: 0.081 ~ 0.901), meteorological conditions (RM2: 0.000 ~ 0.357), time-activity pattern (RM2: 0.000 ~ 0.083) and temporal indicators (RM2: 0.031 ~ 0.562) were also important predictors. Our final models predicted at least 50% of the variance of all personal PM2.5 constituents and even over 90% for K, Pb, and SO42-. LOOCV analysis showed that R2 and RMSE ranged from 0.251 to 0.907 and 0.000 to 0.092 µg/m3, respectively. Our results showed that ambient concentration of most PM2.5 constituents along with time-activity patterns, temporal variables, and meteorological conditions, could adequately predict personal exposure concentration. Prediction models of individual PM2.5 constituent may help to improve the accuracy of exposure measurement in future epidemiological studies.

Lactational exposure of polybrominated diphenyl ethers and its association with infant developmental measurements.

This study was designed to assess the effect of lactational polybrominated diphenyl ether (PBDE) exposure on early physical development of both healthy and fetal growth restriction (FGR) infants. Z scores of head circumference-for-age (ZHC), length-for-age (ZLEN), weight-for-age (ZWEI) and weight-for-length (ZWFL) were calculated according to the WHO Child Growth Standards. FGR infants had a higher PBDE exposure level and faster growth speed from 42 days to 6 months compared with healthy infants. Exposure of lower brominated BDEs (BDE28∼154) and the sum of 18 BDE congeners (BDE28∼209) negatively associated with ZHC [mean difference estimate (95 % CI): -0.71 (-1.22, -0.22) and -0.81 (-1.31, -0.33)] in FGR boys. Both BDE153 and BDE196 exposure had a significant correlation with ZLEN of boys in FGR group [mean difference estimate (95 % CI): -0.28 (-0.48, -0.07) and -0.52 (-0.91, -0.14)]. Each 10 ng/g lipid increase in the concentrations of BDE154 were respectively associated with 0.16 increase in ZWEI among boys in healthy group. No significant association was found in girls. Lactational PBDE exposure had effects on the early growth of both FGR and healthy infants. The encouragement of breastfeeding should therefore be considered in conjunction with PBDE contamination levels.

Clinical and Molecular Prevalence of Lipodystrophy in an Unascertained Large Clinical Care Cohort.

Lipodystrophies are a group of disorders characterized by absence or loss of adipose tissue and abnormal fat distribution, commonly accompanied by metabolic dysregulation. Although considered rare disorders, their prevalence in the general population is not well understood. We aimed to evaluate the clinical and genetic prevalence of lipodystrophy disorders in a large clinical care cohort. We interrogated the electronic health record (EHR) information of >1.3 million adults from the Geisinger Health System for lipodystrophy diagnostic codes. We estimate a clinical prevalence of disease of 1 in 20,000 individuals. We performed genetic analyses in individuals with available genomic data to identify variants associated with inherited lipodystrophies and examined their EHR for comorbidities associated with lipodystrophy. We identified 16 individuals carrying the p.R482Q pathogenic variant in LMNA associated with Dunnigan familial partial lipodystrophy. Four had a clinical diagnosis of lipodystrophy, whereas the remaining had no documented clinical diagnosis despite having accompanying metabolic abnormalities. We observed a lipodystrophy-associated variant carrier frequency of 1 in 3,082 individuals in our cohort with substantial burden of metabolic dysregulation. We estimate a genetic prevalence of disease of ∼1 in 7,000 in the general population. Partial lipodystrophy is an underdiagnosed condition. and its prevalence, as defined molecularly, is higher than previously reported. Genetically guided stratification of patients with common metabolic disorders, like diabetes and dyslipidemia, is an important step toward precision medicine.