Does socioeconomic and environmental burden affect vulnerability to extreme air pollution and heat? A case-crossover study of mortality in California.

BACKGROUND: Extreme heat and air pollution is associated with increased mortality. Recent evidence suggests the combined effects of both is greater than the effects of each individual exposure. Low neighborhood socioeconomic status ("socioeconomic burden") has also been associated with increased exposure and vulnerability to both heat and air pollution. We investigated if neighborhood socioeconomic burden or the combination of socioeconomic and environmental exposures ("socioenvironmental burden") modified the effect of combined exposure to extreme heat and particulate air pollution on mortality in California. METHODS: We used a time-stratified case-crossover design to assess the impact of daily exposure to extreme particulate matter <2.5 µm (PM2.5) and heat on cardiovascular, respiratory, and all-cause mortality in California 2014-2019. Daily average PM2.5 and maximum temperatures based on decedent's residential census tract were dichotomized as extreme or not. Census tract-level socioenvironmental and socioeconomic burden was assessed with the CalEnviroScreen (CES) score and a social deprivation index (SDI), and individual educational attainment was derived from death certificates. Conditional logistic regression was used to estimate associations of heat and PM2.5 with mortality with a product term used to evaluate effect measure modification. RESULTS: During the study period 1,514,292 all-cause deaths could be assigned residential exposures. Extreme heat and air pollution alone and combined were associated with increased mortality, matching prior reports. Decedents in census tracts with higher socioenvironmental and socioeconomic burden experienced more days with extreme PM2.5 exposure. However, we found no consistent effect measure modification by CES or SDI on combined or separate extreme heat and PM2.5 exposure on odds of total, cardiovascular or respiratory mortality. No effect measure modification was observed for individual education attainment. CONCLUSION: We did not find evidence that neighborhood socioenvironmental- or socioeconomic burden significantly influenced the individual or combined impact of extreme exposures to heat and PM2.5 on mortality in California. IMPACT: We investigated the effect measure modification by socioeconomic and socioenvironmental of the co-occurrence of heat and PM2.5, which adds support to the limited previous literature on effect measure modification by socioeconomic and socioenvironmental burden of heat alone and PM2.5 alone. We found no consistent effect measure modification by neighborhood socioenvironmental and socioeconomic burden or individual level SES of the mortality association with extreme heat and PM2.5 co-exposure. However, we did find increased number of days with extreme PM2.5 exposure in neighborhoods with high socioenvironmental and socioeconomic burden. We evaluated multiple area-level and an individual-level SES and socioenvironmental burden metrics, each estimating socioenvironmental factors differently, making our conclusion more robust.

Vitamin D deficiency and the vitamin D receptor (VDR) gene polymorphism rs2228570 (FokI) are associated with an increased susceptibility to hypertension among the Bangladeshi population.

Vitamin D receptor (VDR) gene is implicated in hypertension vulnerability due to its role in regulating the renin-angiotensin system (RAS) and blood pressure. In this case-control study, a carefully selected cohort of 111 hypertensive individuals and 100 healthy controls underwent serum analysis using HPLC to measure 25-hydroxy vitamin D levels. Polymorphic variations in the VDR gene were detected and characterized using the PCR-RFLP method. At first, lower 25-hydroxy vitamin D levels were observed in hypertensive individuals compared to controls (p<0.001). The genotype frequency of the VDR gene TaqI showed no significant difference between cases and controls (p>0.05). Similarly, no significant difference was found in the VDR gene BsmI genotype frequency between hypertensive patients and controls (p>0.05). However, a statistically significant distinction was observed in the VDR gene FokI genotype frequency between cases and controls (p<0.01). The odds ratios for FokI genotypes (CC, CT, TT, and CT+TT) were 1.0, 0.590, 1.566, and 0.963, respectively. Furthermore, serum 25-hydroxy vitamin D levels were significantly higher in control subjects compared to hypertensive patients across all genotypes of VDR (p<0.001). Hypertensive patients, excluding those with the FokI VDR gene CC genotype, exhibited significantly higher systolic blood pressure levels compared to the control group (p<0.05). Similarly, hypertensive subjects displayed elevated diastolic blood pressure levels compared to the control group (p<0.001). Overall, the results suggest the presence of a potential inverse correlation between serum 25-hydroxy vitamin D levels and hypertension. The association analysis conducted indicated that there is no significant association between TaqI and bsmI genotypic variants and the risk of developing hypertension. However, it was observed that VDR gene polymorphisms do have a clear association with hypertension susceptibility, as evidenced by the significantly higher occurrence of FokI genotypic variants in hypertensive patients. Our study therefore introduces the possibility of utilizing 25-hydroxy vitamin D deficiency and VDR gene polymorphisms as a biomarker for hypertension.

Neighborhood Disadvantage and Autism Spectrum Disorder in a Population With Health Insurance.

Importance: Family socioeconomic status has been associated with autism spectrum disorder (ASD) diagnoses. Less is known regarding the role of neighborhood disadvantage in the United States, particularly when children have similar access to health insurance. Objective: To evaluate the association between neighborhood disadvantage and the diagnosis of ASD and potential effect modification by maternal and child demographic characteristics. Design, Setting, and Participants: This cohort study examined a retrospective birth cohort from Kaiser Permanente Southern California (KPSC), an integrated health care system. Children born in 2001 to 2014 at KPSC were followed up through KPSC membership records. Electronic medical records were used to obtain an ASD diagnosis up to December 31, 2019, or the last follow-up. Data were analyzed from February 2022 to September 2023. Exposure: Socioeconomic disadvantage at the neighborhood level, an index derived from 7 US census tract characteristics using principal component analysis. Main Outcomes and Measures: Clinical ASD diagnosis based on electronic medical records. Associations between neighborhood disadvantage and ASD diagnosis were determined by hazard ratios (HRs) from Cox regression models adjusted for birth year, child sex, maternal age at delivery, parity, severe prepregnancy health conditions, maternal race and ethnicity, and maternal education. Effect modification by maternal race and ethnicity, maternal education, and child sex was assessed. Results: Among 318 372 mothers with singleton deliveries during the study period, 6357 children had ASD diagnoses during follow-up; their median age at diagnosis was 3.53 years (IQR, 2.57-5.34 years). Neighborhood disadvantage was associated with a higher likelihood of ASD diagnosis (HR, 1.07; 95% CI, 1.02-1.11, per IQR = 2.70 increase). Children of mothers from minoritized racial and ethnic groups (African American or Black, Asian or Pacific Islander, Hispanic or Latinx groups) had increased likelihood of ASD diagnosis compared with children of White mothers. There was an interaction between maternal race and ethnicity and neighborhood disadvantage (difference in log-likelihood = 21.88; P < .001 for interaction under χ24); neighborhood disadvantage was only associated with ASD among children of White mothers (HR, 1.17; 95% CI, 1.09-1.26, per IQR = 2.00 increase). Maternal education and child sex did not significantly modify the neighborhood-ASD association. Conclusions and Relevance: In this study, children residing in more disadvantaged neighborhoods at birth had higher likelihood of ASD diagnosis among a population with health insurance. Future research is warranted to investigate the mechanisms behind the neighborhood-related disparities in ASD diagnosis, alongside efforts to provide resources for early intervention and family support in communities with a higher likelihood of ASD.

Assessing household fine particulate matter (PM2.5) through measurement and modeling in the Bangladesh cook stove pregnancy cohort study (CSPCS).

Biomass fuel burning is a significant contributor of household fine particulate matter (PM2.5) in the low to middle income countries (LMIC) and assessing PM2.5 levels is essential to investigate exposure-related health effects such as pregnancy outcomes and acute lower respiratory infection in infants. However, measuring household PM2.5 requires significant investments of labor, resources, and time, which limits the ability to conduct health effects studies. It is therefore imperative to leverage lower-cost measurement techniques to develop exposure models coupled with survey information about housing characteristics. Between April 2017 and March 2018, we continuously sampled PM2.5 in three seasonal waves for approximately 48-h (range 46 to 52-h) in 74 rural and semi-urban households among the participants of the Bangladesh Cook Stove Pregnancy Cohort Study (CSPCS). Measurements were taken simultaneously in the kitchen, bedroom, and open space within the household. Structured questionnaires captured household-level information related to the sources of air pollution. With data from two waves, we fit multivariate mixed effect models to estimate 24-h average, cooking time average, daytime and nighttime average PM2.5 in each of the household locations. Households using biomass cookstoves had significantly higher PM2.5 concentrations than those using electricity/liquefied petroleum gas (626 µg/m3 vs. 213 µg/m3). Exposure model performances showed 10-fold cross validated R2 ranging from 0.52 to 0.76 with excellent agreement in independent tests against measured PM2.5 from the third wave of monitoring and ambient PM2.5 from a separate satellite-based model (correlation coefficient, r = 0.82). Significant predictors of household PM2.5 included ambient PM2.5, season, and types of fuel used for cooking. This study demonstrates that we can predict household PM2.5 with moderate to high confidence using ambient PM2.5 and household characteristics. Our results present a framework for estimating household PM2.5 exposures in LMICs, which are often understudied and underrepresented due to resource limitations.

Impact of vitamin D binding protein (GC) and vitamin D receptor (VDR) gene polymorphism on the risk of developing preeclampsia.

Objective: Preeclampsia is a multifactorial disease characterized by high blood pressure and protein in the urine. In this study, we investigated the association of vitamin D binding protein (GC) and vitamin D receptor (VDR) gene polymorphism with the risk of developing preeclampsia. Methods: 25-hydroxyvitamin D was measured using High-performance Liquid Chromatography. Vitamin D binding protein and vitamin D receptor gene polymorphisms were determined by polymerase chain reaction-restriction fragment length polymorphism. Results: The control subjects have significant higher level of 25-hydroxyvitamin D (33.5 ± 1.194 ng/mL) relative to patients (23.97 ± 1.604 ng/mL) (p < 0.05). Vitamin D receptor rs1544410 and rs2228570 dominant model (GA + AA; TC + CC) showed significant higher risk of developing Preeclampsia (OR = 4.11, 95% CI = 0.62-27.09, p < 0.01; OR = 3.58, 95%CI = 0.78-16.38, p < 0.001 respectively). Similarly, vitamin D binding protein rs7041 and rs4588, dominant model (TG + GG; CA + AA) showed higher risk of preeclampsia development compared to control people (OR = 1.69, 95%CI = 0.35-8.19, p < 0.05; OR = 1.06, 95%CI = 0.25-4.44, p < 0.05 respectively). AA genotype of rs4588 of GC gene was significantly associated with 25-hydroxyvitamin D level in serum relative to CC and CA (p < 0.05). Conclusion: From our study, we can conclude that a low level of 25-hydroxyvitamin D, GC (rs1544410 and rs2228570), and VDR (rs4588 and rs7041) gene polymorphism is linked with an increased risk of developing preeclampsia.

Maternal exposure to aircraft emitted ultrafine particles during pregnancy and likelihood of ASD in children.

BACKGROUND: There is increasing evidence for adverse health effects associated with aircraft-emitted particulate matter (PM) exposures, which are largely in the ultrafine (PM0.1) size fraction, but no previous study has examined neurodevelopmental outcomes. OBJECTIVE: To assess associations between maternal exposure to aircraft ultrafine particles (UFP) during pregnancy and offspring autism spectrum disorder (ASD) diagnosis. METHODS: This large, representative cohort study included 370,723 singletons born in a single healthcare system. Demographic data, maternal health information, and child's ASD diagnosis by age 5 were extracted from electronic medical records. Aircraft exposure estimates for PM0.1 were generated by the University of California Davis/California Institute of Technology Source Oriented Chemical Transport model. Cox proportional hazard models were used to assess associations between maternal exposure to aircraft PM0·1 in pregnancy and ASD diagnosis, controlling for covariates. RESULTS: Over the course of follow-up, 4,554 children (1.4 %) were diagnosed with ASD. Increased risk of ASD was associated with maternal exposure to aircraft PM0.1 [hazard ratio, HR: 1.02, (95 % confidence interval (CI): 1.01-1.03) per IQR = 0.02 µg/m3 increase during pregnancy. Associations were robust to adjustment for total PM0.1 and fine particulate matter (PM2.5), near-roadway air pollution, and other covariates. Noise adjustment modestly attenuated estimates of UFP effects, which remained statistically significant. DISCUSSION: The results strengthen the emerging evidence that maternal particulate matter exposure during pregnancy is associated with offspring ASD diagnosis and identify aircraft-derived PM0.1 as novel targets for further study and potential regulation.

Cohort profile: Bangladesh Cook Stove Pregnancy Cohort Study (CSPCS).

PURPOSE: The Cook Stove Pregnancy Cohort Study (CSPCS) was designed to assess the effects of biomass fuel use on household air pollution (HAP) as well as the effects of HAP (fine particulate matter, PM2.5) on birth outcomes and acute lower respiratory infection (ALRI) among infants in Bangladesh. PARTICIPANTS: We recruited 903 women within 18 weeks of pregnancy from rural and semiurban areas of Bangladesh between November 2016 and March 2017. All women and their infants (N=831 pairs) were followed until 12 months after delivery and a subset have undergone respiratory and gut microbiota analysis. METHODS: Questionnaires were administered to collect detailed sociodemographic, medical, nutritional and behavioural information on the mother-child dyads. Anthropometric measurements and biological samples were also collected, as well as household PM2.5 concentrations. FINDINGS TO DATE: Published work in this cohort showed detrimental effects of biomass fuel and health inequity on birth outcomes. Current analysis indicates high levels of household PM2.5 being associated with cooking fuel type and infant ALRI. Lastly, we identified distinct gut and respiratory microbial communities at 6 months of age. FUTURE PLANS: This study provides an economical yet effective framework to conduct pregnancy cohort studies determining the health effects of adverse environmental exposures in low-resource countries. Future analyses in this cohort include assessing the effect of indoor PM2.5 levels on (1) physical growth, (2) neurodevelopment, (3) age of first incidence and frequency of ALRI in infants and (4) the development of the respiratory and gut microbiome. Additional support has allowed us to investigate the effect of in utero exposure to metals on infant neurodevelopment in the first year of life.

Adaptation Resources and Responses to Wildfire Smoke and Other Forms of Air Pollution in Low-Income Urban Settings: A Mixed-Methods Study.

Little is known about how low-income residents of urban communities engage their knowledge, attitudes, behaviors, and resources to mitigate the health impacts of wildfire smoke and other forms of air pollution. We interviewed 40 adults in Los Angeles, California, to explore their threat assessments of days of poor air quality, adaptation resources and behaviors, and the impacts of air pollution and wildfire smoke on physical and mental health. Participants resided in census tracts that were disproportionately burdened by air pollution and socioeconomic vulnerability. All participants reported experiencing days of poor air quality due primarily to wildfire smoke. Sixty percent received advanced warnings of days of poor air quality or routinely monitored air quality via cell phone apps or news broadcasts. Adaptation behaviors included remaining indoors, circulating indoor air, and wearing face masks when outdoors. Most (82.5%) of the participants reported some physical or mental health problem or symptom during days of poor air quality, but several indicated that symptom severity was mitigated by their adaptive behaviors. Although low-income residents perceive themselves to be at risk for the physical and mental health impacts of air pollution, they have also adapted to that risk with limited resources.

Transcriptomic analysis of esophageal cancer reveals hub genes and networks involved in cancer progression.

Esophageal carcinoma (ESCA) has a 5-year survival rate of fewer than 20%. The study aimed to identify new predictive biomarkers for ESCA through transcriptomics meta-analysis to address the problems of ineffective cancer therapy, lack of efficient diagnostic tools, and costly screening and contribute to developing more efficient cancer screening and treatments by identifying new marker genes. Nine GEO datasets of three kinds of esophageal carcinoma were analyzed, and 20 differentially expressed genes were detected in carcinogenic pathways. Network analysis revealed four hub genes, namely RAR Related Orphan Receptor A (RORA), lysine acetyltransferase 2B (KAT2B), Cell Division Cycle 25B (CDC25B), and Epithelial Cell Transforming 2 (ECT2). Overexpression of RORA, KAT2B, and ECT2 was identified with a bad prognosis. These hub genes modulate immune cell infiltration. These hub genes modulate immune cell infiltration. Although this research needs lab confirmation, we found interesting biomarkers in ESCA that may aid in diagnosis and treatment.

Ambient temperature and air pollution associations with suicide and homicide mortality in California: A statewide case-crossover study.

BACKGROUND: Higher ambient temperature and air pollution may contribute to increased risk of behaviors harmful to oneself or to others; however, quantitative evidence is limited. We examined the relationship of deaths due to suicide and homicide with temperature and air pollution in California-a state prone to high levels of both exposures. METHOD: California death certificates from 2014 to 2019 were used to identify deaths due to suicide and homicide. Residential data for decedents were used to assign exposure to daily temperature (maximum[Tmax], minimum[Tmin]) and daily average air pollution concentrations (particulate matter <10 µm[PM10] and < 2.5 µm[PM2.5], nitrogen dioxide[NO2], ozone[O3]). Tmin served as a surrogate for nighttime temperature. A time-stratified case-crossover study design using conditional logistic regression was used to assess the effects of daily exposure to temperature and air pollutants on suicide and homicide mortality, adjusting for relative humidity. Effect modification by sex and age was assessed. RESULTS: We observed 24,387 deaths due to suicide and 10,767 deaths due to homicide. We found a monotonic temperature association for both outcomes. A 5 °C increase in Tmax at lag-2 and Tmin at lag-0 was associated with 3.1 % (95 % confidence interval [CI]: 1.1 %-5.2 %) and 3.8 % (95%CI: 0.9 %-6.8 %) increased odds of death due to suicide, respectively. The increased odds of homicide mortality per 5 °C increase in Tmax at lag-0 and Tmin at lag-1 were 4.9 % (95%CI: 1.6 %-8.1 %) and 6.2 % (95%CI: 1.6 %-11.0 %), respectively. No air pollutant associations were statistically significant. Temperature associations were robust after adjustment for PM2.5. Some temperature effects were larger among women for suicide and men for homicide mortality, and among those over age 65 years for both outcomes. CONCLUSION: Risk of suicide and homicide mortality increases with increasing daily ambient temperatures. Findings have public health relevance given anticipated increases in temperatures due to global climate change.

Prenatal exposure to tailpipe and non-tailpipe tracers of particulate matter pollution and autism spectrum disorders.

BACKGROUND: Traffic-related air pollution exposure is associated with increased risk of autism spectrum disorder (ASD). It is unknown whether carbonaceous material from vehicular tailpipe emissions or redox-active non-tailpipe metals, eg. from tire and brake wear, are responsible. We assessed ASD associations with fine particulate matter (PM2.5) tracers of tailpipe (elemental carbon [EC] and organic carbon [OC]) and non-tailpipe (copper [Cu]; iron [Fe] and manganese [Mn]) sources during pregnancy in a large cohort. METHODS: This retrospective cohort study included 318,750 children born in Kaiser Permanente Southern California (KPSC) hospitals during 2001-2014, followed until age 5. ASD cases were identified by ICD codes. Monthly estimates of PM2.5 and PM2.5 constituents EC, OC, Cu, Fe, and Mn with 4 km spatial resolution were obtained from a source-oriented chemical transport model. These exposures and NO2 were assigned to each maternal address during pregnancy, and associations with ASD were assessed using Cox regression models adjusted for covariates. PM constituent effect estimates were adjusted for PM2.5 and NO2 to assess independent effects. To distinguish ASD risk associated with non-tailpipe from tailpipe sources, the associations with Cu, Fe, and Mn were adjusted for EC and OC, and vice versa. RESULTS: There were 4559 children diagnosed with ASD. In single-pollutant models, increased ASD risk was associated with gestational exposures to tracers of both tailpipe and non-tailpipe emissions. The ASD hazard ratios (HRs) per inter-quartile increment of exposure) for EC, OC, Cu, Fe, and Mn were 1.11 (95% CI: 1.06-1.16), 1.09 (95% CI: 1.04-1.15), 1.09 (95% CI: 1.04-1.13), 1.14 (95% CI: 1.09-1.20), and 1.17 (95% CI: 1.12-1.22), respectively. Estimated effects of Cu, Fe, and Mn (reflecting non-tailpipe sources) were largely unchanged in two-pollutant models adjusting for PM2.5, NO2, EC or OC. In contrast, ASD associations with EC and OC were markedly attenuated by adjustment for non-tailpipe sources. CONCLUSION: Results suggest that non-tailpipe emissions may contribute to ASD. Implications are that reducing tailpipe emissions, especially from vehicles with internal combustion engines, may not eliminate ASD associations with traffic-related air pollution.

Associations of Autism Spectrum Disorder with PM2.5 Components: A Comparative Study Using Two Different Exposure Models.

This retrospective cohort study examined associations of autism spectrum disorder (ASD) with prenatal exposure to major fine particulate matter (PM2.5) components estimated using two independent exposure models. The cohort included 318 750 mother-child pairs with singleton deliveries in Kaiser Permanente Southern California hospitals from 2001 to 2014 and followed until age five. ASD cases during follow-up (N = 4559) were identified by ICD codes. Prenatal exposures to PM2.5, elemental (EC) and black carbon (BC), organic matter (OM), nitrate (NO3-), and sulfate (SO42-) were constructed using (i) a source-oriented chemical transport model and (ii) a hybrid model. Exposures were assigned to each maternal address during the entire pregnancy, first, second, and third trimester. In single-pollutant models, ASD was associated with pregnancy-average PM2.5, EC/BC, OM, and SO42- exposures from both exposure models, after adjustment for covariates. The direction of effect estimates was consistent for EC/BC and OM and least consistent for NO3-. EC/BC, OM, and SO42- were generally robust to adjustment for other components and for PM2.5. EC/BC and OM effect estimates were generally larger and more consistent in the first and second trimester and SO42- in the third trimester. Future PM2.5 composition health effect studies might consider using multiple exposure models and a weight of evidence approach when interpreting effect estimates.

Maternal obesity, diabetes, preeclampsia, and asthma during pregnancy and likelihood of autism spectrum disorder with gastrointestinal disturbances in offspring.

LAY ABSTRACT: Autism spectrum disorder is heterogeneous and often accompanied by co-occurring conditions. Previous studies have shown that maternal health conditions during pregnancy including obesity, diabetes, preeclampsia, and asthma were associated with increased likelihood of autism. However, little has been done examining the likelihood associated with autism with co-occurring conditions. This study assessed these maternal health conditions in relationship to autism and gastrointestinal disturbances, a common co-occurring condition in children diagnosed with autism. Data included 308,536 mother-child pairs from one integrated health care system with comprehensive electronic medical records. Among the study cohort, 5,131 (1.7%) children had a diagnosis of autism by age 5. Gastrointestinal disturbances were present in 35.4% of children diagnosed with autism and 25.1% of children without autism diagnoses. Our results showed that each of the four maternal health conditions during pregnancy was associated with increased likelihood of gastrointestinal disturbances, autism without gastrointestinal disturbances, and autism with gastrointestinal disturbances. For all four maternal health conditions, the association was greatest for likelihood of autism with gastrointestinal disturbances. Given that children diagnosed with autism are more likely to have gastrointestinal disturbances and over 80% of gastrointestinal disturbances in this cohort were diagnosed prior to autism diagnosis, this study suggests that there may be common biological pathways between autism and gastrointestinal disturbances impacted by these maternal exposures. Future studies are warranted to assess associations between different exposures and autism with other co-occurring conditions to increase our understanding of autism heterogeneity.

HvGBSSI mutation at the splicing receptor site affected RNA splicing and decreased amylose content in barley.

Granule-bound starch synthase I (HvGBSSI) is encoded by the barley waxy (Wx-1) gene and is the sole enzyme in the synthesis of amylose. Here, a Wx-1 mutant was identified from an ethyl methane sulfonate (EMS)-mutagenized barley population. There were two single-base mutations G1086A and A2424G in Wx-1 in the mutant (M2-1105). The G1086A mutation is located at the 3' splicing receptor (AG) site of the fourth intron, resulting in an abnormal RNA splicing. The A2424G mutation was a synonymous mutation in the ninth intron. The pre-mRNA of Wx-1 was incorrectly spliced and transcribed into two abnormal transcripts. The type I transcript had a 6 bp deletion in the 5' of fifth exon, leading to a translated HvGBSSI protein lacking two amino acids with a decreased starch-binding capacity. In the type II transcript, the fourth intron was incorrectly cleaved and retained, resulting in the premature termination of the barley Wx-1 gene. The mutations in the Wx-1 decreased the enzymatic activity of the HvGBSSI enzyme and resulted in a decreased level in amylose content. This work sheds light on a new Wx-1 gene inaction mechanism.

Vulnerable, Resilient, or Both? A Qualitative Study of Adaptation Resources and Behaviors to Heat Waves and Health Outcomes of Low-Income Residents of Urban Heat Islands.

Little is known of how low-income residents of urban heat islands engage their knowledge, attitudes, behaviors, and resources to mitigate the health impacts of heat waves. In this qualitative study, we conducted semi-structured interviews with 40 adults in two such neighborhoods in Los Angeles California to explore their adaptation resources and behaviors, the impacts of heat waves on physical and mental health, and threat assessments of future heat waves. Eighty percent of participants received advanced warning of heat waves from television news and social media. The most common resource was air conditioning (AC) units or fans. However, one-third of participants lacked AC, and many of those with AC engaged in limited use due primarily to the high cost of electricity. Adaptation behaviors include staying hydrated, remaining indoors or going to cooler locations, reducing energy usage, and consuming certain foods and drinks. Most of the participants reported some physical or mental health problem or symptom during heat waves, suggesting vulnerability to heat waves. Almost all participants asserted that heat waves were likely to increase in frequency and intensity with adverse health effects for vulnerable populations. Despite limited resources, low-income residents of urban heat islands utilize a wide range of behaviors to minimize the severity of health impacts, suggesting they are both vulnerable and resilient to heat waves.

Heterozygous p.Y955C mutation in DNA polymerase γ leads to alterations in bioenergetics, complex I subunit expression, and mtDNA replication.

In human cells, ATP is generated using oxidative phosphorylation machinery, which is inoperable without proteins encoded by mitochondrial DNA (mtDNA). The DNA polymerase gamma (Polγ) repairs and replicates the multicopy mtDNA genome in concert with additional factors. The Polγ catalytic subunit is encoded by the POLG gene, and mutations in this gene cause mtDNA genome instability and disease. Barriers to studying the molecular effects of disease mutations include scarcity of patient samples and a lack of available mutant models; therefore, we developed a human SJCRH30 myoblast cell line model with the most common autosomal dominant POLG mutation, c.2864A>G/p.Y955C, as individuals with this mutation can present with progressive skeletal muscle weakness. Using on-target sequencing, we detected a 50% conversion frequency of the mutation, confirming heterozygous Y955C substitution. We found mutated cells grew slowly in a glucose-containing medium and had reduced mitochondrial bioenergetics compared with the parental cell line. Furthermore, growing Y955C cells in a galactose-containing medium to obligate mitochondrial function enhanced these bioenergetic deficits. Also, we show complex I NDUFB8 and ND3 protein levels were decreased in the mutant cell line, and the maintenance of mtDNA was severely impaired (i.e., lower copy number, fewer nucleoids, and an accumulation of Y955C-specific replication intermediates). Finally, we show the mutant cells have increased sensitivity to the mitochondrial toxicant 2'-3'-dideoxycytidine. We expect this POLG Y955C cell line to be a robust system to identify new mitochondrial toxicants and therapeutics to treat mitochondrial dysfunction.

The Effects of Coexposure to Extremes of Heat and Particulate Air Pollution on Mortality in California: Implications for Climate Change.

Rationale: Extremes of heat and particulate air pollution threaten human health and are becoming more frequent because of climate change. Understanding the health impacts of coexposure to extreme heat and air pollution is urgent. Objectives: To estimate the association of acute coexposure to extreme heat and ambient fine particulate matter (PM2.5) with all-cause, cardiovascular, and respiratory mortality in California from 2014 to 2019. Methods: We used a case-crossover study design with time-stratified matching using conditional logistic regression to estimate mortality associations with acute coexposures to extreme heat and PM2.5. For each case day (date of death) and its control days, daily average PM2.5 and maximum and minimum temperatures were assigned (0- to 3-day lag) on the basis of the decedent's residence census tract. Measurements and Main Results: All-cause mortality risk increased 6.1% (95% confidence interval [CI], 4.1-8.1) on extreme maximum temperature-only days and 5.0% (95% CI, 3.0-8.0) on extreme PM2.5-only days, compared with nonextreme days. Risk increased by 21.0% (95% CI, 6.6-37.3) on days with exposure to both extreme maximum temperature and PM2.5. Increased risk of cardiovascular and respiratory mortality on extreme coexposure days was 29.9% (95% CI, 3.3-63.3) and 38.0% (95% CI, -12.5 to 117.7), respectively, and were more than the sum of individual effects of extreme temperature and PM2.5 only. A similar pattern was observed for coexposure to extreme PM2.5 and minimum temperature. Effect estimates were larger over age 75 years. Conclusions: Short-term exposure to extreme heat and air pollution alone were individually associated with increased risk of mortality, but their coexposure had larger effects beyond the sum of their individual effects.

Temperature variability associations with cardiovascular and respiratory emergency department visits in Dhaka, Bangladesh.

BACKGROUND: Greenhouse gas emissions are changing the Earth's climate, most directly by modifying temperatures and temperature variability (TV). Residents of low- and middle-income countries (LMICs) are likely more adversely affected, due to lack of air conditioning to compensate. To date, there is no local epidemiological evidence documenting the cardio-respiratory health effects of TV in Dhaka, Bangladesh, one of the most climate change vulnerable cities in the world. OBJECTIVES: We assessed short-term TV associations with daily cardiovascular disease (CVD) and respiratory emergency department (ED) visits, as well as effect modification by age and season. METHODS: TV was calculated from the standard deviations of the daily minimum and maximum temperatures over exposure days. Time-series regression modeling was applied to daily ED visits for respiratory and CVD from January 2014 through December 2017. TV effect sizes were estimated after controlling for long-term trends and seasonality, day-of-week, holidays, and daily mean relative humidity and ambient temperature. RESULTS: A 1 °C increase in TV was associated with a 1.00% (95 %CI: 0.05%, 1.96%) increase in CVD ED visits at lag 0-1 days (TV0-1) and a 2.77% (95 %CI: 0.24%, 5.20%) increase in respiratory ED visits at lag 0-7 days (TV0-7). TV-CVD associations were larger in the monsoon and cold seasons. Respiratory ED visit associations varied by age, with older adults more affected by the TV across all seasons. A 1 °C increase in TV at lag 0-7 days (TV0-7) was associated with a 7.45% (95 %CI: 2.33%, 12.57%) increase in respiratory ED visits among patients above 50 years of age. CONCLUSION: This study provided novel and important evidence that cardio-pulmonary health in Dhaka is adversely affected year-round by day-to-day increases in TV, especially among older adults. TV is a key factor that should be considered in evaluating the potential human health impacts of climate change induced temperature changes.

Identification of Somatic Mitochondrial DNA Mutations, Heteroplasmy, and Increased Levels of Catenanes in Tumor Specimens Obtained from Three Endometrial Cancer Patients.

Endometrial carcinoma (EC) is the most common type of gynecologic malignant epithelial tumor, with the death rate from this disease doubling over the past 20 years. Mitochondria provide cancer cells with necessary anabolic building blocks such as amino acids, lipids, and nucleotides, and EC samples have been shown to increase mitochondrial biogenesis. In cancer, mitochondrial DNA (mtDNA) heteroplasmy studies suggest that heteroplasmic variants encode predicted pathogenic proteins. We investigated the mtDNA genotypes within peri-normal and tumor specimens obtained from three individuals diagnosed with EC. DNA extracts from peri-normal and tumor tissues were used for mtDNA-specific next-generation sequencing and analyses of mtDNA content and topoisomers. The three tumors harbor heteroplasmic somatic mutations, and at least one mutation in each carcinoma is predicted to deleteriously alter a mtDNA-encoded protein. Somatic heteroplasmy linked to two mtDNA tRNA genes was found in separate tumors, and two heteroplasmic non-coding variants were identified in a single EC tumor. While two tumors had altered mtDNA content, all three displayed increased mtDNA catenanes. Our findings support that EC cells require wild-type mtDNA, but heteroplasmic mutations may alter mitochondrial metabolism to help promote cancer cell growth and proliferation.

A hybrid satellite and land use regression model of source-specific PM2.5 and PM2.5 constituents.

Although PM2.5 mass varies in source and composition over time and space, most health effects assessment have made the inherent assumption that all PM2.5 mass has the same health implications, irrespective of composition. Nationwide estimates of source-specific PM2.5 mass and constituents at local-scale would allow for epidemiological studies and health effects assessments that consider the variability in PM2.5 characteristics in their health impact assessments. In response, we developed US models of annual exposures at the census tract level for five major PM2.5 sources (traffic, soil, coal, oil, and biomass combustion) and six trace elements (elemental carbon, sulfur, silicon, selenium, nickel, and non-soil potassium) for 2001 through 2014. We employed Absolute Factor Analysis (APCA) to derive the source-specific PM2.5 impacts at monitoring stations. Random forest algorithms that incorporated predictors derived from satellite, chemical transport model, and census tract resolution land-use data on traffic, meteorology, and emissions, which were rigorously tested by 10-fold cross-validation (CV), were then employed to estimate elemental and source-specific PM2.5 levels at non-monitoring site census-tracts over the study years. Model performances were moderate to good, with CV R2 ranging from 0.41 to 0.95. For PM2.5 sources, the highest CV R2 was attained for traffic PM2.5 (CV R2 = 0.73), followed by coal (CV R2 = 0.65), oil (CV R2 = 0.62), soil (CV R2 = 0.60), and biomass (CV R2 = 0.41). Among constituents, the CV was highest for sulfur (CV R2 = 0.95). Our analyses provided highly resolved spatial estimates of annual elemental and source-specific PM2.5 concentrations at the census-tract level, for 2001 through 2014. This dataset offers exposure estimates in support of future nationwide long-term health effects studies of source-specific PM2.5 mass and constituents, enabling epidemiological research that addresses the fact that not all particles are the same.