Associations between brake and tire wear-related PM2.5 metal components, particulate oxidative stress potential, and autism spectrum disorder in Southern California.

BACKGROUND: Air pollution is a global health concern, with fine particulate matter (PM2.5) constituents posing potential risks to human health, including children's neurodevelopment. Here we investigated associations between exposure during pregnancy and infancy to specific traffic-related PM2.5 components with Autism Spectrum Disorder (ASD) diagnosis. METHODS: For exposure assessment, we estimated PM2.5 components related to traffic exposure (Barium [Ba] as a marker of brake dust and Zinc [Zn] as a tire wear marker, Black Carbon [BC]) and oxidative stress potential (OSP) markers (Hydroxyl Radical [OPOH] formation, Dithiothreitol activity [OPDTT], reactive oxygen species [ROS]) modeled with land use regression with co-kriging based on an intensive air monitoring campaign. We assigned exposures to a cohort of 444,651 children born in Southern California between 2016 and 2019, among whom 11,466 ASD cases were diagnosed between 2018 and 2022, Odds ratios (ORs) and 95% confidence intervals (CIs) were obtained with logistic regression for single pollutant and PM2.5 mass co-adjusted models, also adjusting for sociodemographic characteristics. RESULTS: Among PM2.5 components, we found the strongest positive association with ASD for our brake wear marker Ba (ORper IQR = 1.29, 95 % CI: 1.24, 1.34). This was followed by an increased risk for all PM2.5 oxidative stress potential markers; the strongest association was with ROS formation (ORper IQR = 1.22, 95 % CI: 1.18, 1.25). PM2.5 mass was linked to ASD in Hispanic and Black children, but not White children, while traffic-related PM2.5 and OSP markers increased ASD risk across all groups. In neighborhoods with the lowest socioeconomic status (SES), associations with ASD were stronger for all examined pollutants compared to higher SES areas. CONCLUSIONS: Our findings suggest that brake wear-related PM2.5 and PM2.5 OSP are associated with ASD diagnosis in Southern California. These results suggest that strategies aimed at reducing the public health impacts of PM2.5 need to consider specific sources.

Patient Engagement in and Adaptations to Delivery of Outpatient Care for Opioid Use Disorder During the COVID-19 Pandemic.

OBJECTIVE: The authors investigated adaptations to outpatient care delivery and changes in treatment demand and engagement among patients receiving medications for opioid use disorder (MOUD) in the months after the declaration of the COVID-19 public health emergency in 2020. METHODS: Data were collected through an online survey (June-November 2020) of outpatient MOUD prescribers. The survey obtained information on outpatient practices' adaptations to MOUD treatment and urine drug screening (UDS) and elicited provider views on the effects of the COVID-19 pandemic on patient demand for, and engagement in, treatment. Multivariable regression analyses were used to examine associations among practice characteristics, patient engagement, and service adaptations. RESULTS: Of 516 respondents, 74% reported adaptations to MOUD delivery during the pandemic. Most respondents implemented virtual visits for initial (67%) and follow-up (77%) contacts. Prescribers of buprenorphine were more likely than those who did not prescribe the medication to report MOUD adaptations. Among respondents reporting any MOUD adaptation, 77% made adaptations to their UDS practices. Among 513 respondents who answered COVID-19-related questions, 89% reported that the pandemic had affected the treatment and engagement of their patients. Of these respondents, 30% reported increased difficulty with patient engagement, and 45% reported that their patients preferred virtual visits during this period, whereas 18% endorsed patient preference for in-person visits. CONCLUSIONS: Telehealth and federal regulatory easements in response to the COVID-19 pandemic enabled providers to continue treating patients for opioid use disorder in 2020. The results suggest that care adaptations and changes in patient demand and engagement were common in the practices surveyed.

Neighborhood-level Social Determinants of Health and Waitlist Mortality for Liver Transplantation: The Liver Outcomes and Equity Index.

BACKGROUND AND AIMS: To examine neighborhood-level disparities in waitlist mortality for adult liver transplantation (LT), we developed novel area-based social determinants of health (SDOH) index using a national transplant database. METHODS: ZIP Codes of individuals listed for or received LT in the Scientific Registry of Transplant Recipients database between June 18, 2013, and May 18, 2019, were linked to 36 American Community Survey (ACS) variables across 5 SDOH domains for index development. A step-wise principal component analysis was used to construct the Liver Outcomes and Equity (LOEq) index. We then examined the association between LOEq quintiles (Q1 = worst and Q5 = best neighborhood SDOH) and waitlist mortality with competing risk regression among listed adults in the study period and acuity circle (AC) era. RESULTS: The final LOEq index consisted of 13 ACS variables. Of 59 298 adults waitlisted for LT, 30% resided in LOEq Q5 compared with only 14% in Q1. Q1 neighborhoods with worse SDOH were disproportionately concentrated in transplant regions with low median Model for End-Stage Liver Disease at transplant (MMAT) and shorter wait times. Five years cumulative incidence of waitlist mortality was 33% in Q1 in high MMAT regions versus 16% in Q5 in low MMAT regions. Despite this allocation advantage, LOEq Q1-Q4 were independently associated with elevated risk of waitlist mortality compared with Q5, with highest increased hazard of waitlist deaths of 19% (95% CI, 11%-26%) in Q1. This disparity persisted in the AC era, with 24% (95% CI, 10%-40%) increased hazard of waitlist deaths for Q1 versus Q5. CONCLUSIONS: Neighborhood SDOH independently predicts waitlist mortality in adult LT.

Residential Proximity to a Commercial Pesticide Application Site and Risk of Chronic Rhinosinusitis.

Importance: Environmental and occupational toxicants have been shown to be associated with an increased prevalence of chronic rhinosinusitis (CRS). However, few to no studies have evaluated patients for CRS using objective testing and workup protocols that fulfill guidelines for CRS diagnostic criteria. Furthermore, no study, to our knowledge, has investigated the risks of CRS in the context of residential exposure through proximity to a commercial pesticide application site. Objectives: To evaluate associations of residential proximity to a commercial pesticide application site and the prevalence of CRS with nasal polyps (CRSwNP) and without nasal polyps (CRSwoNP). Design, Setting, and Participants: This was a retrospective cohort study of patients who presented to a tertiary care institution for rhinology evaluation between March 1, 2018, and December 31, 2022. Main Outcomes and Measures: The outcome variable was the clinical diagnosis of CRS (CRSwNP, CRSwoNP, or non-CRS control). Patients' residential addresses were utilized to determine pesticide exposure status based on a validated computational geographic information algorithm based on data from the California Pesticide Use Report System. The dichotomous independent variable of exposure status (exposed or non-exposed) was determined by assessing reports of any pesticide applications within 2000 m of each participant's residence in 2017. Multivariable logistic regressions assessing CRS status and CRS subtypes were conducted with pesticide exposure as the primary covariate of interest. The primary study outcome and measurements as well as study hypothesis were all formulated before data collection. Results: Among a total of 310 patients (90 CRSwNP, 90 CRSwoNP, and 130 control), the mean (SD) age was 50 (17) years; 164 (53%) were female. Race and ethnicity information was not considered. Controlling for patient demographic information, smoking history, county of residence, and medical comorbidities, pesticide exposure was associated with an approximately 2.5-fold increase in odds of CRS (adjusted odds ratio, 2.41; 95% CI, 1.49-3.90). Pesticide exposure was associated with similar risks for CRSwNP (adjusted relative risk ratio [aRRR], 2.34; 95% CI, 1.31-4.18) and CRSwoNP (aRRR, 2.42; 95% CI, 1.37-4.30). Conclusions and Relevance: The findings of this retrospective cohort study and analysis revealed that residential exposure to commercial pesticide application within a 2000-m buffer was independently associated with an approximately 2.5-fold increase in odds of being diagnosed with CRS. If validated by additional research, this association would have substantial implications for public health.

A pesticide and iPSC dopaminergic neuron screen identifies and classifies Parkinson-relevant pesticides.

Parkinson's disease (PD) is a complex neurodegenerative disease with etiology rooted in genetic vulnerability and environmental factors. Here we combine quantitative epidemiologic study of pesticide exposures and PD with toxicity screening in dopaminergic neurons derived from PD patient induced pluripotent stem cells (iPSCs) to identify Parkinson's-relevant pesticides. Agricultural records enable investigation of 288 specific pesticides and PD risk in a comprehensive, pesticide-wide association study. We associate long-term exposure to 53 pesticides with PD and identify co-exposure profiles. We then employ a live-cell imaging screening paradigm exposing dopaminergic neurons to 39 PD-associated pesticides. We find that 10 pesticides are directly toxic to these neurons. Further, we analyze pesticides typically used in combinations in cotton farming, demonstrating that co-exposures result in greater toxicity than any single pesticide. We find trifluralin is a driver of toxicity to dopaminergic neurons and leads to mitochondrial dysfunction. Our paradigm may prove useful to mechanistically dissect pesticide exposures implicated in PD risk and guide agricultural policy.

Autolysin-mediated peptidoglycan hydrolysis is required for the surface display of Staphylococcus aureus cell wall-anchored proteins.

Peptidoglycan hydrolases, or autolysins, play a critical role in cell wall remodeling and degradation, facilitating bacterial growth, cell division, and cell separation. In Staphylococcus aureus, the so-called "major" autolysin, Atl, has long been associated with host adhesion; however, the molecular basis underlying this phenomenon remains understudied. To investigate, we used the type V glycopeptide antibiotic complestatin, which binds to peptidoglycan and blocks the activity of autolysins, as a chemical probe of autolysin function. We also generated a chromosomally encoded, catalytically inactive variant of the Atl enzyme. Autolysin-mediated peptidoglycan hydrolysis, in particular Atl-mediated daughter cell separation, was shown to be critical for maintaining optimal surface levels of S. aureus cell wall-anchored proteins, including the fibronectin-binding proteins (FnBPs) and protein A (Spa). As such, disrupting autolysin function reduced the affinity of S. aureus for host cell ligands, and negatively impacted early stages of bacterial colonization in a systemic model of S. aureus infection. Phenotypic studies revealed that Spa was sequestered at the septum of complestatin-treated cells, highlighting that autolysins are required to liberate Spa during cell division. In summary, we reveal the hydrolytic activities of autolysins are associated with the surface display of S. aureus cell wall-anchored proteins. We demonstrate that by blocking autolysin function, type V glycopeptide antibiotics are promising antivirulence agents for the development of strategies to control S. aureus infections.

Exploring functional interplay amongst Escherichia coli efflux pumps.

Bacterial efflux pumps exhibit functional interplay that can translate to additive or multiplicative effects on resistance to antimicrobial compounds. In diderm bacteria, two different efflux pump structural types - single-component inner membrane efflux pumps and cell envelope-spanning multicomponent systems - cooperatively export antimicrobials with cytoplasmic targets from the cell. Harnessing our recently developed efflux platform, which is built upon an extensively efflux-deficient strain of Escherichia coli, here we explore interplay amongst a panel of diverse E. coli efflux pumps. Specifically, we assessed the effect of simultaneously expressing two efflux pump-encoding genes on drug resistance, including single-component inner membrane efflux pumps (MdfA, MdtK and EmrE), tripartite complexes (AcrAB, AcrAD, MdtEF and AcrEF), and the acquired TetA(C) tetracycline resistance pump. Overall, the expression of two efflux pump-encoding genes from the same structural type did not enhance resistance levels regardless of the antimicrobial compound or efflux pump under investigation. In contrast, a combination of the tripartite efflux systems with single-component pumps sharing common substrates provided multiplicative increases to antimicrobial resistance levels. In some instances, resistance was increased beyond the product of resistance provided by the two pumps individually. In summary, the developed efflux platform enables the isolation of efflux pump function, facilitating the identification of interactions between efflux pumps.

A genetic platform to investigate the functions of bacterial drug efflux pumps.

Efflux pumps are a serious challenge for the development of antibacterial agents. Overcoming efflux requires an in-depth understanding of efflux pump functions, specificities and the development of inhibitors. However, the complexities of efflux networks have limited such studies. To address these challenges, we generated Efflux KnockOut-35 (EKO-35), a highly susceptible Escherichia coli strain lacking 35 efflux pumps. We demonstrate the use of this strain by constructing an efflux platform comprising EKO-35 strains individually producing efflux pumps forming tripartite complexes with TolC. This platform was profiled against a curated diverse compound collection, which enabled us to define physicochemical properties that contribute to transport. We also show the E. coli drug efflux network is conditionally essential for growth, and that the platform can be used to investigate efflux pump inhibitor specificities and efflux pump interplay. We believe EKO-35 and the efflux platform will have widespread application for the study of drug efflux.

Geographic hotspot detection for late-stage hepatocellular carcinoma: novel approach to cancer control.

IMPORTANCE: As hepatocellular carcinoma (HCC)-associated mortality continues to rise in the United States, there is a crucial need for strategies to shift diagnoses from late to early stage in order to improve survival. OBJECTIVE: To describe a population-based geospatial approach to identifying areas with high late-stage HCC burden for intervention. DESIGN: Cross-sectional study between 2008 and 2017. SETTING: Los Angeles County. PARTICIPANTS: All incident cases of HCC with residential address at diagnosis in Los Angeles County were identified from a population-based cancer registry. Late stage included AJCC 7th Edition stages III-IV and unstaged cases. EXPOSURE: Sociodemographic factors. MAIN OUTCOME(S): Geographic "hotspots" or areas with a high density of late-stage HCC, identified using kernel density estimation in ArcMap 10.3.1. RESULTS: 51.8% of 7,519 incident cases of HCC were late stage. We identified a total of 23 late-stage hotspots, including 30.0% of all late-stage cases. Cases within hotspots were more often racial/ethnic minorities, foreign-born, under or uninsured, and of lower socioeconomic status. The age-adjusted incidence rate of late-stage HCC was twofold higher within hotspots (6.85 per 100,000 in hotspots vs 3.38 per 100,000 outside of hotspots). The calculated population-attributable risk was 43%, suggesting that a substantial proportion of late-stage HCC burden could be averted by introducing interventions in hotspot areas. We mapped the relationship between hotspots and federally qualified health centers primary care clinics and subspecialty clinics in Los Angeles County to demonstrate how clinic partnerships can be selected to maximize impact of interventions and resource use. Hotspots can also be utilized to identify "high-risk" neighborhoods that are easily recognizable by patients and the public and to facilitate community partnerships. CONCLUSION AND RELEVANCE: Reducing late-stage HCC through geographic late-stage hotspots may be an efficient approach to improving cancer control and equity.

Area-Based Geocoding: An Approach to Exposure Assessment Incorporating Positional Uncertainty.

While the spatial resolution of exposure surfaces has greatly improved, our ability to locate people in space remains a limiting factor in accurate exposure assessment. In this case-control study, two approaches to geocoding participant locations were used to study the impact of geocoding uncertainty on the estimation of ambient pesticide exposure and breast cancer risk among women living in California's Central Valley. Residential and occupational histories were collected and geocoded using a traditional point-based method along with a novel area-based method. The standard approach to geocoding uses centroid points to represent all geocoded locations, and is unable to adapt exposure areas based on geocode quality, except through the exclusion of low-certainty locations. In contrast, area-based geocoding retains the complete area to which an address matched (the same area from which the centroid is returned), and therefore maintains the appropriate level of precision when it comes to assessing exposure by geography. Incorporating the total potential exposure area for each geocoded location resulted in different exposure classifications and resulting odds ratio estimates than estimates derived from the centroids of those same areas (using a traditional point-based geocoder). The direction and magnitude of these differences varied by pesticide, but in all cases odds ratios differed by at least 6% and up to 35%. These findings demonstrate the importance of geocoding in exposure estimation and suggest it is important to consider geocode certainty and quality throughout exposure assessment, rather than simply using the best available point geocodes.

The Evolutionary Conservation of Escherichia coli Drug Efflux Pumps Supports Physiological Functions.

Bacteria harness an impressive repertoire of resistance mechanisms to evade the inhibitory action of antibiotics. One such mechanism involves efflux pump-mediated extrusion of drugs from the bacterial cell, which significantly contributes to multidrug resistance. Intriguingly, most drug efflux pumps are chromosomally encoded components of the intrinsic antibiotic resistome. In addition, in terms of xenobiotic detoxification, bacterial efflux systems often exhibit significant levels of functional redundancy. Efflux pumps are also considered to be highly conserved; however, the extent of conservation in many bacterial species has not been reported and the majority of genes that encode efflux pumps appear to be dispensable for growth. These observations, in combination with an increasing body of experimental evidence, imply alternative roles in bacterial physiology. Indeed, the ability of efflux pumps to facilitate antibiotic resistance could be a fortuitous by-product of ancient physiological functions. Using Escherichia coli as a model organism, we here evaluated the evolutionary conservation of drug efflux pumps and we provide phylogenetic analysis of the major efflux families. We show the E. coli drug efflux system has remained relatively stable and the majority (∼80%) of pumps are encoded in the core genome. This analysis further supports the importance of drug efflux pumps in E. coli physiology. In this review, we also provide an update on the roles of drug efflux pumps in the detoxification of endogenously synthesized substrates and pH homeostasis. Overall, gaining insight into drug efflux pump conservation, common evolutionary ancestors, and physiological functions could enable strategies to combat these intrinsic and ancient elements.

Crisis Text Line use following the release of Netflix series 13 Reasons Why Season 1: Time-series analysis of help-seeking behavior in youth.

The availability of near real-time data from Crisis Text Line (CTL) and other technology-based platforms on crisis events provides an opportunity for targeted interventions prior to serious mental health outcomes (e.g., suicide, self-harm). This study examined the association between the release of the popular Netflix series 13 Reasons Why (13RW) and CTL usage in a national sample of youth in the US. We implemented interrupted time-series, autoregressive integrated moving average (ARIMA) modeling to examine this association at a daily scale. We observed a significant but momentary rise in CTL conversation volume following the release of 13RW on April 5 and 6, 2017 followed by a significant reduction (12.7%) in conversation volume for the overall study period. This reduction in call volume was sustained for 49 days and is the most sustained reduction in conversation volume in the 365 day dataset. This unexpected trough in conversation volume is concerning in light of elevated search engine volume for terms indicating an increase in suicidal thoughts in the days following the release of the show (Ayers et al., 2017). CTL was featured by the show as a resource for viewers in the recently released Season 2, and our results highlight the reasoning and need for such promotion. Future work should explore whether the promotion of CTL in Season 2 positively impacted conversation volume, as there is a clear need to harness the power of these digital technologies to detect population-based trends in mental health and expand the reach of life saving services.

Adolescents in crisis: A geographic exploration of help-seeking behavior using data from Crisis Text Line.

Nearly 3 out of 4 all lifelong mental disorders occur by the age of twenty-four. Remote crisis support holds great potential in filling a critical gap in complementing and expanding access to mental health services for acute episodes of mental distress in adolescents and young adults; yet little is understood about the individual factors that influence help-seeking behavior in this group. Recent evidence suggests technology-based mental health services have high acceptability among youth and may be used to treat anxiety and depression. The objective of this study was to examine county-level help-seeking behavior among adolescents and young adults using Crisis Text Line (CTL). CTL is a free, text-based crisis counseling service that has been available nationally since 2013. Spatial error regression was used to (1) identify the individual-level factors that correlate with help-seeking behavior for depression, anxiety, and suicidal thoughts and (2) to explore the geographic trends in text-based help-seeking behavior between adolescents and young adults across the rural-urban continuum. Increased rates of text-based help-seeking occurred in counties with higher mean household incomes, higher divorce rates, and lower residential stability. Rurality was the strongest predictor for low rates of help-seeking, and this finding is particularly concerning in light of elevated rates of suicide among rural counties. Rural communities, particularly those with low support-seeking behavior and comparatively high suicide rates, should be the target of future research and outreach.

New-onset congestive heart failure with gemcitabine in ovarian and other solid cancers.

OBJECTIVE: To assess clinical features that may predispose individuals taking gemcitabine to new-onset congestive heart failure. METHODS: A retrospective chart review was conducted with 156 female patients, 51 with ovarian cancer and 105 with breast, lung, pancreas, and bladder cancer, all of whom had received gemcitabine. Patients with new-onset congestive heart failure were compared with patients without new-onset congestive heart failure with the use of Wilcoxon rank-sum test for continuously distributed data and the Fisher exact test for proportions. RESULTS: Seven patients developed new-onset congestive heart failure (4.5%) during their treatment, which was significantly greater than that reported previously (0.76%). Patients with new-onset congestive heart failure did not differ from other patients in the study for age, weight, gravidity, parity, body mass index, and type of cancer. They also did not differ in history of myocardial infarction, hypertension, prior episodes of congestive heart failure, prior treatment with adriamycin, or use of tobacco. However, diabetes mellitus and coronary artery disease were more common, and all patients who developed new-onset congestive heart failure received >17,000 mg/m of gemcitabine. The incidence of new-onset congestive heart failure in this study is significantly higher than previously reported with the use of gemcitabine. CONCLUSIONS: The single-most predictive risk factor for new-onset congestive heart failure in this cohort of patients is the receipt of a minimum dose of 17,000 mg/m. Therefore, additional follow-up may be necessary for all patients receiving >15,000 mg/m of gemcitabine to screen for potential new-onset congestive heart failure.

Verbal fluency indicators of malingering in traumatic brain injury: classification accuracy in known groups.

A known-groups design was used to determine the classification accuracy of verbal fluency variables in detecting Malingered Neurocognitive Dysfunction (MND) in traumatic brain injury (TBI). Participants were 204 TBI and 488 general clinical patients. The Slick et al. (1999) criteria were used to classify the TBI patients into non-MND and MND groups. An educationally corrected FAS Total Correct word T-score proved to be the most accurate of the several verbal fluency indicators examined. Classification accuracy of this variable at specific cutoffs is presented in a cumulative frequency table. This variable accurately differentiated non-MND from MND mild TBI patients but its accuracy was unacceptable in moderate/severe TBI. The clinical application of these findings is discussed.