Cannabis, cocaine, methamphetamine, and opiates increase the risk of incident atrial fibrillation.

AIMS: Atrial fibrillation (AF) is now regarded as a preventable disease, requiring a search for modifiable risk factors. With legalization of cannabis and more lenient laws regarding the use of other illicit substances, investigation into the potential effects of methamphetamine, cocaine, opiate, and cannabis exposure on incident AF is needed. METHODS AND RESULTS: Using Office of Statewide Health Planning and Development databases, a longitudinal analysis was performed of adult Californians ≥18 years of age who received care in an emergency department, outpatient surgery facility, or hospital from 1 January 2005 to 31 December 2015. Associations between healthcare coding for the use of each substance and a new AF diagnosis were assessed. Among 23,561,884 patients, 98 271 used methamphetamine, 48 701 used cocaine, 10 032 used opiates, and 132 834 used cannabis. Of the total population, 998 747 patients (4.2%) developed incident AF during the study period. After adjusting for potential confounders and mediators, use of methamphetamines, cocaine, opiates, and cannabis was each associated with increased incidence of AF: hazard ratios 1.86 [95% confidence interval (CI) 1.81-1.92], 1.61 (95% CI 1.55-1.68), 1.74 (95% CI 1.62-1.87), and 1.35 (95% CI 1.30-1.40), respectively. Negative control analyses in the same cohort failed to reveal similarly consistent positive relationships. CONCLUSION: Methamphetamine, cocaine, opiate, and cannabis uses were each associated with increased risk of developing incident AF. Efforts to mitigate the use of these substances may represent a novel approach to AF prevention.

Association of Social Determinants of Health and Their Cumulative Impact on Hospitalization Among a National Sample of Community-Dwelling US Adults.

IMPORTANCE: While the association between Social Determinants of Health (SDOH) and health outcomes is well known, few studies have explored the impact of SDOH on hospitalization. OBJECTIVE: Examine the independent association and cumulative effect of six SDOH domains on hospitalization. DESIGN: Using cross-sectional data from the 2016-2018 National Health Interview Surveys (NHIS), we used multivariable logistical regression models controlling for sociodemographics and comorbid conditions to assess the association of each SDOH and SDOH burden (i.e., cumulative number of SDOH) with hospitalization. SETTING: National survey of community-dwelling individuals in the US PARTICIPANTS: Adults ≥18 years who responded to the NHIS survey EXPOSURE: Six SDOH domains (economic instability, lack of community, educational deficits, food insecurity, social isolation, and inadequate access to medical care) MEASURES: Hospitalization within 1 year RESULTS: Among all 55,186 respondents, most were ≤50 years old (54.2%), female (51.7%, 95% CI 51.1-52.3), non-Hispanic (83.9%, 95% CI 82.4-84.5), identified as White (77.9%, 95% CI 76.8-79.1), and had health insurance (90%, 95% CI 88.9-91.9). Hospitalized individuals (n=5506; 8.7%) were more likely to be ≥50 years old (61.2%), female (60.7%, 95% CI 58.9-62.4), non-Hispanic (87%, 95% CI 86.2-88.4), and identify as White (78.5%, 95% CI 76.7-80.3), compared to those who were not hospitalized. Hospitalized individuals described poorer overall health, reporting higher incidence of having ≥5 comorbid conditions (38.9%, 95% CI 37.1-40.1) compared to those who did not report a hospitalization (15.9%, 95% CI 15.4-16.5). Hospitalized respondents reported higher rates of economic instability (33%), lack of community (14%), educational deficits (67%), food insecurity (14%), social isolation (34%), and less access to health care (6%) compared to non-hospitalized individuals. In adjusted analysis, food insecurity (OR: 1.36, 95% CI 1.22-1.52), social isolation (OR: 1.17, 95% CI 1.08-1.26), and lower educational attainment (OR: 1.12, 95% CI 1.02-1.25) were associated with hospitalization, while a higher SDOH burden was associated with increased odds of hospitalization (3-4 SDOH [OR: 1.25, 95% CI 1.06-1.49] and ≥5 SDOH [OR: 1.72, 95% CI 1.40-2.06]) compared to those who reported no SDOH. CONCLUSIONS: Among community-dwelling US adults, three SDOH domains: food insecurity, social isolation, and low educational attainment increase an individual's risk of hospitalization. Additionally, risk of hospitalization increases as SDOH burden increases.

FBP1-Altered Carbohydrate Metabolism Reduces Leukemic Viability through Activating P53 and Modulating the Mitochondrial Quality Control System In Vitro.

Acute myeloid leukemia (AML)-the most frequent form of adult blood cancer-is characterized by heterogeneous mechanisms and disease progression. Developing an effective therapeutic strategy that targets metabolic homeostasis and energy production in immature leukemic cells (blasts) is essential for overcoming relapse and improving the prognosis of AML patients with different subtypes. With respect to metabolic regulation, fructose-1,6-bisphosphatase 1 (FBP1) is a gluconeogenic enzyme that is vital to carbohydrate metabolism, since gluconeogenesis is the central pathway for the production of important metabolites and energy necessary to maintain normal cellular activities. Beyond its catalytic activity, FBP1 inhibits aerobic glycolysis-known as the "Warburg effect"-in cancer cells. Importantly, while downregulation of FBP1 is associated with carcinogenesis in major human organs, restoration of FBP1 in cancer cells promotes apoptosis and prevents disease progression in solid tumors. Recently, our large-scale sequencing analyses revealed FBP1 as a novel inducible therapeutic target among 17,757 vitamin-D-responsive genes in MV4-11 or MOLM-14 blasts in vitro, both of which were derived from AML patients with FLT3 mutations. To investigate FBP1's anti-leukemic function in this study, we generated a new AML cell line through lentiviral overexpression of an FBP1 transgene in vitro (named FBP1-MV4-11). Results showed that FBP1-MV4-11 blasts are more prone to apoptosis than MV4-11 blasts. Mechanistically, FBP1-MV4-11 blasts have significantly increased gene and protein expression of P53, as confirmed by the P53 promoter assay in vitro. However, enhanced cell death and reduced proliferation of FBP1-MV4-11 blasts could be reversed by supplementation with post-glycolytic metabolites in vitro. Additionally, FBP1-MV4-11 blasts were found to have impaired mitochondrial homeostasis through reduced cytochrome c oxidase subunit 2 (COX2 or MT-CO2) and upregulated PTEN-induced kinase (PINK1) expressions. In summary, this is the first in vitro evidence that FBP1-altered carbohydrate metabolism and FBP1-activated P53 can initiate leukemic death by activating mitochondrial reprogramming in AML blasts, supporting the clinical potential of FBP1-based therapies for AML-like cancers.

Sample Enrichment for Bioanalytical Assessment of Disinfected Drinking Water: Concentrating the Polar, the Volatiles, and the Unknowns.

Enrichment methods used in sample preparation for the bioanalytical assessment of disinfected drinking water result in the loss of volatile and hydrophilic disinfection byproducts (DBPs) and hence likely tend to underestimate biological effects. We developed and evaluated methods that are compatible with bioassays, for extracting nonvolatile and volatile DBPs from chlorinated and chloraminated drinking water to minimize the loss of analytes. For nonvolatile DBPs, solid-phase extraction (SPE) with TELOS ENV as solid phase performed superior compared to ten other sorbents. SPE yielded >70% recovery of nonpurgeable adsorbable organic halogens (AOX). For volatile DBPs, cryogenic vacuum distillation performed unsatisfactorily. Purge and cold-trap with crushed ice serving as condensation nuclei achieved recoveries of 50-100% for trihalomethanes and haloacetonitriles and approximately 60-90% for purged AOX from tap water. We compared the purgeable versus the nonpurgeable fraction by combining purge-and-trap extraction with SPE. The purgeable DBP fraction enriched with the purge-and-trap method exerted a lower oxidative stress response in mammalian cells than the nonpurgeable DBPs enriched with SPE after purging, while contributions of both fractions to bacterial cytotoxicity was more variable. 37 quantified DBPs explained almost the entire AOX in the purge-and-trap extracts, but <16% in the SPE extracts demonstrating that the nonpurgeable fraction is dominated by unknown DBPs.

Benchmarking organic micropollutants in wastewater, recycled water and drinking water with in vitro bioassays.

Thousands of organic micropollutants and their transformation products occur in water. Although often present at low concentrations, individual compounds contribute to mixture effects. Cell-based bioassays that target health-relevant biological endpoints may therefore complement chemical analysis for water quality assessment. The objective of this study was to evaluate cell-based bioassays for their suitability to benchmark water quality and to assess efficacy of water treatment processes. The selected bioassays cover relevant steps in the toxicity pathways including induction of xenobiotic metabolism, specific and reactive modes of toxic action, activation of adaptive stress response pathways and system responses. Twenty laboratories applied 103 unique in vitro bioassays to a common set of 10 water samples collected in Australia, including wastewater treatment plant effluent, two types of recycled water (reverse osmosis and ozonation/activated carbon filtration), stormwater, surface water, and drinking water. Sixty-five bioassays (63%) showed positive results in at least one sample, typically in wastewater treatment plant effluent, and only five (5%) were positive in the control (ultrapure water). Each water type had a characteristic bioanalytical profile with particular groups of toxicity pathways either consistently responsive or not responsive across test systems. The most responsive health-relevant endpoints were related to xenobiotic metabolism (pregnane X and aryl hydrocarbon receptors), hormone-mediated modes of action (mainly related to the estrogen, glucocorticoid, and antiandrogen activities), reactive modes of action (genotoxicity) and adaptive stress response pathway (oxidative stress response). This study has demonstrated that selected cell-based bioassays are suitable to benchmark water quality and it is recommended to use a purpose-tailored panel of bioassays for routine monitoring.

Contemporary trends in incident ischemic stroke, intracranial hemorrhage, and mortality in individuals with atrial fibrillation.

BACKGROUND: The prognosis for atrial fibrillation (AF) patients is based on data that is decades old. Given evolving standards of clinical practice, we sought to evaluate temporal trends in clinically important outcomes among patients with AF. METHODS: California's Department of Health Care Access and Information databases were used to identify adults aged ≥ 18 years with AF receiving hospital-based care in California. We compared 3 time-periods: 2005-2009, 2010-2014, and 2015-2019. ICD codes were used to identify chronic diseases and acute events. The outcomes were incident ischemic stroke, intracranial hemorrhage, and overall mortality. RESULTS: We included 2 009 832 patients with AF (52.7% males, 70.7% Whites, and mean age of 75.0 years), divided in 3 cohorts: 2005-2009 (n = 738 954), 2010-2014 (n = 609 447), and 2015-2019 (n = 661 431). Each outcome became substantially less common with time: compared to 2005-2009, AF patients diagnosed in 2015-2019 experienced a 34% (adjusted hazard ratio [HR] 0.66, 95% CI 0.64-0.69), 22% (HR 0.78, 0.75-0.82), and 24% (HR 0.76, 0.75-0.77) reduction in risk of incident ischemic stroke, intracranial hemorrhage, and mortality, respectively. Between 2005-2009 and 2015-2019, patients aged ≥ 65 years experienced more reductions in each outcome compared to younger patients (p < 0.001 for all), and declines in each outcome were significantly lower for Hispanics and Blacks compared to white patients. CONCLUSION: The risks of stroke, intracranial hemorrhage, and death have significantly declined among AF patients, although differences in the magnitude of improvement of these outcomes by demographic groups were observed. Commonly described estimates of the prognosis for AF patients should be updated to reflect contemporary care.

Systemic infarcts among patients with atrial fibrillation.

BACKGROUND: The epidemiology of atrial fibrillation (AF)-associated thromboembolic complications outside of ischemic strokes has not been thoroughly elucidated. OBJECTIVE: The aim of this study was to describe the epidemiology of AF-associated systemic infarcts and relevant interactions by sex and race/ethnicity. METHODS: Using the Office of Statewide Health Planning and Development, we performed a longitudinal analysis of patients aged ≥18 years who received ambulatory surgery, emergency, or inpatient medical care in California between 2005 and 2015. We determined the distribution of infarct locations and risks of systemic infarcts for patients with AF. Interaction analyses by sex and race/ethnicity were conducted. RESULTS: Of 1,321,694 patients with AF, the average annual rate of systemic infarct was 2.1% ± 0.18% compared with 0.56% ± 0.06% in the 22,944,488 patients without AF. The increased frequency of these infarcts was observed for every body area investigated. After adjustment for potential confounders and mediators, patients with AF experienced a 45% increased risk of a systemic infarct (hazard ratio, 1.45; 95% confidence interval, 1.44-1.47; P < .001). Women, Asians, Blacks, and Hispanics each exhibited a statistically significant heightened relative risk of systemic infarcts in the presence of AF. CONCLUSION: AF increases the risk of infarcts throughout the body. Susceptibility to these systemic infarcts varies by sex and race/ethnicity in patterns similar to differential risks for stroke. The presence of a systemic infarct in the absence of a clear cause should raise suspicion for AF, and the potential benefits of AF prevention and anticoagulation should be considered beyond only infarcts to the brain.

Cannabis use and incident atrial fibrillation in a longitudinal cohort.

BACKGROUND: Cannabis use is increasing worldwide. While prior studies have reported an association between cannabis use and a higher risk of atrial fibrillation (AF), most were cross-sectional and generally relied on diagnostic coding to identify cannabis users, which may not be representative of the typical recreational cannabis user. OBJECTIVE: The purpose of this study was to examine the association between recreational cannabis use and lifetime AF risk. METHODS: We evaluated the AF risk of participants of the UK Biobank cohort who completed the cannabis use lifestyle questionnaire. Cannabis exposure was categorized as "Occasional Use" for less than 100 times used, "Frequent Use" for more than 100 times used, and "Never" users. AF events were identified using International Classification of Diseases codes. Cox models were used to estimate the hazard ratios (HRs) between cannabis use and incident AF and were subsequently adjusted for age, sex, race, alcohol, coffee, smoking, education, and baseline cardiovascular comorbidities. RESULTS: A total of 150,554 participants (mean age 63.4 ± 7.7 years; 86,487 (57.4%) female; and 33,442 (22.2%) using cannabis at least once) were followed for a mean period of 6.1 ± 0.6 years. After multivariable adjustment, there were no statistically significant differences in incident AF among occasional users (HR 0.98; 95% confidence interval 0.89-1.08) nor frequent users (HR 1.03; 95% confidence interval 0.81-1.32) as compared with never users. CONCLUSION: In a large prospective cohort study, there was no evidence that cannabis use was associated with a higher risk of incident AF. An evaluation of cannabis ingestion methods and quantification was not possible using the current data set.

Fluorescence Lifetime Imaging of Human Retinal Pigment Epithelium in Pentosan Polysulfate Toxicity Using Adaptive Optics Scanning Light Ophthalmoscopy.

Purpose: Fluorescence lifetime ophthalmoscopy (FLIO) is an emerging clinical modality that could provide biomarkers of retinal health beyond fluorescence intensity. Adaptive optics (AO) ophthalmoscopy provides the confocality to measure fluorescence lifetime (FL) primarily from the retinal pigment epithelium (RPE) whereas clinical FLIO has greater influence from fluorophores in the inner retina and lens. Adaptive optics fluorescence lifetime ophthalmoscopy (AOFLIO) measures of FL in vivo could provide insight into RPE health at different stages of disease. In this study, we assess changes in pentosan polysulfate sodium (PPS) toxicity, a recently described toxicity that has clinical findings similar to advanced age-related macular degeneration. Methods: AOFLIO was performed on three subjects with PPS toxicity (57-67 years old) and six age-matched controls (50-64 years old). FL was analyzed with a double exponential decay curve fit and with phasor analysis. Regions of interest (ROIs) were subcategorized based on retinal features on optical coherence tomography (OCT) and compared to age-matched controls. Results: Twelve ROIs from PPS toxicity subjects met the threshold for analysis by curve fitting and 15 ROIs met the threshold for phasor analysis. Subjects with PPS toxicity had prolonged FL compared to age-matched controls. ROIs of RPE degeneration had the longest FLs, with individual pixels extending longer than 900 ps. Conclusions: Our study shows evidence that AOFLIO can provide meaningful information in outer retinal disease beyond what is obtainable from fluorescence intensity alone. More studies are needed to determine the prognostic value of AOFLIO.

Preceding Night Sleep Quality and Atrial Fibrillation Episodes in the I-STOP-AFIB Randomized Trial.

BACKGROUND: Chronic sleep disruption is associated with incident atrial fibrillation (AF), but it is unclear whether poor sleep quality acutely triggers AF. OBJECTIVES: The aim of this study was to characterize the relationship between a given night's sleep quality and the risk of a discrete AF episode. METHODS: Patients with symptomatic paroxysmal AF in the I-STOP-AFIB (Individualized Studies of Triggers of Paroxysmal Atrial Fibrillation) trial reported sleep quality on a daily basis. Participants were also queried daily regarding AF episodes and were provided smartphone-based mobile electrocardiograms (ECGs) (KardiaMobile, AliveCor). RESULTS: Using 15,755 days of data from 419 patients, worse sleep quality on any given night was associated with a 15% greater odds of a self-reported AF episode the next day (OR: 1.15; 95% CI: 1.10-1.20; P < 0.0001) after adjustment for the day of the week. No statistically significant associations between worsening sleep quality and mobile ECG-confirmed AF events were observed (OR: 1.04; 95% CI: 0.95-1.13; P = 0.43), although substantially fewer of these mobile ECG-confirmed events may have limited statistical power. Poor sleep was also associated with longer self-reported AF episodes, with each progressive category of worsening sleep associated with 16 (95% CI: 12-21; P < 0.001) more minutes of AF the next day. CONCLUSIONS: Poor sleep was associated with an immediately heightened risk for self-reported AF episodes, and a dose-response relationship existed such that progressively worse sleep was associated with longer episodes of AF the next day. These data suggest that sleep quality may be a potentially modifiable trigger relevant to the near-term risk of a discrete AF episode.

Near Infrared Autofluorescence Lifetime Imaging of Human Retinal Pigment Epithelium Using Adaptive Optics Scanning Light Ophthalmoscopy.

Purpose: To demonstrate the first near-infrared adaptive optics fluorescence lifetime imaging ophthalmoscopy (NIR-AOFLIO) measurements in vivo of the human retinal pigment epithelial (RPE) cellular mosaic and to visualize lifetime changes at different retinal eccentricities. Methods: NIR reflectance and autofluorescence were captured using a custom adaptive optics scanning light ophthalmoscope in 10 healthy subjects (23-64 years old) at seven eccentricities and in two eyes with retinal abnormalities. Repeatability was assessed across two visits up to 8 weeks apart. Endogenous retinal fluorophores and hydrophobic whole retinal extracts of Abca4-/- pigmented and albino mice were imaged to probe the fluorescence origin of NIR-AOFLIO. Results: The RPE mosaic was resolved at all locations in five of seven younger subjects (<35 years old). The mean lifetime across near-peripheral regions (8° and 12°) was longer compared to near-foveal regions (0° and 2°). Repeatability across two visits showed moderate to excellent correlation (intraclass correlation: 0.88 [τm], 0.75 [τ1], 0.65 [τ2], 0.98 [a1]). The mean lifetime across drusen-containing eyes was longer than in age-matched healthy eyes. Fluorescence was observed in only the extracts from pigmented Abca4-/- mouse. Conclusions: NIR-AOFLIO was repeatable and allowed visualization of the RPE cellular mosaic. An observed signal in only the pigmented mouse extract infers the fluorescence signal originates predominantly from melanin. Variations observed across the retina with intermediate age-related macular degeneration suggest NIR-AOFLIO may act as a functional measure of a biomarker for in vivo monitoring of early alterations in retinal health.

Most oxidative stress response in water samples comes from unknown chemicals: the need for effect-based water quality trigger values.

The induction of adaptive stress response pathways is an early and sensitive indicator of the presence of chemical and non-chemical stressors in cells. An important stress response is the Nrf-2 mediated oxidative stress response pathway where electrophilic chemicals or chemicals that cause the formation of reactive oxygen species initiate the production of antioxidants and metabolic detoxification enzymes. The AREc32 cell line is sensitive to chemicals inducing oxidative stress and has been previously applied for water quality monitoring of organic micropollutants and disinfection byproducts. Here we propose an algorithm for the derivation of effect-based water quality trigger values for this end point that is based on the combined effects of mixtures of regulated chemicals. Mixture experiments agreed with predictions by the mixture toxicity concept of concentration addition. The responses in the AREc32 and the concentrations of 269 individual chemicals were quantified in nine environmental samples, ranging from treated effluent, recycled water, stormwater to drinking water. The effects of the detected chemicals could explain less than 0.1% of the observed induction of the oxidative stress response in the sample, affirming the need to use effect-based trigger values that account for all chemicals present.

Postconcussive symptom reporting among US combat veterans with mild traumatic brain injury from Operation Iraqi Freedom.

OBJECTIVE: To examine the association between postconcussive symptoms and mild traumatic brain injury (MTBI) among combat veterans while adjusting for posttraumatic stress disorder (PTSD) and depression. PATIENTS: Military personnel with provider-diagnosed MTBI (n = 334) or nonhead injury (n = 658) were identified from the Expeditionary Medical Encounter Database. MAIN OUTCOME MEASURES: Post-Deployment Health Assessments and Re-Assessments were used to examine postconcussive symptoms and self-rated health. RESULTS: Personnel with MTBI were more likely to report headache (odds ratio [OR] = 3.37; 95% confidence interval [CI] = 2.19-5.17), back pain (OR = 1.79; 95% CI = 1.23-2.60), memory problems (OR = 1.86; 95% CI = 1.20-2.88), tinnitus (OR = 1.63; 95% CI = 1.10-2.41), and dizziness (OR = 2.13; 95% CI = 1.06-4.29) compared with those with non-head injuries. Among those with MTBI, self-reported decline in health was associated with memory problems (OR = 5.07; 95% CI = 2.56-10.02) and dizziness (OR = 10.60; 95% CI = 3.48-32.27). CONCLUSIONS: Mild traumatic brain injury is associated with reports of negative health consequences among combat veterans even when accounting for co-occurring psychological morbidity. The identification of postconcussive symptoms related to declines in a service member's self-rated health may be important in targeting and prioritizing clinical interventions.

Urban stormwater harvesting and reuse: a probe into the chemical, toxicology and microbiological contaminants in water quality.

Stormwater is one of the last major untapped urban water resources that can be exploited as an alternative water source in Australia. The information in the current Australian Guidelines for Water Recycling relating to stormwater harvesting and reuse only emphasises on a limited number of stormwater quality parameters. In order to supply stormwater as a source for higher value end-uses, a more comprehensive assessment on the potential public health risks has to be undertaken. Owing to the stochastic variations in rainfall, catchment hydrology and also the types of non-point pollution sources that can provide contaminants relating to different anthropogenic activities and catchment land uses, the characterisation of public health risks in stormwater is complex, tedious and not always possible through the conventional detection and analytical methods. In this study, a holistic approach was undertaken to assess the potential public health risks in urban stormwater samples from a medium-density residential catchment. A combined chemical-toxicological assessment was used to characterise the potential health risks arising from chemical contaminants, while a combination of standard culture methods and quantitative polymerase chain reaction (qPCR) methods was used for detection and quantification of faecal indicator bacteria (FIB) and pathogens in urban stormwater. Results showed that the concentration of chemical contaminants and associated toxicity were relatively low when benchmarked against other alternative water sources such as recycled wastewater. However, the concentrations of heavy metals particularly cadmium and lead have exceeded the Australian guideline values, indicating potential public health risks. Also, high numbers of FIB were detected in urban stormwater samples obtained from wet weather events. In addition, qPCR detection of human-related pathogens suggested there are frequent sewage ingressions into the urban stormwater runoff during wet weather events. Further water quality monitoring study will be conducted at different contrasting urban catchments in order to undertake a more comprehensive public health risk assessment for urban stormwater.

Erratum: Adaptive optics fluorescence lifetime imaging ophthalmoscopy of in vivo human retinal pigment epithelium: erratum.

[This corrects the article on p. 1737 in vol. 13, PMID: 35414970.].

Bioanalytical assessment of the formation of disinfection byproducts in a drinking water treatment plant.

Disinfection of drinking water is the most successful measure to reduce water-borne diseases and protect health. However, disinfection byproducts (DBPs) formed from the reaction of disinfectants such as chlorine and monochloramine with organic matter may cause bladder cancer and other adverse health effects. In this study the formation of DBPs through a full-scale water treatment plant serving a metropolitan area in Australia was assessed using in vitro bioanalytical tools, as well as through quantification of halogen-specific adsorbable organic halogens (AOXs), characterization of organic matter, and analytical quantification of selected regulated and emerging DBPs. The water treatment train consisted of coagulation, sand filtration, chlorination, addition of lime and fluoride, storage, and chloramination. Nonspecific toxicity peaked midway through the treatment train after the chlorination and storage steps. The dissolved organic matter concentration decreased after the coagulation step and then essentially remained constant during the treatment train. Concentrations of AOXs increased upon initial chlorination and continued to increase through the plant, probably due to increased chlorine contact time. Most of the quantified DBPs followed a trend similar to that of AOXs, with maximum concentrations observed in the final treated water after chloramination. The mostly chlorinated and brominated DBPs formed during treatment also caused reactive toxicity to increase after chlorination. Both genotoxicity with and without metabolic activation and the induction of the oxidative stress response pathway showed the same pattern as the nonspecific toxicity, with a maximum activity midway through the treatment train. Although measured effects cannot be directly translated to adverse health outcomes, this study demonstrates the applicability of bioanalytical tools to investigate DBP formation in a drinking water treatment plant, despite bioassays and sample preparation not yet being optimized for volatile DBPs. As such, the bioassays are useful as monitoring tools as they provide sensitive responses even at low DBP levels.

In vitro bioassay for reactive toxicity towards proteins implemented for water quality monitoring.

Reactive organic chemicals comprise a large number of compounds with a variety of reactive moieties. While most assays for reactive toxicity focus on DNA damage, reactivity towards proteins can also lead to irreparable damage, but reactivity towards proteins is typically not included in any test battery for water quality assessment. Glutathione (GSH) is a small tripeptide whose cysteine moiety can serve as a model for nucleophilic sites on proteins. GSH is also an important indicator of detoxification processes and the redox status of cells and due to its protective role, depletion of GSH ultimately leads to adverse effects. A bioassay based on genetically modified Escherichia coli strains was used to quantify the specific reactivity towards the protein-like biological nucelophile GSH. The significance of GSH for detoxification was assessed by comparing the growth inhibition induced by reference chemicals or water samples in a GSH-deficient strain to its fully functional parent strain. The GSH deficient strain showed the same sensitivity as the GSH proficient strain to non-reactive and DNA damaging chemicals, but was more sensitive to chemicals that attack cysteine in proteins. The difference in effect concentrations for 50% inhibition of growth assessed as biomass increase (EC(50)) between the two strains indicates the relevance of GSH conjugation as a detoxification step as well as direct reactivity with cysteine-containing proteins. Seven reference compounds serving as positive and negative controls were investigated. The E. coli strain that lacks GSH was four times more sensitive towards the positive control Sea-Nine, while negative controls benzo[a]pyrene, 2-aminoanthracene, phenol, t-butylhydroquinone, methyl methane sulfonate and 4-nitroquinoline oxide showed equal effect concentrations in both strains. Water samples collected across an indirect potable reuse scheme representing the complete water cycle from sewage to drinking water in South East Queensland, Australia were used to evaluate the applicability of the E. coli assay for reactive toxicity in water samples. While the EC(50) values of the GSH+ strain showed similar trends as in other biological endpoints over the various treatment chains, the specific response indicative of protein damage was only observed in samples that had undergone chlorination as a disinfection process. High natural organic matter or other matrix components disturbed the bioassay so much that we recommend it for future routine testing only in tertiary treated water or drinking water.

Water quality assessment using the AREc32 reporter gene assay indicative of the oxidative stress response pathway.

The reporter gene assay AREc32 is based on the induction of the Nrf2 mediated oxidative stress response pathway in the human breast cancer cell line MCF7, where eight copies of the antioxidant response element (ARE) are linked to a reporter gene encoding for luciferase. The Nrf2-ARE pathway is responsive to many chemicals that cause oxidative stress, among them a large number of pesticides and skin irritants. We adopted and validated the AREc32 bioassay for water quality testing. tert-Butylhydroquinone served as the positive control, phenol as the negative control and other reactive chemicals were assessed for their specificity. An environmentally relevant reference chemical, benzo(a)pyrene was the most potent inducer of all tested chemicals. The concentration causing an induction ratio (IR) of 1.5 (EC(IR1.5)) was chosen as the effect benchmark value. The assay was applied to 21 water samples ranging from sewage to drinking water, including secondary treatment and various tertiary treatment options (ozonation, biologically activated carbon filtration, membrane filtration, reverse osmosis, advanced oxidation, chlorination, chloramination). The samples were enriched by solid phase extraction. In most samples the oxidative stress response was far more sensitive than cytotoxicity. The primary and secondary treated effluent exceeded the effect threshold IR 1.5 at a relative enrichment factor (REF) of 1, i.e., the native samples were active. All tertiary treated samples were less potent and their EC(IR1.5) lay between REF 1 and 10. The Nrf2 pathway was induced at a REF of approximately 10 for surface waters and drinking water, and above this enrichment cytotoxicity took over in most samples and quenched the induction. The blank (ultrapure water run through the sample enrichment process) was cytotoxic at an REF of 100, which is the limit of concentrations range that can be evaluated. Treatment typically decreased both the cytotoxicity and oxidative stress response apart from drinking water treatment where chlorination caused an increase in oxidative stress response, presumably due to the formation of disinfection by-products. This study demonstrates the relevance and applicability of the oxidative stress response pathway for water quality monitoring.

Digital Health Skillsets and Digital Preparedness: Comparison of Veterans Health Administration Users and Other Veterans Nationally.

BACKGROUND: As health care systems shift to greater use of telemedicine and digital tools, an individual's digital health literacy has become an important skillset. The Veterans Health Administration (VA) has invested resources in providing digital health care; however, to date, no study has compared the digital health skills and preparedness of veterans receiving care in the VA to veterans receiving care outside the VA. OBJECTIVE: The goal of the research was to describe digital health skills and preparedness among veterans who receive care within and outside the VA health care system and examine whether receiving care in the VA is associated with digital preparedness (reporting more than 2 digital health skills) after accounting for demographic and social risk factors. METHODS: We used cross-sectional data from the 2016-2018 National Health Interview Survey to identify veterans (aged over 18 years) who obtain health care either within or outside the VA health care system. We used multivariable logistic regression models to examine the association of sociodemographic (age, sex, race, ethnicity), social risk factors (economic instability, disadvantaged neighborhood, low educational attainment, and social isolation), and health care delivery location (VA and non-VA) with digital preparedness. RESULTS: Those who received health care within the VA health care system (n=3188) were younger (age 18-49 years: 33.3% [95% CI 30.7-36.0] vs 24.2% [95% CI 21.9-26.5], P<.01), were more often female (34.7% [95% CI 32.0-37.3] vs 6.6% [95% CI 5.5-7.6], P<.01) and identified as Black (13.1% [95% CI 11.2-15.0] vs 10.2% [95% CI 8.7-11.8], P<.01), and reported greater economic instability (8.3% [95% CI 6.9-9.8] vs 5.5% [95% CI 4.6-6.5], P<.01) and social isolation (42.6% [95% CI 40.3-44.9] vs 35.4% [95% CI 33.4-37.5], P<.01) compared to veterans who received care outside the VA (n=3393). Veterans who obtained care within the VA reported more digital health skills than those who obtained care outside the VA, endorsing greater rates of looking up health information on the internet (51.8% [95% CI 49.2-54.4] vs 45.0% [95% CI 42.6-47.3], P<.01), filling a prescription using the internet (16.2% [95% CI 14.5-18.0] vs 11.3% [95% CI 9.6-13.0], P<.01), scheduling a health care appointment on the internet (14.1% [95% CI 12.4-15.8] vs 11.6% [95% CI 10.1-13.1], P=.02), and communicating with a health care provider by email (18.0% [95% CI 16.1-19.8] vs 13.3% [95% CI 11.6-14.9], P<.01). Following adjustment for sociodemographic and social risk factors, receiving health care from the VA was the only characteristic associated with higher odds (adjusted odds ratio [aOR] 1.36, 95% CI 1.12-1.65) of being digitally prepared. CONCLUSIONS: Despite these demographic disadvantages to digital uptake, veterans who receive care in the VA reported more digital health skills and appear more digitally prepared than veterans who do not receive care within the VA, suggesting a positive, system-level influence on this cohort.