Exposure, Retention, Exhalation, Symptoms, and Environmental Accumulation of Chemicals During JUUL Vaping.

Little is known about the chemical exposures that electronic cigarette (EC) users receive and emit during JUUL vaping and if exposures produce symptoms dose dependently. This study examined chemical exposure (dose), retention, symptoms during vaping, and the environmental accumulation of exhaled propylene glycol (PG), glycerol (G), nicotine, and menthol in a cohort of human participants who vaped JUUL "Menthol" ECs. We refer to this environmental accumulation as "EC exhaled aerosol residue" (ECEAR). Chemicals were quantified using gas chromatography/mass spectrometry in JUUL pods before and after use, lab-generated aerosols, human exhaled aerosols, and in ECEAR. Unvaped JUUL "Menthol" pods contained ∼621.3 mg/mL of G, ∼264.9 mg/mL of PG, ∼59.3 mg/mL of nicotine, ∼13.3 mg/mL of menthol, and ∼0.1 mg/mL of the coolant WS-23. Eleven experienced male EC users (aged 21-26) provided exhaled aerosol and residue samples before and after vaping JUUL pods. Participants vaped ad libitum for 20 min, while their average puff count (22 ± 6.4) and puff duration (4.4 ± 2.0) were recorded. The transfer efficiency of nicotine, menthol, and WS-23 from the pod fluid into the aerosol varied with each chemical and was generally similar across flow rates (9-47 mL/s). At 21 mL/s, the average mass of each chemical retained by the participants who vaped 20 min was 53.2 ± 40.3 mg for G, 18.9 ± 14.3 mg for PG, 3.3 ± 2.7 mg for nicotine, and 0.5 ± 0.4 mg for menthol, with retention deduced to be ∼90-100% for each chemical. There was a significant positive relationship between the number of symptoms during vaping and total chemical mass retained. ECEAR accumulated on enclosed surfaces where it could contribute to passive exposure. These data will be valuable to researchers studying human exposure to EC aerosols and agencies that regulate EC products.

Correlation between biomarkers of exposure, effect and potential harm in the urine of electronic cigarette users.

OBJECTIVES: To determine if urinary biomarkers of effect and potential harm are elevated in electronic cigarette users compared with non-smokers and if elevation correlates with increased concentrations of metals in urine. STUDY DESIGN AND SETTING: This was a cross-sectional study of biomarkers of exposure, effect and potential harm in urine from non-smokers (n=20), electronic cigarette users (n=20) and cigarette smokers (n=13). Participant's screening and urine collection were performed at the Roswell Park Comprehensive Cancer Center, and biomarker analysis and metal analysis were performed at the University of California, Riverside. RESULTS: Metallothionein was significantly elevated in the electronic cigarette group (3761±3932 pg/mg) compared with the non-smokers (1129±1294 pg/mg, p=0.05). 8-OHdG (8-hydroxy-2'-deoxyguanosine) was significantly elevated in electronic cigarette users (442.8±300.7 ng/mg) versus non-smokers (221.6±157.8 ng/mg, p=0.01). 8-Isoprostane showed a significant increase in electronic cigarette users (750.8±433 pg/mg) versus non-smokers (411.2±287.4 pg/mg, p=0.03). Linear regression analysis in the electronic cigarette group showed a significant correlation between cotinine and total metal concentration; total metal concentration and metallothionein; cotinine and oxidative DNA damage; and total metal concentration and oxidative DNA damage. Zinc was significantly elevated in the electronic cigarette users (584.5±826.6 µg/g) compared with non-smokers (413.6±233.7 µg/g, p=0.03). Linear regression analysis showed a significant correlation between urinary zinc concentration and 8-OHdG in the electronic cigarette users. CONCLUSIONS: This study is the first to investigate biomarkers of potential harm and effect in electronic cigarette users and to show a linkage to metal exposure. The biomarker levels in electronic cigarette users were similar to (and not lower than) cigarette smokers. In electronic cigarette users, there was a link to elevated total metal exposure and oxidative DNA damage. Specifically, our results demonstrate that zinc concentration was correlated to oxidative DNA damage.

Genomic features, whole-genome phylogenetic and comparative genomic analysis of extreme-drug-resistant ventilator-associated-pneumonia Acinetobacter baumannii strain in a Vietnam hospital.

OBJECTIVES: Acinetobacter baumannii is a major cause of ventilator-associated-pneumonia (VAP) worldwide due to its impressive propensity to rapidly acquire resistance elements to a wide range of antibacterial agents. We sought to explore the genomic features of this pathogen from a sputum specimen of a VAP male patient. METHODS: Whole genome analysis of A. baumannii DMS06670 included de novo assembly; functional annotation, whole-genome-phylogenetic analysis, antibiotics genes identification, prophage regions, virulent factor and pan-genome analysis. RESULTS: Assembly of whole-genome shotgun sequences of strain DMS06670 yielded an estimated genome size of 3.8 Mb with Sequence Type 447. Functional annotation and orthologous protein cluster analysis identified several potential antibiotic resistance genes was conducted (with 1 novel gene), prophage regions, virulent factors. The clusters of orthologous groups (COGs) analysis in protein sequence of the A. baumannii strain was compared with the other five genomes showed that the orthologous protein clusters responsible for multi-drug exist inside highly antimicrobial resistant strains. Whole-genome phylogenetic and in silico MLST analysis revealed that this A. baumannii strain is in the same clade as strains LAC-4 and BJAB0715. Comparative analysis of 23 available genomes of A. baumannii revealed a pan-genome consisting of 15,883 genes. CONCLUSION: Our findings provide insight into the virulence-associated genes and then compared with the genomes of other A. baumannii strains by calculation of ANI values and pan-genome analysis. Functional studies of these pathogens are required to validate these findings.

Health Effects Associated With Electronic Cigarette Use: Automated Mining of Online Forums.

BACKGROUND: Our previous infodemiological study was performed by manually mining health-effect data associated with electronic cigarettes (ECs) from online forums. Manual mining is time consuming and limits the number of posts that can be retrieved. OBJECTIVE: Our goal in this study was to automatically extract and analyze a large number (>41,000) of online forum posts related to the health effects associated with EC use between 2008 and 2015. METHODS: Data were annotated with medical concepts from the Unified Medical Language System using a modified version of the MetaMap tool. Of over 1.4 million posts, 41,216 were used to analyze symptoms (undiagnosed conditions) and disorders (physician-diagnosed terminology) associated with EC use. For each post, sentiment (positive, negative, and neutral) was also assigned. RESULTS: Symptom and disorder data were categorized into 12 organ systems or anatomical regions. Most posts on symptoms and disorders contained negative sentiment, and affected systems were similar across all years. Health effects were reported most often in the neurological, mouth and throat, and respiratory systems. The most frequently reported symptoms and disorders were headache (n=939), coughing (n=852), malaise (n=468), asthma (n=916), dehydration (n=803), and pharyngitis (n=565). In addition, users often reported linked symptoms (eg, coughing and headache). CONCLUSIONS: Online forums are a valuable repository of data that can be used to identify positive and negative health effects associated with EC use. By automating extraction of online information, we obtained more data than in our prior study, identified new symptoms and disorders associated with EC use, determined which systems are most frequently adversely affected, identified specific symptoms and disorders most commonly reported, and tracked health effects over 7 years.

Identification of Cytotoxic Flavor Chemicals in Top-Selling Electronic Cigarette Refill Fluids.

We identified the most popular electronic cigarette (EC) refill fluids using an Internet survey and local and online sales information, quantified their flavor chemicals, and evaluated cytotoxicities of the fluids and flavor chemicals. "Berries/Fruits/Citrus" was the most popular EC refill fluid flavor category. Twenty popular EC refill fluids were purchased from local shops, and the ingredient flavor chemicals were identified and quantified by gas chromatography-mass spectrometry. Total flavor chemical concentrations ranged from 0.6 to 27.9 mg/ml, and in 95% of the fluids, total flavor concentration was greater than nicotine concentration. The 20 most popular refill fluids contained 99 quantifiable flavor chemicals; each refill fluid contained 22 to 47 flavor chemicals, most being esters. Some chemicals were found frequently, and several were present in most products. At a 1% concentration, 80% of the refill fluids were cytotoxic in the MTT assay. Six pure standards of the flavor chemicals found at the highest concentrations in the two most cytotoxic refill fluids were effective in the MTT assay, and ethyl maltol, which was in over 50% of the products, was the most cytotoxic. These data show that the cytotoxicity of some popular refill fluids can be attributed to their high concentrations of flavor chemicals.

New eight genes identified at the clinical multidrug-resistant Acinetobacter baumannii DMS06669 strain in a Vietnam hospital.

BACKGROUND: Acinetobacter baumannii is an important nosocomial pathogen that can develop multidrug resistance. In this study, we characterized the genome of the A. baumannii strain DMS06669 (isolated from the sputum of a male patient with hospital-acquired pneumonia) and focused on identification of genes relevant to antibiotic resistance. METHODS: Whole genome analysis of A. baumannii DMS06669 from hospital-acquired pneumonia patients included de novo assembly; gene prediction; functional annotation to public databases; phylogenetics tree construction and antibiotics genes identification. RESULTS: After sequencing the A. baumannii DMS06669 genome and performing quality control, de novo genome assembly was carried out, producing 24 scaffolds. Public databases were used for gene prediction and functional annotation to construct a phylogenetic tree of the DMS06669 strain with 21 other A. baumannii strains. A total of 18 possible antibiotic resistance genes, conferring resistance to eight distinct classes of antibiotics, were identified. Eight of these genes have not previously been reported to occur in A. baumannii. CONCLUSIONS: Our results provide important information regarding mechanisms that may contribute to antibiotic resistance in the DMS06669 strain, and have implications for treatment of patients infected with A. baumannii.

Potential health effects of electronic cigarettes: A systematic review of case reports.

The health risks associated with electronic cigarettes (ECs) are largely unknown. The purpose of this systematic review was to evaluate published case reports that deal with health effects attributed to EC use. An Internet search was conducted to identify case reports dealing with the effects of EC use on health. Twenty-six case reports representing 27 individuals (one study contained reports for two individuals) were published between April 2012 and January 2016, and these were grouped into categories of effect according to their health outcomes. Of the 27 individuals, 25 had negative effects subsequent to use or exposure to ECs and their refill fluids, while two reported improvement in chronic immune and gastrointestinal conditions. Three categories of negative health effects were identified: systemic effects, nicotine poisoning, and mechanical injury. Thirteen cases reported EC effects on different systems including: respiratory (6), gastrointestinal or developing intestine of an infant (3), cardiovascular (2), neurological (1), and immune (1). Twelve cases involved nicotine poisoning resulting from accidental (N = 3), misuse/abuse (N = 1), or suicidal/intentional ingestion (N = 8); four of these involved children and three resulted in adult fatalities. Two cases reported mechanical injury caused by an EC battery explosion. Most case reports show that the health of children and adults can be negatively affected by EC products and that if death does not occur, negative effects can be reversed. Data further indicate that EC use can cause negative health effects in previously healthy individuals and exacerbate pre-existing conditions.

Puffing topography and nicotine intake of electronic cigarette users.

BACKGROUND: Prior electronic cigarette (EC) topography data are based on two video analyses with limited parameters. Alternate methods for measuring topography are needed to understand EC use and nicotine intake. OBJECTIVES: This study evaluated EC topography with a CReSS Pocket device and quantified nicotine intake. METHODS: Validation tests on pressure drop, flow rate, and volume confirmed reliable performance of the CReSS Pocket device. Twenty participants used Blu Cigs and V2 Cigs for 10 minute intervals with a 10-15 minute break between brands. Brand order was reversed and repeated within 7 days Data were analyzed to determine puff duration, puff count, volume, flow rate, peak flow, and inter-puff interval. Nicotine intake was estimated from cartomizer fluid consumption and topography data. RESULTS: Nine patterns of EC use were identified. The average puff count and inter-puff interval were 32 puffs and 17.9 seconds. All participants, except one, took more than 20 puffs/10 minutes. The averages for puff duration (2.65 seconds/puff), volume/puff (51 ml/puff), total puff volume (1,579 ml), EC fluid consumption (79.6 mg), flow rate (20 ml/s), and peak flow rate (27 ml/s) were determined for 10-minute sessions. All parameters except total puff count were significantly different for Blu versus V2 EC. Total volume for Blu versus V2 was four-times higher than for conventional cigarettes. Average nicotine intake for Blu and V2 across both sessions was 1.2 ± 0.5 mg and 1.4 ± 0.7 mg, respectively, which is similar to conventional smokers. CONCLUSIONS: EC puffing topography was variable among participants in the study, but often similar within an individual between brands or days. Puff duration, inter-puff interval, and puff volume varied from conventional cigarette standards. Data on total puff volume and nicotine intake are consistent with compensatory usage of EC. These data can contribute to the development of a standard protocol for laboratory testing of EC products.

Health-related effects reported by electronic cigarette users in online forums.

BACKGROUND: The health effects caused by electronic cigarette (e-cigarette) use are not well understood. OBJECTIVE: Our purpose was to document the positive and negative short-term health effects produced by e-cigarette use through an analysis of original posts from three online e-cigarettes forums. METHODS: Data were collected into Microsoft Access databases and analyzed using Cytoscape association graphics, frequency distributions, and interactomes to determine the number and type of health effects reported, the organ systems affected the frequency of specific effects, and systems interactions. RESULTS: A total of 405 different symptoms due to e-cigarette use were reported from three forums. Of these, 78 were positive, 326 were negative, and one was neutral. While the reported health effects were similar in all three forums, the forum with the most posts was analyzed in detail. Effects, which were reported for 12 organ systems/anatomical regions, occurred most often in the mouth and throat and in the respiratory, neurological, sensory, and digestive systems. Users with negative symptoms often reported more than one symptom, and in these cases interactions were often seen between systems, such as the circulatory and neurological systems. Positive effects usually occurred singly and most frequently affected the respiratory system. CONCLUSIONS: This is the first compilation and analysis of the health effects reported by e-cigarette users in online forums. These data show that e-cigarette use can have wide ranging positive and negative effects and that online forums provide a useful resource for examining how e-cigarette use affects health.

Neuronavigation-guided focused ultrasound-induced blood-brain barrier opening: a preliminary study in swine.

BACKGROUND AND PURPOSE: FUS-induced BBB opening is a promising technique for noninvasive and local delivery of drugs into the brain. Here we propose the novel use of a neuronavigation system to guide the FUS-induced BBB opening procedure and investigate its feasibility in vivo in large animals. MATERIALS AND METHODS: We developed an interface between the neuronavigator and FUS to allow guidance of the focal energy produced by the FUS transducer. The system was tested in 29 swine by more than 40 sonication procedures and evaluated by MR imaging. Gd-DTPA concentration was quantitated in vivo by MR imaging R1 relaxometry and compared with ICP-OES assay. Brain histology after FUS exposure was investigated using H&E and TUNEL staining. RESULTS: Neuronavigation could successfully guide the focal beam, with precision comparable to neurosurgical stereotactic procedures (2.3 ± 0.9 mm). A FUS pressure of 0.43 MPa resulted in consistent BBB opening. Neuronavigation-guided BBB opening increased Gd-DTPA deposition by up to 1.83 mmol/L (a 140% increase). MR relaxometry demonstrated high correlation with ICP-OES measurements (r(2) = 0.822), suggesting that Gd-DTPA deposition can be directly measured by imaging. CONCLUSIONS: Neuronavigation provides sufficient precision for guiding FUS to temporally and locally open the BBB. Gd-DTPA deposition in the brain can be quantified by MR relaxometry, providing a potential tool for the in vivo quantification of therapeutic agents in CNS disease treatment.

Mining data on usage of electronic nicotine delivery systems (ENDS) from YouTube videos.

OBJECTIVE: The objective was to analyse and compare puff and exhalation duration for individuals using electronic nicotine delivery systems (ENDS) and conventional cigarettes in YouTube videos. METHODS: Video data from YouTube videos were analysed to quantify puff duration and exhalation duration during use of conventional tobacco-containing cigarettes and ENDS. For ENDS, comparisons were also made between 'advertisers' and 'non-advertisers', genders, brands of ENDS, and models of ENDS within one brand. RESULTS: Puff duration (mean =2.4 s) for conventional smokers in YouTube videos (N=9) agreed well with prior publications. Puff duration was significantly longer for ENDS users (mean =4.3 s) (N = 64) than for conventional cigarette users, and puff duration varied significantly among ENDS brands. For ENDS users, puff duration and exhalation duration were not significantly affected by 'advertiser' status, gender or variation in models within a brand. Men outnumbered women by about 5:1, and most users were between 19 and 35 years of age. CONCLUSIONS: YouTube videos provide a valuable resource for studying ENDS usage. Longer puff duration may help ENDS users compensate for the apparently poor delivery of nicotine from ENDS. As with conventional cigarette smoking, ENDS users showed a large variation in puff duration (range =1.9-8.3 s). ENDS puff duration should be considered when designing laboratory and clinical trials and in developing a standard protocol for evaluating ENDS performance.

Bcl-xL-inhibitory BH3 mimetics can induce a transient thrombocytopathy that undermines the hemostatic function of platelets.

BH3 mimetics are a new class of proapo-ptotic anticancer agents that have shown considerable promise in preclinical animal models and early-stage human trials. These agents act by inhibiting the pro-survival function of one or more Bcl-2-related proteins. Agents that inhibit Bcl-x(L) induce rapid platelet death that leads to thrombocytopenia; however, their impact on the function of residual circulating platelets remains unclear. In this study, we demonstrate that the BH3 mimetics, ABT-737 or ABT-263, induce a time- and dose-dependent decrease in platelet adhesive function that correlates with ectodomain shedding of the major platelet adhesion receptors, glycoprotein Ibα and glycoprotein VI, and functional down-regulation of integrin α(IIb)ß(3). Analysis of platelets from mice treated with higher doses of BH3 mimetics revealed the presence of a subpopulation of circulating platelets undergoing cell death that have impaired activation responses to soluble agonists. Functional analysis of platelets by intravital microscopy revealed a time-dependent defect in platelet aggregation at sites of vascular injury that correlated with an increase in tail bleeding time. Overall, these studies demonstrate that Bcl-x(L)-inhibitory BH3 mimetics not only induce thrombocytopenia but also a transient thrombocytopathy that can undermine the hemostatic function of platelets.