Stephanie S. Buehler

Effectiveness of Practices To Increase Timeliness of Providing Targeted Therapy for Inpatients with Bloodstream Infections: a Laboratory Medicine Best Practices Systematic Review and Meta-analysis

SUMMARY Background. Bloodstream infection (BSI) is a major cause of morbidity and mortality throughout the world. Rapid identification of bloodstream pathogens is a laboratory practice that supports strategies for rapid transition to direct targeted therapy by providing for timely and effective patient care. In fact, the more rapidly that appropriate antimicrobials are prescribed, the lower the mortality for patients with sepsis. Rapid identification methods may have multiple positive impacts on patient outcomes, including reductions in mortality, morbidity, hospital lengths of stay, and antibiotic use. In addition, the strategy can reduce the cost of care for patients with BSIs. Objectives. The purpose of this review is to evaluate the evidence for the effectiveness of three rapid diagnostic practices in decreasing the time to targeted therapy for hospitalized patients with BSIs. The review was performed by applying the Centers for Disease Control and Preventions (CDCs) Laboratory Medicine Best Practices Initiative (LMBP) systematic review methods for quality improvement (QI) practices and translating the results into evidence-based guidance (R. H. Christenson et al., Clin Chem 57:816–825, 2011, http://dx.doi.org/10.1373/clinchem.2010.157131). Search strategy. A comprehensive literature search was conducted to identify studies with measurable outcomes. A search of three electronic bibliographic databases (PubMed, Embase, and CINAHL), databases containing “gray” literature (unpublished academic, government, or industry evidence not governed by commercial publishing) (CIHI, NIHR, SIGN, and other databases), and the Cochrane database for English-language articles published between 1990 and 2011 was conducted in July 2011. Dates of search. The dates of our search were from 1990 to July 2011. Selection criteria. Animal studies and non-English publications were excluded. The search contained the following medical subject headings: bacteremia; bloodstream infection; time factors; health care costs; length of stay; morbidity; mortality; antimicrobial therapy; rapid molecular techniques, polymerase chain reaction (PCR); in situ hybridization, fluorescence; treatment outcome; drug therapy; patient care team; pharmacy service, hospital; hospital information systems; Gram stain; pharmacy service; and spectrometry, mass, matrix-assisted laser desorption-ionization. Phenotypic as well as the following key words were searched: targeted therapy; rapid identification; rapid; Gram positive; Gram negative; reduce(ed); cost(s); pneumoslide; PBP2; tube coagulase; matrix-assisted laser desorption/ionization time of flight; MALDI TOF; blood culture; EMR; electronic reporting; call to provider; collaboration; pharmacy; laboratory; bacteria; yeast; ICU; and others. In addition to the electronic search being performed, a request for unpublished quality improvement data was made to the clinical laboratory community. Main results. Rapid molecular testing with direct communication significantly improves timeliness compared to standard testing. Rapid phenotypic techniques with direct communication likely improve the timeliness of targeted therapy. Studies show a significant and homogeneous reduction in mortality associated with rapid molecular testing combined with direct communication. Authors conclusions. No recommendation is made for or against the use of the three assessed practices of this review due to insufficient evidence. The overall strength of evidence is suggestive; the data suggest that each of these three practices has the potential to improve the time required to initiate targeted therapy and possibly improve other patient outcomes, such as mortality. The meta-analysis results suggest that the implementation of any of the three practices may be more effective at increasing timeliness to targeted therapy than routine microbiology techniques for identification of the microorganisms causing BSIs. Based on the included studies, results for all three practices appear applicable across multiple microorganisms, including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-sensitive S. aureus (MSSA), Candida species, and Enterococcus species.

Role of sweet and other flavours in liking and disliking of electronic cigarettes

Objective To examine the extent to which the perception of sweet and other flavours is associated with liking and disliking of flavoured electronic cigarettes (e-cigarettes). Methods 31 participants (13 females/18 males; 12 sole/19 dual users) vaped 6 commercially available flavours of blu Tanks: Classic Tobacco (CT), Magnificent Menthol (MM), Cherry Crush (CC), Vivid Vanilla (VV), Piña Colada (PC) and Peach Schnapps (PS); all ‘medium’ strength, 12 mg/mL nicotine concentration. For each flavoured e-cigarette, participants first rated liking/disliking on the Labeled Hedonic Scale, followed by perceived intensities of sweetness, coolness, bitterness, harshness and specific flavour on the generalised version of the Labeled Magnitude Scale. The psychophysical testing was conducted individually in an environmental chamber. Results PC was perceived as sweetest and liked the most; CT was perceived as least sweet and liked the least. Across all flavours, liking was correlated with sweetness (r=0.31), coolness (r=0.25), bitterness (r=−0.25) and harshness (r=−0.29, all p<0.001). Specifically, liking was positively correlated with sweetness of PS (r=0.56, p=0.001) and PC (r=0.36, p=0.048); and with coolness of MM, CT and VV (r=0.41–0.52, p<0.05). In contrast, harshness was negatively correlated with liking for CC, PC and PS (r=0.37–0.40, p<0.05). In a multivariate model, sweetness had the greatest positive impact on liking followed by coolness; harshness had the greatest negative impact on liking. Conclusions Our findings indicate that bitterness and harshness, most likely from nicotine, have negative impacts on the liking of e-cigarettes, but the addition of flavourants that elicit sweetness or coolness generally improves liking. The results suggest that flavours play an important role in e-cigarette preference and most likely use.

Concentrations of Selected Chemical Species in the Airliner Cabin Environment

Reported here are the concentrations of carbon monoxide (CO), carbon dioxide (CO2), fine particulate matter (PM2.5), ozone (O3), and volatile organic compounds (VOC) measured in the cabin and bleed air, and semivolatile organic compounds (SVOC) measured in only the cabin air, on four different commercial airliners in revenue service within the continental United States. Sampling was conducted over various time intervals including boarding, takeoff, cruise, and descent. Bleed air CO was never measured above the instrument detection limit of 2 ppm, and cabin CO only exceeded the detection limit briefly on one flight. The concentration of CO2 in bleed air was at ambient background levels for all flights, and cabin concentrations of CO2 were always well below the 5000 ppm Federal Aviation Administration standard. PM2.5 concentrations were well below levels of concern, with the exception of boarding and deplaning during one flight only. Ozone was present at elevated levels in bleed air compared to cabin air, and was higher in the cabin during cruise than during boarding or deplaning for all four flights. Ozone cabin air/bleed air concentration ratios ranged from 0.37 to 0.80, and on one flight the cabin ozone concentration exceeded the National Ambient Air Quality Standard (NAAQS) of 0.12 ppm for over one hour, and nearly exceeded the FAA standard of 0.1 ppm for a three-hour average. Ethanol and acetone were the dominant VOCs observed on all flights; other VOCs, such as toluene, tetrachloroethene, and 1,4-dichlorobenzene were found, but at significantly lower concentrations. The polycyclic aromatic hydrocarbons naphthalene, acenaphthene, and phenanthrene were found in the cabin air on all flights. Other SVOCs, such as the pesticide permethrin, were detected, but isomers of tricresyl phosphate were not. Concentrations reported here are compared to applicable regulatory standards and to similar measurements performed during previous cabin air quality studies.

Mentholation affects the cigarette microbiota by selecting for bacteria resistant to harsh environmental conditions and selecting against potential bacterial pathogens

BackgroundThere is a paucity of data regarding the microbial constituents of tobacco products and their impacts on public health. Moreover, there has been no comparative characterization performed on the bacterial microbiota associated with the addition of menthol, an additive that has been used by tobacco manufacturers for nearly a century. To address this knowledge gap, we conducted bacterial community profiling on tobacco from user- and custom-mentholated/non-mentholated cigarette pairs, as well as a commercially-mentholated product. Total genomic DNA was extracted using a multi-step enzymatic and mechanical lysis protocol followed by PCR amplification of the V3-V4 hypervariable regions of the 16S rRNA gene from five cigarette products (18 cigarettes per product for a total of 90 samples): Camel Crush, user-mentholated Camel Crush, Camel Kings, custom-mentholated Camel Kings, and Newport Menthols. Sequencing was performed on the Illumina MiSeq platform and sequences were processed using the Quantitative Insights Into Microbial Ecology (QIIME) software package.ResultsIn all products, Pseudomonas was the most abundant genera and included Pseudomonas oryzihabitans and Pseudomonas putida, regardless of mentholation status. However, further comparative analysis of the five products revealed significant differences in the bacterial compositions across products. Bacterial community richness was higher among non-mentholated products compared to those that were mentholated, particularly those that were custom-mentholated. In addition, mentholation appeared to be correlated with a reduction in potential human bacterial pathogens and an increase in bacterial species resistant to harsh environmental conditions.ConclusionsTaken together, these data provide preliminary evidence that the mentholation of commercially available cigarettes can impact the bacterial community of these products.

Determination of nicotine, glycerol, propylene glycol and water in electronic cigarette fluids using quantitative 1H NMR

Electronic cigarettes (e-cigarettes) or electronic nicotine delivery systems allow the user to inhale nicotine without burning or heating tobacco, and their use has been described as safer than tobacco cigarettes and as a means to smoking cessation. As ecigarettes are currently unregulated in the USA, studies have been undertaken to determine whether their use poses any potential health hazards. The fluid (e-liquid) contained within e-cigarettes has been described as containing less than 10wt% water and 50– 99wt% organic solvent. The manufacturer’s labels indicate that they contain water with the organic solvent being 1,2-propylene glycol (PG), and/or vegetable glycerol (VG), referred to here as glycerol as its origin was not verified. The e-liquids usually contain nicotine and flavorings, too. However, the actual chemical composition and amounts of these components vary considerably in individual e-liquids. These factors can play an important role in potential toxic and carcinogenic exposures from e-cigarette use. For example, e-liquids are corrosive to the metal components of the e-cigarette devices and may lead to inhalation of high levels of tin, lead and nickel. Being able to quantitatively determine the composition of the primary carrier solution of an e-liquid is an important aspect for understanding the potential health implications of their use. Because of nicotine’s addictive properties, quantifying its concentration is important for determining the addiction potential of an e-liquid. However, published data indicates that manufacturer’s labeling of e-liquid nicotine content does not necessarily agree with the independently measured nicotine content. Reported analytical methods for e-liquids are predominately based on gas chromatography (GC) and HPLC quantification techniques. However, none of the reported methods has been used to simultaneously determine the amount of water, PG, glycerol and nicotine that may be present in e-liquids in a single analysis. The use of H NMR for the quantitative analysis of e-cigarette chemical components has been reported in a few cases with quantification achieved by comparison to an external calibration curve. None of these methods included the use of an internal standard in the NMR sample for quantification. Each of these used a solvent (D2O, DMSO-d6) in which hydrogen/deuterium exchange can occur, making these solvents unsuitable for determining the amount ofwater present in the e-liquid. Whenwaterwasmeasured, a separate analysis, Karl Fischer coulometric titration, was used. As part of our ongoing investigations into the chemicals contained in e-liquids, we considered H NMR as a single analytical method to identify and quantify the most abundant components, PG, glycerol, water and nicotine. These chemicals were selected because variation in the relative proportions of these components may influence the amount of nicotine, flavorings and the type or amount of byproducts inhaled by the user during vaping. In pursuing H NMR, proper selection of the solvent was critical. Not only did the solvent have to dissolve the e-liquids at a concentration sufficient to readily determine the relatively low concentration of nicotine present in the e-liquid (≤2.4mg/ml), but it could not possess exchangeable protons, which would interfere with determining the amount of water present. Additionally, the residual H solvent signals could not interfere with those of the e-liquid components. To fulfill these requirements, perdeuterated N,N-dimethylformamide (DMF-d7) was selected as the solvent. We also selected to use an internal standard, 1,2,4,5-tetrachloro-3nitrobenzene, to support our quantitation efforts. This solvent and internal standard combination was tested first against a surrogate e-liquid (prepared from HPLC water and/or laboratory-grade PG, glycerol and nicotine) and then applied to e-liquids removed from non-refillable, retail e-cigarettes cartridges as well as those available for refillable e-cigarette cartridges.

Temporal Variations in Cigarette Tobacco Bacterial Community Composition and Tobacco-Specific Nitrosamine Content Are Influenced by Brand and Storage Conditions

Tobacco products, specifically cigarettes, are home to microbial ecosystems that may play an important role in the generation of carcinogenic tobacco-specific nitrosamines (TSNAs), as well as the onset of multiple adverse human health effects associated with the use of these products. Therefore, we conducted time-series experiments with five commercially available brands of cigarettes that were either commercially mentholated, custom-mentholated, user-mentholated, or non-mentholated. To mimic user storage conditions, the cigarettes were incubated for 14 days under three different temperatures and relative humidities (i.e., pocket, refrigerator, and room). Overall, 360 samples were collected over the course of 2 weeks and total DNA was extracted, PCR amplified for the V3V4 hypervariable region of the 16S rRNA gene and sequenced using Illumina MiSeq. A subset of samples (n = 32) was also analyzed via liquid chromatography with tandem mass spectrometry for two TSNAs: N’-nitrosonornicotine (NNN) and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Comparative analyses of the five tobacco brands revealed bacterial communities dominated by Pseudomonas, Pantoea, and Bacillus, with Pseudomonas relatively stable in abundance regardless of storage condition. In addition, core bacterial operational taxonomic units (OTUs) were identified in all samples and included Bacillus pumilus, Rhizobium sp., Sphingomonas sp., unknown Enterobacteriaceae, Pantoea sp., Pseudomonas sp., Pseudomonas oryzihabitans, and P. putida. Additional OTUs were identified that significantly changed in relative abundance between day 0 and day 14, influenced by brand and storage condition. In addition, small but statistically significant increases in NNN levels were observed in user- and commercially mentholated brands between day 0 and day 14 at pocket conditions. These data suggest that manufacturing and user manipulations, such as mentholation and storage conditions, may directly impact the microbiome of cigarette tobacco as well as the levels of carcinogens.

Custom mentholation of commercial cigarettes for research purposes

Highlights • We developed a simple and repeatable technique to create research cigarettes that differ only in menthol content.• We qualified a method by which the menthol and nicotine content of a cigarette can be quantified.• We investigated the rate of loss of menthol from our custom-mentholated cigarettes over time during storage.• We are currently using these custom-mentholated cigarettes in human exposure studies.• Our custom-mentholated cigarettes will help to elucidate the effects of menthol on the toxicity of tobacco smoke.

Little Cigars vs 3R4F Cigarette: Physical Properties and HPHC Yields

Objective Our objective was to characterize physical properties and semivolatile harmful and potentially harmful constituent yields in the mainstream smoke (MSS) of 4 popular little cigars compared to the 3R4F reference cigarette. Methods We used the ISO and Canadian Intense Regimen protocols to generate MSS for Cheyenne (Full Flavor and Menthol) and Swisher Sweets (Original and Sweet Cherry) little cigars; and the 3R4F. We examined physical properties such as length, tobacco filler mass, pressure drop, and ventilation for each product. Nicotine, benzo[a]pyrene, and tobacco-specific nitrosamine (TSNA) yields were determined in the MSS. Results Little cigars were longer (~15mm), contained more tobacco filler (100-200 mg), and had a higher pressure drop (~1.3X) compared to the 3R4F. Ventilation holes were found only on the filter paper of the 3R4F. Nicotine transmitted to the MSS was similar for all products under the intense smoking protocol. The highest yields of TSNAs and benzo(a)pyrene were measured for the little cigars. Conclusions Little cigars may deliver similar levels of nicotine but higher levels of carcinogens to the MSS compared to cigarettes. Thus, previous reports on the toxicity of tobacco smoke based on cigarettes might not apply to little cigar products.