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Abstract Background Physiotherapy for people with low back pain frequently includes assessment and modification of lumbo-pelvic movement. Interventions commonly aim to restore normal movement and thereby reduce pain and improve activity limitation. The objective of this systematic review was to investigate: (i) the effect of movement-based interventions on movement patterns (muscle activation, lumbo-pelvic kinematics or postural patterns) of people with low back pain (LBP), and (ii) the relationship between changes in movement patterns and subsequent changes in pain and activity limitation. Methods MEDLINE, Cochrane Central, EMBASE, AMI, CINAHL, Scopus, AMED, ISI Web of Science were searched from inception until January 2012. Randomised controlled trials or controlled clinical trials of people with LBP were eligible for inclusion. The intervention must have been designed to influence (i) muscle activity patterns, (ii) lumbo-pelvic kinematic patterns or (iii) postural patterns, and included measurement of such deficits before and after treatment, to allow determination of the success of the intervention on the lumbo-pelvic movement. Twelve trials (25% of retrieved studies) met the inclusion criteria. Two reviewers independently identified, assessed and extracted data. The PEDro scale was used to assess method quality. Intervention effects were described using standardised differences between group means and 95% confidence intervals. Results The included trials showed inconsistent, mostly small to moderate intervention effects on targeted movement patterns. There was considerable heterogeneity in trial design, intervention type and outcome measures. A relationship between changes to movement patterns and improvements in pain or activity limitation was observed in one of six studies on muscle activation patterns, one of four studies that examined the flexion relaxation response pattern and in two of three studies that assessed lumbo-pelvic kinematics or postural characteristics. Conclusions Movement-based interventions were infrequently effective for changing observable movement patterns. A relationship between changes in movement patterns and improvement in pain or activity limitation was also infrequently observed. No independent studies confirm any observed relationships. Challenges for future research include defining best methods for measuring (i) movement aberrations, (ii) improvements in movements, and (iii) the relationship between changes in how people move and associated changes in other health indicators such as activity limitation.

Abstract Introduction Chiropractors commonly provide care to people with acute low-back pain (LBP). The aim of this survey was to determine how chiropractors intend to support and manage people with acute LBP and if this management is in accordance with two recommendations from an Australian evidence-based acute LBP guideline. The two recommendations were directed at minimising the use of plain x-ray and encouraging the patient to stay active. Methods This is a cross sectional survey of chiropractors in Australia. This paper is part of the ALIGN study in which a targeted implementation strategy was developed to improve the management of acute LBP in a chiropractic setting. This implementation strategy was subsequently tested in a cluster randomised controlled trial. In this survey phase of the ALIGN study we approached a random sample of 880 chiropractors in three States of Australia. The mailed questionnaire consisted of five patient vignettes designed to represent people who would typically present to chiropractors with acute LBP. Four vignettes represented people who, according to the guideline, would not require a plain lumbar x-ray, and one vignette represented a person with a suspected vertebral fracture. Respondents were asked, for each vignette, to indicate which investigation(s) they would order, and which intervention(s) they would recommend or undertake. Results Of the 880 chiropractors approached, 137 were deemed ineligible to participate, mostly because they were not currently practising, or mail was returned to sender. We received completed questionnaires from 274 chiropractors (response rate of 37%). Male chiropractors made up 66% of respondents, 75% practised in an urban location and their mean number of years in practice was 15. Across the four vignettes where an x-ray was not indicated 68% (95% Confidence Intervals (CI): 64%, 71%) of chiropractors responded that they would order or take an x-ray. In addition 51% (95%CI: 47%, 56%) indicated they would give advice to stay active when it was indicated. For the vignette where a fracture was suspected, 95% (95% CI: 91%, 97%) of chiropractors would order an x-ray. Conclusion The intention of chiropractors surveyed in this study shows low adherence to two recommendations from an evidence-based guideline for acute LBP. Quality of care for these patients could be improved through effective implementation of evidence-based guidelines. Further research to find cost-effective methods to increase implementation is warranted.

Abstract Background Aquatic and land based exercise are frequently prescribed to maintain function for people with arthritis. The relative efficacy of these rehabilitation strategies for this population has not been established. This review investigated the effects of aquatic compared to land based exercise on function, mobility or participants' perception of programs for people with arthritis. Methods Medline, CINAHL, AMED and the Cochrane Central Register of Controlled Clinical Trials were searched up to July 2010. Ten randomised, controlled clinical trials that compared land to aquatic exercise for adults with arthritis were included. Study quality was assessed with the PEDro scale. Data relevant to the review question were systematically extracted by two independent reviewers. Standardised mean differences between groups for key outcomes were calculated. Meta-analyses were performed for function, mobility and indices that pooled health outcomes across multiple domains. Results No differences in outcomes were observed for the two rehabilitation strategies in meta-analysis. There was considerable variability between trials in key program characteristics including prescribed exercises and design quality. Components of exercise programs were poorly reported by the majority of trials. No research was found that examined participant preferences for aquatic compared to land based exercise, identifying this as an area for further research. Conclusion Outcomes following aquatic exercise for adults with arthritis appear comparable to land based exercise. When people are unable to exercise on land, or find land based exercise difficult, aquatic programs provide an enabling alternative strategy.

Abstract Background Variability between clinical practice guideline recommendations and actual clinical practice exists in many areas of health care. A 2004 systematic review examining the effectiveness of guideline implementation interventions concluded there was a lack of evidence to support decisions about effective interventions to promote the uptake of guidelines. Further, the review recommended the use of theory in the development of implementation interventions. A clinical practice guideline for the management of acute low-back pain has been developed in Australia (2003). Acute low-back pain is a common condition, has a high burden, and there is some indication of an evidence-practice gap in the allied health setting. This provides an opportunity to develop and test a theory-based implementation intervention which, if effective, may provide benefits for patients with this condition. Aims This study aims to estimate the effectiveness of a theory-based intervention to increase allied health practitioners' (physiotherapists and chiropractors in Victoria, Australia) compliance with a clinical practice guideline for acute non-specific low back pain (LBP), compared with providing practitioners with a printed copy of the guideline. Specifically, our primary objectives are to establish if the intervention is effective in reducing the percentage of acute non-specific LBP patients who are either referred for or receive an x-ray, and improving mean level of disability for patients three months post-onset of acute LBP. Methods The design of the study is a cluster randomised trial. Restricted randomisation was used to randomise 210 practices (clusters) to an intervention or control group. Practitioners in the control group received a printed copy of the guideline. Practitioners in the intervention group received a theory-based intervention developed to address prospectively identified barriers to practitioner compliance with the guideline. The intervention primarily consisted of an educational symposium. Patients aged 18 years or older who visit a participating practitioner for acute non-specific LBP of less than three months duration over a two-week data collection period, three months post the intervention symposia, are eligible for inclusion. Sample size calculations are based on recruiting between 15 to 40 patients per practice. Outcome assessors will be blinded to group allocation. Trial registration Australian New Zealand Clinical Trials Registry ACTRN12609001022257 (date registered 25th November 2009)

Abstract Background The de Morton Mobility Index (DEMMI) is a new mobility instrument that overcomes the limitations of existing instruments. It is the first mobility instrument that accurately measures the mobility of all older adults. The aim of this study was to provide a detailed report of investigations of the validity, responsiveness to change and minimal clinically important difference (MCID) of the DEMMI during its development in an older acute medical population. Methods This study was conducted using a head to head comparison design in two independent samples of older acute medical patients (development sample, n = 86; validation sample, n = 106). Consecutive patients (≥ 65 years) were assessed using the DEMMI, Barthel Index (BI) and Hierarchical Assessment of Balance and Mobility (HABAM) within 48 hours of hospital admission and discharge. Convergent and discriminant validity were investigated using Spearman's rho and known groups validity was investigated using a independent t test to compare DEMMI scores for patients who were discharged to home compared to inpatient rehabilitation. Criterion and distribution based methods were employed for estimating instrument responsiveness to change and the MCID. Results Significant moderate to high correlations were identified between DEMMI and BI scores (r = 0.76 and r = 0.68) and DEMMI and HABAM scores (r = 0.91 and r = 0.92) in both samples. In both samples, DEMMI scores for patients who were discharged to home were significantly higher than for patients discharged to inpatient rehabilitation and provided evidence of known groups validity. Patients who were discharged to inpatient rehabilitation (n = 8) had a mean DEMMI score of 50.75 (sd = 11.29) at acute hospital discharge compared to patients who were discharged to home (n = 70) with a mean DEMMI score of 62.14 (sd = 18.41). MCID estimates were similar across samples using distribution and criterion based methods. The MCID for the DEMMI was 10 points on the 100 point interval scale. The DEMMI was significantly more responsive to change than the BI using criterion and distribution based methods in the validation sample. Conclusion This study has validated the DEMMI in two independent samples of older acute medical patients. Estimates of its responsiveness and MCID have also been established. This study confirms that the DEMMI overcomes the limitations of the BI and HABAM and provides an advanced method for objectively assessing mobility for older acute medical patients.

Abstract Background There is considerable clinician and researcher interest in whether the outcomes for patients with low back pain, and the efficiency of the health systems that treat them, can be improved by 'subgrouping research'. Subgrouping research seeks to identify subgroups of people who have clinically important distinctions in their treatment needs or prognoses. Due to a proliferation of research methods and variability in how subgrouping results are interpreted, it is timely to open discussion regarding a conceptual framework for the research designs and statistical methods available for subgrouping studies (a method framework). The aims of this debate article are: (1) to present a method framework to inform the design and evaluation of subgrouping research in low back pain, (2) to describe method options when investigating prognostic effects or subgroup treatment effects, and (3) to discuss the strengths and limitations of research methods suitable for the hypothesis-setting phase of subgroup studies. Discussion The proposed method framework proposes six phases for studies of subgroups: studies of assessment methods, hypothesis-setting studies, hypothesis-testing studies, narrow validation studies, broad validation studies, and impact analysis studies. This framework extends and relabels a classification system previously proposed by McGinn et al (2000) as suitable for studies of clinical prediction rules. This extended classification, and its descriptive terms, explicitly anchor research findings to the type of evidence each provides. The inclusive nature of the framework invites appropriate consideration of the results of diverse research designs. Method pathways are described for studies designed to test and quantify prognostic effects or subgroup treatment effects, and examples are discussed. The proposed method framework is presented as a roadmap for conversation amongst researchers and clinicians who plan, stage and perform subgrouping research. Summary This article proposes a research method framework for studies of subgroups in low back pain. Research designs and statistical methods appropriate for sequential phases in this research are discussed, with an emphasis on those suitable for hypothesis-setting studies of subgroups of people seeking care.

Abstract Background Non-specific chronic low back pain (NSCLBP) has become a significant problem due to high healthcare utilization, rising costs of care and perceived limitations of effectiveness of many current treatments. Systematic reviews have repeatedly concluded that, on average across participants, exercise for NSCLBP appears effective in decreasing pain and improving function. Not all people with NSCLBP benefit from exercise programs and it would assist care-providers and care-seekers if factors that impact on program effectiveness and success were identified. Methods and design The study will be a randomised controlled trial comparing an exercise rehabilitation program informed by a participant preferences questionnaire compared to a program without this guideline for patients with chronic low back pain. A sample of 150 patients will be recruited in Melbourne, Australia through community-based healthcare clinics that provide supervised exercise rehabilitation programs for people with non-specific chronic low back pain. Clinicians will be randomly assigned to exercise preferences questionnaire or no questionnaire and participants will be allocated in a concealed manner. A qualitative focus group study of exercise instructor feedback about the exercise preferences instrument will be embedded in the research design. Two qualitative focus group studies will also be conducted for participants in the intervention and the control groups to obtain feedback about participants' experiences of the two types of exercise programs. The primary outcomes will be functional ability, pain, fear avoidance, exercise adherence. Discussion This trial will evaluate the effectiveness of individualised exercise prescription compared to usual exercise prescription for NSCLP and, using feedback following the trial, refine the exercise preferences questionnaire.

Abstract Background Existing instruments for measuring mobility are inadequate for accurately assessing older people across the broad spectrum of abilities. Like other indices that monitor critical aspects of health such as blood pressure tests, a mobility test for all older acute medical patients provides essential health data. We have developed and validated an instrument that captures essential information about the mobility status of older acute medical patients. Methods Items suitable for a new mobility instrument were generated from existing scales, patient interviews and focus groups with experts. 51 items were pilot tested on older acute medical inpatients. An interval-level unidimensional mobility measure was constructed using Rasch analysis. The final item set required minimal equipment and was quick and simple to administer. The de Morton Mobility Index (DEMMI) was validated on an independent sample of older acute medical inpatients and its clinimetric properties confirmed. Results The DEMMI is a 15 item unidimensional measure of mobility. Reliability (MDC90), validity and the minimally clinically important difference (MCID) of the DEMMI were consistent across independent samples. The MDC90 and MCID were 9 and 10 points respectively (on the 100 point Rasch converted interval DEMMI scale). Conclusion The DEMMI provides clinicians and researchers with a valid interval-level method for accurately measuring and monitoring mobility levels of older acute medical patients. DEMMI validation studies are underway in other clinical settings and in the community. Given the ageing population and the importance of mobility for health and community participation, there has never been a greater need for this instrument.

Abstract Background Independent mobility is a key factor in determining readiness for discharge for older patients following acute hospitalisation and has also been identified as a predictor of many important outcomes for this patient group. This review aimed to identify a physical performance instrument that is not disease specific that has the properties required to accurately measure and monitor the mobility of older medical patients in the acute hospital setting. Methods Databases initially searched were Medline, Cinahl, Embase, Cochrane Database of Systematic Reviews and the Cochrane Central Register of Controlled Trials without language restriction or limits on year of publication until July 2005. After analysis of this yield, a second step was the systematic search of Medline, Cinahl and Embase until August 2005 for evidence of the clinical utility of each potentially suitable instrument. Reports were included in this review if instruments described had face validity for measuring from bed bound to independent levels of ambulation, the items were suitable for application in an acute hospital setting and the instrument required observation (rather than self-report) of physical performance. Evidence of the clinical utility of each potentially suitable instrument was considered if data on measurement properties were reported. Results Three instruments, the Elderly Mobility Scale (EMS), Hierarchical Assessment of Balance and Mobility (HABAM) and the Physical Performance Mobility Examination (PPME) were identified as potentially relevant. Clinimetric evaluation indicated that the HABAM has the most desirable properties of these three instruments. However, the HABAM has the limitation of a ceiling effect in an older acute medical patient population and reliability and minimally clinically important difference (MCID) estimates have not been reported for the Rasch refined HABAM. These limitations support the proposal that a new mobility instrument is required for older acute medical patients. Conclusion No existing instrument has the properties required to accurately measure and monitor mobility of older acute medical patients.

Current data-dependent acquisition (DDA) approaches select precursor ions for tandem mass spectrometry (MS/MS) characterization based on their absolute intensity, known as a TopN approach. Low-abundance species may not be identified as biomarkers in a TopN approach. Herein, a new DDA approach is proposed, DiffN, which uses the relative differential intensity of ions between two samples to selectively target species undergoing the largest fold changes for MS/MS. Using a dual nano-electrospray (nESI) ionization source which allows samples contained in separate capillaries to be analyzed in parallel, the DiffN approach was developed and validated with well-defined lipid extracts. A dual nESI source and DiffN DDA approach was applied to quantify the differences in lipid abundance between two colorectal cancer cell lines. The SW480 and SW620 lines represent a matched pair from the same patient: the SW480 cells from a primary tumor and the SW620 cells from a metastatic lesion. A comparison of TopN and DiffN DDA approaches on these cancer cell samples highlights the ability of DiffN to increase the likelihood of biomarker discovery and the decreased probability of TopN to efficiently select lipid species that undergo large fold changes. The ability of the DiffN approach to efficiently select precursor ions of interest makes it a strong candidate for lipidomic analyses. This DiffN DDA approach may also apply to other molecule classes (e.g., other metabolites or proteins) that are amenable to shotgun analyses.

Introduction: The use of flavors in electronic cigarettes appeals to adults and never-smoking youth. Consumption has rapidly increased over the last decade, and in the U.S. market alone, there are over 8000 unique flavors. The U.S. Food and Drug Administration (FDA) has begun to regulate e-liquids, but many have not been tested, and their impact, both at the cellular level, and on human health remains unclear., Methods: We tested e-liquids on the human cell line HEK293T and measured toxicity, mitochondrial membrane potential (ΔΨ  m), reactive oxygen species production (ROS), and cellular membrane potential (Vm) using high-throughput screening (HTS) approaches. Our HTS efforts included single-dose and 16-point dose-response curves, which allowed testing of ≥90 commercially available e-liquids in parallel to provide a rapid assessment of cellular effects as a proof of concept for a fast, preliminary toxicity method. We also investigated the chemical composition of the flavors via gas chromatography-mass spectrometry., Results: We found that e-liquids caused a decrease in ΔΨ  m and Vm and an increase in ROS production and toxicity in a dose-dependent fashion. In addition, the presence of five specific chemical components: vanillin, benzyl alcohol, acetoin, cinnamaldehyde, and methyl-cyclopentenolone, but not nicotine, were linked with the changes observed in the cellular traits studied., Conclusion: Our data suggest that ΔΨ  m, ROS, Vm, and toxicity may be indicative of the extent of cell death upon e-liquid exposure. Further research on the effect of flavors should be prioritized to help policy makers such as the FDA to regulate e-liquid composition., Implications: E-liquid cellular toxicity can be predicted using parameters amenable to HTS. Our data suggest that ΔΨ  m, ROS, Vm, and toxicity may be indicative of the extent of cell death upon e-liquid exposure, and this toxicity is linked to the chemical composition, that is, flavoring components. Further research on the effect of flavors should be prioritized to help policy makers such as the FDA to regulate e-liquid composition., (© The Author(s) 2020. Published by Oxford University Press on behalf of the Society for Research on Nicotine and Tobacco.)

Smoking remains a leading cause of preventable morbidity and mortality worldwide. Despite a downward trend in cigarette use, less-regulated tobacco products, such as cigarillos, which are often flavored to appeal to specific demographics, such as younger people, are becoming increasingly popular. Cigar/cigarillo smoking has been considered a safer alternative to cigarettes; however, the health risks associated with cigar in comparison with cigarette smoking are not well understood. To address this knowledge gap, we characterized the effects of multiple brands of cigarillos on the airway epithelium using ex vivo and in vivo models. To analyze these effects, we assessed the cellular viability and integrity of smoke-exposed primary airway cell cultures. We also investigated the protein compositions of apical secretions from cigarillo-exposed airway epithelial cultures and BAL fluid of cigarillo-exposed mice through label-free quantitative proteomics and determined the chemical composition of smoke collected from the investigated cigarillo products. We found that cigarillo smoke exerts similar or greater effects than cigarette smoke in terms of reduced cell viability; altered protein levels, including those of innate immune proteins; induced oxidative-stress markers; and greater nicotine delivery to cells. The analysis of the chemical composition of the investigated cigarillo products revealed differences that might be linked to the differential effects of these products on cell viability and protein abundance profiles, which have been associated with a range of health risks in the context of airway biology. These findings contradict the assumption that cigarillos might be safer and less harmful than cigarettes. Instead, our results indicate that cigarillo smoke is associated with equal or greater health risks and the same or increased airway toxicity compared with cigarette smoke.

Tandem mass spectrometry (MS/MS) is a highly sensitive and selective method for the detection of tumor-associated peptide antigens. These short, nontryptic sequences may lack basic residues, resulting in the formation of predominantly [peptide + H] + ions in electrospray. These singly charged ions tend to undergo inefficient dissociation, leading to issues in sequence determination. Addition of alkali metal salts to the electrospray solvent can drive the formation of [peptide + H + metal] 2+ ions that have enhanced dissociation characteristics relative to [peptide + H] + ions. Both previously identified tumor-associated antigens and predicted neoantigen sequences were investigated. The previously reported rearrangement mechanism in MS/MS of sodium-cationized peptides is applied here to demonstrate complete C-terminal sequencing of tumor-associated peptide antigens. Differential ion mobility spectrometry (DIMS) is shown to selectively enrich [peptide + H + metal] 2+ species by filtering out singly charged interferences at relatively low field strengths, offsetting the decrease in signal intensity associated with the use of alkali metal cations.

E-cigarettes are noncombustible, electronic nicotine-delivery devices that aerosolize an e-liquid, i.e., nicotine, in a propylene glycol-vegetable glycerin vehicle that also contains flavors. While the effects of nicotine are relatively well understood, more information regarding the potential biological effects of the other e-liquid constituents is needed. This is a serious concern, because e-liquids are available in >7,000 distinct flavors. We previously demonstrated that many e-liquids affect cell growth/viability through an unknown mechanism. Since Ca 2+ is a ubiquitous second messenger that regulates cell growth, we characterized the effects of e-liquids on cellular Ca 2+ homeostasis. To better understand the extent of this effect, we screened e-liquids for their ability to alter cytosolic Ca 2+ levels and found that 42 of 100 flavored e-liquids elicited a cellular Ca 2+ response. Banana Pudding (BP) e-liquid, a representative e-liquid from this group, caused phospholipase C activation, endoplasmic reticulum (ER) Ca 2+ release, store-operated Ca 2+ entry (SOCE), and protein kinase C (PKCα) phosphorylation. However, longer exposures to BP e-liquid depleted ER Ca 2+ stores and inhibited SOCE, suggesting that this e-liquid may alter Ca 2+ homeostasis by short- and long-term mechanisms. Since dysregulation of Ca 2+ signaling can cause chronic inflammation, ER stress, and abnormal cell growth, flavored e-cigarette products that can elicit cell Ca 2+ responses should be further screened for potential toxicity.

T-cell responses to minor histocompatibility antigens (mHAs) mediate both antitumor immunity (graft-versus-leukemia [GVL]) and graft-versus-host disease (GVHD) in allogeneic stem cell transplant. Identifying mHAs with high allele frequency, tight binding affinity to common HLA molecules, and narrow tissue restriction could enhance immunotherapy against leukemia. Genotyping and HLA allele data from 101 HLA-matched donor-recipient pairs (DRPs) were computationally analyzed to predict both class I and class II mHAs likely to induce either GVL or GVHD. Roughly twice as many mHAs were predicted in HLA-matched unrelated donor (MUD) stem cell transplantation (SCT) compared with HLA-matched related transplants, an expected result given greater genetic disparity in MUD SCT. Computational analysis predicted 14 of 18 previously identified mHAs, with 2 minor antigen mismatches not being contained in the patient cohort, 1 missed mHA resulting from a noncanonical translation of the peptide antigen, and 1 case of poor binding prediction. A predicted peptide epitope derived from GRK4, a protein expressed in acute myeloid leukemia and testis, was confirmed by targeted differential ion mobility spectrometry-tandem mass spectrometry. T cells specific to UNC-GRK4-V were identified by tetramer analysis both in DRPs where a minor antigen mismatch was predicted and in DRPs where the donor contained the allele encoding UNC-GRK4-V, suggesting that this antigen could be both an mHA and a cancer-testis antigen. Computational analysis of genomic and transcriptomic data can reliably predict leukemia-associated mHA and can be used to guide targeted mHA discovery., (© 2018 by The American Society of Hematology.)

Current lipidomics workflows are centered around acquisition of large data sets followed by lengthy data processing. A dual nESI-DIMS-MS platform was developed to perform real-time relative quantification between samples, providing data required for biomarker discovery and validation more quickly than traditional ESI-MS approaches. Nanosprayer activity and DIMS compensation field settings were controlled by a LabVIEW program synced to the accumulation portion of the ion trap scan function, allowing for full integration of the platform with a commercial mass spectrometer. By comparing samples with short electrospray pulses rather than constant electrospray, the DIMS and MS performance is normalized within an experiment, as signals are compared between individual mass spectra (ms time scale) rather than individual experiments (min-hr time scale). The platform was validated with lipid standards and extracts from nitrogen-deprived microalgae. Dual nESI-DIMS requires minimal system modification and is compatible with all traditional ion activation techniques and mass analyzers, making it a versatile improvement to shotgun lipidomics workflows.

The e-liquids used in electronic cigarettes (E-cigs) consist of propylene glycol (PG), vegetable glycerin (VG), nicotine, and chemical additives for flavoring. There are currently over 7,700 e-liquid flavors available, and while some have been tested for toxicity in the laboratory, most have not. Here, we developed a 3-phase, 384-well, plate-based, high-throughput screening (HTS) assay to rapidly triage and validate the toxicity of multiple e-liquids. Our data demonstrated that the PG/VG vehicle adversely affected cell viability and that a large number of e-liquids were more toxic than PG/VG. We also performed gas chromatography-mass spectrometry (GC-MS) analysis on all tested e-liquids. Subsequent nonmetric multidimensional scaling (NMDS) analysis revealed that e-liquids are an extremely heterogeneous group. Furthermore, these data indicated that (i) the more chemicals contained in an e-liquid, the more toxic it was likely to be and (ii) the presence of vanillin was associated with higher toxicity values. Further analysis of common constituents by electron ionization revealed that the concentration of cinnamaldehyde and vanillin, but not triacetin, correlated with toxicity. We have also developed a publicly available searchable website (www.eliquidinfo.org). Given the large numbers of available e-liquids, this website will serve as a resource to facilitate dissemination of this information. Our data suggest that an HTS approach to evaluate the toxicity of multiple e-liquids is feasible. Such an approach may serve as a roadmap to enable bodies such as the Food and Drug Administration (FDA) to better regulate e-liquid composition.

The rapid release of new tobacco products requires high-throughput quantitative methods to support tobacco research. Sample preparation for LC-MS and GC-MS is time consuming and limits throughput. Paper spray tandem mass spectrometry (PS-MS/MS) is proposed and validated as a simple and rapid method for quantification of nicotine and cotinine in complex matrices to support tobacco-related research. Air liquid interface (ALI) human tracheobronchial epithelial cell (HTBEC) cultures were exposed to tobacco smoke using a Vitrocell VC-10 smoking machine. Apical culture washes (phosphate buffered saline, PBS) and basolateral media were analyzed with the PS-MS/MS method. GC-MS/MS was used as a comparative quantitative technique. The PS-MS/MS approach allowed for direct spotting of samples on the paper substrate, whereas the GC-MS/MS method required additional sample preparation in the form of solvent-solvent extraction. Limits of quantitation (LOQs) were higher with the PS-MS/MS approach than GC-MS/MS, but still below the relevant concentrations found in HTBEC smoke exposure experiments as well as most clinical applications. PS-MS/MS is readily achieved on mass spectrometers that include atmospheric pressure inlets, and allows for convenient quantification from complex matrices that would otherwise require additional sample preparation and chromatographic separation., Competing Interests: Conflicts of interest There are no conflicts to declare.

Innate immune cells of the respiratory tract are the first line of defense against pathogenic and environmental insults. Failure of these cells to perform their immune functions leaves the host susceptible to infection and may contribute to impaired resolution of inflammation. While combustible tobacco cigarettes have been shown to suppress respiratory immune cell function, the effects of flavored electronic cigarette liquids (e-liquids) and individual flavoring agents on respiratory immune cell responses are unknown. We investigated the effects of seven flavored nicotine-free e-liquids on primary human alveolar macrophages, neutrophils, and natural killer (NK) cells. Cells were challenged with a range of e-liquid dilutions and assayed for their functional responses to pathogenic stimuli. End points included phagocytic capacity (neutrophils and macrophages), neutrophil extracellular trap formation, proinflammatory cytokine production, and cell-mediated cytotoxic response (NK cells). E-liquids were then analyzed via mass spectrometry to identify individual flavoring components. Three cinnamaldehyde-containing e-liquids exhibited dose-dependent broadly immunosuppressive effects. Quantitative mass spectrometry was used to determine concentrations of cinnamaldehyde in each of the three e-liquids, and cells were subsequently challenged with a range of cinnamaldehyde concentrations. Cinnamaldehyde alone recapitulated the impaired function observed with e-liquid exposures, and cinnamaldehyde-induced suppression of macrophage phagocytosis was reversed by addition of the small-molecule reducing agent 1,4-dithiothreitol. We conclude that cinnamaldehyde has the potential to impair respiratory immune cell function, illustrating an immediate need for further toxicological evaluation of chemical flavoring agents to inform regulation governing their use in e-liquid formulations., (Copyright © 2017 the American Physiological Society.)

A state-operated residential facility has for the past five years been using performance feedback as the primary method for improving direct care staff interactions with clients. The major problem with this approach is determining when staff performance is significantly above or below average. Statistical process control charts are being used to determine whether variations in staff performance are the result of common or special causes. Analysis of staff performance for one year suggests that variation in staff performance may be due to special causes, such as the characteristics of the clients served and the type of service that is provided to these clients. Services were adapted to the characteristics of these clients, which improved staff performance and reduced variation.