Tobacco Harm Reduction with Vaporised Nicotine (THRiVe): A Feasibility Trial of Nicotine Vaping Products for Smoking Cessation Among People Living with HIV.

People living with HIV (PLHIV) have high rates of tobacco smoking. Nicotine vaping products (NVPs) may promote tobacco smoking cessation and/or harm reduction. This study aimed to trial the feasibility of NVPs for promoting tobacco smoking cessation among PLHIV. The Tobacco Harm Reduction with Vaporised Nicotine (THRiVe) study was a mixed-methods trial among 29 PLHIV who used tobacco daily. Participants trialled a 12-week intervention of NVPs. This study reports descriptive analyses of quantitative data on tobacco abstinence and associated adverse events. Short-term abstinence (7-day point prevalence; i.e., no tobacco use for 7 days) was achieved by 35% of participants at Week 12 and 31% reported short-term abstinence at Week 24. Sustained medium-term abstinence (8 weeks' abstinence) was achieved by 15% of participants at Week 12 and 31% at Week 24. Most adverse events were mild. NVPs may represent a feasible and potentially effective short-to-medium term tobacco smoking cessation aid and/or harm reduction strategy among PLHIV.

Views and preferences of people living with HIV about smoking, quitting and use of nicotine products.

AIMS AND BACKGROUND: People living with HIV (PLHIV) have a higher rate of smoking and experience a greater burden of tobacco-related disease than the general population. This study aimed to understand the role smoking plays in the lives of PLHIV, participants' views of traditionally available nicotine products (e.g., nicotine replacement therapy or NRT) and novel nicotine products (e.g., nicotine vaping products or NVPs) as both short-term quit aids and long-term substitutes for cigarettes. METHODS: Semi-structured focus groups were conducted with PLHIV who smoked. Focus groups were transcribed and analysed using a combination of deductive and inductive thematic analysis. A brief questionnaire of nicotine product use and interest was also completed and the quantitative data presented using descriptive statistics. RESULTS: Fifty-four participants took part in 11 focus groups. Participants' views of smoking, quitting and nicotine products were diverse. Commitment to smoking and interest in quitting were categorised into three groups across a smoking-quitting continuum: committed to smoking, ambivalent about smoking and reluctantly smoking. NRT was criticised for a range of side effects and primarily considered as a short-term cessation aid. NVPs generated debate. NVPs that closely resembled cigarettes were viewed as the most acceptable product and were considered to be more suitable than NRT for long-term use. DISCUSSION AND CONCLUSIONS: Understanding the unique needs, goals and views of PLHIV related to smoking, quitting smoking and using nicotine products could inform development of novel and tailored smoking interventions for PLHIV. NVPs should be further examined as potential long-term substitutes for PLHIV who are ambivalent about smoking. However, traditional smoking cessation assistance (approved cessation aids and counselling) is likely to be most appropriate for PLHIV who are reluctantly smoking.

Studies pertaining to the monitoring of volatile halogenated anaesthetics in breath by proton transfer reaction mass spectrometry.

Post-operative isoflurane has been observed to be present in the end-tidal breath of patients who have undergone major surgery, for several weeks after the surgical procedures. A major new non-controlled, non-randomized, and open-label approved study will recruit patients undergoing various surgeries under different inhalation anaesthetics, with two key objectives, namely (1) to record the washout characteristics following surgery, and (2) to investigate the influence of a patient's health and the duration and type of surgery on elimination. In preparation for this breath study using proton transfer reaction time-of-flight mass spectrometry (PTR-TOF-MS), it is important to identify first the analytical product ions that need to be monitored and under what operating conditions. In this first paper of this new research programme, we present extensive PTR-TOF-MS studies of three major anaesthetics used worldwide, desflurane (CF3CHFOCHF2), sevoflurane ((CF3)2CHOCH2F), and isoflurane (CF3CHClOCHF2) and a fourth one, which is used less extensively, enflurane (CHF2OCF2CHFCl), but is of interest because it is an isomer of isoflurane. Product ions are identified as a function of reduced electric field (E/N) over the range of approximately 80 Td to 210 Td, and the effects of operating the drift tube under 'normal' or 'humid' conditions on the intensities of the product ions are presented. To aid in the analyses, density functional theory (DFT) calculations of the proton affinities and the gas-phase basicities of the anaesthetics have been determined. Calculated energies for the ion-molecule reaction pathways leading to key product ions, identified as ideal for monitoring the inhalation anaesthetics in breath with a high sensitivity and selectivity, are also presented.

Addressing smoking among people living with HIV: a cross-sectional survey of Australian HIV health practitioners' practices and attitudes.

People living with HIV (PLHIV) have high rates of tobacco smoking, and smoking is a leading cause of premature mortality and morbidity. It is important to understand HIV healthcare providers' practices and attitudes towards addressing smoking with their patients. An online survey that measured: (i) use of the 5A framework for addressing smoking (Ask, Assess, Advise, Assist, Arrange) and (ii) attitudes and barriers to addressing smoking cessation was distributed by relevant professional bodies. Eligible participants were Australian health practitioners providing healthcare to PLHIV. Of the 179 respondents, most reported practising at least one of the 5As: Ask (94%); Assess (78%); Advise (82%); Assist (89%); and Arrange (73%). Practising the full 5A framework (completing at least one activity from each A) was less common (62%) and associated with having undertaken smoking cessation training (OR 2.1, CI 1.1-3.9), being a medical practitioner (OR 6.0, CI 3.1-11.6), having greater perceived knowledge and resources (OR 1.7, CI 1.3-2.4) and more positive attitudes (OR 1.5, CI 1.1-2.0). Common barriers to delivering cessation assistance related to knowledge and availability of resources. Development and greater dissemination of effective smoking cessation training and resources may be required to ensure healthcare practitioners have the capacity to complete all aspects of the 5A framework for smoking cessation and support their patients with HIV who smoke.

Use of Rapid Reduced Electric Field Switching to Enhance Compound Specificity for Proton Transfer Reaction-Mass Spectrometry.

The high sensitivity of proton transfer reaction-mass spectrometry (PTR-MS) makes it a suitable analytical tool for detecting trace compounds. Its specificity is primarily determined by the accuracy of identifying the m/ z of the product ions specific to a particular compound. However, specificity can be enhanced by changing the product ions (concentrations and types) through modifying the reduced electric field. For current PTR-MS systems, this is not possible for trace compounds that would only be present in the reaction chamber of a PTR-MS for a short time (seconds). For such circumstances, it is necessary to change the reduce electric field swiftly if specificity enhancements are to be achieved. In this paper we demonstrate such a novel approach, which permits any compound that may only be present in the drift tube for seconds to be thoroughly investigated. Specifically, we have developed hardware and software which permits the reaction region's voltages to be rapidly switched at a frequency of 0.1-5 Hz. We show how this technique can be used to provide a higher confidence in the identification of compounds than is possible by keeping to one reduced electric field value through illustrating the detection of explosives. Although demonstrated for homeland security applications, this new technique has applications in other analytical areas and disciplines where rapid changes in a compound's concentration can occur, for example, in the Earth's atmosphere, plant emissions and in breath. Importantly, this adaptation provides a method for improved selectivity without expensive instrumental changes or the need for high mass resolution instruments.

Water-soluble substituted chitosan derivatives as technology platform for inhalation delivery of siRNA.

Despite research efforts full potential of siRNA-based therapeutics has not yet been fully realized due to a need for suitable, effective delivery formulations. Here, we examine a potential of a new class of water-soluble chitosans as siRNA platform for pulmonary delivery. The system is based on piperazine-substituted chitosans, a material designed to integrate established, safe application of chitosan for mucosal administration with novel properties: the piperazine-substituted chitosans are freely water-soluble at physiological pH, possess low cytotoxicity (no significant reduction in cell viability up to 0.1 mg/ml), and provide efficient incorporation of siRNA into sub-300 nm colloidal complexes (at relatively low polymer/siRNA ratio of 5:1). In vitro, the complexes achieved silencing of a model gene at a level of 40-80%, when tested in a panel of lung epithelial cells. Considering the formulation 'developability', there were no significant changes in the complexes' size and integrity on aerosolisation by microsprayer (PenCentury™) device. Following intratracheal aerolisation, the complexes deposited throughout the lung, although relatively inhomogeneously, as judged from IVIS imaging of the isolated mouse lung (visualizing DY647-siRNA). In vivo data illustrate absence of adverse effects on repeated administration of complexes and significant tumor reduction in atopical lung cancer model in mice. Altogether, the data illustrates potential of substituted chitosan derivatives to be utilized as a safe system for inhalation delivery of siRNA.

Ion Mobility Studies on the Negative Ion-Molecule Chemistry of Isoflurane and Enflurane.

In the present work we present an investigation of the negative ion-molecule chemistry of the anaesthetics isoflurane, ISOF, and enflurane, ENF, in an ion mobility spectrometry/mass spectrometry (IMS/MS), in both air and nitrogen. Hexachloroethane (HCE) was introduced in both air and nitrogen to produce Cl- as a reactant ion. This study was undertaken owing to uncertainties in the chemical processes, which lead to the cluster ions reported in other work (Eiceman et al. Anal. Chem. 61, 1093-1099, 1). In particular for ISOF the product ion observed was ISOF.Cl-, and it was suggested that the Cl- was formed by dissociative electron attachment (DEA) although there was mention of a chlorine containing contaminant. We show in this study that ISOF and ENF do not produce Cl- in an IMS system either by capture of free electrons or reaction with O2-. This demonstrates that the Cl- containing ions, reported in the earlier study, must have been the result of a chlorine containing contaminant as suggested. The failure of ISOF and ENF to undergo DEA was initially surprising given the high calculated electron affinities, but further calculations showed that this was a result of the large positive vertical attachment energies (VAEs). This experimental work has been supported by electronic structure calculations at the B3LYP level, and is consistent with those obtained in a crossed electron-molecular beam two sector field mass spectrometer. An unusual observation is that the monomer complexes of ISOF and ENF with O2- are relatively unstable compared with the dimer complexes. Graphical Abstract ᅟ.

Enhancement of Compound Selectivity Using a Radio Frequency Ion-Funnel Proton Transfer Reaction Mass Spectrometer: Improved Specificity for Explosive Compounds.

A key issue with any analytical system based on mass spectrometry with no initial separation of compounds is to have a high level of confidence in chemical assignment. This is particularly true for areas of security, such as airports, and recent terrorist attacks have highlighted the need for reliable analytical instrumentation. Proton transfer reaction mass spectrometry is a useful technology for these purposes because the chances of false positives are small owing to the use of a mass spectrometric analysis. However, the detection of an ion at a given m/z for an explosive does not guarantee that that explosive is present. There is still some ambiguity associated with any chemical assignment owing to the presence of isobaric compounds and, depending on mass resolution, ions with the same nominal m/z. In this article we describe how for the first time the use of a radio frequency ion-funnel (RFIF) in the reaction region (drift tube) of a proton transfer reaction-time-of-flight-mass spectrometer (PTR-ToF-MS) can be used to enhance specificity by manipulating the ion-molecule chemistry through collisional induced processes. Results for trinitrotoluene, dinitrotoluenes, and nitrotoluenes are presented to demonstrate the advantages of this new RFIF-PTR-ToF-MS for analytical chemical purposes.

Insight into the relationship between the cell culture model, cell trafficking and siRNA silencing efficiency.

Despite research efforts, cell uptake processes determining siRNA silencing efficiency remain unclear. Here, we examine the relationship between in vitro cell culture models, cellular trafficking and siRNA silencing efficiency to provide a mechanistic insight on siRNA delivery system design. Model siRNA-polyplexes, based on chitosan as a 'classical' condensing agent, were applied to a panel of lung epithelial cell lines, H1299, A549 and Calu-3 and cell internalization levels, trafficking pathways and gene silencing assessed on exposure to pharmacological inhibitors. The data reveal striking differences in the internalization behaviour and gene silencing efficiency in the tested cell lines, despite their common lung epithelial origins. The model system's silencing was lower where clathrin internalization pathway predominated in Calu-3, relative to silencing in H1299 cells where a non-clathrin internalization appears dominant. Increased silencing on endosomal disruption was apparent in Calu-3 cells, but absent when cellular internalization was not predominantly clathrin-mediated in A549 cells. This highlights that identifying cell trafficking pathways before incorporation of functional components to siRNA delivery systems (e.g. endosomolytic compounds) is crucial. The study hence stresses the importance of selection of appropriate cell culture model, relevant to in vivo target, to assess the gene silencing efficiency and decide which functionalities the 'stratified siRNA silencing vector' requires.

Development of in vitro models to demonstrate the ability of PecSys®, an in situ nasal gelling technology, to reduce nasal run-off and drip.

UNLABELLED: Many of the increasing number of intranasal products available for either local or systemic action can be considered sub-optimal, most notably where nasal drip or run-off give rise to discomfort/tolerability issues or reduced/variable efficacy. PecSys, an in situ gelling technology, contains low methoxy (LM) pectin which gels due to interaction with calcium ions present in nasal fluid. PecSys is designed to spray readily, only forming a gel on contact with the mucosal surface. The present study employed two in vitro models to confirm that gelling translates into a reduced potential for drip/run-off: (i) Using an inclined TLC plate treated with a simulated nasal electrolyte solution (SNES), mean drip length [±SD, n = 10] was consistently much shorter for PecSys (1.5 ± 0.4 cm) than non-gelling control (5.8 ± 1.6 cm); (ii) When PecSys was sprayed into a human nasal cavity cast model coated with a substrate containing a physiologically relevant concentration of calcium, PecSys solution was retained at the site of initial deposition with minimal redistribution, and no evidence of run-off/drip anteriorly or down the throat. In contrast, non-gelling control was significantly more mobile and consistently redistributed with run-off towards the throat. CONCLUSION: In both models PecSys significantly reduced the potential for run-off/drip ensuring that more solution remained at the deposition site. In vivo, this enhancement of retention will provide optimum patient acceptability, modulate drug absorption and maximize the ability of drugs to be absorbed across the nasal mucosa and thus reduce variability in drug delivery.

Nasal delivery of fentanyl.

Fentanyl, a potent opioid analgesic, is rapidly and efficiently absorbed from the nasal cavity, giving significant potential for nasally administered fentanyl to be used in pain management. Many reported clinical studies have used nasally administered IV solution, often as drops, which requires high volumes of solution to deliver an effective dose, resulting in insignificant runoff and drip which, in turn, compromises absorption and efficacy. More recently, products have been developed and commercialised with features intended to overcome these drawbacks, notably delivering the dose as a spray in a lower volume of solution and, for one of the products, incorporating an in situ gelling agent with the aim of both reducing runoff/drip and modifying the fentanyl absorption profile. The commercial fentanyl nasal spray products (PecFent/Lazanda and Instanyl) are currently licensed solely for the treatment of breakthrough pain in cancer patients; they have a number of advantages over oral transmucosal (buccal/sublingual) products used in the same indication, including faster onset of action and easier administration, especially in patients suffering from oral cavity disorders associated with cancer treatment. Given the nature of fentanyl, regulatory agencies will expect that appropriate safety features are incorporated into the primary and secondary packaging in products intended for use by patients in the home and may also impose risk management protocols to control the distribution and prescription of controlled substances. These demands notwithstanding, intranasal fentanyl offers much future promise, including for additional indications and paediatric use.

The rise and fall of complementary medicine in National Health Service hospitals in England.

Whilst Complementary and Alternative Medicine (CAM) has never been systematically integrated into National Health Service (NHS) provision, there has been some limited evidence of a developing presence of CAM in NHS hospital based nursing and midwifery. This paper reports on a qualitative study that sought to document the nature and extent of such integrative practice in England, and the interpersonal and organisational factors that facilitated or impeded it. The data revealed a history in which attempts to integrate CAM had some initial success underpinned by the enthusiasm of individual practitioners and a relatively permissive organisational context. However, this was followed by a decline in service provision. The fact that the services were established by individuals left them vulnerable when more restrictive funding and governance regimes emerged. Whilst the data revealed a consistent story about CAM within the NHS, it must be recognised that the use of a snowball sample limits the generalizability of the findings.

Chitosan-based delivery systems for mucosal vaccines.

INTRODUCTION: Mucosal vaccine development faces several challenges and opportunities. Critical issues for effective mucosal vaccination include the antigen-retention period that enables interaction with the lymphatic system, choice of adjuvant that is nontoxic and induces the required immune response and possibly an ability to mimic mucosal pathogens. Chitosan-based delivery systems are reviewed here as they address these issues and hence represent the most promising candidates for the delivery of mucosal vaccines. AREAS COVERED: A comprehensive literature search was conducted, to locate relevant studies published within the last 5 years. Mucosal delivery via nasal and oral routes is evaluated with respect to chitosan type, dosage forms, co-adjuvanting with novel adjuvants and modulation of the immune system. EXPERT OPINION: It is concluded that chitosan derivatives offer advantageous opportunities such as nanoparticle and surface charge manipulation that facilitate vaccine targeting. Nevertheless, these technologies represent a longer-term goal. By contrast, chitosan (unmodified form) with or without a co-adjuvant has significant toxicology and human data to support safe mucosal administration, and thus has the potential for earlier product introduction into the market.

Proton transfer reaction mass spectrometry and the unambiguous real-time detection of 2,4,6 trinitrotoluene.

Fears of terrorist attacks have led to the development of various technologies for the real-time detection of explosives, but all suffer from potential ambiguities in the assignment of threat agents. Using proton transfer reaction mass spectrometry (PTR-MS), an unusual bias dependence in the detection sensitivity of 2,4,6 trinitrotoluene (TNT) on the reduced electric field (E/N) has been observed. For protonated TNT, rather than decreasing signal intensity with increasing E/N, which is the more usual sensitivity pattern observed in PTR-MS studies, an anomalous behavior is first observed, whereby the signal intensity initially rises with increasing E/N. We relate this to unexpected ion-molecule chemistry based upon comparisons of measurements taken with related nitroaromatic compounds (1,3,5 trinitrobenzene, 1,3 dinitrobenzene, and 2,4 dinitrotoluene) and electronic structure calculations. This dependence provides an easily measurable signature that can be used to provide a rapid highly selective analytical procedure to minimize false positives for the detection of TNT. This has major implications for Homeland Security and, in addition, has the potential of making instrumentation cost-effective for use in security areas. This study shows that an understanding of fundamental ion-molecule chemistry occurring in low-pressure drift tubes is needed to exploit selectivity and sensitivity for analytical purposes.

Negotiating competency, professionalism and risk: the integration of complementary and alternative medicine by nurses and midwives in NHS hospitals.

This qualitative interview study examined the use of complementary and alternative medicine (CAM) by nurses and midwives in NHS hospital settings in 2008 in the UK. It showed that the groundswell of interest in CAM in the 1990s had diminished by this time due to changes to policy and funding, and increasingly stringent clinical governance. Nevertheless, CAM provided an opportunity for committed and self-motivated practitioners to extend their therapeutic repertoire and develop affective dimensions of practice. However, the integration of CAM did not afford the autonomy, status and material gains traditionally associated with a collective professional project. In practice, occupational strategies were individualistic, and grounded in the assertion of competency through expressions of professionalism rather than the credentialism which underpins classic professionalisation. Central to these strategies was CAM related risk, which became a means by which to claim occupational space. However, the extent to which the adoption of CAM enhanced the nurses' and midwives' roles was limited by traditional medical authority; the uncertain status of CAM knowledge; and the absence of collective strategies - which together often left practitioners in a position of vulnerability.

Re-formulating drugs and vaccines for intranasal delivery: maximum benefits for minimum risks?

The challenges being faced by the pharmaceutical industry in terms of patent expiries and a sparse pipeline of new products are well documented, as are the risks and costs associated with developing new molecular entities. Major pharmaceutical companies are increasingly looking to augment their traditional core expertise in the discovery of small molecules with the development of biologicals (e.g. peptide-based, protein-based, antibody-based and nucleic-acid-based therapies), which are seen as a key element in achieving long-term growth. There is also considerable current interest in vaccines, both in the traditional area of mass immunization against infections and as a novel approach to disease treatment.

Real-time trace detection and identification of chemical warfare agent simulants using recent advances in proton transfer reaction time-of-flight mass spectrometry.

This work demonstrates for the first time the potential of using recent developments in proton transfer reaction mass spectrometry for the rapid detection and identification of chemical warfare agents (CWAs) in real-time. A high-resolution (m/Deltam up to 8000) and high-sensitivity (approximately 50 cps/ppbv) proton transfer reaction time-of-flight mass spectrometer (PTR-TOF 8000 from Ionicon Analytik GmBH) has been successfully used to detect a number of CWA simulants at room temperature; namely dimethyl methylphosphonate, diethyl methylphosphonate, diisopropyl methylphosphonate, dipropylene glycol monomethyl ether and 2-chloroethyl ethyl sulfide. Importantly, we demonstrate in this paper the potential to identify CWAs with a high level of confidence in complex chemical environments, where multiple threat agents and interferents could also be present in trace amounts, thereby reducing the risk of false positives. Instantaneous detection and identification of trace quantities of chemical threats using proton transfer reaction mass spectrometry could form the basis for a timely warning system capability with greater precision and accuracy than is currently provided by existing analytical technologies.

PecSys: in situ gelling system for optimised nasal drug delivery.

PecSys (PS) is a proprietary pectin-based drug delivery system designed to gel when applied to mucosal surfaces and with potential areas of application for drugs used in local and systemic disease therapy. The current area of focus is intranasal drug delivery where PS is being used to optimise absorption of lipophilic drugs into the systemic circulation. Pectin is described as GRAS (generally regarded as safe) with an excellent regulatory position through its long history of pharmaceutical and food usage. Tests to measure the functional gelling properties of pectin raw material and PS have been devised and validated. The PS-based products at the most advanced stages of development are intranasal formulations containing opioid analgesics intended to provide rapid pain relief with simple and convenient dosing and minimal side effects. The profile of such drugs may not be optimal through current routes of delivery and the ability of PS to modulate their pharmacokinetic profiles, such as attenuation of the peak plasma concentration (Cmax), has been demonstrated in clinical testing. The lead product using PS is a fentanyl nasal spray formulation (NasalFent), which has successfully met the primary objective in a pivotal Phase III clinical study and is scheduled for regulatory filings in the first half of 2009.

The development of industry-specific odor impact criteria for feedlots using models.

Emissions from feedlot operations are known to vary by environmental conditions and few if any techniques or models exist to predict the variability of odor emission rates from feedlots. The purpose of this paper is to outline and summarize unpublished reports that are the result of a collective effort to develop industry-specific odor impact criteria for Australian feedlots. This effort used over 250 olfactometry samples collected with a wind tunnel and past research to develop emission models for pads, sediment basins, holding ponds, and manure storage areas over a range of environmental conditions and tested using dynamic olfactometry. A process was developed to integrate these emission models into odor dispersion modeling for the development of impact criteria. The approach used a feedlot hydrology model to derive daily feedlot pad moisture, temperature, and thickness. A submodel converted these daily data to hourly data. A feedlot pad emissions model was developed that predicts feedlot pad emissions as a function of temperature, moisture content, and pad depth. Emissions from sediment basins and holding ponds were predicted using a basin emissions model as a function of days since rain, inflow volume, inflow ratio (pond volume), and temperature. This is the first attempt to model all odor source emissions from a feedlot as variable hourly emissions on the basis of climate, management, and site-specific conditions. Results from the holding pond, sediment basin, and manure storage emission models performed well, but additional work on the pad emissions model may be warranted. This methodology mimics the variable odor emissions and odor impact expected from feedlots due to climate and management effects. The main outcome of the work is the recognition that an industry-specific odor impact criterion must be expressed in terms of all of the components of the assessment methodology.