Assessing the impact of protonating acid combinations in e-cigarette liquids: a randomised, crossover study on nicotine pharmacokinetics.

The addition of protonating acids to e-cigarette liquid formulations (e-liquids) enhances nicotine bioavailability in e-cigarette use. However, little is known about the impact of different combinations of protonating acid on nicotine pharmacokinetics. The objectives of this study were to compare pharmacokinetics of nicotine absorption following use of a closed-system e-cigarette, containing e-liquids with two different nicotine levels and with different ratios of three common protonating acids-lactic, benzoic and levulinic. In a randomised, controlled, crossover study, nicotine pharmacokinetics and product liking were assessed for prototype e-liquids used in a Vuse e-cigarette containing either 3.5% or 5% nicotine and varying ratios of lactic, benzoic and/or levulinic acid. During an 8-day confinement period, 32 healthy adult current cigarette smokers/e-cigarette dual users used a single study e-liquid each day during 10-min fixed and ad libitum use periods after overnight nicotine abstinence. For most comparisons, Cmax and AUC0-60 following both fixed and ad libitum puffing were significantly higher for e-liquids containing 5% nicotine compared with 3.5% nicotine. However, Cmax and AUC0-60 were not statistically different for 5% nicotine e-liquids containing varying ratios of lactic, levulinic and benzoic acid when compared to an e-liquid containing lactic acid only. Mean scores for product liking were similar for all e-liquid formulations assessed, regardless of nicotine concentration, acid content, and whether the product was used in a fixed or ad libitum puffing regimen. While e-liquid nicotine concentration significantly affected users' nicotine uptake, the different combinations of benzoic, levulinic and lactic acid in the e-liquids assessed had limited impact on nicotine pharmacokinetics and product liking scores.

Biomarkers of exposure and potential harm in exclusive users of electronic cigarettes and current, former, and never smokers.

Electronic cigarette (EC) aerosol emissions generally contain fewer and lower concentrations of harmful and potentially harmful constituents, compared with cigarette smoke. Further studies are needed to establish whether decreased emissions translate to reduced health risks for EC users. In a cross-sectional study, biomarkers of exposure (BoE) to certain tobacco smoke toxicants and biomarkers of potential harm (BoPH), associated with biological processes linked to the potential development of smoking-related diseases and oxidative stress, were assessed in solus Vuse ECs users and current, former, and never smokers. In total, 213 participants were enrolled, and smoking status was confirmed by urinary cotinine, exhaled carbon monoxide, and N-(2-cyanoethyl)valine levels (EC users and former smokers only). During confinement participants used their usual product (EC or cigarette) as normal and BoE and BoPHs were assessed via blood, 24-h urine, and physiological assessment. Significantly lower levels of all urinary BoE; MHBMA, HMPMA, 3-HPMA, NNN, 3-OH-B[a]P, S-PMA, NNAL (all p < 0.0001), and TNeq (p = 0.0074) were observed in EC users when compared with smokers. Moreover, significantly lower levels were observed in EC users for 3 of the 7 BoPH measured, carboxyhaemoglobin (p < 0.0001), soluble intercellular adhesion molecule-1 (p = 0.0028), and 11-dehydrothromboxane B2 (p = 0.0012), when compared with smokers. As compared with smokers, solus Vuse EC users have significantly lower exposure to tobacco toxicants for the BoE, and 3 BoPH measured. These results add to the weight of evidence supporting EC as part of a tobacco harm reduction strategy.

Longitudinal assessment of undergraduate dental students: Building evidence for validity.

PURPOSE: To investigate the content and criterion validity, and reliability of longitudinal clinical assessment of undergraduate dental student clinical competence by determining patterns of clinical performance and comparing them with validated standalone undergraduate examinations. METHODS: Group-based trajectory models tracking students' clinical performance over time were produced from LIFTUPP© data for three dental student cohorts (2017-19; n = 235) using threshold models based on the Bayesian information criterion. Content validity was investigated using LIFTUPP© performance indicator 4 as the threshold for competence. Criterion validity was investigated using performance indicator 5 to create distinct trajectories of performance before linking and cross-tabulating trajectory group memberships with a 'top 20%' performance in the final Bachelor of Dental Surgery (BDS) examinations. Reliability was calculated using Cronbach's alpha. RESULTS: Threshold 4 models showed all students followed a single upward trajectory in all three cohorts, showing clear progression in competence over three clinical BDS years. A threshold 5 model produced two distinct trajectories, and in each cohort a 'better performing' trajectory was identified. Students allocated to the 'better performing' trajectories scored higher on average in the final examinations for cohort 2 (29% vs 18% (BDS4); 33% vs. 15% (BDS5)) and cohort 3 (19% vs. 16% (BDS4); 21% vs. 16% (BDS5)). Reliability for the undergraduate examinations was high for all three cohorts (≥0.8815) and did not change appreciably when longitudinal assessment was included. CONCLUSIONS: There is some evidence to support that longitudinal data have a degree of content and criterion validity for assessing the development of clinical competence in undergraduate dental students, which should increase confidence in decisions based on these data. The findings also provide a good foundation for subsequent research.

Assessment of biomarkers of exposure and potential harm, and physiological and subjective health measures in exclusive users of nicotine pouches and current, former and never smokers.

Background: Oral nicotine pouches (NPs) are smokeless, tobacco-free products that have a potential role in tobacco harm reduction strategies.Methods: In a cross-sectional study in Sweden/Denmark, several recognised biomarkers of potential harm (BoPHs) linked to smoking-related diseases/their initiating biological processes, and biomarkers of exposure (BoEs) to tobacco/tobacco smoke toxicants were compared among exclusive adult users of Velo NPs and current/former/never smokers. Over 24 h, participants used their usual product (Velo NP or cigarette) as normal, and BoEs/BoPHs were assessed via blood/24-h urine/exhaled breath/physiological assessments.Results: Among the primary endpoints, total NNAL (16.9 ± 29.47 vs 187.4 ± 228.93 pg/24 h), white blood cell count (5.59 ± 1.223 vs 6.90 ± 1.758 × 109/L), and COHb (4.36 ± 0.525 vs 8.03 ± 2.173% saturation) were significantly lower among Velo users than among smokers (91%, 19% and 46% lower, respectively, all P < 0.0001), while fractional exhaled NO, previously shown to be lower in smokers, was significantly higher (23.18 ± 17.909 vs 11.20 ± 6.980 ppb) among Velo users (107% higher, P < 0.0001). Furthermore, sICAM-1 tended to be lower (185.9 ± 42.88 vs 204.5 ± 64.85 ng/mL) among Velo users than smokers (9% lower). Several secondary endpoints, including six BoEs (3-HPMA (246.7 ± 91.07 vs 1165.7 ± 718.35 µg/24 h), 3-OH-B[a]P (82.4 ± 217.58 vs 258.3 ± 190.20 pg/24 h), HMPMA (135.1 ± 77.85 vs 368.8 ± 183.15 µg/24 h), MHBMA (0.22 ± 0.166 vs 3.39 ± 2.943 µg/24 h), S-PMA (0.10 ± 0.059 vs 3.53 ± 2.736 µg/24 h) and total NNN (7.5 ± 24.84 vs 9.7 ± 5.93 ng/24 h)), were significantly lower among Velo users (78.8%, 68.1%, 63.4%, 93.5%, 97.2% and 22.7% lower, respectively, P < 0.0001-0.0011), while total nicotine equivalents was significantly higher among Velo users (22.6 ± 12.69 vs 12.1 ± 7.92 mg/24 h, P < 0.0001), although Velo user levels are comparable to those previously reported among oral tobacco users, and Velo user and smoker mean levels were similar in Denmark.Conclusion: As compared with smokers, exclusive users of Velo NPs have significantly less exposure to tobacco toxicants and more favourable BoPHs associated with initiating biological processes of smoking-related diseases.International Standard Registered Clinical Trial number: ISRCTN16988167.

Biomarkers of Exposure and Potential Harm in Exclusive Users of Nicotine Pouches and Current, Former, and Never Smokers: Protocol for a Cross-sectional Clinical Study.

BACKGROUND: Tobacco harm reduction (THR) aims to reduce the health burden of cigarettes by encouraging smokers to switch to using alternative tobacco or nicotine products. Nicotine pouches (NPs) are smokeless, tobacco-free, oral products that may be beneficial as part of a THR strategy. OBJECTIVE: This 2-center, cross-sectional confinement study conducted in Denmark and Sweden aimed to determine whether biomarkers of exposure (BoEs) to tobacco toxicants and biomarkers of potential harm (BoPHs) in exclusive users of NPs show favorable differences compared with current smokers. METHODS: Participants were healthy NP users (target n=100) and current, former, or never smokers (target n=40 each), as confirmed by urinary cotinine and exhaled carbon monoxide concentrations. During a 24-hour confinement period, participants were asked to use their usual product (NP or cigarette) as normal, and BoEs and BoPHs were measured in blood and 24-hour urine samples, with compliance determined using anabasine, anatabine, and N-(2-cyanoethyl)valine. BoEs and BoPHs were compared between NP users and current, former, and never smokers. Urinary total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol (BoE to nicotine-derived nitrosamine ketone) and urinary 8-epi-prostaglandin F2α type III, exhaled nitric oxide, blood carboxyhemoglobin, white blood cell count, soluble intercellular adhesion molecule-1, and high-density lipoprotein cholesterol (BoPHs) were evaluated as primary outcomes. Other measures included urinary 11-dehydrothromboxane B2, forced expiratory volume, carotid intima-media thickness, self-reported quality of life, and oral health. RESULTS: The results of this study were received in mid-2022 and will be published in late 2022 to early 2023. CONCLUSIONS: The results of this study will provide information on toxicant exposure and biomarkers associated with the development of smoking-related diseases among users of NPs compared with smokers, as well as on the potential role of NPs in THR. TRIAL REGISTRATION: International Standard Randomised Controlled Trial Number (ISRCTN) ISRCTN16988167; https://www.isrctn.com/ISRCTN16988167. INTERNATIONAL REGISTERED REPORT IDENTIFIER (IRRID): DERR1-10.2196/39785.

Changes in biomarkers of exposure and biomarkers of potential harm after 360 days in smokers who either continue to smoke, switch to a tobacco heating product or quit smoking.

The aim of this study was to investigate whether biomarkers of exposure (BoE) and potential harm (BoPH) are modified when smokers either continue to smoke or switch from smoking cigarettes to exclusive use of a tobacco heating product (THP) in an ambulatory setting over the period of a year, and to compare any changes with smokers who quit tobacco use completely and with never smokers' biomarker levels. Participants in this year-long ambulatory study were healthy smokers with a self-reported low intent to quit assigned either to continue smoking or switch to a THP; a group of smokers with a self-reported high intent to quit who abstained from tobacco use; and a group of never smokers. Various BoE and BoPH related to oxidative stress, cardiovascular and respiratory diseases and cancer were assessed at baseline and up to 360 days. Substantial and sustained reductions in BoE levels were found at 360 days for both participants who switched from smoking to THP use and participants who quit smoking, in many cases the reductions being of a similar order for both groups. The never smoker group typically had lower levels of the measured BoEs than either of these groups, and much lower levels than participants who continued to smoke. Several BoPHs were found to change in a favourable direction (towards never smoker levels) over the year study for participants who completely switched to THP or quit, while BoPHs such as soluble intercellular adhesion molecule-1 were found to change in an unfavourable direction (away from never smoker levels) in participants who continued to smoke. Our findings, alongside chemical and toxicological studies undertaken on the THP used in this study, lead to the conclusion that smokers who would have otherwise continued to smoke and instead switch entirely to the use of this THP, will reduce their exposure to tobacco smoke toxicants and as a consequence are reasonably likely to reduce disease risks compared to those continuing to smoke.

An abuse liability assessment of the glo tobacco heating product in comparison to combustible cigarettes and nicotine replacement therapy.

Tobacco heating products (THPs) have reduced emissions of toxicants compared with cigarette smoke, and as they expose user to lower levels than smoking, have for a role to play in tobacco harm reduction. One key concern of Public Health is that new tobacco and nicotine products should not be more addictive than cigarettes. To assess their abuse liability, we determined nicotine pharmacokinetics and subjective effects of two THPs compared with conventional cigarettes and a nicotine replacement therapy (Nicotine inhaler). In a randomised, controlled, open-label, crossover study healthy adult smokers used a different study product in a 5 min ad libitum use session in each of four study periods. Product liking, overall intent to use again, urge for product and urge to smoke questionnaires were utilised to assess subjective effects. Nicotine uptake was greater for the cigarette (Cmax = 22.7 ng/mL) than for either THP (8.6 and 10.5 ng/mL) and the NRT (2.3 ng/mL). Median Tmax was significantly longer for the NRT (15.03 min) than for the tobacco products (4.05-6.03 min). Product liking and overall intent to use again was highest for the cigarette, and higher for the THPs than the NRT. Urge to smoke was reduced more by the cigarette than by the other three products. Urge to use the THPs was greater than the NRT. These findings suggest that the abuse liability of the THPs lies between that of subjects usual brand cigarettes and the NRT.

A randomised study to assess the nicotine pharmacokinetics of an oral nicotine pouch and two nicotine replacement therapy products.

Nicotine replacement therapies (NRTs) are intended for short-term use to help cigarette smokers to quit. Some smokers find NRTs ineffective or seek a more satisfactory source of nicotine. Tobacco-free oral nicotine pouch (NP) products have emerged as a potential reduced risk product compared with cigarettes and other tobacco products. In a randomised crossover clinical study, thirty-four healthy adult smokers were enrolled and their nicotine Cmax and AUC0-T determined for three 4 mg nicotine products (NP, gum, lozenge) under fasting conditions. The NP, lozenge and gum mean Cmax values were 8.5, 8.3 and 4.4 ng/mL, AUC0-T values were 30.6, 31.5 and 14.3 ng*h/mL, respectively. The NP showed similar nicotine bioavailability to the lozenge (p = 0.6526 (Cmax), p = 1.0000 (AUC0-T)), and superior bioavailability to the gum (p < 0.0001 for Cmax and AUC0-T). Compared with the lozenge, the NP demonstrated greater product satisfaction with a higher number of positive responses to subjective satisfaction questions. All products were judged to be well-tolerated; the incidence of minor adverse events was lower for the NP (18.2%) than the lozenge (33.3%) or gum (18.8%). In summary, NPs may provide smokers with a more satisfying alternative nicotine source as compared to the reference NRTs.Study Registry/Registered Trial No: ISRCTN/ISRCTN65708311.

A novel clinical method to measure skin staining reveals activation of skin damage pathways by cigarette smoke.

BACKGROUND: Long-term use of cigarettes can result in localised staining and aging of smokers' skin. The use of tobacco heating products (THPs) and electronic cigarettes (ECs) has grown on a global scale; however, the long-term effect of these products' aerosols on consumers' skin is unknown. This pilot clinical study aimed to determine whether THP or EC aerosol exposure results in skin staining or activation of biomarkers associated with oxidative stress. MATERIALS AND METHODS: Eight areas were identified on the backs of 10 subjects. Two areas were used for air control, and two areas exposed to 32-puffs of cigarette smoke (CS), THP or EC aerosols, which were delivered to the skin using a 3-cm diameter exposure chamber and smoke engine. Skin colour was measured using a Chromameter. Squalene (SQ), SQ monohydroperoxide (SQOOH) and malondialdehyde (MDA) levels were measured in sebum samples by mass spectrometry and catalase colorimetry. RESULTS: CS exposure significantly increased skin staining, SQOOH and MDA levels and SQOOH/SQ ratio. THP and EC values were significantly lower than CS; EC values being comparable to air control. THP values were comparable to EC and air control at all endpoints, apart from skin staining. SQ and catalase levels did not change with exposure. CONCLUSIONS: CS stained skin and activated pathways known to be associated with skin damage. THPs and ECs produced significantly lower values, suggesting they could offer hygiene and cosmetic benefits for consumers who switch exclusively from smoking cigarettes. Further studies are required to assess longer-term effects of ECs and THPs on skin function.

A Randomised Study to Investigate the Nicotine Pharmacokinetics of Oral Nicotine Pouches and a Combustible Cigarette.

BACKGROUND AND OBJECTIVES: Nicotine pouches (NPs) are a relatively new type of oral smokeless tobacco-free nicotine product. Currently, few data are available on the nicotine pharmacokinetics or subjective effects of NP use. The objective of this study was to determine and compare the pharmacokinetics of nicotine absorption into the blood from different NP variants and a combustible cigarette. METHODS: In a randomised, controlled, crossover clinical study, nicotine pharmacokinetics and subjective effects were compared among commercially available NPs (five different brands; 6-10 mg nicotine/pouch) and a combustible cigarette. During an 8-day confinement period, 35 healthy adult participants who were current dual users of snus and combustible cigarettes used one study product each day for a defined period following overnight nicotine abstinence. RESULTS: Nicotine maximum plasma concentration (Cmax) and area under the plasma concentration-time curve between 0 and 6 h (AUC0-6h) were significantly greater for the Lyft 10 mg NP than for the cigarette (both p < 0.0001), while the other NPs had Cmax and AUC0-6h values that were either greater than or similar to those of the cigarette. Plasma nicotine concentration was not associated with the nicotine contents of the NPs. Time to reach maximum plasma concentration (Tmax) was higher for all NPs (60-65 min) than for the cigarette (7 min). Regarding subjective effects, liking and intent to use product again scores were higher for the cigarette than for any NP and were lowest for the NP with the lowest nicotine content. CONCLUSIONS: This study provides important insight into nicotine pharmacokinetics and subjective effects during NP use, and demonstrates that NPs can provide nicotine in amounts sufficient to replicate cigarette smokers' nicotine uptake following a switch from conventional cigarettes to these potentially less harmful NP products. Further studies are required to ascertain how physical characteristics of NPs other than nicotine content may affect nicotine delivery, pharmacokinetics and subjective responses. ISRCTN CLINICAL TRIAL REGISTRY: ISRCTN17828518.

Understanding the effectiveness and underlying mechanisms of lifestyle modification interventions in adults with learning disabilities: protocol for a mixed-methods systematic review.

BACKGROUND: Adults with learning disabilities have an increased disposition to unhealthy lifestyle behaviours which often occur simultaneously. Existing studies focus on complex interventions targeting unhealthy diet, physical inactivity, sedentary behaviour, smoking, and alcohol use to reduce health risks experienced. It is essential to understand how well these interventions work, what works, for whom, in what context and why. This study aims to investigate the effectiveness and underlying mechanisms of lifestyle modification interventions for adults with learning disabilities. METHODS: This is a mixed-methods systematic review consisting of a network meta-analysis (NMA) and realist synthesis. Electronic databases (ASSIA, CINAHL, EMBASE, MEDLINE, and PsycINFO) will be searched from inception to 14 January 2021 with no language restriction. Additionally, trial registries, grey literature databases and references lists will be searched. Studies related to lifestyle modification interventions on the adult population (>18 years) with learning disabilities will be eligible for inclusion. Two independent researchers will screen studies, extract data and assess its quality and risk of bias using the Cochrane Collaboration's Risk of Bias Assessment Tool (RoB Version 2) and ROBINS-I. The strength of the body of evidence will be assessed based on the GRADE approach. The NMA will incorporate results from RCTs and quasi-experimental studies to estimate the effectiveness of various lifestyle interventions. Where appropriate, a component NMA (CNMA) will be used to estimate effectiveness. The realist synthesis will complement and explain the findings of NMA and CNMA by including additional qualitative and mixed-methods studies. Studies will be included based on their relevance to the programme theory and the rigour of their methods, as determined by quality appraisal tools appropriate to the study design. Results from both syntheses will be incorporated into a logic model. DISCUSSION: The paucity of population-specific lifestyle interventions contributes to the challenges of behaviour change in adults with learning disabilities. This study will provide an evidence-base from which various stakeholders can develop effective interventions for adults with learning disabilities. The evidence will also help prioritise and inform research recommendations for future primary research so that people with learning disabilities live happier, healthier and longer lives. TRIAL REGISTRATION: PROSPERO CRD 42020223290.

Changes in biomarkers after 180 days of tobacco heating product use: a randomised trial.

The aim of this study was to investigate whether biomarkers of exposure (BoE) and potential harm (BoPH) are modified when smokers switch from smoking cigarettes to exclusive use of a tobacco heating product (THP) in an ambulatory setting. Participants in this randomised, controlled study were healthy volunteer smokers assigned either to continue smoking or switch to a THP, and a control group of smokers who abstained from cigarette smoking. Various BoE and BoPH related to oxidative stress, cardiovascular and respiratory diseases, and cancer were assessed at baseline and up to 180 days. In continuing smokers, BoE and BoPH remained stable between baseline and day 180, while THP users' levels of most BoE reduced significantly, becoming similar to those in controls abstaining from cigarette smoking. Also at 180 days, significant changes in numerous BoPH, including total 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanol, 8-epi-prostaglandin F2α type III, fractional concentration of exhaled nitric oxide and white blood cell count, were directionally consistent with lessened health impact. Our findings support the notion that the deleterious health impacts of cigarette smoking may be reduced in smokers who completely switch to using THPs.

A randomized controlled study in healthy participants to explore the exposure continuum when smokers switch to a tobacco heating product or an E-cigarette relative to cessation.

BACKGROUND: Cigarette smoking is associated with a number of diseases, such as cancer and cardiovascular diseases. Recently, there has been an increase in the use of electronic cigarettes (ECs) and tobacco-heating products (THPs) as an alternative to cigarettes, which may reduce the health burden associated with smoking. However, an exposure continuum when smokers switch to ECs or THPs compared to complete smoking cessation is not well established. METHODS: 148 healthy smokers were randomized to either continue smoking cigarettes, switch to using the glo THP or a prototype EC, or completely quit any nicotine or tobacco product use for 5 days, after a 2-day baseline period. During this study breath and 24-h urine samples were collected for Biomarker of Exposure (BoE) analysis. RESULTS: After a 5-day switching period BoE levels showed a substantial significant decrease in levels from baseline in the groups using the glo THP, the prototype EC, and having quit all nicotine and tobacco use. On an exposure continuum, smokers who completely quit nicotine had the lowest levels of assessed BoEs, followed by those who switched to the EC and then those who switched to glo THP use. Participants who continued to smoke had the highest levels of BoEs. CONCLUSIONS: THP or EC use over a 5-day period resulted in significant reductions in exposure to smoke toxicants, in some cases to levels similar to those for nicotine cessation. These results show that on an exposure continuum, nicotine cessation gives the greatest reduction in exposure to tobacco smoke toxicants, closely followed by the EC and the glo THP. These significant reductions in exposure to toxicants suggest that the glo THP and EC have the potential to be Reduced Risk Products. STUDY REGISTRATION: ISRCTN80651909.

Changes in Biomarkers of Exposure on Switching From a Conventional Cigarette to the glo Tobacco Heating Product: A Randomized, Controlled Ambulatory Study.

INTRODUCTION: Tobacco heating products (THPs) generate lower machine yields of toxicants compared to those found in conventional cigarette smoke. During use, these products are likely to expose users to lower levels of particulate matter and harmful and potentially harmful compounds compared with smoking cigarettes. AIMS AND METHODS: This randomized, controlled study is investigating whether biomarkers of exposure (BoE) to smoke toxicants are reduced when smokers switch from smoking cigarettes to using the glo THP in a naturalistic, ambulatory setting. Control groups include smokers who are abstaining from cigarette smoking and never-smokers. At a baseline study visit, 24-hour urine samples and spot blood samples were taken for BoE analysis, and exhaled carbon monoxide was also measured. N-(2-cyanoethyl) valine (CEVal) was used as a marker of compliance in subjects asked to refrain from combustible cigarette smoking. Subjects are being followed up at periodic intervals for 360 days; this article presents data following a planned interim analysis at day 90. RESULTS: In continuing smokers, BoE remained stable between baseline (day 1) and day 90. In both per-protocol and CEVal-compliant analysis populations, reductions in BoE were observed in subjects switching to using glo or undergoing smoking cessation. These reductions were statistically significant for a number of BoE when switching to glo was compared with continued smoking. Furthermore, in both populations, reductions observed in subjects switching to using glo were comparable to those seen with smoking cessation and were also to levels similar to those seen in never-smokers. CONCLUSION: glo is a reduced-exposure tobacco product. IMPLICATIONS: This clinical study builds on a previous 5-day confinement study and demonstrates that when smokers switched from smoking combustible cigarettes to using the glo THP in a naturalistic, ambulatory setting, their exposure to tobacco smoke toxicants was significantly decreased. For most BoE examined, this was to the same extent as that seen when a control group of smokers ceased cigarette smoking, or even to levels seen in never-smoker controls. This indicates that glo is a reduced-exposure product with the potential to be a reduced-risk tobacco product, when used by smokers whose cigarette consumption is displaced completely. CLINICAL TRIAL REGISTRATION: ISRCTN81075760.

Detection of additional abnormalities or co-morbidities in women with suspected intrahepatic cholestasis of pregnancy.

BACKGROUND: Current guidelines recommend viral, autoimmune, coagulation and liver ultrasound testing in intrahepatic cholestasis of pregnancy to exclude alternative diagnoses. METHODS: Electronic health records were searched for investigations and diagnoses in women with raised bile acid concentrations (>10 µmol/L) between January 2016 and December 2017 at two UK maternity units. RESULTS: Five hundred and thirty-one women had a raised bile acid concentration (median (IQR): 18 (13-32 µmol/L)) at a median gestation of 35.1 (IQR 31.8-37.0) weeks. Out of 531 women, 250 (47.1%) had full virology, autoimmune and ultrasound tests, and 348 (65.5%) had coagulation performed. Positive hepatitis B and C results were previously known. No new Epstein-Barr virus, cytomegalovirus or hepatitis A diagnoses were made. There were 11 positive autoimmune results, but no new diagnoses. No woman had an unexplained prolonged prothrombin time. No ultrasound liver (n = 38) or gallbladder (n = 85) abnormalities were of acute clinical significance. CONCLUSION: Intrahepatic cholestasis of pregnancy investigations provided no new diagnoses that influenced clinical management during pregnancy.

A randomised controlled single-centre open-label pharmacokinetic study to examine various approaches of nicotine delivery using electronic cigarettes.

Smokers who switch completely to e-cigarettes may reduce their relative risk of tobacco-related disease. Effective nicotine delivery from e-cigarettes is important in consumer acceptance. We assessed whether protonated nicotine and e-cigarette devices delivering greater aerosol mass increase nicotine delivery and product liking. A randomised controlled non-blinded eight-arm crossover study was used to assess plasma nicotine pharmacokinetics and product liking for two e-cigarettes (Vype ePen3 and Vype ePen) with various nicotine e-liquid formulations and a conventional cigarette among 24 healthy dual-users of cigarettes and e-cigarettes. Product use and puff count were also assessed. Results show that nicotine bioavailability was greater for Vype ePen3 with greater aerosol mass delivery than for Vype ePen (Cmax, p = 0.0073; AUC0-120 min, p = 0.0102). Protonated nicotine (18 mg/mL, medium protonation) e-liquid yielded higher nicotine bioavailability than unprotonated nicotine (18 mg/mL) e-liquid (Cmax, p = 0.0001; AUC0-120 min, p = 0.0026). There was no significant difference in Tmax between e-liquids. Nicotine bioavailability did not differ between nicotine benzoate formulation (30 mg/mL nicotine, high protonation) and combustible cigarettes (Cmax, p = 0.79; AUC0-120 min, p = 0.13). Vype ePen3 with protonated nicotine delivers nicotine more efficiently with the potential to increase product liking relative to earlier devices using unprotonated e-liquid.

Assessment of priority tobacco additives per the requirements of the EU Tobacco Products Directive (2014/40/EU): Part 3, Smoking behavior and plasma nicotine pharmacokinetics.

This publication is part of a series of 3 publications and describes the clinical assessment performed to fulfill the regulatory requirement per Art. 6 (2) of the EU Tobacco Products Directive 2014/40/EU under which Member States require manufacturers and importers of cigarettes and Roll Your Own tobacco containing an additive that is included in the priority list established by Commission Implementing Decision (EU) 2016/787 to carry out comprehensive studies (European Union, 2016). In our clinical study, two distinct end points were investigated, namely measuring plasma nicotine pharmacokinetics as a measure of nicotine uptake, and analyses of changes in smoker puffing behavior as a measure of cigarette smoke inhalation. This clinical study indicated that the inclusion of none of the priority additives either as single additive or as part of a chemical mixture, facilitated nicotine uptake. Furthermore, the data did not suggest that differences in the inhalation pattern of cigarette smoke of any of the Priority Additives tested occurred when compared to the additive-free reference cigarette. Finally, it is concluded that neither the scientific literature nor our study gave circumstantial indications of increased addictiveness for cigarettes containing these priority additives.

Management of venous thromboembolism secondary to ovarian hyperstimulation syndrome: A case report documenting the first use of a superior vena caval filter for upper limb venous thromboembolism in pregnancy, and the difficulties and complications relating to anticoagulation in antenatal and peri-partum periods.

The management of venous thromboembolism and subsequent pulmonary embolism in pregnancy remains hugely challenging. In this case, we report the first use of a superior vena caval filter in pregnancy as an adjunct to pharmacological anticoagulation. This is the first reported use of a superior vena caval filter in pregnancy. We discuss the complexities of managing thromboembolism in pregnancy and the peri-partum period.

Urinary biomarkers of smokers' exposure to tobacco smoke constituents in tobacco products assessment: a fit for purpose approach.

There are established guidelines for bioanalytical assay validation and qualification of biomarkers. In this review, they were applied to a panel of urinary biomarkers of tobacco smoke exposure as part of a "fit for purpose" approach to the assessment of smoke constituents exposure in groups of tobacco product smokers. Clinical studies have allowed the identification of a group of tobacco exposure biomarkers demonstrating a good doseresponse relationship whilst others such as dihydroxybutyl mercapturic acid and 2-carboxy-1-methylethylmercapturic acid - did not reproducibly discriminate smokers and non-smokers. Furthermore, there are currently no agreed common reference standards to measure absolute concentrations and few inter-laboratory trials have been performed to establish consensus values for interim standards. Thus, we also discuss in this review additional requirements for the generation of robust data on urinary biomarkers, including toxicant metabolism and disposition, method validation and qualification for use in tobacco products comparison studies.